Basic & clinical pharmacology 4

For women, the result should be multiplied by 0.85 (because of reduced muscle mass). It must be emphasized that this estimate is, at best, a population estimate and may not apply to a particular patient. If the patient has normal renal function (up to one third of elderly patients), a dose corrected on the basis of this estimate will be too low—but a low dose is initially desirable if one is uncertain of the renal function in any patient. Simple online calculators using the more modern MDRD (Modification of Diet in Renal Disease) formula are available, eg, http://nkdep.nih.gov/lab-evaluation/gfr-calculators.shtml.

If a precise measure is needed, a standard 12- or 24-hour creatinine clearance determination should be obtained. As indicated above, nutritional changes alter pharmacokinetic parameters. A patient who is severely dehydrated (not uncommon in patients with stroke or other motor impairment) may have an additional marked reduction in renal drug clearance that is completely reversible by rehydration.

The lungs are important for the excretion of volatile drugs. As a result of reduced respiratory capacity (Figure 60–1) and the increased prevalence of active pulmonary disease in the elderly, the use of inhalation anesthesia is less common and intravenous agents more common in this age group. (See Chapter 25.)

Pharmacodynamic Changes It was long believed that geriatric patients were much more “sensitive” to the action of many drugs, implying a change in the pharmacodynamic interaction of the drugs with their receptors. It is now recognized that many—perhaps most—of these apparent changes result from altered pharmacokinetics or diminished homeostatic responses. Clinical studies have supported the idea that the elderly are more sensitive to some sedative-hypnotics and analgesics. In addition, some data from animal studies suggest actual changes with age in the characteristics or numbers of a few receptors. The most extensive studies suggest a decrease in responsiveness to βadrenoceptor agonists. Other examples are discussed below.

Certain homeostatic control mechanisms appear to be blunted in the elderly. Since homeostatic responses are often important components of the overall response to a drug, these physiologic alterations may change the pattern or intensity of drug response. In the cardiovascular system, the cardiac output increment required by mild or moderate exercise is successfully provided until at least age 75 (in individuals without obvious cardiac disease), but the increase is the result primarily of increased stroke volume in the elderly and not tachycardia, as in young adults. Average blood pressure goes up with age (in most Western countries), but the incidence of symptomatic orthostatic hypotension also increases markedly. It is thus particularly important to check for orthostatic hypotension on every visit.

Similarly, the average 2-hour postprandial blood glucose level increases by about 1 mg/dL for each year of age above 50. Temperature regulation is also impaired, and hypothermia is poorly tolerated by the elderly.

Behavioral & Lifestyle Changes Major changes in the conditions of daily life accompany the aging process and have an impact on health. Some of these (eg, forgetting to take one’s pills) are the result of cognitive changes associated with vascular or other pathology. One of the most important changes is the loss of a spouse. Others relate to economic stresses associated with greatly reduced income and, frequently, increased expenses due to illness.

MAJOR DRUG GROUPS CENTRAL NERVOUS SYSTEM DRUGS Sedative-Hypnotics The half-lives of many benzodiazepines and barbiturates increase by 50–150% between ages 30 and 70. Much of this change occurs during the decade from 60 to 70. For some of the benzodiazepines, both the parent molecule and its metabolites (produced in the liver) are pharmacologically active (see Chapter 22). The age-related decline in renal function and liver disease, if present, both contribute to the reduction in elimination of these compounds. In addition, an increased volume of distribution has been reported for some of these drugs. Lorazepam and oxazepam may be less affected by these changes than the other benzodiazepines. In addition to these pharmacokinetic factors, it is generally believed that the elderly vary more in their sensitivity to the sedative-hypnotic drugs on a pharmacodynamic basis as well. Among the toxicities of these drugs, ataxia and other stability impairments lead to increased falls and fractures.

Analgesics The opioid analgesics show variable changes in pharmacokinetics with age. However, the elderly are often markedly more sensitive to the respiratory effects of these agents because of age-related changes in respiratory function. Therefore, this group of drugs should be used with caution until the sensitivity of the particular patient has been evaluated, and the patient should then be dosed appropriately for full effect. Unfortunately, studies show that opioids are consistently underutilized in patients who require strong analgesics for chronic painful conditions such as cancer. There is no justification for underutilization of these drugs, especially in the care of the elderly, and good pain management plans are readily available (see Morrison, 2006; Rabow, 2011).

Antipsychotic & Antidepressant Drugs The traditional antipsychotic agents (phenothiazines and haloperidol) have been very heavily used (and probably misused) in the management of a variety of psychiatric conditions in the elderly. There is no doubt that they are useful in the management of schizophrenia in old age, and also in the treatment of some symptoms associated with delirium, dementia, agitation, combativeness, and a paranoid syndrome that occurs in some geriatric patients (see Chapter 29). However, they are not fully satisfactory in these geriatric conditions, and dosage should not be increased on the assumption that full control is possible. There is no evidence that these drugs have any beneficial effects in Alzheimer’s dementia, and on theoretical grounds the antimuscarinic effects of the phenothiazines might be expected to worsen memory impairment and intellectual dysfunction (see below).

Much of the apparent improvement in agitated and combative patients may simply reflect the sedative effects of the drugs. When a sedative antipsychotic is desired, a phenothiazine such as thioridazine is appropriate. If sedation is to be avoided, haloperidol or an atypical antipsychotic is more appropriate. Haloperidol has increased extrapyramidal toxicity, however, and should be avoided in patients with preexisting extrapyramidal disease. The phenothiazines, especially older drugs such as chlorpromazine, often induce orthostatic hypotension because of their α-adrenoceptor-blocking effects. They are even more prone to do so in the elderly. Dosage of these drugs should usually be started at a fraction of that used in young adults. The atypical antipsychotic agents (clozapine, olanzapine, quetiapine, risperidone, aripiprazole) do not appear to be significantly superior to the traditional agents although they have fewer autonomic adverse effects. Evidence supporting the benefits of olanzapine is somewhat stronger than that for the other atypical agents.

Lithium is often used in the treatment of mania in the aged. Because it is cleared by the kidneys, dosages must be adjusted appropriately and blood levels monitored. Concurrent use of thiazide diuretics reduces the clearance of lithium and should be accompanied by further reduction in dosage and more frequent measurement of lithium blood levels.

Psychiatric depression is thought to be underdiagnosed and undertreated in the elderly. The suicide rate in the over-65 age group (twice the national average) supports this view. Unfortunately, the apathy, flat affect, and social withdrawal of major depression may be mistaken for senile dementia. Clinical evidence suggests that the elderly are as responsive to antidepressants (of all types) as younger patients but are more likely to experience adverse effects. This factor along with the reduced clearance of some of these drugs underlines the importance of careful dosing and strict attention to the appearance of toxic effects. Some authorities prefer selective serotonin reuptake inhibitors (SSRIs) to tricyclic antidepressants because the SSRIs have fewer autonomic adverse effects. If a tricyclic is to be used, a drug with reduced antimuscarinic effects should be selected, eg, nortriptyline or desipramine (see Table 30–2).

Drugs Used in Alzheimer’s Disease Alzheimer’s disease (AD) is characterized by progressive memory impairment, dementia, and cognitive dysfunction, and may lead to a completely vegetative state, resulting in massive socioeconomic disruption, and early death. Prevalence increases with age and may be as high as 20% in individuals over 85. The annual cost of dementia in the United States is estimated at $150–215 billion annually. Both familial and sporadic forms have been identified. Early onset of Alzheimer’s disease is associated with several gene defects, including trisomy 21 (chromosome 21), a mutation of the gene for presenilin-1 on chromosome 14, and an abnormal allele, ε4, for the lipidassociated protein, ApoE, on chromosome 19. Unlike the common forms (ApoE ε2 and ε3), the ε4 form strongly correlates with the formation of amyloid β deposits (see below).

Pathologic changes include increased deposits of amyloid beta (Aβ) peptide in the cerebral cortex, which eventually forms extracellular plaques and cerebral vascular lesions, and intra- and interneuronal fibrillary tangles consisting of the tau protein (Figure 60–2). There is a progressive loss of neurons, especially cholinergic neurons, and thinning of the cortex. The loss of cholinergic neurons results in a marked decrease in choline acetyltransferase and other markers of cholinergic activity. Patients with Alzheimer’s disease are often exquisitely sensitive to the central nervous system toxicities of drugs with antimuscarinic effects. Some evidence implicates excess excitation by glutamate as a contributor to neuronal death. In addition, abnormalities of mitochondrial function may contribute to neuronal death.

FIGURE 60–2 Some processes involved in Alzheimer’s disease. From the left: mitochondrial dysfunction, possibly involving glucose utilization; synthesis of protein tau and aggregation in filamentous tangles; synthesis of amyloid beta (Aβ) and secretion into the extracellular space, where it may interfere with synaptic signaling and accumulates in plaques. (Reproduced, with permission, from Roberson ED, Mucke L: 100 years and counting: Prospects for defeating Alzheimer’s disease. Science 2006;314:781. Reprinted with permission from AAAS.) Many methods of treatment of Alzheimer’s disease have been explored (Table 60–3). Much attention has been focused on the cholinomimetic drugs because of the evidence of loss of cholinergic neurons. Monoamine oxidase (MAO) type B inhibition with selegiline (L-deprenyl) has been suggested to have some beneficial effects. One drug that inhibits N-methyl-D-aspartate (NMDA) glutamate receptors is available (see below), and “ampakines,” substances that facilitate synaptic activity at glutamate AMPA receptors, are under intense study. Some evidence suggests that lipid-lowering statins are beneficial. Rosiglitazone, a PPAR-γ (peroxisome proliferatoractivated receptor-gamma) antidiabetic agent, has also been reported to have beneficial effects in a preliminary study. Unfortunately, this drug may be associated with increased cardiovascular risk and its use has been restricted (see Chapter 41). So-called cerebral vasodilators are ineffective.

TABLE 60–3 Some potential strategies for the prevention or treatment of Alzheimer’s disease.

Tacrine (tetrahydroaminoacridine, THA), a long-acting cholinesterase inhibitor and muscarinic modulator, was the first drug shown to have any benefit in Alzheimer’s disease. Because of its hepatic toxicity, tacrine has been replaced in clinical use by newer cholinesterase inhibitors: donepezil, rivastigmine, and galantamine. These agents are orally active, have adequate penetration into the central nervous system, and are much less toxic than tacrine. Although evidence for the benefit of cholinesterase inhibitors (and memantine; see below) is statistically significant, the amount of benefit is modest and does not prevent the progression of the disease.

The cholinesterase inhibitors cause significant adverse effects, including nausea and vomiting, and other peripheral cholinomimetic effects. These drugs should be used with caution in patients receiving other drugs that inhibit cytochrome P450 enzymes (eg, ketoconazole, quinidine; see Chapter 4). Preparations available are listed in Chapter 7.

Excitotoxic activation of glutamate transmission via NMDA receptors has been postulated to contribute to the pathophysiology of Alzheimer’s disease. Memantine binds to NMDA receptor channels in a use-dependent manner and produces a noncompetitive blockade. Its modest efficacy in Alzheimer’s disease is similar to or smaller than that of the cholinesterase inhibitors. However, this drug may be better tolerated and less toxic than the cholinesterase inhibitors. Combination therapy with both memantine and one of the cholinesterase inhibitors has produced mixed results. Memantine is available as Namenda in 5 and 10 mg oral tablets.

Recent research has focussed on amyloid beta, because the characteristic plaques consist mostly of this peptide. Unfortunately, two anti-amyloid antibodies, solanezumab and bapineuzumab, both failed to improve cognition or slow progression in recent phase 2 clinical trials. Another effort suggests that the accumulation of filamentous tangles of tau protein is a critical component of neuronal damage in Alzheimer’s and several other neurodegenerative conditions. Accumulation of tau appears to be associated with dissociation from microtubules in neurons, which has stimulated interest in drugs that inhibit microtubule disassembly, such as epothilone-D.

CARDIOVASCULAR DRUGS Antihypertensive Drugs Blood pressure, especially systolic pressure, increases with age in Western countries and in most cultures in which salt intake is high. In women, the increase is more marked after age 50. Although sometimes ignored in the past, most clinicians now believe that hypertension should be treated in the elderly.

The basic principles of therapy are not different in the geriatric age group from those described in Chapter 11, but the usual cautions regarding altered pharmacokinetics and blunted compensatory mechanisms apply. Because of its safety, nondrug therapy (weight reduction in the obese and salt restriction) should be encouraged. Thiazides are a reasonable first step in drug therapy. The hypokalemia, hyperglycemia, and hyperuricemia caused by these agents are more relevant in the elderly because of the higher prevalence in these patients of arrhythmias, type 2 diabetes, and gout. Thus, use of low antihypertensive doses—rather than maximum diuretic doses—is important. Calcium channel blockers are effective and safe if titrated to the appropriate response. They are especially useful in patients who also have atherosclerotic angina (see Chapter 12). Beta blockers are potentially hazardous in patients with obstructive airway disease and are considered less useful than calcium channel blockers in older patients unless chronic heart failure is present. Angiotensinconverting enzyme inhibitors are also considered less useful in the elderly unless heart failure or diabetes is present. The most powerful drugs, such as minoxidil, are rarely needed. Every patient receiving antihypertensive drugs should be checked regularly for orthostatic hypotension because of the danger of cerebral ischemia and falls.

Positive Inotropic Agents Heart failure is a common and particularly lethal disease in the elderly. Fear of this condition is one reason why physicians overuse cardiac glycosides in this age group. The toxic effects of digoxin are particularly dangerous in the geriatric population, since the elderly are more susceptible to arrhythmias. The clearance of digoxin is usually decreased in the older age group, and although the volume of distribution is often decreased as well, the half-life of this drug may be increased by 50% or more. Because the drug is cleared mostly by the kidneys, renal function must be considered in designing a dosage regimen. There is no evidence that there is any increase in pharmacodynamic sensitivity to the therapeutic effects of the cardiac glycosides; in fact, animal studies suggest a possible decrease in therapeutic sensitivity. On the other hand, there is probably an increase in sensitivity to the toxic arrhythmogenic actions. Hypokalemia, hypomagnesemia, hypoxemia (from pulmonary disease), and coronary atherosclerosis all contribute to the high incidence of digitalisinduced arrhythmias in geriatric patients. The less common toxicities of digitalis such as delirium, visual changes, and endocrine abnormalities (see Chapter 13) also occur more often in older than in younger patients.

Antiarrhythmic Agents The treatment of arrhythmias in the elderly is particularly challenging because of the lack of good hemodynamic reserve, the frequency of electrolyte disturbances, and the high prevalence of significant coronary disease. The clearances of quinidine and procainamide decrease and their half-lives increase with age. Disopyramide should probably be avoided in the geriatric population because its major toxicities—antimuscarinic action, leading to voiding problems in men; and negative inotropic cardiac effects, leading to heart failure—are

particularly undesirable in these patients. The clearance of lidocaine appears to be little changed, but the half-life is increased in the elderly. Although this observation implies an increase in the volume of distribution, it has been recommended that the loading dose of this drug be reduced in geriatric patients because of their greater sensitivity to its toxic effects.

Recent evidence indicates that many patients with atrial fibrillation—a very common arrhythmia in the elderly—do as well with simple control of ventricular rate as with conversion to normal sinus rhythm. Measures (such as anticoagulant drugs) should be taken to reduce the risk of thromboembolism in chronic atrial fibrillation.

ANTIMICROBIAL THERAPY Several age-related changes contribute to the high incidence of infections in geriatric patients. There appears to be a reduction in host defenses in the elderly, manifested in the increase in both serious infections and cancer. This may reflect an alteration in T-lymphocyte function. In the lungs, a major age and tobacco-dependent decrease in mucociliary clearance significantly increases susceptibility to infection. In the urinary tract, the incidence of serious infection is greatly increased by urinary retention and catheterization in men.

Preventive immunizations should be maintained: influenza vaccine should be given annually, tetanus toxoid every 10 years, and pneumococcal and zoster vaccines once.

Since 1940, the antimicrobial drugs have contributed more to the prolongation of life than any other drug group because they can compensate to some extent for this deterioration in natural defenses. The basic principles of therapy of the elderly with these agents are no different from those applicable in younger patients and have been presented in Chapter 51. The major pharmacokinetic changes relate to decreased renal function; because most of the β-lactam, aminoglycoside, and fluoroquinolone antibiotics are excreted by this route, important changes in half-life may be expected. This is particularly important in the case of the aminoglycosides, because they cause concentration- and time-dependent toxicity in the kidney and in other organs. The half-lives of gentamicin, kanamycin, and netilmicin are more than doubled. The increase may be less marked for tobramycin.

ANTI-INFLAMMATORY DRUGS Osteoarthritis is a very common disease of the elderly. Rheumatoid arthritis is less exclusively a geriatric problem, but the same drug therapy is usually applicable to both types of disease. The basic principles laid down in Chapter 36 and the properties of the antiinflammatory drugs described there apply fully here.

The nonsteroidal anti-inflammatory agents (NSAIDs) must be used with special care in geriatric patients because they cause toxicities to which the elderly are very susceptible. In the case of aspirin, the most important of these is gastrointestinal irritation and bleeding. In the case of the newer NSAIDs, the most important is renal damage, which may be irreversible. Because they are cleared primarily by the kidneys, these drugs accumulate more rapidly in the geriatric patient and especially in the patient whose renal function is already compromised beyond the average range for his or her age. A vicious circle is easily set up in which cumulation of the NSAID causes more renal damage, which causes more cumulation. There is no evidence that the cyclooxygenase (COX)-2 selective NSAIDs are safer with regard to renal function. Elderly patients receiving high doses of any NSAID should be carefully monitored for changes in renal function.

Corticosteroids are extremely useful in elderly patients who cannot tolerate full doses of NSAIDs. However, they consistently cause a dose- and duration-related increase in osteoporosis, an especially hazardous toxic effect in the elderly. It is not certain whether this drug-induced effect can be reduced by increased calcium and vitamin D intake, but it would be prudent to consider these agents (and bisphosphonates if osteoporosis is already present) and to encourage frequent exercise in any patient taking corticosteroids.

OPHTHALMIC DRUGS Drugs Used in Glaucoma Glaucoma is more common in the elderly, but its treatment does not differ from that of glaucoma of earlier onset. Management of glaucoma is discussed in Chapter 10.

Macular Degeneration Age-related macular degeneration (AMD) is the most common cause of blindness in the elderly in the developed world. Two forms of advanced AMD are recognized: the neovascular “wet” form, which is associated with intrusion of new blood vessels in the subretinal space, and a more common “dry” form, which is not associated with abnormal vascularization. Although the cause of AMD is not known, smoking is a documented risk factor, and oxidative stress has long been thought to play a role. On this premise, antioxidants have been used to prevent or delay the onset of AMD. Proprietary oral formulations of vitamins C and E, β-carotene, zinc oxide, and cupric oxide are available. Evidence for the efficacy of these antioxidants is modest or absent. Oral drugs in clinical trials include the

carotenoids lutein and zeaxanthin, and n-3 long-chain polyunsaturated fatty acids.

In advanced AMD, treatment has been moderately successful but only for the neovascular form. Neovascular AMD can now be treated with laser phototherapy or with antibodies against vascular endothelial growth factor (VEGF). Two antibodies are available: bevacizumab (Avastin, used off-label) and ranibizumab (Lucentis), as well as the oligopeptide pegaptanib (Macugen). The latter two are approved for neovascular AMD. These agents are injected into the vitreous for local effect. Ranibizumab is extremely expensive. Fusion proteins and RNA agents that bind VEGF are under study.

ADVERSE DRUG REACTIONS IN THE ELDERLY The relation between the number of drugs taken and the incidence of adverse drug reactions has been well documented. In long-term care facilities, in which a high percentage of the population is elderly, the average number of prescriptions per patient varies between 6 and 8. Studies have shown that the percentage of patients with adverse reactions increases from about 10% when a single drug is being taken to nearly 100% when 10 drugs are taken. Thus, it may be expected that about half of patients in long-term care facilities will have recognized or unrecognized reactions at some time. Patients living at home may see several different practitioners for different conditions and accumulate multiple prescriptions for drugs with overlapping actions. It is useful to conduct a “brown bag” analysis in such patients.

The brown bag analysis consists of asking the patient to bring to the practitioner a bag containing all the medications, supplements, vitamins, etc, that he or she is currently taking. Some prescriptions will be found to be duplicates, others unnecessary. The total number of medications taken can often be reduced by 30–50%.

The overall incidence of drug reactions in geriatric patients is estimated to be at least twice that in the younger population. Reasons for this high incidence undoubtedly include errors in prescribing on the part of the practitioner and errors in drug usage by the patient.

Practitioner errors sometimes occur because the physician does not appreciate the importance of changes in pharmacokinetics with age and age-related diseases. Some errors occur because the practitioner is unaware of incompatible drugs prescribed by other practitioners for the same patient. For example, cimetidine, an H2 -blocking drug heavily prescribed (or recommended in its over-the-counter form) to the elderly, causes a much higher incidence of untoward effects (eg, confusion, slurred speech) in the geriatric population than in younger patients. It also inhibits the hepatic metabolism of many drugs, including phenytoin, warfarin, β blockers, and other agents. A patient who has been taking one of the latter agents without untoward effect may develop markedly elevated blood levels and severe toxicity if cimetidine is added to the regimen without adjustment of dosage of the other drugs. Additional examples of drugs that inhibit liver microsomal enzymes and lead to adverse reactions are described in Chapters 4 and 66.

Patient errors may result from nonadherence for reasons described below. In addition, they often result from use of nonprescription drugs taken without the knowledge of the physician. As noted in Chapters 63 and 64, many over-the-counter agents and herbal medications contain “hidden ingredients” with potent pharmacologic effects. For example, many antihistamines have significant sedative effects and are inherently more hazardous in patients with impaired cognitive function. Similarly, their antimuscarinic action may precipitate urinary retention in geriatric men or glaucoma in patients with a narrow anterior chamber angle. If the patient is also taking a metabolism inhibitor such as cimetidine, the probability of an adverse reaction is greatly increased. A patient taking an herbal medication containing gingko is more likely to experience bleeding while taking low doses of aspirin.

PRACTICAL ASPECTS OF GERIATRIC PHARMACOLOGY The quality of life in elderly patients can be greatly improved and life span can be prolonged by the intelligent use of drugs. However, the prescriber must recognize several practical obstacles to compliance.

The expense of drugs can be a major disincentive in patients receiving marginal retirement incomes who are not covered or inadequately covered by health insurance. The prescriber must be aware of the cost of the prescription and of cheaper alternative therapies. For example, the monthly cost of arthritis therapy with newer NSAIDs may exceed $100, whereas that for generic ibuprofen and naproxen, two older but equally effective NSAIDs, about $20.

Nonadherence may result from forgetfulness or confusion, especially if the patient has several prescriptions and different dosing intervals. A survey carried out in 1986 showed that the population over 65 years of age accounted for 32% of drugs prescribed in the USA, although these patients represented only 11–12% of the population at that time. Since the prescriptions are often written by several different practitioners, there is usually no attempt to design “integrated” regimens that use drugs with similar dosing intervals for the conditions being treated. Patients may forget instructions regarding the need to complete a fixed duration of therapy when a course of anti-infective drug is being given. The disappearance of symptoms is often regarded as the best reason to halt drug taking, especially if the prescription was expensive.

Nonadherence may also be deliberate. A decision not to take a drug may be based on prior experience with it. There may be excellent reasons for such “intelligent” noncompliance, and the practitioner should try to elicit them. Such efforts may also improve compliance with alternative drug regimens, because enlisting the patient as a participant in therapeutic decisions increases the motivation to succeed.

Some errors in drug taking are caused by physical disabilities. Arthritis, tremor, and visual problems may all contribute. Liquid

medications that are to be measured “by the spoonful” are especially inappropriate for patients with any type of tremor or motor disability. Use of a dosing syringe may be helpful in such cases. Because of decreased production of saliva, older patients often have difficulty swallowing large tablets. “Childproof” containers are often “elder-proof” if the patient has arthritis. Cataracts and macular degeneration occur in a large number of patients over 70. Therefore, labels on prescription bottles should be large enough for the patient with diminished vision to read or should be color-coded if the patient can see but can no longer read. Because of impaired hearing, even carefully delivered instructions regarding drug use may not be understood by the patient; written instructions may be helpful.

Drug therapy has considerable potential for both helpful and harmful effects in the geriatric patient. The balance may be tipped in the right direction by adherence to a few principles: 1. Take a careful drug history. The disease to be treated may be drug-induced, or drugs being taken may lead to interactions with drugs to be prescribed.

2. Prescribe only for a specific and rational indication. Do not prescribe omeprazole for “dyspepsia.” Expert guidelines are published regularly by national organizations and websites such as UpToDate.com.

3. Define the goal of drug therapy. Then start with small doses and titrate to the response desired. Wait at least three half-lives (adjusted for age) before increasing the dose. If the expected response does not occur at the normal adult dosage, check blood levels.

If the expected response does not occur at the appropriate blood level, switch to a different drug.

4. Maintain a high index of suspicion regarding drug reactions and interactions. Know what other drugs the patient is taking, including over-the-counter and botanical (herbal) drugs.

5. Simplify the regimen as much as possible. When multiple drugs are prescribed, try to use drugs that can be taken at the same time of day. Whenever possible, reduce the number of drugs being taken.

REFERENCES American College of Cardiology Foundation T ask Force: ACCF/AHA 2011 Expert consensus document on hypertension in the elderly. J Am Coll Cardiol 2011;57:2037.

Ancolli-Israel S, Ayalon L: Diagnosis and treatment of sleep disorders in older adults. Am J Geriatr Psychiatry 2006;14:95.

Aronow WS: Drug treatment of systolic and diastolic heart failure in elderly persons. J Gerontol A Biol Med Sci 2005;60:1597.

Calcado RT , Young NS: T elomere diseases. N Engl J Med 2009;361:2353.

Chatap G, Giraud K, Vincent JP: Atrial fibrillation in the elderly: Facts and management. Drugs Aging 2002;19:819.

Cockcroft DW, Gault MH: Prediction of creatinine clearance from serum creatinine. Nephron 1976;16:31.

Dergal JM et al: Potential interactions between herbal medicines and conventional drug therapies used by older adults attending a memory clinic. Drugs Aging 2002;19:879.

Docherty JR: Age-related changes in adrenergic neuroeffector transmission. Auton Neurosci 2002;96:8.

Drugs for cognitive loss and dementia. T reatment Guidelines 2013;11:95.

Ferrari AU: Modifications of the cardiovascular system with aging. Am J Geriatr Cardiol 2002;11:30.

Gandy S: Lifelong management of amyloid-beta metabolism to prevent Alzheimer’s disease. N Engl J Med 2012;367:864.

Guarente L: Sirtuins, aging, and medicine. N Engl J Med 2011;364:2235.

Hubbard BP, Sinclair DA: Small molecule SIRT 1 activators for the treatment of aging and age-related diseases. T rends Pharmacol Sci 2014;35:146.

Jager RD, Mieler WF, Miller JW: Age-related macular degeneration. N Engl J Med 2008;358:2606.

Kennedy BK, Pennypacker JK: Drugs that modulate aging: the promising yet difficult path ahead. T ranslat Res 2013;163:1.

Kirby J et al: A systematic review of the clinical and cost-effectiveness of memantine in patients with moderately severe to severe Alzheimer’s disease. Drugs Aging 2006;23:227.

Lamming DW et al: Rapamycin-induced insulin resistance is mediated by mT ORC2 loss and uncoupled from longevity. Science 2012;335:1638.

Levey AS et al: Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Int Med 2006;145:247.

Mangoni AA: Cardiovascular drug therapy in elderly patients: Specific age-related pharmacokinetic, pharmacodynamic and therapeutic considerations. Drugs Aging 2005;22:913.

Moreno JA et al: Oral treatment targeting the unfolded protein response prevents neurodegeneration and clinical disease in prion-infected mice. Sci T ransl Med 2013;5:206ra138.

Morrison LJ, Morrison RS: Palliative care and pain management. Med Clin N Am 2006;90:983.

Palmer AM: Neuroprotective therapeutics for Alzheimer’s disease: Progress and prospects. T rends Pharmacol Sci 2011;32:141.

Press D, Alexander M: T reatment of dementia. www.uptodate.com 2014; topic 5073.

Qato DM et al: Use of prescription and over-the-counter medications and dietary supplements among older adults in the United States. JAMA 2008;300:2867.

Rabow MW, Pantilat SZ: Care at the end of life. In: McPhee SJ, Papadakis MA (editors): Current Medical Diagnosis & Treatment, 50th ed. McGraw-Hill, 2011.

Roberson ED, Mucke L: 100 Years and counting: Prospects for defeating Alzheimer’s disease. Science 2006;314:781.

Rodriguez EG et al: Use of lipid-lowering drugs in older adults with and without dementia: A community-based epidemiological study. J Am Geriatr Soc 2002;50:1852.

Sawhney R, Sehl M, Naeim A: Physiologic aspects of aging: Impact on cancer management and decision making, part I. Cancer J 2005;11:449.

Staskin DR: Overactive bladder in the elderly: A guide to pharmacological management. Drugs Aging 2005;22:1013.

Steinman MA, Hanlon JT : Managing medications in clinically complex elders. JAMA 2010;304:1592.

Vik SA et al: Medication nonadherence and subsequent risk of hospitalisation and mortality among older adults. Drugs Aging 2006;23:345.

Wade PR: Aging and neural control of the GI tract. I. Age-related changes in the enteric nervous system. Am J Physiol Gastrointest Liver Physiol 2002;283:G489.

CASE STUDY ANSWER This patient has several conditions that warrant careful treatment. Hypertension is eminently treatable; the steps described in Chapter 11 are appropriate and effective in the elderly as well as in young patients. Patient education is critical in combating his reluctance to take his medications. Alzheimer’s disease may respond temporarily to one of the anticholinesterase agents (donepezil, rivastigmine, galantamine). Alternatively, memantine may be tried. Unfortunately, age-related macular degeneration (the most likely cause of his visual difficulties) is not readily treated, but the “wet� (neovascular) variety may respond well to one of the drugs currently available (bevacizumab, ranibizumab, pegaptanib). However, these therapies are expensive.

CHAPTER

61 Dermatologic Pharmacology Dirk B. Robertson, MD & Howard I. Maibach, MD

CASE STUDY A 22-year-old woman presents with a complaint of worsening psoriasis. She has a strong family history of the disease and has had lesions on her scalp and elbows for several years. She recently noted new lesions developing on her knees and the soles of her feet.

She has been using topical over-the-counter hydrocortisone cream but admits that this treatment does not seem to help. What therapeutic options are available for the treatment of this chronic disease?

Diseases of the skin offer special opportunities to the clinician. In particular, the topical administration route is especially appropriate for skin diseases, although some dermatologic diseases respond as well or better to drugs administered systemically.

The general pharmacokinetic principles governing the use of drugs applied to the skin are the same as those involved in other routes of administration (see Chapters 1 and 3). Although often depicted as a simple three-layered structure, human skin is a complex series of diffusion barriers (Figure 61–1). Quantitation of the flux of drugs and drug vehicles through these barriers is the basis for pharmacokinetic analysis of dermatologic therapy, and techniques for making such measurements are rapidly increasing in number and sensitivity.

FIGURE 61–1 Schematic diagram of percutaneous absorption. (Redrawn from Orkin M, Maibach HI, Dahl MV: Dermatology.

Appleton & Lange, 1991.)

Major variables that determine pharmacologic response to drugs applied to the skin include the following: 1. Regional variation in drug penetration: For example, the scrotum, face, axilla, and scalp are far more permeable than the forearm and may require less drug for equivalent effect.

2. Concentration gradient: Increasing the concentration gradient increases the mass of drug transferred per unit time, just as in the case of diffusion across other barriers (see Chapter 1). Thus, resistance to topical corticosteroids can sometimes be overcome by use of higher concentrations of drug.

3. Dosing schedule: Because of its physical properties, the skin acts as a reservoir for many drugs. As a result, the “local half-life” may be long enough to permit once-daily application of drugs with short systemic half-lives. For example, once-daily application of corticosteroids appears to be just as effective as multiple applications in many conditions.

4. Vehicles and occlusion: An appropriate vehicle maximizes the ability of the drug to penetrate the outer layers of the skin. In addition, through their physical properties (moistening or drying effects), vehicles may themselves have important therapeutic effects.

Occlusion (application of a plastic wrap to hold the drug and its vehicle in close contact with the skin) is extremely effective in maximizing efficacy.

REACTIONS TO DERMATOLOGIC MEDICATIONS The skin reacts to many systemic medications with a variety of symptom-generating responses. In addition, some dermatologic medications themselves cause skin reactions. The major types of reactions are summarized in Table 61–1.

TABLE 61–1 Local cutaneous reactions to topical medications.

DERMATOLOGIC VEHICLES

Topical medications usually consist of active ingredients incorporated in a vehicle that facilitates cutaneous application. Important considerations in vehicle selection include the solubility of the active agent in the vehicle; the rate of release of the agent from the vehicle; the ability of the vehicle to hydrate the stratum corneum, thus enhancing penetration; the stability of the therapeutic agent in the vehicle; and interactions, chemical and physical, of the vehicle, stratum corneum, and active agent.

Depending upon the vehicle, dermatologic formulations may be classified as tinctures, wet dressings, lotions, gels, aerosols, powders, pastes, creams, foams, and ointments. The ability of the vehicle to retard evaporation from the surface of the skin increases in this series, being least in tinctures and wet dressings and greatest in ointments. In general, acute inflammation with oozing, vesiculation, and crusting is best treated with drying preparations such as tinctures, wet dressings, and lotions, whereas chronic inflammation with xerosis, scaling, and lichenification is best treated with more lubricating preparations such as creams and ointments. Tinctures, lotions, gels, foams, and aerosols are convenient for application to the scalp and hairy areas. Emulsified vanishing-type creams may be used in intertriginous areas without causing maceration.

Emulsifying agents provide homogeneous, stable preparations when mixtures of immiscible liquids such as oil-in-water creams are compounded. Some patients develop irritation from these agents. Substituting a preparation that does not contain them or using one containing a lower concentration may resolve the problem.

ANTIBACTERIAL AGENTS TOPICAL ANTIBACTERIAL PREPARATIONS Topical antibacterial agents may be useful in preventing infections in clean wounds, in the early treatment of infected dermatoses and wounds, in reducing colonization of the nares by staphylococci, in axillary deodorization, and in the management of acne vulgaris. The efficacy of antibiotics in these topical applications is not uniform. The general pharmacology of the antimicrobial drugs is discussed in Chapters 43–51.

Some topical anti-infectives contain corticosteroids in addition to antibiotics. There is no convincing evidence that topical corticosteroids inhibit the antibacterial effect of antibiotics when the two are incorporated in the same preparation. In the treatment of secondarily infected dermatoses, which are usually colonized with streptococci, staphylococci, or both, combination therapy may prove superior to corticosteroid therapy alone. Antibiotic-corticosteroid combinations may be useful in treating diaper dermatitis, otitis externa, and impetiginized eczema.

The selection of a particular antibiotic depends upon the diagnosis and, when appropriate, in vitro culture and sensitivity studies of clinical samples. The pathogens isolated from most infected dermatoses are group A β-hemolytic streptococci, Staphylococcus aureus, or both. The pathogens present in surgical wounds will be those resident in the environment. Information about regional patterns of drug resistance is therefore important in selecting a therapeutic agent. Prepackaged topical antibacterial preparations that contain multiple antibiotics are available in fixed dosages well above the therapeutic threshold. These formulations offer the advantages of efficacy in mixed infections, broader coverage for infections due to undetermined pathogens, and delayed microbial resistance to any single component antibiotic.

BACITRACIN & GRAMICIDIN Bacitracin and gramicidin are peptide antibiotics, active against gram-positive organisms such as streptococci, pneumococci, and staphylococci. In addition, most anaerobic cocci, neisseriae, tetanus bacilli, and diphtheria bacilli are sensitive. Bacitracin is compounded in an ointment base alone or in combination with neomycin, polymyxin B, or both. The use of bacitracin in the anterior nares may temporarily decrease colonization by pathogenic staphylococci. Microbial resistance may develop following prolonged use. Bacitracininduced contact urticaria syndrome, including anaphylaxis, occurs rarely. Allergic contact dermatitis occurs frequently, and immunologic allergic contact urticaria rarely. Bacitracin is poorly absorbed through the skin, so systemic toxicity is rare.

Gramicidin is available only for topical use, in combination with other antibiotics such as neomycin, polymyxin, bacitracin, and nystatin.

Systemic toxicity limits this drug to topical use. The incidence of sensitization following topical application is exceedingly low in therapeutic concentrations.

MUPIROCIN Mupirocin (pseudomonic acid A) is structurally unrelated to other currently available topical antibacterial agents. Most gram-positive aerobic bacteria, including methicillin-resistant S aureus (MRSA), are sensitive to mupirocin (see Chapter 50). It is effective in the treatment of impetigo caused by S aureus and group A β-hemolytic streptococci.

Intranasal mupirocin ointment for eliminating nasal carriage of S aureus may be associated with irritation of mucous membranes caused by the polyethylene glycol vehicle. Mupirocin is not appreciably absorbed systemically after topical application to intact skin.

RETAPAMULIN Retapamulin is a semisynthetic pleromutilin derivative effective in the treatment of uncomplicated superficial skin infection caused by group A β-hemolytic streptococci and S aureus, excluding MRSA. Topical retapamulin 1% ointment is indicated for use in adult and pediatric patients, 9 months or older, for the treatment of impetigo. Recommended treatment regimen is twice-daily application for 5 days. Retapamulin is well tolerated with only occasional local irritation of the treatment site. To date only four cases of allergic contact dermatitis have been reported.

POLYMYXIN B SULFATE Polymyxin B is a peptide antibiotic effective against gram-negative organisms, including Pseudomonas aeruginosa, Escherichia coli, enterobacter, and klebsiella. Most strains of proteus and serratia are resistant, as are all gram-positive organisms. Topical preparations may be compounded in either a solution or ointment base. Numerous prepackaged antibiotic combinations containing polymyxin B are available. Detectable serum concentrations are difficult to achieve from topical application, but the total daily dose applied to denuded skin or open wounds should not exceed 200 mg in order to reduce the likelihood of neurotoxicity and nephrotoxicity. Allergic contact dermatitis to topically applied polymyxin B sulfate is uncommon.

NEOMYCIN & GENTAMICIN Neomycin and gentamicin are aminoglycoside antibiotics active against gram-negative organisms, including E coli, proteus, klebsiella, and enterobacter. Gentamicin generally shows greater activity against P aeruginosa than neomycin. Gentamicin is also more active against staphylococci and group A β-hemolytic streptococci. Widespread topical use of gentamicin, especially in a hospital environment, should be avoided to slow the appearance of gentamicin-resistant organisms.

Neomycin is available in numerous topical formulations, both alone and in combination with polymyxin, bacitracin, and other antibiotics. It is also available as a sterile powder for topical use. Gentamicin is available as an ointment or cream.

Topical application of neomycin rarely results in detectable serum concentrations. However, in the case of gentamicin, serum concentrations of 1–18 mcg/mL are possible if the drug is applied in a water-miscible preparation to large areas of denuded skin, as in burned patients. Both drugs are water-soluble and are excreted primarily in the urine. Renal failure may permit the accumulation of these antibiotics, with possible nephrotoxicity, neurotoxicity, and ototoxicity.

Neomycin frequently causes allergic contact dermatitis, particularly if applied to eczematous dermatoses or if compounded in an ointment vehicle. When sensitization occurs, cross-sensitivity to streptomycin, kanamycin, paromomycin, and gentamicin is possible.

TOPICAL ANTIBIOTICS IN ACNE Several systemic antibiotics that have traditionally been used in the treatment of acne vulgaris have been shown to be effective when applied topically. Currently, four antibiotics are so utilized: clindamycin phosphate, erythromycin base, metronidazole, and sulfacetamide.

The effectiveness of topical therapy is less than that achieved by systemic administration of the same antibiotic. Therefore, topical therapy is generally suitable only in mild to moderate cases of inflammatory acne.

Clindamycin Clindamycin has in vitro activity against Propionibacterium acnes; this has been postulated as the mechanism of its beneficial effect in acne therapy. Approximately 10% of an applied dose is absorbed, and rare cases of bloody diarrhea and pseudomembranous colitis have been reported following topical application. The hydroalcoholic vehicle and foam formulation (Evoclin) may cause drying and irritation of the skin, with complaints of burning and stinging. The water-based gel and lotion formulations are well tolerated and less likely to cause irritation. Allergic contact dermatitis is uncommon. Clindamycin is also available in fixed-combination topical gels with benzoyl peroxide (Acanya, BenzaClin, Duac), and with tretinoin (Ziana).

Erythromycin In topical preparations, erythromycin base rather than a salt is used to facilitate penetration. The mechanism of action of topical erythromycin in inflammatory acne vulgaris is unknown but is presumed to be due to its inhibitory effects on P acnes. One of the possible complications of topical therapy is the development of antibiotic-resistant strains of organisms, including staphylococci. If this occurs in association with a clinical infection, topical erythromycin should be discontinued and appropriate systemic antibiotic therapy started.

Adverse local reactions to erythromycin solution may include a burning sensation at the time of application and drying and irritation of the

skin. The topical water-based gel is less drying and may be better tolerated. Allergic contact dermatitis is uncommon. Erythromycin is also available in a fixed combination preparation with benzoyl peroxide (Benzamycin) for topical treatment of acne vulgaris.

Metronidazole Topical metronidazole is effective in the treatment of rosacea. The mechanism of action is unknown, but it may relate to the inhibitory effects of metronidazole on Demodex brevis; alternatively, the drug may act as an anti-inflammatory agent by direct effect on neutrophil cellular function. Oral metronidazole has been shown to be a carcinogen in susceptible rodent species, and topical use during pregnancy and by nursing mothers and children is therefore not recommended.

Adverse local effects of the water-based gel formulation (MetroGel) include dryness, burning, and stinging. Less drying formulations may be better tolerated (MetroCream, MetroLotion, and Noritate cream). Caution should be exercised when applying metronidazole near the eyes to avoid excessive tearing.

Sodium Sulfacetamide Topical sulfacetamide is available alone as a 10% lotion (Klaron) and as a 10% wash (Ovace), and in several preparations in combination with sulfur for the treatment of acne vulgaris and acne rosacea. The mechanism of action is thought to be inhibition of P acnes by competitive inhibition of p-aminobenzoic acid utilization. Approximately 4% of topically applied sulfacetamide is absorbed percutaneously, and its use is therefore contraindicated in patients having a known hypersensitivity to sulfonamides.

Dapsone Topical dapsone is available as a 5% gel (Aczone) for the treatment of acne vulgaris. The mechanism of action is unknown. Topical use in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency has not been shown to cause clinically relevant hemolysis or anemia. However, a slight decrease in hemoglobin concentration was noted in patients with G6PD deficiency, suggestive of mild hemolysis. To date, serious adverse reactions associated with oral dapsone use as delineated in Chapter 47 have not been reported with topical use. Adverse local side effects include mild dryness, redness, oiliness, and skin peeling. Application of dapsone gel followed by benzoyl peroxide may result in a temporary yellow discoloration of the skin and hair.

ANTIFUNGAL AGENTS The treatment of superficial fungal infections caused by dermatophytic fungi may be accomplished (1) with topical antifungal agents, eg, clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, sulconazole, sertaconazole, ciclopirox olamine, naftifine, terbinafine, butenafine, and tolnaftate; or (2) with orally administered agents, ie, griseofulvin, terbinafine, fluconazole, and itraconazole. Their mechanisms of action are described in Chapter 48. Superficial infections caused by candida species may be treated with topical applications of clotrimazole, miconazole, econazole, ketoconazole, oxiconazole, ciclopirox olamine, nystatin, or amphotericin B.

TOPICAL ANTIFUNGAL PREPARATIONS TOPICAL AZOLE DERIVATIVES The topical imidazoles, which currently include clotrimazole, econazole, ketoconazole, miconazole, oxiconazole, sulconazole, and sertaconazole, have a wide range of activity against dermatophytes (epidermophyton, microsporum, and trichophyton) and yeasts, including Candida albicans and Pityrosporum orbiculare (see Chapter 48).

Miconazole (Monistat, Micatin) is available for topical application as a cream or lotion and as vaginal cream or suppositories for use in vulvovaginal candidiasis. Clotrimazole (Lotrimin, Mycelex) is available for topical application to the skin as a cream or lotion and as vaginal cream and tablets for use in vulvovaginal candidiasis. Econazole (Spectazole) is available as a cream for topical application.

Oxiconazole (Oxistat) is available as a cream and lotion for topical use. Ketoconazole (Nizoral) is available as a cream for topical treatment of dermatophytosis and candidiasis and as a shampoo or foam for the treatment of seborrheic dermatitis. Sulconazole (Exelderm) is available as a cream or solution. Sertaconazole (Ertaczo) is available as a cream. Topical antifungal-corticosteroid fixed combinations have been introduced on the basis of providing more rapid symptomatic improvement than an antifungal agent alone.

Clotrimazole-betamethasone dipropionate cream (Lotrisone) is one such combination.

Once- or twice-daily application to the affected area will generally result in clearing of superficial dermatophyte infections in 2–3 weeks, although the medication should be continued until eradication of the organism is confirmed. Paronychial and intertriginous candidiasis can be treated effectively by any of these agents when applied three or four times daily. Seborrheic dermatitis should be treated with twice-daily applications of ketoconazole until clinical clearing is obtained.

Adverse local reactions to the imidazoles may include stinging, pruritus, erythema, and local irritation. Allergic contact dermatitis is

uncommon.

CICLOPIROX OLAMINE Ciclopirox olamine is a synthetic broad-spectrum antimycotic agent with inhibitory activity against dermatophytes, candida species, and P orbiculare. This agent appears to inhibit the uptake of precursors of macromolecular synthesis; the site of action is probably the fungal cell membrane.

Pharmacokinetic studies indicate that 1–2% of the dose is absorbed when applied as a solution on the back under an occlusive dressing. Ciclopirox olamine is available as a 1% cream and lotion (Loprox) for the topical treatment of dermatomycosis, candidiasis, and tinea versicolor. The incidence of adverse reactions has been low. Pruritus and worsening of clinical disease have been reported. The potential for allergic contact dermatitis is small.

Topical 8% ciclopirox olamine (Penlac nail lacquer) has been approved for the treatment of mild to moderate onychomycosis of fingernails and toenails. Although well tolerated with minimal side effects, the overall cure rates in clinical trials are less than 12%.

ALLYLAMINES: NAFTIFINE & TERBINAFINE Naftifine hydrochloride and terbinafine (Lamisil) are allylamines that are highly active against dermatophytes but less active against yeasts. The antifungal activity derives from selective inhibition of squalene epoxidase, a key enzyme for the synthesis of ergosterol (see Figure 48–1).

They are available as 1% creams and other forms for the topical treatment of dermatophytosis, to be applied on a twice-daily dosing schedule. Adverse reactions include local irritation, burning sensation, and erythema. Contact with mucous membranes should be avoided.

BUTENAFINE Butenafine hydrochloride (Mentax) is a benzylamine that is structurally related to the allylamines. As with the allylamines, butenafine inhibits the epoxidation of squalene, thus blocking the synthesis of ergosterol, an essential component of fungal cell membranes.

Butenafine is available as a 1% cream to be applied once daily for the treatment of superficial dermatophytosis.

TOLNAFTATE Tolnaftate is a synthetic antifungal compound that is effective topically against dermatophyte infections caused by epidermophyton, microsporum, and trichophyton. It is also active against P orbiculare but not against candida.

Tolnaftate (Aftate, Tinactin) is available as a cream, solution, powder, or powder aerosol for application twice daily to infected areas.

Recurrences following cessation of therapy are common, and infections of the palms, soles, and nails are usually unresponsive to tolnaftate alone. The powder or powder aerosol may be used chronically following initial treatment in patients susceptible to tinea infections. Tolnaftate is generally well tolerated and rarely causes irritation or allergic contact dermatitis.

NYSTATIN & AMPHOTERICIN B Nystatin and amphotericin B are useful in the topical therapy of C albicans infections but ineffective against dermatophytes. Nystatin is limited to topical treatment of cutaneous and mucosal candida infections because of its narrow spectrum and negligible absorption from the gastrointestinal tract following oral administration. Amphotericin B has a broader antifungal spectrum and is used intravenously in the treatment of many systemic mycoses (see Chapter 48) and to a lesser extent in the treatment of cutaneous candida infections.

The recommended dosage for topical preparations of nystatin in treating paronychial and intertriginous candidiasis is application two or three times a day. Oral candidiasis (thrush) is treated by holding 5 mL (infants, 2 mL) of nystatin oral suspension in the mouth for several minutes four times daily before swallowing. An alternative therapy for thrush is to retain a vaginal tablet in the mouth until dissolved four times daily. Recurrent or recalcitrant perianal, vaginal, vulvar, and diaper area candidiasis may respond to oral nystatin, 0.5–1 million units in adults (100,000 units in children) four times daily, in addition to local therapy. Vulvovaginal candidiasis may be treated by insertion of 1 vaginal tablet twice daily for 14 days, then nightly for an additional 14–21 days.

Amphotericin B (Fungizone) is available for topical use in cream and lotion form. The recommended dosage in the treatment of paronychial and intertriginous candidiasis is application two to four times daily to the affected area.

Adverse effects associated with oral administration of nystatin include mild nausea, diarrhea, and occasional vomiting. Topical application is nonirritating, and allergic contact hypersensitivity is exceedingly uncommon. Topical amphotericin B is well tolerated and

only occasionally locally irritating. The drug may cause a temporary yellow staining of the skin, especially when the cream vehicle is used.

ORAL ANTIFUNGAL AGENTS ORAL AZOLE DERIVATIVES Azole derivatives currently available for oral treatment of candida and dermatophyte infections include fluconazole (Diflucan) and itraconazole (Sporanox). As discussed in Chapter 48, imidazole derivatives act by affecting the permeability of the cell membrane of sensitive cells through alterations of the biosynthesis of lipids, especially sterols, in the fungal cell.

Fluconazole and itraconazole are effective in the therapy of cutaneous infections caused by epidermophyton, microsporum, and trichophyton species as well as candida. Tinea versicolor is responsive to short courses of oral azoles.

Fluconazole is well absorbed following oral administration, with a plasma half-life of 30 hours. In view of this long half-life, daily doses of 100 mg are sufficient to treat mucocutaneous candidiasis; alternate-day doses are sufficient for dermatophyte infections. The plasma half-life of itraconazole is similar to that of fluconazole, and detectable therapeutic concentrations remain in the stratum corneum for up to 28 days following termination of therapy. Itraconazole is effective for the treatment of onychomycosis in a dosage of 200 mg daily taken with food to ensure maximum absorption for 3 consecutive months. Recent reports of heart failure in patients receiving itraconazole for onychomycosis have resulted in recommendations that it not be given for treatment of onychomycosis in patients with ventricular dysfunction. Additionally, routine evaluation of hepatic function is recommended for patients receiving itraconazole for onychomycosis.

Administration of oral azoles with midazolam or triazolam has resulted in elevated plasma concentrations and may potentiate and prolong hypnotic and sedative effects of these agents. Administration with HMG-CoA reductase inhibitors has been shown to cause a significant risk of rhabdomyolysis. Therefore, administration of the oral azoles with midazolam, triazolam, or HMG-CoA inhibitors is contraindicated.

GRISEOFULVIN Griseofulvin is effective orally against dermatophyte infections caused by epidermophyton, microsporum, and trichophyton. It is ineffective against candida and P orbiculare. Griseofulvin’s mechanism of antifungal action is not fully understood, but it is active only against growing cells.

Following the oral administration of 1 g of micronized griseofulvin, drug can be detected in the stratum corneum 4–8 hours later.

Reducing the particle size of the medication greatly increases absorption of the drug. Formulations that contain the smallest particle size are labeled “ultramicronized.” Ultramicronized griseofulvin achieves bioequivalent plasma levels with half the dose of micronized drug. In addition, solubilizing griseofulvin in polyethylene glycol enhances absorption even further. Micronized griseofulvin is available as 250 mg and 500 mg tablets, and ultramicronized drug is available as 125 mg, 165 mg, 250 mg, and 330 mg tablets and as 250 mg capsules.

The usual adult dosage of the micronized (“microsize”) form of the drug is 500 mg daily in single or divided doses with meals; occasionally, 1 g/d is indicated in the treatment of recalcitrant infections. The pediatric dosage is 10 mg/kg of body weight daily in single or divided doses with meals. An oral suspension is available for use in children.

Griseofulvin is most effective in treating tinea infections of the scalp and glabrous (nonhairy) skin. In general, infections of the scalp respond to treatment in 4–6 weeks, and infections of glabrous skin will respond in 3–4 weeks. Dermatophyte infections of the nails respond only to prolonged administration of griseofulvin. Fingernails may respond to 6 months of therapy, whereas toenails are quite recalcitrant to treatment and may require 8–18 months of therapy; relapse almost invariably occurs.

Adverse effects seen with griseofulvin therapy include headaches, nausea, vomiting, diarrhea, photosensitivity, peripheral neuritis, and occasionally mental confusion. Griseofulvin is derived from a penicillium mold, and cross-sensitivity with penicillin may occur. It is contraindicated in patients with porphyria or hepatic failure or those who have had hypersensitivity reactions to it in the past. Its safety in pregnant patients has not been established. Leukopenia and proteinuria have occasionally been reported. Therefore, in patients undergoing prolonged therapy, routine evaluation of the hepatic, renal, and hematopoietic systems is advisable. Coumarin anticoagulant activity may be altered by griseofulvin, and anticoagulant dosage may require adjustment.

TERBINAFINE Terbinafine (described above) is quite effective given orally for the treatment of onychomycosis. Recommended oral dosage is 250 mg daily for 6 weeks for fingernail infections and 12 weeks for toenail infections. Patients receiving terbinafine for onychomycosis should be monitored closely with periodic laboratory evaluations for possible hepatic dysfunction.

TOPICAL ANTIVIRAL AGENTS ACYCLOVIR, VALACYCLOVIR, PENCICLOVIR, & FAMCICLOVIR Acyclovir, valacyclovir, penciclovir, and famciclovir are synthetic guanine analogs with inhibitory activity against members of the herpesvirus family, including herpes simplex types 1 and 2. Their mechanism of action, indications, and usage in the treatment of cutaneous infections are discussed in Chapter 49.

Topical acyclovir (Zovirax) is available as a 5% ointment; topical penciclovir (Denavir), as a 1% cream for the treatment of recurrent orolabial herpes simplex virus infection in immunocompetent adults. Adverse local reactions to acyclovir and penciclovir may include pruritus and mild pain with transient stinging or burning.

IMMUNOMODULATORS IMIQUIMOD Imiquimod is available as 5% cream (Aldara) for the treatment of external genital and perianal warts in adults, actinic keratoses on the face and scalp, and biopsy-proven primary basal cell carcinomas on the trunk, neck, and extremities. A lower 3.75% concentration cream (Zyclara) is available for the treatment of face and scalp actinic keratoses. The mechanism of its action is thought to be related to imiquimod’s ability to stimulate peripheral mononuclear cells to release interferon alpha and to stimulate macrophages to produce interleukins-1, -6, and -8, and tumor necrosis factor-α (TNF-α).

Imiquimod should be applied to the wart tissue three times per week and left on the skin for 6–10 hours prior to washing off with mild soap and water. Treatment should be continued until eradication of the warts is accomplished, but not for more than a total of 16 weeks.

Recommended treatment of actinic keratoses consists of twice-weekly applications of the 5% cream on the contiguous area of involvement or nightly applications of the 3.75% cream. The cream is removed after approximately 8 hours with mild soap and water.

Treatment of superficial basal cell carcinoma consists of five-times-per-week application to the tumor, including a 1 cm margin of surrounding skin, for a 6-week course of therapy.

Percutaneous absorption is minimal, with less than 0.9% absorbed following a single-dose application. Adverse effects consist of local inflammatory reactions, including pruritus, erythema, and superficial erosion.

TACROLIMUS & PIMECROLIMUS Tacrolimus (Protopic) and pimecrolimus (Elidel) are macrolide immunosuppressants that have been shown to be of significant benefit in the treatment of atopic dermatitis. Both agents inhibit T-lymphocyte activation and prevent the release of inflammatory cytokines and mediators from mast cells in vitro after stimulation by antigen-IgE complexes. Tacrolimus is available as 0.03% and 0.1% ointments, and pimecrolimus is available as a 1% cream. Both are indicated for short-term and intermittent long-term therapy for mild to moderate atopic dermatitis. Tacrolimus 0.03% ointment and pimecrolimus 1% cream are approved for use in children older than 2 years of age, although all strengths are approved for adult use. Recommended dosing of both agents is twice-daily application to affected skin until clearing is noted. Neither medication should be used with occlusive dressings. The most common side effect of both drugs is a burning sensation in the applied area that improves with continued use. The FDA has added a black box warning regarding the long-term safety of topical tacrolimus and pimecrolimus because of animal tumorigenicity data.

ECTOPARASITICIDES PERMETHRIN Permethrin is toxic to Pediculus humanus, Pthirus pubis, and Sarcoptes scabiei. Less than 2% of an applied dose is absorbed percutaneously. Residual drug persists up to 10 days following application. Resistance to permethrin is becoming more widespread.

It is recommended that permethrin 1% cream rinse (Nix) be applied undiluted to affected areas of pediculosis for 10 minutes and then rinsed off with warm water. For the treatment of scabies, a single application of 5% cream (Elimite, Acticin) is applied to the body from the neck down, left on for 8–14 hours, and then washed off. Adverse reactions to permethrin include transient burning, stinging, and pruritus. Cross-sensitization to pyrethrins or chrysanthemums has been alleged but inadequately documented.

SPINOSAD Spinosad (Natroba) suspension is approved for the topical treatment of head lice in patients 4 years of age and older. Spinosad is toxic to P humanus with no appreciable absorption from topical application. It is recommended that the 0.9% suspension be applied to the hair

and scalp for 10 minutes and then rinsed out. A repeat treatment may be applied 1 week later if live lice are present.

IVERMECTIN Ivermectin (Sklice) 0.5% lotion is approved for the treatment of head lice in patients 6 months of age and older. Ivermectin is toxic to P humanus, resulting in paralysis and death of the parasite. The lotion should be applied to the hair and scalp and rinsed out after 10 minutes. Ivermectin is for single use only and should not be repeated without health care provider recommendation.

LINDANE (HEXACHLOROCYCLOHEXANE) The gamma isomer of hexachlorocyclohexane was commonly called gamma benzene hexachloride, a misnomer, since no benzene ring is present in this compound. Percutaneous absorption studies using a solution of lindane in acetone have shown that almost 10% of a dose applied to the forearm is absorbed, to be subsequently excreted in the urine over a 5-day period. After absorption, lindane is concentrated in fatty tissues, including the brain.

Lindane is available as a 1% shampoo or lotion. For pediculosis capitis or pubis, 30 mL of shampoo is applied to dry hair on the scalp or genital area for 4 minutes and then rinsed off. No additional application is indicated unless living lice are present 1 week after treatment. Then reapplication may be required.

Recent concerns about the toxicity of lindane have altered treatment guidelines for its use in scabies; the current recommendation calls for a single 60 mL application to the entire body from the neck down, left on for 8–12 hours, and then washed off. Patients should be retreated only if active mites can be demonstrated, and never within 1 week of initial treatment.

Concerns about neurotoxicity and hematotoxicity have resulted in warnings that lindane should be used with caution in infants, children, and pregnant women. The current USA package insert recommends that it not be used as a scabicide in premature infants and in patients with known seizure disorders. Local irritation may occur, and contact with the eyes and mucous membranes should be avoided.

CROTAMITON Crotamiton, N-ethyl-o-crotonotoluidide, is a scabicide with some antipruritic properties. Its mechanism of action is not known. Studies on percutaneous absorption have revealed detectable levels of crotamiton in the urine following a single application on the forearm.

Crotamiton (Eurax) is available as a 10% cream or lotion. Suggested guidelines for scabies treatment call for two applications to the entire body from the chin down at 24-hour intervals, with a cleansing bath 48 hours after the last application. Crotamiton is an effective agent that can be used as an alternative to lindane. Allergic contact dermatitis and primary irritation may occur, necessitating discontinuance of therapy. Application to acutely inflamed skin or to the eyes or mucous membranes should be avoided.

SULFUR Sulfur has a long history of use as a scabicide. Although it is nonirritating, it has an unpleasant odor, is staining, and is thus disagreeable to use. It has been replaced by more aesthetic and effective scabicides in recent years, but it remains a possible alternative drug for use in infants and pregnant women. The usual formulation is 5% precipitated sulfur in petrolatum.

MALATHION Malathion is an organophosphate cholinesterase inhibitor that is hydrolyzed and inactivated by plasma carboxylesterases much faster in humans than in insects, thereby providing a therapeutic advantage in treating pediculosis (see Chapter 7). Malathion is available as a 0.5% lotion (Ovide) that should be applied to the hair when dry; 4–6 hours later, the hair is combed to remove nits and lice.

BENZYL ALCOHOL Benzyl alcohol (Ulesfia) is available as a 5% lotion for the treatment of head lice in patients older than 6 months. The lotion is applied to dry hair and left on for 10 minutes prior to rinsing off with water. Because the drug is not ovicidal, the treatment must be repeated after 7 days. Eye irritation and allergic contact dermatitis have been reported.

AGENTS AFFECTING PIGMENTATION HYDROQUINONE, MONOBENZONE, & MEQUINOL

Hydroquinone, monobenzone (Benoquin, the monobenzyl ether of hydroquinone), and mequinol (the monomethyl ether of hydroquinone) are used to reduce hyperpigmentation of the skin. Topical hydroquinone and mequinol usually result in temporary lightening, whereas monobenzone causes irreversible depigmentation.

The mechanism of action of these compounds appears to involve inhibition of the enzyme tyrosinase, thus interfering with the biosynthesis of melanin. In addition, monobenzone may be toxic to melanocytes, resulting in permanent loss of these cells. Some percutaneous absorption of these compounds takes place, because monobenzone may cause hypopigmentation at sites distant from the area of application. Both hydroquinone and monobenzone may cause local irritation. Allergic contact dermatitis to these compounds can occur. Prescription combinations of hydroquinone, fluocinolone acetonide, and retinoic acid (Tri-Luma) and mequinol and retinoic acid (Solagé) are more effective than their individual components.

TRIOXSALEN & METHOXSALEN Trioxsalen and methoxsalen are psoralens used for the repigmentation of depigmented macules of vitiligo. With the recent development of high-intensity long-wave ultraviolet fluorescent lamps, photochemotherapy with oral methoxsalen for psoriasis and with oral trioxsalen for vitiligo has been under intensive investigation.

Psoralens must be photoactivated by long-wavelength ultraviolet light in the range of 320–400 nm (ultraviolet A [UVA]) to produce a beneficial effect. Psoralens intercalate with DNA and, with subsequent UVA irradiation, cyclobutane adducts are formed with pyrimidine bases. Both monofunctional and bifunctional adducts may be formed, the latter causing interstrand cross-links. These DNA photoproducts may inhibit DNA synthesis. The major long-term risks of psoralen photochemotherapy are cataracts and skin cancer.

SUNSCREENS Topical medications useful in protecting against sunlight contain either chemical compounds that absorb ultraviolet light, called sunscreens, or opaque materials such as titanium dioxide that reflect light, called sunshades. The three classes of chemical compounds most commonly used in sunscreens are p-aminobenzoic acid (PABA) and its esters, the benzophenones, and the dibenzoylmethanes.

Most sunscreen preparations are designed to absorb ultraviolet light in the ultraviolet B (UVB) wavelength range from 280 to 320 nm, which is the range responsible for most of the erythema and sunburn associated with sun exposure and tanning. Chronic exposure to light in this range induces aging of the skin and photocarcinogenesis. Para-aminobenzoic acid and its esters are the most effective available absorbers in the B region. Ultraviolet in the longer UVA range, 320–400 nm, is also associated with skin aging and cancer.

The benzophenones include oxybenzone, dioxybenzone, and sulisobenzone. These compounds provide a broader spectrum of absorption from 250 to 360 nm, but their effectiveness in the UVB erythema range is less than that of PABA. The dibenzoylmethanes include Parasol and Eusolex. These compounds absorb wavelengths throughout the longer UVA range, with maximum absorption at 360 nm. Patients particularly sensitive to UVA wavelengths include individuals with polymorphous light eruption, cutaneous lupus erythematosus, and drug-induced photosensitivity. In these patients, dibenzoylmethane-containing sunscreen may provide improved photoprotection. Ecamsule (Mexoryl) appears to provide greater UVA protection than the dibenzoylmethanes and is less prone to photodegradation.

The sun protection factor (SPF) of a given sunscreen is a measure of its effectiveness in absorbing erythrogenic ultraviolet light. It is determined by measuring the minimal erythema dose with and without the sunscreen in a group of normal people. The ratio of the minimal erythema dose with sunscreen to the minimal erythema dose without sunscreen is the SPF. Recently updated FDA regulations limit the claimed maximum SPF value on sunscreen labels to 50+ because data are insufficient to show that products with SPF values higher than 50 provide greater protection for users. These regulations require that sunscreens labeled “broad spectrum” pass a standard test comparing the amount of UVA radiation protection in relation to the amount of UVB protection. Broad spectrum sunscreens with SPF values of 15 or higher help protect against not only sunburn, but also skin cancer and early skin aging when used as directed. Sunscreens with an SPF value between 2 and 14 can only claim that they help prevent sunburn.

In addition, products claiming to be water resistant must indicate whether they remain effective for 40 minutes or 80 minutes while swimming or sweating, based on standard testing.

ACNE PREPARATIONS RETINOIC ACID & DERIVATIVES Retinoic acid, also known as tretinoin or all-trans-retinoic acid, is the acid form of vitamin A. It is an effective topical treatment for acne vulgaris. Several analogs of vitamin A, eg, 13-cis-retinoic acid (isotretinoin), have been shown to be effective in various dermatologic diseases when given orally. Vitamin A alcohol is the physiologic form of vitamin A. The topical therapeutic agent, retinoic acid, is formed by the oxidation of the alcohol group, with all four double bonds in the side chain in the trans configuration as shown.

Retinoic acid is insoluble in water but soluble in many organic solvents. Topically applied retinoic acid remains chiefly in the epidermis, with less than 10% absorption into the circulation. The small quantities of retinoic acid absorbed following topical application are metabolized by the liver and excreted in bile and urine.

Retinoic acid has several effects on epithelial tissues. It stabilizes lysosomes, increases ribonucleic acid polymerase activity, increases prostaglandin E2 , cAMP, and cGMP levels, and increases the incorporation of thymidine into DNA. Its action in acne has been attributed to decreased cohesion between epidermal cells and increased epidermal cell turnover. This is thought to result in the expulsion of open comedones and the transformation of closed comedones into open ones.

Topical retinoic acid is applied initially in a concentration sufficient to induce slight erythema with mild peeling. The concentration or frequency of application may be decreased if too much irritation occurs. Topical retinoic acid should be applied to dry skin only, and care should be taken to avoid contact with the corners of the nose, eyes, mouth, and mucous membranes. During the first 4–6 weeks of therapy, comedones not previously evident may appear and give the impression that the acne has been aggravated by the retinoic acid.

However, with continued therapy, the lesions will clear, and in 8–12 weeks optimal clinical improvement should occur. A timed-release formulation of tretinoin containing microspheres (Retin-A Micro) delivers the medication over time and may be less irritating for sensitive patients.

The effects of tretinoin on keratinization and desquamation offer benefits for patients with photo-damaged skin. Prolonged use of tretinoin promotes dermal collagen synthesis, new blood vessel formation, and thickening of the epidermis, which helps diminish fine lines and wrinkles. Specially formulated moisturizing 0.05% cream (Renova, Refissa) is marketed for this purpose.

The most common adverse effects of topical retinoic acid are erythema and dryness that occur in the first few weeks of use, but these can be expected to resolve with continued therapy. Animal studies suggest that this drug may increase the tumorigenic potential of ultraviolet radiation. In light of this, patients using retinoic acid should be advised to avoid or minimize sun exposure and use a protective sunscreen. Allergic contact dermatitis to topical retinoic acid is rare.

Adapalene (Differin) is a derivative of naphthoic acid that resembles retinoic acid in structure and effects. It is available for daily application as a 0.1% gel, cream, or lotion and a 0.3% gel. Unlike tretinoin, adapalene is photochemically stable and shows little decrease in efficacy when used in combination with benzoyl peroxide. Adapalene is less irritating than tretinoin and is most effective in patients with mild to moderate acne vulgaris. Adapalene is also available in a fixed-dose combination gel with benzoyl peroxide (Epiduo).

Tazarotene (Tazorac, Fabior) is an acetylenic retinoid that is available as a 0.1% gel, cream, and foam for the treatment of mild to moderately severe facial acne. Topical tazarotene should be used by women of childbearing age only after contraceptive counseling. It is recommended that tazarotene should not be used by pregnant women.

ISOTRETINOIN Isotretinoin is a synthetic retinoid currently restricted to the oral treatment of severe cystic acne that is recalcitrant to standard therapies.

The precise mechanism of action of isotretinoin in cystic acne is not known, although it appears to act by inhibiting sebaceous gland size and function. The drug is well absorbed, extensively bound to plasma albumin, and has an elimination half-life of 10–20 hours. Recently, a lipid solubilized formulation, CIP-isotretinoin (Absorica), has been approved which provides more consistent absorption and can be taken with or without food.

Most patients with cystic acne respond to 1–2 mg/kg, given in two divided doses daily for 4–5 months. If severe cystic acne persists following this initial treatment, after a period of 2 months, a second course of therapy may be initiated. Common adverse effects resemble hypervitaminosis A and include dryness and itching of the skin and mucous membranes. Less common side effects are headache, corneal opacities, pseudotumor cerebri, inflammatory bowel disease, anorexia, alopecia, and muscle and joint pains. These effects are all reversible on discontinuance of therapy. Skeletal hyperostosis has been observed in patients receiving isotretinoin with premature closure of epiphyses noted in children treated with this medication. Lipid abnormalities (triglycerides, high-density lipoproteins) are frequent; their clinical relevance is unknown at present.

Teratogenicity is a significant risk in patients taking isotretinoin; therefore, women of childbearing potential must use an effective form of contraception for at least 1 month before, throughout isotretinoin therapy, and for one or more menstrual cycles following discontinuance of treatment. A negative serum pregnancy test must be obtained within 2 weeks before starting therapy in these patients, and therapy should be initiated only on the second or third day of the next normal menstrual period. In the USA, health care

professionals, pharmacists, and patients must utilize the mandatory iPLEDGE registration and follow-up system.

BENZOYL PEROXIDE Benzoyl peroxide is an effective topical agent in the treatment of acne vulgaris. It penetrates the stratum corneum or follicular openings unchanged and is converted metabolically to benzoic acid within the epidermis and dermis. Less than 5% of an applied dose is absorbed from the skin in an 8-hour period. It has been postulated that the mechanism of action of benzoyl peroxide in acne is related to its antimicrobial activity against P acnes and to its peeling and comedolytic effects.

To decrease the likelihood of irritation, application should be limited to a low concentration (2.5%) once daily for the first week of therapy and increased in frequency and strength if the preparation is well tolerated. Fixed-combination formulations of 5% benzoyl peroxide with 3% erythromycin base (Benzamycin) or 1% clindamycin (BenzaClin, Duac), and 2.5% benzoyl peroxide with 1.2% clindamycin (Acanya) or 0.1% adapalene (Epiduo) appear to be more effective than individual agents alone.

Benzoyl peroxide is a potent contact sensitizer in experimental studies, and this adverse effect may occur in up to 1% of acne patients. Care should be taken to avoid contact with the eyes and mucous membranes. Benzoyl peroxide is an oxidant and may rarely cause bleaching of the hair or colored fabrics.

AZELAIC ACID Azelaic acid is a straight-chain saturated dicarboxylic acid that is effective in the treatment of acne vulgaris (in the form of Azelex) and acne rosacea (Finacea). Its mechanism of action has not been fully determined, but preliminary studies demonstrate antimicrobial activity against P acnes as well as in vitro inhibitory effects on the conversion of testosterone to dihydrotestosterone. Initial therapy is begun with once-daily applications of the 20% cream or 15% gel to the affected areas for 1 week and twice-daily applications thereafter. Most patients experience mild irritation with redness and dryness of the skin during the first week of treatment. Clinical improvement is noted in 6–8 weeks of continuous therapy.

BRIMONIDINE Brimonidine (Mirvaso) is an α2 -adrenergic agonist indicated for the topical treatment of persistent facial erythema of rosacea in adults 18 years of age or older. Daily topical application of brimonidine 0.33% gel may reduce erythema through direct vasoconstriction.

Exacerbation of facial erythema and flushing may occur, ranging from 30 minutes to several hours after application. Alpha 2 agonists can lower blood pressure (see Chapter 11); therefore, brimonidine should be used with caution in patients with severe, unstable, or uncontrolled cardiovascular disease.

DRUGS FOR PSORIASIS ACITRETIN Acitretin (Soriatane), a metabolite of the aromatic retinoid etretinate, is quite effective in the treatment of psoriasis, especially pustular forms. It is given orally at a dosage of 25–50 mg/d. Adverse effects attributable to acitretin therapy are similar to those seen with isotretinoin and resemble hypervitaminosis A. Elevations in cholesterol and triglycerides may be noted with acitretin, and hepatotoxicity with liver enzyme elevations has been reported. Acitretin is more teratogenic than isotretinoin in the animal species studied to date, which is of special concern in view of the drug’s prolonged elimination time (more than 3 months) after chronic administration. In cases where etretinate is formed by concomitant administration of acitretin and ethanol, etretinate may be found in plasma and subcutaneous fat for many years.

Acitretin must not be used by women who are pregnant or may become pregnant while undergoing treatment or at any time for at least 3 years after treatment is discontinued. Ethanol must be strictly avoided during treatment with acitretin and for 2 months after discontinuing therapy. Patients must not donate blood during treatment and for 3 years after acitretin is stopped.

TAZAROTENE Tazarotene (Tazorac) is a topical acetylenic retinoid prodrug that is hydrolyzed to its active form by an esterase. The active metabolite, tazarotenic acid, binds to retinoic acid receptors, resulting in modified gene expression. The precise mechanism of action in psoriasis is unknown but may relate to both anti-inflammatory and antiproliferative actions. Tazarotene is absorbed percutaneously, and teratogenic systemic concentrations may be achieved if applied to more than 20% of total body surface area. Women of childbearing potential must therefore be advised of the risk prior to initiating therapy, and adequate birth control measures must be utilized while on therapy.

Treatment of psoriasis should be limited to once-daily application of either 0.05% or 0.1% gel not to exceed 20% of total body surface area. Adverse local effects include a burning or stinging sensation (sensory irritation) and peeling, erythema, and localized edema of the skin (irritant dermatitis). Potentiation of photosensitizing medication may occur, and patients should be cautioned to minimize sunlight exposure and to use sunscreens and protective clothing.

CALCIPOTRIENE & CALCITRIOL Calcipotriene (Dovonex, Sorilux) is a synthetic vitamin D3 derivative (available as a 0.005% cream, scalp lotion, and foam) that is effective in the treatment of plaque-type psoriasis vulgaris of moderate severity. Improvement of psoriasis was generally noted following 2 weeks of therapy, with continued improvement for up to 8 weeks of treatment. However, fewer than 10% of patients demonstrate total clearing while on calcipotriene as single-agent therapy. Adverse effects include burning, itching, and mild irritation, with dryness and erythema of the treatment area. Care should be taken to avoid facial contact, which may cause ocular irritation. A once-daily twocompound ointment containing calcipotriene and betamethasone dipropionate (Taclonex) is available. This combination is more effective than its individual ingredients and is well tolerated, with a safety profile similar to betamethasone dipropionate.

Calcitriol (Vectical) contains 1,25-dihydroxycholecalciferol, the hormonally active form of vitamin D 3 . Calcitriol 3 mcg/g ointment is similar in efficacy to calcipotriene 0.005% ointment for the treatment of plaque-type psoriasis on the body and is better tolerated in intertriginous and sensitive areas of the skin. Clinical studies show comparable safety data regarding adverse cutaneous and systemic reactions between topical calcitriol and calcipotriene ointment.

BIOLOGIC AGENTS Biologic agents useful in treating adult patients with moderate to severe chronic plaque psoriasis include the T-cell modulator alefacept; the TNF-α inhibitors etanercept, infliximab, and adalimumab; and the cytokine inhibitor ustekinumab. TNF-α inhibitors are also discussed in Chapters 36 and 55.

ALEFACEPT Alefacept (Amevive) is an immunosuppressive dimeric fusion protein that consists of the extracellular CD2-binding portion of the human leukocyte function antigen-3 linked to the Fc portion of human IgG1 . Alefacept interferes with lymphocyte activation, which plays a role in the pathophysiology of psoriasis, and causes a reduction in subsets of CD2 T lymphocytes and circulating total CD4 and CD8 Tlymphocyte counts. The recommended dosage is 7.5 mg given once weekly as an intravenous bolus or 15 mg once weekly as an intramuscular injection for a 12-week course of treatment. Patients should have CD4 lymphocyte counts monitored weekly while taking alefacept, and dosing should be withheld if CD4 counts are below 250 cells/μL. The drug should be discontinued if the counts remain below 250 cells/μL for 1 month. Alefacept is an immunosuppressive agent and should not be administered to patients with clinically significant infection. Because of the possibility of an increased risk of malignancy, it should not be administered to patients with a history of systemic malignancy.

TNF INHIBITORS: ETANERCEPT, INFLIXIMAB, & ADALIMUMAB Etanercept (Enbrel) is a dimeric fusion protein consisting of the extracellular ligand-binding portion of the human TNF receptor linked to the Fc portion of human IgG1 . Etanercept binds selectively to TNF-α and -β and blocks interaction with cell surface TNF receptors that play a role in the inflammatory process of plaque psoriasis. The recommended dosage of etanercept in psoriasis is a 50 mg subcutaneous injection given twice weekly for 3 months followed by a maintenance dose of 50 mg weekly.

Infliximab (Remicade) is a chimeric IgG1 monoclonal antibody composed of human constant and murine variable regions. Infliximab binds to the soluble and transmembrane forms of TNF-α and inhibits binding of TNF-α with its receptors. The recommended dose of infliximab is 5 mg/kg given as an intravenous infusion followed by similar doses at 2 and 6 weeks after the first infusion and then every 8 weeks thereafter.

Adalimumab (Humira) is a recombinant 1gG1 monoclonal antibody that binds specifically to TNF-α and blocks its interaction with cell surface TNF receptors. The recommended dose for adalimumab in psoriasis is an initial dose of 80 mg administered subcutaneously followed by 40 mg given every other week starting 1 week after the initial dose.

Serious life-threatening infections, including sepsis and pneumonia, have been reported with the use of TNF inhibitors. Patients should be evaluated for tuberculosis risk factors and tested for latent tuberculosis infection prior to starting therapy. Concurrent use with other immunosuppressive therapy should be avoided. In clinical trials of all TNF-blocking agents more cases of lymphoma were observed compared with control patients. Patients with a prior history of prolonged phototherapy treatment should be monitored for nonmelanoma skin cancers.

USTEKINUMAB Ustekinumab (Stelara) is a human IgG1 κ monoclonal antibody that binds with high affinity and specificity to interleukin (IL)-12 and IL-23 cytokines inhibiting TH1 and TH17 cell-mediated responses, which are involved in the pathogenesis of psoriasis. The recommended treatment protocol is 45 mg for patients weighing less than 100 kg, and 90 mg for patients weighing more than 100 kg given as a subcutaneous injection initially, followed by the same dose 4 weeks later, and then once every 12 weeks. Serious allergic reactions including angioedema and anaphylaxis have occurred and caution should be exercised in patients receiving allergy immunotherapy.

Serious infections, especially from mycobacterial organisms, are possible and patients must be evaluated for tuberculosis prior to initiating therapy. Live vaccines, including bacillus Calmette-Guérin (BCG), should not be given with ustekinumab. One case of reversible posterior leukoencephalopathy syndrome has been reported.

FUMARIC ACID ESTERS Fumaric acid esters (Fumaderm) are licensed in Germany for the oral treatment of psoriasis. They are considered homeopathic treatment in the USA and are not approved or regulated by the FDA for the treatment of psoriasis. Dimethyl fumarate (Tecfidera) has recently been approved by the FDA for treatment of multiple sclerosis. The mechanism of action of dimethyl fumarate in psoriasis may be due to immunomodulatory effects on lymphocytes and keratinocytes resulting in a shift away from a psoriatic cytokine profile. It should be noted that four cases of progressive multifocal leukoencephalopathy have been reported in psoriasis patients treated with fumaric acid esters.

ANTI-INFLAMMATORY AGENTS TOPICAL CORTICOSTEROIDS The remarkable efficacy of topical corticosteroids in the treatment of inflammatory dermatoses was noted soon after the introduction of hydrocortisone in 1952. Numerous analogs are now available that offer extensive choices of potencies, concentrations, and vehicles. The therapeutic effectiveness of topical corticosteroids is based primarily on their anti-inflammatory activity. Definitive explanations of the effects of corticosteroids on endogenous mediators of inflammation await further experimental clarification. The antimitotic effects of corticosteroids on human epidermis may account for an additional mechanism of action in psoriasis and other dermatologic diseases associated with increased cell turnover. The general pharmacology of these endocrine agents is discussed in Chapter 39.

Chemistry & Pharmacokinetics The original topical glucocorticosteroid was hydrocortisone, the natural glucocorticosteroid of the adrenal cortex. The 9α-fluoro derivative of hydrocortisone was active topically, but its salt-retaining properties made it undesirable even for topical use. Prednisolone and methylprednisolone are as active topically as hydrocortisone (Table 61–2). The 9α-fluorinated steroids dexamethasone and betamethasone did not have any advantage over hydrocortisone. However, triamcinolone and fluocinolone, the acetonide derivatives of the fluorinated steroids, do have a distinct efficacy advantage in topical therapy. Similarly, betamethasone is not very active topically, but attaching a 5-carbon valerate chain to the 17-hydroxyl position results in a compound over 300 times as active as hydrocortisone for topical use. Fluocinonide is the 21-acetate derivative of fluocinolone acetonide; the addition of the 21-acetate enhances the topical activity about fivefold. Fluorination of the corticoid is not required for high potency.

TABLE 61–2 Relative efficacy of some topical corticosteroids in various formulations.

Corticosteroids are only minimally absorbed following application to normal skin; for example, approximately 1% of a dose of hydrocortisone solution applied to the ventral forearm is absorbed. Long-term occlusion with an impermeable film such as plastic wrap is an effective method of enhancing penetration, yielding a tenfold increase in absorption. There is a marked regional anatomic variation in corticosteroid penetration. Compared with the absorption from the forearm, hydrocortisone is absorbed 0.14 times as well through the plantar foot arch, 0.83 times as well through the palm, 3.5 times as well through the scalp, 6 times as well through the forehead, 9 times as well through vulvar skin, and 42 times as well through scrotal skin. Penetration is increased severalfold in the inflamed skin of atopic dermatitis; and in severe exfoliative diseases, such as erythrodermic psoriasis, there appears to be little barrier to penetration.

Experimental studies on the percutaneous absorption of hydrocortisone fail to reveal a significant increase in absorption when applied on a repetitive basis and a single daily application may be effective in most conditions. Ointment bases tend to give better activity to the corticosteroid than do cream or lotion vehicles. Increasing the concentration of a corticosteroid increases the penetration but not proportionately. For example, approximately 1% of a 0.25% hydrocortisone solution is absorbed from the forearm. A tenfold increase in concentration causes only a fourfold increase in absorption. Solubility of the corticosteroid in the vehicle is a significant determinant of the percutaneous absorption of a topical steroid. Marked increases in efficacy are noted when optimized vehicles are used, as demonstrated by newer formulations of betamethasone dipropionate and diflorasone diacetate.

Table 61–2 groups topical corticosteroid formulations according to approximate relative efficacy. Table 61–3 lists major dermatologic diseases in order of their responsiveness to these drugs. In the first group of diseases, low- to medium-efficacy corticosteroid preparations often produce clinical remission. In the second group, it is often necessary to use high-efficacy preparations, occlusion therapy, or both. Once a remission has been achieved, every effort should be made to maintain the improvement with a low-efficacy corticosteroid.

TABLE 61–3 Dermatologic disorders responsive to topical corticosteroids ranked in order of sensitivity.

The limited penetration of topical corticosteroids can be overcome in certain clinical circumstances by the intralesional injection of relatively insoluble corticosteroids, eg, triamcinolone acetonide, triamcinolone diacetate, triamcinolone hexacetonide, and betamethasone acetate-phosphate. When these agents are injected into the lesion, measurable amounts remain in place and are gradually released for 3– 4 weeks. This form of therapy is often effective for the lesions listed in Table 61–3 that are generally unresponsive to topical corticosteroids. The dosage of the triamcinolone salts should be limited to 1 mg per treatment site, ie, 0.1 mL of 10 mg/mL suspension, to decrease the incidence of local atrophy (see below).

Adverse Effects All absorbable topical corticosteroids possess the potential to suppress the pituitary-adrenal axis (see Chapter 39). Although most patients with pituitary-adrenal axis suppression demonstrate only a laboratory test abnormality, cases of severely impaired stress response can occur. Iatrogenic Cushing’s syndrome may occur as a result of protracted use of topical corticosteroids in large quantities. Applying potent corticosteroids to extensive areas of the body for prolonged periods, with or without occlusion, increases the likelihood of systemic effects. Fewer of these factors are required to produce adverse systemic effects in children, and growth retardation is of particular concern in the pediatric age group.

Adverse local effects of topical corticosteroids include the following: atrophy, which may present as depressed, shiny, often wrinkled “cigarette paper”-appearing skin with prominent telangiectases and a tendency to develop purpura and ecchymosis; corticoid rosacea, with persistent erythema, telangiectatic vessels, pustules, and papules in central facial distribution; perioral dermatitis, steroid acne, alterations of cutaneous infections, hypopigmentation, hypertrichosis; increased intraocular pressure; and allergic contact dermatitis. The latter may be confirmed by patch testing with high concentrations of corticosteroids, ie, 1% in petrolatum, because topical corticosteroids are not irritating. Screening for allergic contact dermatitis potential is performed with tixocortol pivalate, budesonide, and hydrocortisone valerate or butyrate. Topical corticosteroids are contraindicated in individuals who demonstrate hypersensitivity to them. Some sensitized subjects develop a generalized flare when dosed with adrenocorticotropic hormone or oral prednisone.

TAR COMPOUNDS Tar preparations are used mainly in the treatment of psoriasis, dermatitis, and lichen simplex chronicus. The phenolic constituents endow these compounds with antipruritic properties, making them particularly valuable in the treatment of chronic lichenified dermatitis. Acute dermatitis with vesiculation and oozing may be irritated by even weak tar preparations, which should be avoided. However, in the subacute and chronic stages of dermatitis and psoriasis, these preparations are quite useful and offer an alternative to the use of topical corticosteroids.

The most common adverse reaction to coal tar compounds is an irritant folliculitis, necessitating discontinuance of therapy to the affected areas for a period of 3–5 days. Photoirritation and allergic contact dermatitis may also occur. Tar preparations should be avoided in patients who have previously exhibited sensitivity to them.

KERATOLYTIC & DESTRUCTIVE AGENTS SALICYLIC ACID Salicylic acid has been extensively used in dermatologic therapy as a keratolytic agent. The mechanism by which it produces its keratolytic and other therapeutic effects is poorly understood. The drug may solubilize cell surface proteins that keep the stratum corneum intact, thereby resulting in desquamation of keratotic debris. Salicylic acid is keratolytic in concentrations of 3–6%. In concentrations greater than 6%, it can be destructive to tissues.

Salicylism and death have occurred following topical application. In an adult, 1 g of a topically applied 6% salicylic acid preparation will raise the serum salicylate level not more than 0.5 mg/dL of plasma; the threshold for toxicity is 30–50 mg/dL. Higher serum levels are possible in children, who are therefore at a greater risk for salicylism. In cases of severe intoxication, hemodialysis is the treatment of

choice (see Chapter 58). It is advisable to limit both the total amount of salicylic acid applied and the frequency of application. Urticarial, anaphylactic, and erythema multiforme reactions may occur in patients who are allergic to salicylates. Topical use may be associated with local irritation, acute inflammation, and even ulceration with the use of high concentrations of salicylic acid. Particular care must be exercised when using the drug on the extremities of patients with diabetes or peripheral vascular disease.

PROPYLENE GLYCOL Propylene glycol is used extensively in topical preparations because it is an excellent vehicle for organic compounds. It has been used alone as a keratolytic agent in 40–70% concentrations, with plastic occlusion, or in gel with 6% salicylic acid.

Only minimal amounts of a topically applied dose are absorbed through normal stratum corneum. Percutaneously absorbed propylene glycol is oxidized by the liver to lactic acid and pyruvic acid, with subsequent utilization in general body metabolism. Approximately 12– 45% of the absorbed agent is excreted unchanged in the urine.

Propylene glycol is an effective keratolytic agent for the removal of hyperkeratotic debris. It is also an effective humectant and increases the water content of the stratum corneum. The hygroscopic characteristics of propylene glycol may help it to develop an osmotic gradient through the stratum corneum, thereby increasing hydration of the outermost layers by drawing water out from the inner layers of the skin.

Propylene glycol is used under polyethylene occlusion or with 6% salicylic acid for the treatment of ichthyosis, palmar and plantar keratodermas, psoriasis, pityriasis rubra pilaris, keratosis pilaris, and hypertrophic lichen planus.

In concentrations greater than 10%, propylene glycol may act as an irritant in some patients; those with eczematous dermatitis may be more sensitive. Allergic contact dermatitis occurs with propylene glycol, and a 4% aqueous propylene glycol solution is recommended for the purpose of patch testing.

UREA Urea in a compatible cream vehicle or ointment base has a softening and moisturizing effect on the stratum corneum. It has the ability to make creams and lotions feel less greasy, and this has been utilized in dermatologic preparations to decrease the oily feel of a preparation that otherwise might feel unpleasant. It is a white crystalline powder with a slight ammonia odor when moist.

Urea is absorbed percutaneously, although the amount absorbed is minimal. It is distributed predominantly in the extracellular space and excreted in urine. Urea is a natural product of metabolism, and systemic toxicities with topical application do not occur.

Urea increases the water content of the stratum corneum, presumably as a result of the hygroscopic characteristics of this naturally occurring molecule. Urea is also keratolytic. The mechanism of action appears to involve alterations in prekeratin and keratin, leading to increased solubilization. In addition, urea may break hydrogen bonds that keep the stratum corneum intact.

As a humectant, urea is used in concentrations of 2–20% in creams and lotions. As a keratolytic agent, it is used in 20% concentration in diseases such as ichthyosis vulgaris, hyperkeratosis of palms and soles, xerosis, and keratosis pilaris. Concentrations of 30–50% applied to the nail plate have been useful in softening the nail prior to avulsion.

PODOPHYLLUM RESIN & PODOFILOX Podophyllum resin, an alcoholic extract of Podophyllum peltatum, commonly known as mandrake root or May apple, is used in the treatment of condyloma acuminatum and other verrucae. It is a mixture of podophyllotoxin, α and β peltatin, desoxypodophyllotoxin, dehydropodophyllotoxin, and other compounds. It is soluble in alcohol, ether, chloroform, and compound tincture of benzoin.

Percutaneous absorption of podophyllum resin occurs, particularly in intertriginous areas and from applications to large moist condylomas. It is soluble in lipids and therefore is distributed widely throughout the body, including the central nervous system.

The major use of podophyllum resin is in the treatment of condyloma acuminatum. Podophyllotoxin and its derivatives are active cytotoxic agents with specific affinity for the microtubule protein of the mitotic spindle. Normal assembly of the spindle is prevented, and epidermal mitoses are arrested in metaphase. A 25% concentration of podophyllum resin in compound tincture of benzoin is recommended for the treatment of condyloma acuminatum. Application should be restricted to wart tissue only, to limit the total amount of medication used and to prevent severe erosive changes in adjacent tissue. In treating cases of large condylomas, it is advisable to limit application to sections of the affected area to minimize systemic absorption. The patient is instructed to wash off the preparation 2–3 hours after the initial application, because the irritant reaction is variable. Depending on the individual patient’s reaction, this period can be extended to 6–8 hours on subsequent applications. If three to five applications have not resulted in significant resolution, other methods of treatment should be considered.

Toxic symptoms associated with excessively large applications include nausea, vomiting, alterations in sensorium, muscle weakness, neuropathy with diminished tendon reflexes, coma, and even death. Local irritation is common, and inadvertent contact with the eye may cause severe conjunctivitis. Use during pregnancy is contraindicated in view of possible cytotoxic effects on the fetus.

Pure podophyllotoxin (podofilox) is approved for use as either a 0.5% solution or gel (Condylox) for application by the patient in the treatment of genital condylomas. The low concentration of podofilox significantly reduces the potential for systemic toxicity. Most men with penile warts may be treated with less than 70 μL per application. At this dose, podofilox is not routinely detected in the serum.

Treatment is self-administered in treatment cycles of twice-daily application for 3 consecutive days followed by a 4-day drug-free period.

Local adverse effects include inflammation, erosions, burning pain, and itching.

SINECATECHINS Sinecatechins 15% ointment (Veregen) is a prescription botanical drug product of a partially purified fraction of the water extract of green tea leaves from Camellia sinensis containing a mixture of catechins. Sinecatechins ointment is indicated for the topical treatment of external genital and perianal warts in immunocompetent patients 18 years and older. The mechanism of action is unknown.

Sinecatechins ointment should be applied three times daily to the warts until complete clearance, not to exceed 16 weeks of therapy.

FLUOROURACIL Fluorouracil is a fluorinated pyrimidine antimetabolite that resembles uracil, with a fluorine atom substituted for the 5-methyl group. Its systemic pharmacology is described in Chapter 54. Fluorouracil is used topically for the treatment of multiple actinic keratoses.

Approximately 6% of a topically applied dose is absorbed—an amount insufficient to produce adverse systemic effects. Most of the absorbed drug is metabolized and excreted as carbon dioxide, urea, and α-fluoro-β-alanine. A small percentage is eliminated unchanged in the urine. Fluorouracil inhibits thymidylate synthetase activity, interfering with the synthesis of DNA and, to a lesser extent, RNA. These effects are most marked in atypical, rapidly proliferating cells.

Fluorouracil is available in multiple formulations containing 0.5%, 1%, 2%, and 5% concentrations. The response to treatment begins with erythema and progresses through vesiculation, erosion, superficial ulceration, necrosis, and finally reepithelialization. Fluorouracil should be continued until the inflammatory reaction reaches the stage of ulceration and necrosis, usually in 3–4 weeks, at which time treatment should be terminated. The healing process may continue for 1–2 months after therapy is discontinued. Local adverse reactions may include pain, pruritus, a burning sensation, tenderness, and residual postinflammatory hyperpigmentation. Excessive exposure to sunlight during treatment may increase the intensity of the reaction and should be avoided. Allergic contact dermatitis to fluorouracil has been reported, and its use is contraindicated in patients with known hypersensitivity.

INGENOL MEBUTATE Ingenol mebutate (Picato) is derived from the sap of the Euphorbia peplus plant and has recently been approved for the topical treatment of actinic keratoses. The mechanism by which ingenol mebutate induces keratinocyte cell death is unknown. For the treatment of actinic keratoses on the face and scalp, the 0.015% gel should be applied once daily for 3 consecutive days. For actinic keratoses on the trunk and extremities, the 0.05% gel should be applied to the affected area daily for 2 consecutive days. Local skin reactions are to be expected with crusting, swelling, vesiculation, and possible ulceration. Caution must be taken to prevent eye exposure. Patients must wash their hands well after applying the gel and avoid transfer of the drug to the periocular area during and after application.

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS A topical 3% gel formulation of the nonsteroidal anti-inflammatory drug diclofenac (Solaraze) has shown moderate effectiveness in the treatment of actinic keratoses. The mechanism of action is unknown. As with other NSAIDs, anaphylactoid reactions may occur with diclofenac, and it should be given with caution to patients with known aspirin hypersensitivity (see Chapter 36).

AMINOLEVULINIC ACID Aminolevulinic acid (ALA) is an endogenous precursor of photosensitizing porphyrin metabolites. When exogenous ALA is provided to the cell through topical applications, protoporphyrin IX (PpIX) accumulates in the cell. When exposed to light of appropriate wavelength and energy, the accumulated PpIX produces a photodynamic reaction resulting in the formation of cytotoxic superoxide and hydroxyl radicals. Photosensitization of actinic keratoses using ALA (Levulan Kerastick) and illumination with a blue light photodynamic therapy illuminator (BLU-U) is the basis for ALA photodynamic therapy.

Treatment consists of applying ALA 20% topical solution to individual actinic keratoses followed by blue light photodynamic illumination 14–18 hours later. Transient stinging or burning at the treatment site occurs during the period of light exposure. Patients must avoid exposure to sunlight or bright indoor lights for at least 40 hours after ALA application. Redness, swelling, and crusting of the actinic

keratoses will occur and gradually resolve over a 3- to 4-week time course. Allergic contact dermatitis to methyl ester may occur.

ANTIPRURITIC AGENTS DOXEPIN Topical doxepin hydrochloride 5% cream (Zonalon) may provide significant antipruritic activity when utilized in the treatment of pruritus associated with atopic dermatitis or lichen simplex chronicus. The precise mechanism of action is unknown but may relate to the potent H1 - and H2 -receptor antagonist properties of dibenzoxepin tricyclic compounds. Percutaneous absorption is variable and may result in significant drowsiness in some patients. In view of the anticholinergic effect of doxepin, topical use is contraindicated in patients with untreated narrow-angle glaucoma or a tendency to urinary retention.

Plasma levels of doxepin similar to those achieved during oral therapy may be obtained with topical application; the usual drug interactions associated with tricyclic antidepressants may occur. Therefore, monoamine oxidase inhibitors must be discontinued at least 2 weeks prior to the initiation of doxepin cream. Topical application of the cream should be performed four times daily for up to 8 days of therapy. The safety and efficacy of chronic dosing has not been established. Adverse local effects include marked burning and stinging of the treatment site which may necessitate discontinuation of the cream in some patients. Allergic contact dermatitis appears to be frequent, and patients should be monitored for symptoms of hypersensitivity.

PRAMOXINE Pramoxine hydrochloride is a topical anesthetic that can provide temporary relief from pruritus associated with mild eczematous dermatoses. Pramoxine is available as a 1% cream, lotion, or gel and in combination with hydrocortisone acetate. Application to the affected area two to four times daily may provide short-term relief of pruritus. Local adverse effects include transient burning and stinging. Care should be exercised to avoid contact with the eyes.

ANTISEBORRHEA AGENTS Table 61–4 lists topical formulations for the treatment of seborrheic dermatitis. These are of variable efficacy and may necessitate concomitant treatment with topical corticosteroids for severe cases.

TABLE 61–4 Antiseborrhea agents.

TRICHOGENIC & ANTITRICHOGENIC AGENTS

MINOXIDIL Topical minoxidil (Rogaine) is effective in reversing the progressive miniaturization of terminal scalp hairs associated with androgenic alopecia. Vertex balding is more responsive to therapy than frontal balding. The mechanism of action of minoxidil on hair follicles is unknown. Chronic dosing studies have demonstrated that the effect of minoxidil is not permanent, and cessation of treatment will lead to hair loss in 4–6 months. Percutaneous absorption of minoxidil in normal scalp is minimal, but possible systemic effects on blood pressure (see Chapter 11) should be monitored in patients with cardiac disease.

FINASTERIDE Finasteride (Propecia) is a 5α-reductase inhibitor that blocks the conversion of testosterone to dihydrotestosterone (see Chapter 40), the androgen responsible for androgenic alopecia in genetically predisposed men. Oral finasteride, 1 mg/d, promotes hair growth and prevents further hair loss in a significant proportion of men with androgenic alopecia. Treatment for at least 3–6 months is necessary to see increased hair growth or prevent further hair loss. Continued treatment with finasteride is necessary to sustain benefit. Reported adverse effects include decreased libido, ejaculation disorders, and erectile dysfunction, which resolve in most men who remain on therapy and in all men who discontinue finasteride.

There are no data to support the use of finasteride in women with androgenic alopecia. Pregnant women should not be exposed to finasteride either by use or by handling crushed tablets because of the risk of hypospadias developing in a male fetus.

BIMATOPROST Bimatoprost (Latisse) is a prostaglandin analog that is available as a 0.03% ophthalmic solution to treat hypotrichosis of the eyelashes.

The mechanism of action is unknown. Treatment consists of nightly application to the skin of the upper eyelid margins at the base of the eyelashes using a separate disposable applicator for each eyelid. Contact lenses should be removed prior to bimatoprost application. Side effects include pruritus, conjunctival hyperemia, skin pigmentation, and erythema of the eyelids. Although iris darkening has not been reported with applications confined to the upper eyelid skin, increased brown iris pigmentation, which is likely to be permanent, has occurred when bimatoprost ophthalmic solution was instilled onto the eye.

EFLORNITHINE Eflornithine (Vaniqa) is an irreversible inhibitor of ornithine decarboxylase, which catalyzes the rate-limiting step in the biosynthesis of polyamines. Polyamines are required for cell division and differentiation, and inhibition of ornithine decarboxylase affects the rate of hair growth. Topical eflornithine has been shown to be effective in reducing facial hair growth in approximately 30% of women when applied twice daily for 6 months of therapy. Hair growth was observed to return to pretreatment levels 8 weeks after discontinuation. Local adverse effects include stinging, burning, and folliculitis.

AGENTS FOR MELANOMA BRAF INHIBITORS: VEMURAFENIB, DABRAFENIB, & TRAMETINIB BRAF inhibitors are indicated for the treatment of unresectable or metastatic melanoma with BRAF mutations as detected by an FDAapproved test. These agents are not approved for treatment of BRAF wild-type melanoma. Vemurafenib (Zelboraf) and dabrafenib (Tafinalar) are kinase inhibitors of BRAF V600E mutation. Trametinib (Mekinist) is a kinase inhibitor of BRAF V600E and V600K mutations. Vemurafenib and dabrafenib increase the risk for new primary cutaneous malignancies including squamous cell carcinoma, keratoacanthoma, and new primary melanomas. Trametinib use is associated with a defined risk of cardiomyopathy. All BRAF inhibitors are associated with serious hypersensitivity reactions, including severe dermatologic reactions as well as ophthalmologic complications.

IPILIMUMAB Ipilimumab (Yervoy) is a cytotoxic T-lymphocyte antigen 4 (CTLA-4) blocker antibody recently approved for the treatment of unresectable or metastatic melanoma. Ipilimumab may act by increasing T-cell-mediated antitumor immune responses (see Chapter 55).

Its use can result in severe and fatal immune-mediated adverse reactions due to T-cell activation and proliferation. The most common adverse reactions are enterocolitis, hepatitis, dermatitis, neuropathy, and endocrinopathy.

PEGYLATED INTERFERON Pegylated interferon alpha-2b (Sylatron) was recently approved by the FDA for adjuvant therapy of stage III node-positive melanoma patients. The effectiveness of once-weekly pegylated interferon versus the standard high-dose interferon regimen is yet to be proven.

The FDA did not specifically approve the use of pegylated interferon as a replacement for standard interferon therapy. Clinical trials to determine the optimum interferon treatment parameters for stage III melanoma are ongoing.

OTHER ANTINEOPLASTIC AGENTS Alitretinoin (Panretin) is a topical formulation of 9-cis-retinoic acid which is approved for the treatment of cutaneous lesions in patients with AIDS-related Kaposi’s sarcoma. Localized reactions may include intense erythema, edema, and vesiculation necessitating discontinuation of therapy. Patients who are applying alitretinoin should not concurrently use products containing DEET, a common component of insect repellant products.

Bexarotene (Targretin) is a member of a subclass of retinoids that selectively binds and activates retinoid X receptor subtypes. It is available both in an oral formulation and as a topical gel for the treatment of cutaneous T-cell lymphoma. Teratogenicity is a significant risk for both systemic and topical treatment with bexarotene, and women of childbearing potential must avoid becoming pregnant throughout therapy and for at least 1 month following discontinuation of the drug. Bexarotene may increase levels of triglycerides and cholesterol; therefore, lipid levels must be monitored during treatment.

Vismodegib (Erivedge) is the first hedgehog pathway inhibitor available for the oral treatment of metastatic basal cell carcinoma or locally advanced basal cell carcinoma in adults who are not candidates for surgery or radiation. The recommended dosage of vismodegib is 150 mg daily. The most common adverse effects include dysgeusia and ageusia, alopecia, fatigue, and muscle spasms. It is highly effective in patients with basal cell nevus syndrome.

Vorinostat (Zolinza) and romidepsin (Istodax) are histone deacetylase inhibitors that are approved for the treatment of cutaneous T-cell lymphoma in patients with progressive, persistent, or recurrent disease after prior systemic therapy. Adverse effects include thrombocytopenia, anemia, and gastrointestinal disturbances. Pulmonary embolism, which has occurred with vorinostat, has not been reported to date with romidepsin.

MISCELLANEOUS MEDICATIONS A number of drugs used primarily for other conditions also find use as oral therapeutic agents for dermatologic conditions. A few such preparations are listed in Table 61–5.

TABLE 61–5 Miscellaneous medications and the dermatologic conditions in which they are used.

REFERENCES General Bronaughs R, Maibach HI: Percutaneous Penetration: Principles and Practices, 4th ed. T aylor & Francis, 2005.

Wakelin S, Maibach HI: Systemic Drugs in Dermatology. Manson, 2004.

Wolverton S: Comprehensive Dermatologic Drug Therapy, 2nd ed. Saunders, 2007.

Antibacterial, Antifungal, & Antiviral Drugs Baddour LM: Skin abscesses, furuncles, and carbuncles. UpT oDate 2014; topic 7656.

James WD: Clinical practice. Acne. N Engl J Med 2005;352:1463.

Ectoparasiticides Leone PA: Scabies and pediculosis pubis: An update of treatment regimens and general review. Clin Infect Dis. 2007;44 (Suppl 3):S153.

Agents Affecting Pigmentation Levitt J: T he safety of hydroquinone. J Am Acad Dermatol 2007;57:854.

Stolk LML, Siddiqui AH: Biopharmaceutics, pharmacokinetics, and pharmacology of psoralens. Gen Pharmacol 1988;19:649.

Retinoids & Other Acne Preparations T zellos T et al: T opical retinoids for the treatment of acne vulgaris. Cochrane Database Syst Rev 2013;(8):CD009470.

Shalita AR et al: T azarotene gel is safe and effective in the treatment of acne vulgaris. A multicenter, double-blind, vehicle-controlled study. Cutis 1999;63:349.

T hami GP, Sarkar R: Coal tar: Past, present and future. Clin Exp Dermatol 2002;27:99.

Anti-Inflammatory Agents Brazzini B, Pimpinelli N: New and established topical corticosteroids in dermatology: Clinical pharmacology and therapeutic use. Am J Clin Dermatol 2002;3:47.

Williams JD, Griffiths CE: Cytokine blocking agents in dermatology. Clin Exp Dermatol 2002;27:585.

Keratolytic & Destructive Agents Samarasekera EJ et al: T opical therapies for the treatment of plaque psoriasis: Systematic review and network meta-analyses. Br J Dermatol 2013;168:954.

CASE STUDY ANSWER Initial therapy consisting of twice-daily applications of a medium-strength topical corticosteroid combined with once-daily topical calcipotriene or calcitriol should provide adequate control for this patient’s localized psoriasis. A coal tar shampoo should be initiated for her scalp psoriasis with nightly application of a corticosteroid solution to recalcitrant plaques.

CHAPTER

62 Drugs Used in the Treatment of Gastrointestinal Diseases Kenneth R. McQuaid, MD

CASE STUDY A 21-year-old woman comes with her parents to discuss therapeutic options for her Crohn’s disease. She was diagnosed with Crohn’s disease 2 years ago, and it involves her terminal ileum and proximal colon, as confirmed by colonoscopy and small bowel radiography. She was initially treated with mesalamine and budesonide with good response, but over the last 2 months, she has had a relapse of her symptoms. She is experiencing fatigue, cramping, abdominal pains, and nonbloody diarrhea up to 10 times daily, and she has had a 15-lb weight loss.

She has no other significant medical or surgical history. Her current medications are mesalamine 2.4 g/d and budesonide 9 mg/d.

She appears thin and tired. Abdominal examination reveals tenderness without guarding in the right lower quadrant; no masses are palpable. On perianal examination, there is no tenderness, fissure, or fistula. Her laboratory data are notable for anemia and elevated C-reactive protein. What are the options for immediate control of her symptoms and disease? What are the long-term management options?

INTRODUCTION Many of the drug groups discussed elsewhere in this book have important applications in the treatment of diseases of the gastrointestinal tract and other organs. Other groups are used almost exclusively for their effects on the gut; these are discussed in the following text according to their therapeutic uses.

DRUGS USED IN ACID-PEPTIC DISEASES Acid-peptic diseases include gastroesophageal reflux, peptic ulcer (gastric and duodenal), and stress-related mucosal injury. In all these conditions, mucosal erosions or ulceration arise when the caustic effects of aggressive factors (acid, pepsin, bile) overwhelm the defensive factors of the gastrointestinal mucosa (mucus and bicarbonate secretion, prostaglandins, blood flow, and the processes of restitution and regeneration after cellular injury). Over 90% of peptic ulcers are caused by infection with the bacterium Helicobacter pylori or by use of nonsteroidal anti-inflammatory drugs (NSAIDs). Drugs used in the treatment of acid-peptic disorders may be divided into two classes: agents that reduce intragastric acidity and agents that promote mucosal defense.

AGENTS THAT REDUCE INTRAGASTRIC ACIDITY PHYSIOLOGY OF ACID SECRETION The parietal cell contains receptors for gastrin (CCK-B), histamine (H2 ), and acetylcholine (muscarinic, M3 ) (Figure 62–1). When acetylcholine (from vagal postganglionic nerves) or gastrin (released from antral G cells into the blood) bind to the parietal cell receptors, they cause an increase in cytosolic calcium, which in turn stimulates protein kinases that stimulate acid secretion from a H+/K+-ATPase (the proton pump) on the canalicular surface.

FIGURE 62–1 Schematic model for physiologic control of hydrogen ion (acid) secretion by the parietal cells of the gastric fundic glands. Parietal cells are stimulated to secrete acid (H+) by gastrin (acting on gastrin/CCK-B receptor), acetylcholine (M3 receptor), and histamine (H2 receptor). Acid is secreted across the parietal cell canalicular membrane by the H+/K+-ATPase proton pump into the gastric lumen. Gastrin is secreted by antral G cells into blood vessels in response to intraluminal dietary peptides. Within the gastric body, gastrin passes from the blood vessels into the submucosal tissue of the fundic glands, where it binds to gastrin-CCK-B receptors on parietal cells and enterochromaffin-like (ECL) cells. The vagus nerve stimulates postganglionic neurons of the enteric nervous system to release acetylcholine (ACh), which binds to M3 receptors on parietal cells and ECL cells. Stimulation of ECL cells by gastrin (CCK-B receptor) or acetylcholine (M3 receptor) stimulates release of histamine. Within the gastric antrum, vagal stimulation of postganglionic

enteric neurons enhances gastrin release directly by stimulation of antral G cells (through gastrin-releasing peptide, GRP) and indirectly by inhibition of somatostatin secretion from antral D cells. Acid secretion must eventually be turned off. Antral D cells are stimulated to release somatostatin by the rise in intraluminal H+ concentration and by CCK that is released into the bloodstream by duodenal I cells in response to proteins and fats (not shown). Binding of somatostatin to receptors on adjacent antral G cells inhibits further gastrin release.

ATPase, H+/K+-ATPase proton pump; CCK, cholecystokinin; M3 -R, muscarinic receptors.

In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells also have receptors for gastrin and acetylcholine, which stimulate histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP) and activates protein kinases that stimulate acid secretion by the H+/K+-ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. In contrast, acetylcholine provides potent direct parietal cell stimulation.

ANTACIDS Antacids have been used for centuries in the treatment of patients with dyspepsia and acid-peptic disorders. They were the mainstay of treatment for acid-peptic disorders until the advent of H2−receptor antagonists and proton-pump inhibitors (PPIs). They continue to be used commonly by patients as nonprescription remedies for the treatment of intermittent heartburn and dyspepsia.

Antacids are weak bases that react with gastric hydrochloric acid to form a salt and water. Their principal mechanism of action is reduction of intragastric acidity. After a meal, approximately 45 mEq/h of hydrochloric acid is secreted. A single dose of 156 mEq of antacid given 1 hour after a meal effectively neutralizes gastric acid for up to 2 hours. However, the acid-neutralization capacity among different proprietary formulations of antacids is highly variable, depending on their rate of dissolution (tablet versus liquid), water solubility, rate of reaction with acid, and rate of gastric emptying.

Sodium bicarbonate (eg, baking soda, Alka Seltzer) reacts rapidly with hydrochloric acid (HCl) to produce carbon dioxide and sodium chloride. Formation of carbon dioxide results in gastric distention and belching. Unreacted alkali is readily absorbed, potentially causing metabolic alkalosis when given in high doses or to patients with renal insufficiency. Sodium chloride absorption may exacerbate fluid retention in patients with heart failure, hypertension, and renal insufficiency. Calcium carbonate (eg, Tums, Os-Cal) is less soluble and reacts more slowly than sodium bicarbonate with HCl to form carbon dioxide and calcium chloride (CaCl2 ). Like sodium bicarbonate, calcium carbonate may cause belching or metabolic alkalosis. Calcium carbonate is used for a number of other indications apart from its antacid properties (see Chapter 42). Excessive doses of either sodium bicarbonate or calcium carbonate with calcium-containing dairy products can lead to hypercalcemia, renal insufficiency, and metabolic alkalosis (milk-alkali syndrome).

Formulations containing magnesium hydroxide or aluminum hydroxide react slowly with HCl to form magnesium chloride or aluminum chloride and water. Because no gas is generated, belching does not occur. Metabolic alkalosis is also uncommon because of the efficiency of the neutralization reaction. Because unabsorbed magnesium salts may cause an osmotic diarrhea and aluminum salts may cause constipation, these agents are commonly administered together in proprietary formulations (eg, Gelusil, Maalox, Mylanta) to minimize the impact on bowel function. Both magnesium and aluminum are absorbed and excreted by the kidneys. Hence, patients with renal insufficiency should not take these agents long-term.

All antacids may affect the absorption of other medications by binding the drug (reducing its absorption) or by increasing intragastric pH so that the drug’s dissolution or solubility (especially weakly basic or acidic drugs) is altered. Therefore, antacids should not be given within 2 hours of doses of tetracyclines, fluoroquinolones, itraconazole, and iron.

H2-RECEPTOR ANTAGONISTS From their introduction in the 1970s until the early 1990s, H2 -receptor antagonists (commonly referred to as H2 blockers) were the most commonly prescribed drugs in the world (see Clinical Uses). With the recognition of the role of H pylori in ulcer disease (which may be treated with appropriate antibacterial therapy) and the advent of PPIs, the use of prescription H2 blockers has declined markedly.

Chemistry & Pharmacokinetics Four H2 antagonists are in clinical use: cimetidine, ranitidine, famotidine, and nizatidine. All four agents are rapidly absorbed from the intestine. Cimetidine, ranitidine, and famotidine undergo first-pass hepatic metabolism resulting in a bioavailability of approximately 50%.

Nizatidine has little first-pass metabolism. The serum half-lives of the four agents range from 1.1 to 4 hours; however, duration of action depends on the dose given (Table 62–1). H2 antagonists are cleared by a combination of hepatic metabolism, glomerular filtration, and renal tubular secretion. Dose reduction is required in patients with moderate to severe renal (and possibly severe hepatic) insufficiency.

In the elderly, there is a decline of up to 50% in drug clearance as well as a significant reduction in volume of distribution.

TABLE 62–1 Clinical comparisons of H2 -receptor blockers.

Pharmacodynamics The H2 antagonists exhibit competitive inhibition at the parietal cell H2 receptor and suppress basal and meal-stimulated acid secretion (Figure 62–2) in a linear, dose-dependent manner. They are highly selective and do not affect H 1 or H3 receptors (see Chapter 16). The volume of gastric secretion and the concentration of pepsin are also reduced.

FIGURE 62–2 Twenty-four-hour median intragastric acidity pretreatment (red) and after 1 month of treatment with either ranitidine, 150 mg twice daily (blue, H2 block), or omeprazole, 20 mg once daily (green, PPI). Note that H2 -receptor antagonists have a marked effect on nocturnal acid secretion but only a modest effect on meal-stimulated secretion. Proton pump inhibitors (PPIs) markedly suppress meal-stimulated and nocturnal acid secretion. (Data from Lanzon-Miller S et al: Twenty-four-hour intragastric acidity and plasma gastrin concentration before and during treatment with either ranitidine or omeprazole. Aliment Pharmacol Ther 1987;1:239.)

H2 antagonists reduce acid secretion stimulated by histamine as well as by gastrin and cholinomimetic agents through two mechanisms. First, histamine released from ECL cells by gastrin or vagal stimulation is blocked from binding to the parietal cell H 2 receptor. Second, direct stimulation of the parietal cell by gastrin or acetylcholine has a diminished effect on acid secretion in the presence of H2 -receptor blockade.

The potencies of the four H2 -receptor antagonists vary over a 50-fold range (Table 62–1). When given in usual prescription doses however, all inhibit 60–70% of total 24-hour acid secretion. H 2 antagonists are especially effective at inhibiting nocturnal acid secretion (which depends largely on histamine), but they have a modest impact on meal-stimulated acid secretion (which is stimulated by gastrin and acetylcholine as well as histamine). Therefore, nocturnal and fasting intragastric pH is raised to 4–5 but the impact on the daytime, meal-stimulated pH profile is less. Recommended prescription doses maintain greater than 50% acid inhibition for 10 hours; hence, these drugs are commonly given twice daily. At doses available in over-the-counter formulations, the duration of acid inhibition is less than 6 hours.

Clinical Uses H2 -receptor antagonists continue to be prescribed but PPIs (see below) are steadily replacing H2 antagonists for most clinical indications.

However, the over-the-counter preparations of the H2 antagonists are heavily used by the public.

1. Gastroesophageal reflux disease (GERD)—Patients with infrequent heartburn or dyspepsia (fewer than 3 times per week) may

take either antacids or intermittent H2 antagonists. Because antacids provide rapid acid neutralization, they afford faster symptom relief than H2 antagonists. However, the effect of antacids is short-lived (1–2 hours) compared with H 2 antagonists (6–10 hours). H2 antagonists may be taken prophylactically before meals in an effort to reduce the likelihood of heartburn. Frequent heartburn is better treated with twice-daily H2 antagonists (Table 62–1) or PPIs. In patients with erosive esophagitis (approximately 50% of patients with GERD), H2 antagonists afford healing in less than 50% of patients; hence PPIs are preferred because of their superior acid inhibition.

2. Peptic ulcer disease—PPIs have largely replaced H2 antagonists in the treatment of acute peptic ulcer disease. Nevertheless, H2 antagonists are still sometimes used. Nocturnal acid suppression by H2 antagonists affords effective ulcer healing in most patients with uncomplicated gastric and duodenal ulcers. Hence, all the agents may be administered once daily at bedtime, resulting in ulcer healing rates of more than 80–90% after 6–8 weeks of therapy. For patients with ulcers caused by aspirin or other NSAIDs, the NSAID should be discontinued. If the NSAID must be continued for clinical reasons despite active ulceration, a PPI should be given instead of an H2 antagonist to more reliably promote ulcer healing. For patients with acute peptic ulcers caused by H pylori, H2 antagonists no longer play a significant therapeutic role. H pylori should be treated with a 10- to 14-day course of therapy including a PPI and two antibiotics (see below).

3. Nonulcer dyspepsia—H2 antagonists are commonly used as over-the-counter agents and prescription agents for treatment of intermittent dyspepsia not caused by peptic ulcer. However, benefit compared with placebo has never been convincingly demonstrated.

4. Prevention of bleeding from stress-related gastritis—Clinically important bleeding from upper gastrointestinal erosions or ulcers occurs in 1–5% of critically ill patients as a result of impaired mucosal defense mechanisms caused by poor perfusion. Although most critically ill patients have normal or decreased acid secretion, numerous studies have shown that agents that increase intragastric pH (H2 antagonists or PPIs) reduce the incidence of clinically significant bleeding. However, the optimal agent is uncertain at this time. For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferable over intravenous PPIs because of their proven efficacy and lower cost. Continuous infusions of H2 antagonists are generally preferred to bolus infusions because they achieve more consistent, sustained elevation of intragastric pH.

Adverse Effects H2 antagonists are extremely safe drugs. Adverse effects occur in less than 3% of patients and include diarrhea, headache, fatigue, myalgias, and constipation. Some studies suggest that intravenous H2 antagonists (or PPIs) may increase the risk of nosocomial pneumonia in critically ill patients.

Mental status changes (confusion, hallucinations, agitation) may occur with administration of intravenous H2 antagonists, especially in patients in the intensive care unit who are elderly or who have renal or hepatic dysfunction. These events may be more common with cimetidine. Mental status changes rarely occur in ambulatory patients.

Cimetidine inhibits binding of dihydrotestosterone to androgen receptors, inhibits metabolism of estradiol, and increases serum prolactin levels. When used long-term or in high doses, it may cause gynecomastia or impotence in men and galactorrhea in women.

These effects are specific to cimetidine and do not occur with the other H2 antagonists.

Although there are no known harmful effects on the fetus, H2 antagonists cross the placenta. Therefore, they should not be administered to pregnant women unless absolutely necessary. The H 2 antagonists are secreted into breast milk and may therefore affect nursing infants.

H2 antagonists may rarely cause blood dyscrasias. Blockade of cardiac H2 receptors may cause bradycardia, but this is rarely of clinical significance. Rapid intravenous infusion may cause bradycardia and hypotension through blockade of cardiac H2 receptors; therefore, intravenous injections should be given over 30 minutes. H2 antagonists rarely cause reversible abnormalities in liver chemistry.

Drug Interactions Cimetidine interferes with several important hepatic cytochrome P450 drug metabolism pathways, including those catalyzed by CYP1A2, CYP2C9, CYP2D6, and CYP3A4 (see Chapter 4). Hence, the half-lives of drugs metabolized by these pathways may be prolonged.

Ranitidine binds 4–10 times less avidly than cimetidine to cytochrome P450. Negligible interaction occurs with nizatidine and famotidine.

H2 antagonists compete with creatinine and certain drugs (eg, procainamide) for renal tubular secretion. All of these agents except famotidine inhibit gastric first-pass metabolism of ethanol, especially in women. Although the importance of this is debated, increased bioavailability of ethanol could lead to increased blood ethanol levels.

PROTON-PUMP INHIBITORS (PPIS)

Since their introduction in the late 1980s, these efficacious acid inhibitory agents have assumed the major role for the treatment of acidpeptic disorders. PPIs are now among the most widely prescribed drugs worldwide due to their outstanding efficacy and safety.

Chemistry & Pharmacokinetics Six PPIs are available for clinical use: omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, and pantoprazole. All are substituted benzimidazoles that resemble H2 antagonists in structure (Figure 62–3) but have a completely different mechanism of action. Omeprazole and lansoprazole are racemic mixtures of R- and S-isomers. Esomeprazole is the S-isomer of omeprazole and dexlansoprazole the R-isomer of lansoprazole. All are available in oral formulations. Esomeprazole and pantoprazole are also available in intravenous formulations (Table 62–2).

FIGURE 62–3 Molecular structure of the proton pump inhibitors: omeprazole, lansoprazole, pantoprazole, and the sodium salt of rabeprazole. Omeprazole and esomeprazole have the same chemical structure (see text).

TABLE 62–2 Pharmacokinetics of proton pump inhibitors.

PPIs are administered as inactive prodrugs. To protect the acid-labile prodrug from rapid destruction within the gastric lumen, oral products are formulated for delayed release as acid-resistant, enteric-coated capsules or tablets. After passing through the stomach into the alkaline intestinal lumen, the enteric coatings dissolve and the prodrug is absorbed. For children or patients with dysphagia or enteral feeding tubes, capsule formulations (but not tablets) may be opened and the microgranules mixed with apple or orange juice or mixed with soft foods (eg, applesauce). Esomeprazole, omeprazole, and pantoprazole are also available as oral suspensions. Lansoprazole is available as a tablet formulation that disintegrates in the mouth, and rabeprazole is available in a formulation that may be sprinkled on food. Omeprazole is also available as a powder formulation (capsule or packet) that contains sodium bicarbonate (1100–1680 mg NaHCO3 ; 304–460 mg of sodium) to protect the naked (non-enteric-coated) drug from acid degradation. When administered on an empty stomach by mouth or enteral tube, this “immediate-release” suspension results in rapid omeprazole absorption (Tmax < 30 minutes) and onset of acid inhibition.

The PPIs are lipophilic weak bases (pKa 4–5) and after intestinal absorption diffuse readily across lipid membranes into acidified compartments (eg, the parietal cell canaliculus). The prodrug rapidly becomes protonated within the canaliculus and is concentrated more than 1000-fold by Henderson-Hasselbalch trapping (see Chapter 1). There, it rapidly undergoes a molecular conversion to the active form, a reactive thiophilic sulfenamide cation, which forms a covalent disulfide bond with the H+/K+-ATPase, irreversibly inactivating the enzyme.

The pharmacokinetics of available PPIs are shown in Table 62–2. Immediate-release omeprazole has a faster onset of acid inhibition than other oral formulations. Although differences in pharmacokinetic profiles may affect speed of onset and duration of acid inhibition in the first few days of therapy, they are of little clinical importance with continued daily administration. The bioavailability of all agents is decreased approximately 50% by food; hence, the drugs should be administered on an empty stomach. In a fasting state, only 10% of proton pumps are actively secreting acid and susceptible to inhibition. PPIs should be administered approximately 1 hour before a meal (usually breakfast), so that the peak serum concentration coincides with the maximal activity of proton-pump secretion. The drugs have a short serum half-life of about 1.5 hours, but acid inhibition lasts up to 24 hours owing to the irreversible inactivation of the proton pump.

At least 18 hours are required for synthesis of new H+/K+-ATPase pump molecules. Because not all proton pumps are inactivated with the first dose of medication, up to 3–4 days of daily medication are required before the full acid-inhibiting potential is reached. Similarly, after stopping the drug, it takes 3–4 days for full acid secretion to return.

PPIs undergo rapid first-pass and systemic hepatic metabolism and have negligible renal clearance. Dose reduction is not needed for patients with renal insufficiency or mild to moderate liver disease but should be considered in patients with severe liver impairment.

Although other proton pumps exist in the body, the H +/K+-ATPase appears to exist only in the parietal cell and is distinct structurally and functionally from other H+-transporting enzymes.

The intravenous formulations of esomeprazole and pantoprazole have characteristics similar to those of the oral drugs. When given to a fasting patient, they inactivate acid pumps that are actively secreting, but they have no effect on pumps in quiescent, nonsecreting vesicles. Because the half-life of a single injection of the intravenous formulation is short, acid secretion returns several hours later as pumps move from the tubulovesicles to the canalicular surface. Thus, to provide maximal inhibition during the first 24–48 hours of treatment, the intravenous formulations must be given as a continuous infusion or as repeated bolus injections. The optimal dosing of

intravenous PPIs to achieve maximal blockade in fasting patients is not yet established.

From a pharmacokinetic perspective, PPIs are ideal drugs: they have a short serum half-life, they are concentrated and activated near their site of action, and they have a long duration of action.

Pharmacodynamics In contrast to H2 antagonists, PPIs inhibit both fasting and meal-stimulated secretion because they block the final common pathway of acid secretion, the proton pump. In standard doses, PPIs inhibit 90–98% of 24-hour acid secretion (Figure 62–2). When administered at equivalent doses, the different agents show little difference in clinical efficacy. In a crossover study of patients receiving long-term therapy with five PPIs, the mean 24-hour intragastric pH varied from 3.3 (pantoprazole, 40 mg) to 4.0 (esomeprazole, 40 mg) and the mean number of hours the pH was higher than 4 varied from 10.1 (pantoprazole, 40 mg) to 14.0 (esomeprazole, 40 mg). Although dexlansoprazole has a delayed-release formulation that results in a longer Tmax and greater AUC than other PPIs, it appears comparable to other agents in the ability to suppress acid secretion. This is because acid suppression is more dependent upon irreversible inactivation of the proton pump than the pharmacokinetics of different agents.

Clinical Uses 1. Gastroesophageal reflux disease—PPIs are the most effective agents for the treatment of nonerosive and erosive reflux disease, esophageal complications of reflux disease (peptic stricture or Barrett’s esophagus), and extraesophageal manifestations of reflux disease. Once-daily dosing provides effective symptom relief and tissue healing in 85–90% of patients; up to 15% of patients require twice-daily dosing.

GERD symptoms recur in over 80% of patients within 6 months after discontinuation of a PPI. For patients with erosive esophagitis or esophageal complications, long-term daily maintenance therapy with a full-dose or half-dose PPI is usually needed. Many patients with nonerosive GERD may be treated successfully with intermittent courses of PPIs or H2 antagonists taken as needed (“on demand”) for recurrent symptoms.

In current clinical practice, many patients with symptomatic GERD are treated empirically with medications without prior endoscopy, ie, without knowledge of whether the patient has erosive or nonerosive reflux disease. Empiric treatment with PPIs provides sustained symptomatic relief in 70–80% of patients, compared with 50–60% with H2 antagonists. Because of recent cost reductions, PPIs are used increasingly as first-line therapy for patients with symptomatic GERD. Sustained acid suppression with twice-daily PPIs for at least 3 months is used to treat extraesophageal complications of reflux disease (asthma, chronic cough, laryngitis, and noncardiac chest pain).

2. Peptic ulcer disease—Compared with H2 antagonists, PPIs afford more rapid symptom relief and faster ulcer healing for duodenal ulcers and, to a lesser extent, gastric ulcers. All the pump inhibitors heal more than 90% of duodenal ulcers within 4 weeks and a similar percentage of gastric ulcers within 6–8 weeks. a. H pylori-associated ulcers—For H pylori-associated ulcers, there are two therapeutic goals: to heal the ulcer and to eradicate the organism. The most effective regimens for H pylori eradication are combinations of two antibiotics and a PPI. PPIs promote eradication of H pylori through several mechanisms: direct antimicrobial properties (minor) and—by raising intragastric pH—lowering the minimal inhibitory concentrations of antibiotics against H pylori. The best treatment regimen consists of a 14-day regimen of “triple therapy”: a PPI twice daily; clarithromycin, 500 mg twice daily; and either amoxicillin, 1 g twice daily, or metronidazole, 500 mg twice daily. After completion of triple therapy, the PPI should be continued once daily for a total of 4–6 weeks to ensure complete ulcer healing.

Alternatively, 10 days of “sequential treatment” consisting on days 1–5 of a PPI twice daily plus amoxicillin, 1 g twice daily, and followed on days 6–10 by five additional days of a PPI twice daily, plus clarithromycin, 500 mg twice daily, and tinidazole, 500 mg twice daily, has been shown to be a highly effective treatment regimen. b. NSAID-associated ulcers—For patients with ulcers caused by aspirin or other NSAIDs, either H2 antagonists or PPIs provide rapid ulcer healing so long as the NSAID is discontinued; however continued use of the NSAID impairs ulcer healing. In patients with NSAID-induced ulcers who require continued NSAID therapy, treatment with a once- or twice-daily PPI more reliably promotes ulcer healing.

Asymptomatic peptic ulceration develops in 10–20% of people taking frequent NSAIDs, and ulcer-related complications (bleeding, perforation) develop in 1–2% of persons per year. PPIs taken once daily are effective in reducing the incidence of ulcers and ulcer complications in patients taking aspirin or other NSAIDs. c. Prevention of rebleeding from peptic ulcers—In patients with acute gastrointestinal bleeding due to peptic ulcers, the risk of rebleeding from ulcers that have a visible vessel or adherent clot is increased. Rebleeding of this subset of high-risk ulcers is reduced significantly with PPIs administered for 3–5 days either as high-dose oral therapy (eg, omeprazole, 40 mg orally twice daily) or as a

continuous intravenous infusion. It is believed that an intragastric pH higher than 6 may enhance coagulation and platelet aggregation.

The optimal dose of intravenous PPI needed to achieve and maintain this level of near-complete acid inhibition is unknown; however, initial bolus administration of esomeprazole or pantoprazole (80 mg) followed by constant infusion (8 mg/h) is commonly recommended.

3. Nonulcer dyspepsia—PPIs have modest efficacy for treatment of nonulcer dyspepsia, benefiting 10–20% more patients than placebo. Despite their use for this indication, superiority to H2 antagonists (or even placebo) has not been conclusively demonstrated.

4. Prevention of stress-related mucosal bleeding—As discussed previously (see H2 -Receptor Antagonists) PPIs (given orally, by nasogastric tube, or by intravenous infusions) may be administered to reduce the risk of clinically significant stress-related mucosal bleeding in critically ill patients. The only PPI approved by the FDA for this indication is an oral immediate-release omeprazole formulation, which is administered by nasogastric tube twice daily on the first day, then once daily. Although not FDA approved for this indication, other PPI suspension formulations (esomeprazole, omeprazole, pantoprazole) may also be used. For patients with nasoenteric tubes, PPI suspensions may be preferred to intravenous H2 antagonists or PPIs because of comparable efficacy, lower cost, and ease of administration.

For patients without a nasoenteric tube or with significant ileus, intravenous H2 antagonists are preferred to intravenous PPIs because of their proven efficacy. Although PPIs are increasingly used, there are no controlled trials demonstrating efficacy or optimal dosing.

5. Gastrinoma and other hypersecretory conditions—Patients with isolated gastrinomas are best treated with surgical resection. In patients with metastatic or unresectable gastrinomas, massive acid hypersecretion results in peptic ulceration, erosive esophagitis, and malabsorption. Previously, these patients required vagotomy and extraordinarily high doses of H 2 antagonists, which still resulted in suboptimal acid suppression. With PPIs, excellent acid suppression can be achieved in all patients. Dosage is titrated to reduce basal acid output to less than 5–10 mEq/h. Typical doses of omeprazole are 60–120 mg/d.

Adverse Effects 1. General—PPIs are extremely safe. Diarrhea, headache, and abdominal pain are reported in 1–5% of patients, although the frequency of these events is only slightly increased compared with placebo. Increasing cases of acute interstitial nephritis have been reported. PPIs are not teratogenic in animal models; however, safety during pregnancy has not been established.

2. Nutrition—Acid is important in releasing vitamin B12 from food. A minor reduction in oral cyanocobalamin absorption occurs during proton pump inhibition, potentially leading to subnormal B12 levels with prolonged therapy. Acid also promotes absorption of food-bound minerals (non-heme iron, insoluble calcium salts, magnesium). Several case-control studies have suggested a modest increase in the risk of hip fracture in patients taking PPIs over a long term compared with matched controls. Although a causal relationship is unproven, PPIs may reduce calcium absorption or inhibit osteoclast function. Pending further studies, patients who require long-term PPIs— especially those with risk factors for osteoporosis—should have monitoring of bone density and should be provided calcium supplements.

Cases of severe, life-threatening hypomagnesemia with secondary hypocalcemia due to PPIs have been reported; however, the mechanism of action is unknown.

3. Respiratory and enteric infections—Gastric acid is an important barrier to colonization and infection of the stomach and intestine from ingested bacteria. Increases in gastric bacterial concentrations are detected in patients taking PPIs, which is of unknown clinical significance. Some studies have reported an increased risk of both community-acquired respiratory infections and nosocomial pneumonia among patients taking PPIs. There is a two- to threefold increased risk for hospital- and community-acquired Clostridium difficile infection in patients taking PPIs. There also is a small increased risk of other enteric infections (eg, Salmonella, Shigella, Escherichia coli, Campylobacter), which should be considered particularly when traveling in underdeveloped countries.

4. Potential problems due to increased serum gastrin—Gastrin levels are regulated by intragastric acidity. Acid suppression alters normal feedback inhibition so that median serum gastrin levels rise 1.5- to twofold in patients taking PPIs. Although gastrin levels remain within normal limits in most patients, they exceed 500 pg/mL (normal, < 100 pg/mL) in 3%. Upon stopping the drug, the levels normalize within 4 weeks. The rise in serum gastrin levels may stimulate hyperplasia of ECL and parietal cells, which may cause transient rebound acid hypersecretion with increased dyspepsia or heartburn after drug discontinuation, which abate within 2–4 weeks after gastrin and acid secretion normalize. In female rats given PPIs for prolonged periods, hypergastrinemia caused gastric carcinoid tumors that developed in areas of ECL hyperplasia. Although humans who take PPIs for a long time also may exhibit ECL hyperplasia, carcinoid tumor formation has not been documented. At present, routine monitoring of serum gastrin levels is not recommended in patients receiving prolonged PPI therapy.

5. Other potential problems due to decreased gastric acidityâ&#x20AC;&#x201D;Among patients infected with H pylori, long-term acid suppression leads to increased chronic inflammation in the gastric body and decreased inflammation in the antrum. Concerns have been raised that increased gastric inflammation may accelerate gastric gland atrophy (atrophic gastritis) and intestinal metaplasiaâ&#x20AC;&#x201D;known risk factors for gastric adenocarcinoma. A special FDA Gastrointestinal Advisory Committee concluded that there is no evidence that prolonged PPI therapy produces the kind of atrophic gastritis (multifocal atrophic gastritis) or intestinal metaplasia that is associated with increased risk of adenocarcinoma. Routine testing for H pylori is not recommended in patients who require long-term PPI therapy. Long-term PPI therapy is associated with the development of small benign gastric fundic-gland polyps in a small number of patients, which may disappear after stopping the drug and are of uncertain clinical significance.

Drug Interactions Decreased gastric acidity may alter absorption of drugs for which intragastric acidity affects drug bioavailability, eg, ketoconazole, itraconazole, digoxin, and atazanavir. All PPIs are metabolized by hepatic P450 cytochromes, including CYP2C19 and CYP3A4.

Because of the short half-lives of PPIs, clinically significant drug interactions are rare. Omeprazole may inhibit the metabolism of warfarin, diazepam, and phenytoin. Esomeprazole also may decrease metabolism of diazepam. Lansoprazole may enhance clearance of theophylline. Rabeprazole and pantoprazole have no significant drug interactions.

The FDA has issued a warning about a potentially important adverse interaction between clopidogrel and PPIs. Clopidogrel is a prodrug that requires activation by the hepatic P450 CYP2C19 isoenzyme, which also is involved to varying degrees in the metabolism of PPIs (especially omeprazole, esomeprazole, lansoprazole, and dexlansoprazole). Thus, PPIs could reduce clopidogrel activation (and its antiplatelet action) in some patients. Several large retrospective studies have reported an increased incidence of serious cardiovascular events in patients taking clopidogrel and a PPI. In contrast, three smaller prospective randomized trials have not detected an increased risk. Pending further studies, PPIs should be prescribed to patients taking clopidogrel only if they have an increased risk of gastrointestinal bleeding or require them for chronic gastro-esophageal reflux or peptic ulcer disease, in which case agents with minimal CYP2C19 inhibition (pantoprazole or rabeprazole) are preferred.

MUCOSAL PROTECTIVE AGENTS The gastroduodenal mucosa has evolved a number of defense mechanisms to protect itself against the noxious effects of acid and pepsin. Both mucus and epithelial cell-cell tight junctions restrict back diffusion of acid and pepsin. Epithelial bicarbonate secretion establishes a pH gradient within the mucous layer in which the pH ranges from 7 at the mucosal surface to 1â&#x20AC;&#x201C;2 in the gastric lumen.

Blood flow carries bicarbonate and vital nutrients to surface cells. Areas of injured epithelium are quickly repaired by restitution, a process in which migration of cells from gland neck cells seals small erosions to reestablish intact epithelium. Mucosal prostaglandins appear to be important in stimulating mucus and bicarbonate secretion and mucosal blood flow. A number of agents that potentiate these mucosal defense mechanisms are available for the prevention and treatment of acid-peptic disorders.

SUCRALFATE Chemistry & Pharmacokinetics Sucralfate is a salt of sucrose complexed to sulfated aluminum hydroxide. In water or acidic solutions it forms a viscous, tenacious paste that binds selectively to ulcers or erosions for up to 6 hours. Sucralfate has limited solubility, breaking down into sucrose sulfate (strongly negatively charged) and an aluminum salt. Less than 3% of intact drug and aluminum is absorbed from the intestinal tract; the remainder is excreted in the feces.

Pharmacodynamics A variety of beneficial effects have been attributed to sucralfate, but the precise mechanism of action is unclear. It is believed that the negatively charged sucrose sulfate binds to positively charged proteins in the base of ulcers or erosion, forming a physical barrier that restricts further caustic damage and stimulates mucosal prostaglandin and bicarbonate secretion.

Clinical Uses Sucralfate is administered in a dosage of 1 g four times daily on an empty stomach (at least 1 hour before meals). At present, its clinical uses are limited. Sucralfate (administered as a slurry through a nasogastric tube) reduces the incidence of clinically significant upper gastrointestinal bleeding in critically ill patients hospitalized in the intensive care unit, although it is slightly less effective than intravenous H2 antagonists. Sucralfate is still used by many clinicians for prevention of stress-related bleeding because of concerns that acid inhibitory therapies (antacids, H2 antagonists, and PPIs) may increase the risk of nosocomial pneumonia.

Adverse Effects Because it is not absorbed, sucralfate is virtually devoid of systemic adverse effects. Constipation occurs in 2% of patients due to the aluminum salt. Because a small amount of aluminum is absorbed, it should not be used for prolonged periods in patients with renal insufficiency.

Drug Interactions Sucralfate may bind to other medications, impairing their absorption.

PROSTAGLANDIN ANALOGS Chemistry & Pharmacokinetics The human gastrointestinal mucosa synthesizes a number of prostaglandins (see Chapter 18); the primary ones are prostaglandins E and F. Misoprostol, a methyl analog of PGE1 , has been approved for gastrointestinal conditions. After oral administration, it is rapidly absorbed and metabolized to a metabolically active free acid. The serum half-life is less than 30 minutes; hence, it must be administered 3–4 times daily. It is excreted in the urine; however, dose reduction is not needed in patients with renal insufficiency.

Misoprostol has both acid inhibitory and mucosal protective properties. It is believed to stimulate mucus and bicarbonate secretion and enhance mucosal blood flow. Misoprostol can reduce the incidence of NSAID-induced ulcers to less than 3% and the incidence of ulcer complications by 50%. It is approved for prevention of NSAID-induced ulcers in high-risk patients; however, misoprostol has never achieved widespread use owing to its high adverse-effect profile and need for multiple daily dosing.

BISMUTH COMPOUNDS Chemistry & Pharmacokinetics Two bismuth compounds are available: bismuth subsalicylate, a nonprescription formulation containing bismuth and salicylate, and bismuth subcitrate potassium. In the USA, bismuth subcitrate is available only as a combination prescription product that also contains metronidazole and tetracycline for the treatment of H pylori. Bismuth subsalicylate undergoes rapid dissociation within the stomach, allowing absorption of salicylate. Over 99% of the bismuth appears in the stool. Although minimal (< 1%), bismuth is absorbed; it is stored in many tissues and has slow renal excretion. Salicylate (like aspirin) is readily absorbed and excreted in the urine.

Pharmacodynamics The precise mechanisms of action of bismuth are unknown. Bismuth coats ulcers and erosions, creating a protective layer against acid and pepsin. It may also stimulate prostaglandin, mucus, and bicarbonate secretion. Bismuth subsalicylate reduces stool frequency and liquidity in acute infectious diarrhea, due to salicylate inhibition of intestinal prostaglandin and chloride secretion. Bismuth has direct antimicrobial effects and binds enterotoxins, accounting for its benefit in preventing and treating traveler’s diarrhea. Bismuth compounds have direct antimicrobial activity against H pylori.

Clinical Uses In spite of the lack of comparative trials, nonprescription bismuth compounds (eg, Pepto-Bismol, Kaopectate) are widely used by patients for the nonspecific treatment of dyspepsia and acute diarrhea. Bismuth subsalicylate also is used for the prevention of traveler’s diarrhea (30 mL or 2 tablets four times daily).

Bismuth compounds are used in 4-drug regimens for the eradication of H pylori infection. One regimen consists of a PPI twice daily combined with bismuth subsalicylate (2 tablets; 262 mg each), tetracycline (250–500 mg), and metronidazole (500 mg) four times daily for 10–14 days. Another regimen consists of a PPI twice daily combined with three capsules of a combination prescription formulation (each capsule containing bismuth subcitrate 140 mg, metronidazole 125 mg, and tetracycline 125 mg) taken four times daily for 10 days.

Although these are effective, standard “triple therapy” regimens (ie, PPI, clarithromycin, and amoxicillin or metronidazole twice daily for 14 days) generally are preferred for first-line therapy because of twice-daily dosing and superior compliance. Bismuth-based quadruple therapies are commonly used as second-line therapies.

Adverse Effects All bismuth formulations have excellent safety profiles. Bismuth causes harmless blackening of the stool, which may be confused with

gastrointestinal bleeding. Liquid formulations may cause harmless darkening of the tongue. Bismuth agents should be used for short periods only and should be avoided in patients with renal insufficiency. Prolonged usage of some bismuth compounds may rarely lead to bismuth toxicity, resulting in encephalopathy (ataxia, headaches, confusion, seizures). However, such toxicity is not reported with bismuth subsalicylate or bismuth citrate. High dosages of bismuth subsalicylate may lead to salicylate toxicity.

DRUGS STIMULATING GASTROINTESTINAL MOTILITY Drugs that can selectively stimulate gut motor function (prokinetic agents) have significant potential clinical usefulness. Agents that increase lower esophageal sphincter pressures may be useful for GERD. Drugs that improve gastric emptying may be helpful for gastroparesis and postsurgical gastric emptying delay. Agents that stimulate the small intestine may be beneficial for postoperative ileus or chronic intestinal pseudo-obstruction. Finally, agents that enhance colonic transit may be useful in the treatment of constipation.

Unfortunately, only a limited number of agents in this group are available for clinical use at this time.

PHYSIOLOGY OF THE ENTERIC NERVOUS SYSTEM The enteric nervous system (see also Chapter 6) is composed of interconnected networks of ganglion cells and nerve fibers mainly located in the submucosa (submucosal plexus) and between the circular and longitudinal muscle layers (myenteric plexus). These networks give rise to nerve fibers that connect with the mucosa and muscle. Although extrinsic sympathetic and parasympathetic nerves project onto the submucosal and myenteric plexuses, the enteric nervous system can independently regulate gastrointestinal motility and secretion. Extrinsic primary afferent neurons project via the dorsal root ganglia or vagus nerve to the central nervous system (Figure 62â&#x20AC;&#x201C; 4). Release of serotonin (5-HT) from intestinal mucosa enterochromaffin (EC) cells stimulates 5-HT3 receptors on the extrinsic afferent nerves, stimulating nausea, vomiting, or abdominal pain. Serotonin also stimulates submucosal 5-HT1P receptors of the intrinsic primary afferent nerves (IPANs), which contain calcitonin gene-related peptide (CGRP) and acetylcholine and project to myenteric plexus interneurons. 5-HT4 receptors on the presynaptic terminals of the IPANs appear to enhance release of CGRP or acetylcholine. The myenteric interneurons are important in controlling the peristaltic reflex, promoting release of excitatory mediators proximally and inhibitory mediators distally. Motilin may stimulate excitatory neurons or muscle cells directly. Dopamine acts as an inhibitory neurotransmitter in the gastrointestinal tract, decreasing the intensity of esophageal and gastric contractions.

FIGURE 62–4 Release of serotonin (5-HT) by enterochromaffin (EC) cells from gut distention stimulates submucosal intrinsic primary afferent neurons (IPANs) via 5-HT1P receptors and extrinsic primary afferent neurons via 5-HT3 receptors (5-HT1P R, 5-HT3 R).

Submucosal IPANs activate the enteric neurons responsible for peristaltic and secretory reflex activity. Stimulation of 5-HT4 receptors (5-HT4 R) on presynaptic terminals of IPANs enhances release of acetylcholine (ACh) and calcitonin gene-related peptide (CGRP), promoting reflex activity. CNS, central nervous system; ENS, enteric nervous system. (Data from Gershon MD: Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Dis 2003;3[Suppl 2]:S25.)

Although there are at least 14 serotonin receptor subtypes, 5-HT drug development for gastrointestinal applications to date has focused on 5-HT3 -receptor antagonists and 5-HT4 -receptor agonists. These agents—which have effects on gastrointestinal motility and visceral afferent sensation—are discussed under Drugs Used for the Treatment of Irritable Bowel Syndrome and Antiemetic Agents. Other drugs acting on 5-HT receptors are discussed in Chapters 16, 29, and 30.

CHOLINOMIMETIC AGENTS Cholinomimetic agonists such as bethanechol stimulate muscarinic M3 receptors on muscle cells and at myenteric plexus synapses (see Chapter 7). Bethanechol was used in the past for the treatment of GERD and gastroparesis. Owing to multiple cholinergic effects and the advent of less toxic agents, it is now seldom used. The acetylcholinesterase inhibitor neostigmine can enhance gastric, small intestine, and colonic emptying. Intravenous neostigmine is used for the treatment of hospitalized patients with acute large bowel distention

(known as acute colonic pseudo-obstruction or Ogilvie’s syndrome). Administration of 2 mg results in prompt colonic evacuation of flatus and feces in the majority of patients. Cholinergic effects include excessive salivation, nausea, vomiting, diarrhea, and bradycardia.

METOCLOPRAMIDE & DOMPERIDONE Metoclopramide and domperidone are dopamine D2 -receptor antagonists. Within the gastrointestinal tract activation of dopamine receptors inhibits cholinergic smooth muscle stimulation; blockade of this effect is believed to be the primary prokinetic mechanism of action of these agents. These agents increase esophageal peristaltic amplitude, increase lower esophageal sphincter pressure, and enhance gastric emptying but have no effect on small intestine or colonic motility. Metoclopramide and domperidone also block dopamine D2 receptors in the chemoreceptor trigger zone of the medulla (area postrema), resulting in potent antinausea and antiemetic action.

Clinical Uses 1. Gastroesophageal reflux disease—Metoclopramide is available for clinical use in the USA; domperidone is available in many other countries. These agents are sometimes used in the treatment of symptomatic GERD but are not effective in patients with erosive esophagitis. Because of the superior efficacy and safety of antisecretory agents in the treatment of heartburn, prokinetic agents are used mainly in combination with antisecretory agents in patients with regurgitation or refractory heartburn.

2. Impaired gastric emptying—These agents are widely used in the treatment of patients with delayed gastric emptying due to postsurgical disorders (vagotomy, antrectomy) and diabetic gastroparesis. Metoclopramide is sometimes administered in hospitalized patients to promote advancement of nasoenteric feeding tubes from the stomach into the duodenum.

3. Nonulcer dyspepsia—These agents lead to symptomatic improvement in a small number of patients with chronic dyspepsia.

4. Prevention of vomiting—Because of their potent antiemetic action, metoclopramide and domperidone are used for the prevention and treatment of emesis.

5. Postpartum lactation stimulation—Domperidone is sometimes recommended to promote postpartum lactation (see also Adverse Effects).

Adverse Effects The most common adverse effects of metoclopramide involve the central nervous system. Restlessness, drowsiness, insomnia, anxiety, and agitation occur in 10–20% of patients, especially the elderly. Extrapyramidal effects (dystonias, akathisia, parkinsonian features) due to central dopamine receptor blockade occur acutely in 25% of patients given high doses and in 5% of patients receiving long-term therapy. Tardive dyskinesia, sometimes irreversible, has developed in patients treated for a prolonged period with metoclopramide. For this reason, long-term use should be avoided unless absolutely necessary, especially in the elderly. Elevated prolactin levels (caused by both metoclopramide and domperidone) can cause galactorrhea, gynecomastia, impotence, and menstrual disorders.

Domperidone is extremely well tolerated. Because it does not cross the blood-brain barrier to a significant degree, neuropsychiatric and extrapyramidal effects are rare.

MACROLIDES Macrolide antibiotics such as erythromycin directly stimulate motilin receptors on gastrointestinal smooth muscle and promote the onset of a migrating motor complex. Intravenous erythromycin (3 mg/kg) is beneficial in some patients with gastroparesis; however, tolerance rapidly develops. It may be used in patients with acute upper gastrointestinal hemorrhage to promote gastric emptying of blood before endoscopy.

LAXATIVES The overwhelming majority of people do not need laxatives; yet they are self-prescribed by a large portion of the population. For most people, intermittent constipation is best prevented with a high-fiber diet, adequate fluid intake, regular exercise, and the heeding of nature’s call. Patients not responding to dietary changes or fiber supplements should undergo medical evaluation before initiating longterm laxative treatment. Laxatives may be classified by their major mechanism of action, but many work through more than one mechanism.

BULK-FORMING LAXATIVES Bulk-forming laxatives are indigestible, hydrophilic colloids that absorb water, forming a bulky, emollient gel that distends the colon and promotes peristalsis. Common preparations include natural plant products (psyllium, methylcellulose) and synthetic fibers (polycarbophil). Bacterial digestion of plant fibers within the colon may lead to increased bloating and flatus.

STOOL SURFACTANT AGENTS (SOFTENERS) These agents soften stool material, permitting water and lipids to penetrate. They may be administered orally or rectally. Common agents include docusate (oral or enema) and glycerin suppository. In hospitalized patients, docusate is commonly prescribed to prevent constipation and minimize straining. Mineral oil is a clear, viscous oil that lubricates fecal material, retarding water absorption from the stool. It is used to prevent and treat fecal impaction in young children and debilitated adults. It is not palatable but may be mixed with juices. Aspiration can result in a severe lipid pneumonitis. Long-term use can impair absorption of fat-soluble vitamins (A, D, E, K).

OSMOTIC LAXATIVES The colon can neither concentrate nor dilute fecal fluid: fecal water is isotonic throughout the colon. Osmotic laxatives are soluble but nonabsorbable compounds that result in increased stool liquidity due to an obligate increase in fecal fluid.

Nonabsorbable Sugars or Salts These agents may be used for the treatment of acute constipation or the prevention of chronic constipation. Magnesium hydroxide (milk of magnesia) is a commonly used osmotic laxative. It should not be used for prolonged periods in patients with renal insufficiency due to the risk of hypermagnesemia. Sorbitol and lactulose are nonabsorbable sugars that can be used to prevent or treat chronic constipation. These sugars are metabolized by colonic bacteria, producing severe flatus and cramps.

High doses of osmotically active agents produce prompt bowel evacuation (purgation) within 1–3 hours. The rapid movement of water into the distal small bowel and colon leads to a high volume of liquid stool followed by bowel evacuation. Several purgatives are available, which may be used for the treatment of acute constipation or to cleanse the bowel prior to medical procedures (eg, colonoscopy). These include magnesium citrate, sulfate solution, and a proprietary combination of magnesium oxide, sodium picosulfate, and citrate (Prepopik). When taking these purgatives, it is very important that patients maintain adequate hydration by taking increased oral liquids to compensate for fecal fluid loss. Sodium phosphate also is available—by prescription—as a tablet formulation but is infrequently used due to the risk of hyperphosphatemia, hypocalcemia, hypernatremia, and hypokalemia. Although these electrolyte abnormalities are clinically insignificant in most patients, they may lead to cardiac arrhythmias or acute renal failure due to tubular deposition of calcium phosphate (nephrocalcinosis). Sodium phosphate preparations should not be used in patients who are frail or elderly, have renal insufficiency, have significant cardiac disease, or are unable to maintain adequate hydration during bowel preparation.

Balanced Polyethylene Glycol Lavage solutions containing polyethylene glycol (PEG) are commonly used for complete colonic cleansing before gastrointestinal endoscopic procedures. These balanced, isotonic solutions contain an inert, nonabsorbable, osmotically active sugar (PEG) with sodium sulfate, sodium chloride, sodium bicarbonate, and potassium chloride. The solution is designed so that no significant intravascular fluid or electrolyte shifts occur. Therefore, they are safe for all patients. For optimal bowel cleansing, 1–2 L of solution should be ingested rapidly (over 1–2 hours) on the evening before the procedure and again 4–6 hours before the procedure. For treatment or prevention of chronic constipation, smaller doses of PEG powder may be mixed with water or juices (17 g/8 oz) and ingested daily. In contrast to sorbitol or lactulose, PEG does not produce significant cramps or flatus.

STIMULANT LAXATIVES Stimulant laxatives (cathartics) induce bowel movements through a number of poorly understood mechanisms. These include direct stimulation of the enteric nervous system and colonic electrolyte and fluid secretion. There has been concern that long-term use of cathartics could lead to dependence and destruction of the myenteric plexus, resulting in colonic atony and dilation. More recent research suggests that long-term use of these agents probably is safe in most patients. Cathartics may be required on a long-term basis, especially in patients who are neurologically impaired and in bed-bound patients in long-term care facilities.

Anthraquinone Derivatives Aloe, senna, and cascara occur naturally in plants. These laxatives are poorly absorbed and after hydrolysis in the colon, produce a bowel movement in 6–12 hours when given orally and within 2 hours when given rectally. Chronic use leads to a characteristic brown pigmentation of the colon known as “melanosis coli.” There has been some concern that these agents may be carcinogenic, but epidemiologic studies do not suggest a relation to colorectal cancer.

Diphenylmethane Derivatives Bisacodyl is available in tablet and suppository formulations for the treatment of acute and chronic constipation. It also is used in conjunction with PEG solutions for colonic cleansing prior to colonoscopy. It induces a bowel movement within 6–10 hours when given orally and 30–60 minutes when taken rectally. It has minimal systemic absorption and appears to be safe for acute and long-term use.

CHLORIDE CHANNEL ACTIVATORS Lubiprostone is a prostanoic acid derivative labeled for use in chronic constipation and irritable bowel syndrome (IBS) with predominant constipation. It acts by stimulating the type 2 chloride channel (ClC-2) in the small intestine. This increases chloride-rich fluid secretion into the intestine, which stimulates intestinal motility and shortens intestinal transit time. Over 50% of patients experience a bowel movement within 24 hours of taking one dose. A dose of 24 mcg orally twice daily is the recommended dose for treatment of chronic constipation. There appears to be no loss of efficacy with long-term therapy. After discontinuation of the drug, constipation may return to its pretreatment severity. Lubiprostone has minimal systemic absorption but is designated category C for pregnancy because of increased fetal loss in guinea pigs. Lubiprostone may cause nausea in up to 30% of patients due to delayed gastric emptying.

Linaclotide is a minimally absorbed, 14-amino acid peptide that stimulates intestinal chloride secretion through a different mechanism but is also approved for the treatment of chronic constipation and IBS with predominant constipation. Linaclotide binds to and activates guanylyl cyclase-C on the luminal intestinal epithelial surface, resulting in increased intracellular and extracellular cGMP that leads to activation of the cystic fibrosis transmembrane conductance regulator (CFTR) leading to increased chloride-rich secretion and acceleration of intestinal transit. Linaclotide (145 mcg orally once daily) results in an average increase of 1–2 bowel movements per week that usually occurs within the first week of treatment. Upon discontinuation of the drug, bowel movement frequency returns to normal within one week. The most common side effect is diarrhea, which occurs in up to 20% of patients, with severe diarrhea in 2%.

Linaclotide has negligible absorption at standard doses but is designated category C for pregnancy because of increased maternal death in rats when administered in massive doses (> 8000 times the recommended human dose). It is also contraindicated in pediatric patients due to increased mortality in juvenile mice. (Crofelemer is a small molecule with the opposite effect: it is an inhibitor of the CFTR channel and has recently been approved for the treatment of HIV-drug-induced diarrhea.)

OPIOID RECEPTOR ANTAGONISTS Acute and chronic therapy with opioids may cause constipation by decreasing intestinal motility, which results in prolonged transit time and increased absorption of fecal water (see Chapter 31). Use of opioids after surgery for treatment of pain as well as endogenous opioids also may prolong the duration of postoperative ileus. These effects are mainly mediated through intestinal mu (μ)-opioid receptors. Two selective antagonists of the μ-opioid receptor are commercially available: methylnaltrexone bromide and alvimopan.

Because these agents do not readily cross the blood-brain barrier, they inhibit peripheral μ-opioid receptors without impacting analgesic effects within the central nervous system. Methylnaltrexone is approved for the treatment of opioid-induced constipation in patients receiving palliative care for advanced illness who have had inadequate response to other agents. It is administered as a subcutaneous injection (0.15 mg/kg) every 2 days. Alvimopan is approved for short-term use to shorten the period of postoperative ileus in hospitalized patients who have undergone small or large bowel resection. Alvimopan (12 mg capsule) is administered orally within 5 hours before surgery and twice daily after surgery until bowel function has recovered, but for no more than 7 days. Because of possible cardiovascular toxicity, alvimopan currently is restricted to short-term use in hospitalized patients only.

SEROTONIN 5-HT4-RECEPTOR AGONIST Stimulation of 5-HT4 receptors on the presynaptic terminal of submucosal intrinsic primary afferent nerves enhances the release of their neurotransmitters, including calcitonin gene-related peptide, which stimulates second-order enteric neurons to promote the peristaltic reflex (Figure 62–4). These enteric neurons stimulate proximal bowel contraction (via acetylcholine and substance P) and distal bowel relaxation (via nitric oxide and vasoactive intestinal peptide).

Tegaserod is a serotonin 5-HT4 partial agonist that has high affinity for 5-HT4 receptors but no appreciable binding to 5-HT3 or

dopamine receptors. Tegaserod was approved for the treatment of patients with chronic constipation and IBS with predominant constipation. It has since been withdrawn. Prucalopride is a high-affinity 5-HT4 agonist that is available in Europe (but not in the USA) for the treatment of chronic constipation in women. In contrast to cisapride and tegaserod, it does not appear to have significant affinities for either hERG K+ channels or 5-HT1B. In three 12-week clinical trials of patients with severe chronic constipation, it resulted in a significant increase in bowel movements compared with placebo. The long-term efficacy and safety of this agent require further study.

ANTIDIARRHEAL AGENTS Antidiarrheal agents may be used safely in patients with mild to moderate acute diarrhea. However, these agents should not be used in patients with bloody diarrhea, high fever, or systemic toxicity because of the risk of worsening the underlying condition. They should be discontinued in patients whose diarrhea is worsening despite therapy. Antidiarrheals are also used to control chronic diarrhea caused by such conditions as IBS or inflammatory bowel disease (IBD).

OPIOID AGONISTS As previously noted, opioids have significant constipating effects (see Chapter 31). They increase colonic phasic segmenting activity through inhibition of presynaptic cholinergic nerves in the submucosal and myenteric plexuses and lead to increased colonic transit time and fecal water absorption. They also decrease mass colonic movements and the gastrocolic reflex. Although all opioids have antidiarrheal effects, central nervous system effects and potential for addiction limit the usefulness of most.

Loperamide is a nonprescription opioid agonist that does not cross the blood-brain barrier and has no analgesic properties or potential for addiction. Tolerance to long-term use has not been reported. It is typically administered in doses of 2 mg taken one to four times daily. Diphenoxylate is a prescription opioid agonist that has no analgesic properties in standard doses; however, higher doses have central nervous system effects, and prolonged use can lead to opioid dependence. Commercial preparations commonly contain small amounts of atropine to discourage overdosage (2.5 mg diphenoxylate with 0.025 mg atropine). The anticholinergic properties of atropine may contribute to the antidiarrheal action.

COLLOIDAL BISMUTH COMPOUNDS See the section under Mucosal Protective Agents in earlier text.

BILE SALT-BINDING RESINS Conjugated bile salts are normally absorbed in the terminal ileum. Disease of the terminal ileum (eg, Crohnâ&#x20AC;&#x2122;s disease) or surgical resection leads to malabsorption of bile salts, which may cause colonic secretory diarrhea. The bile salt-binding resins cholestyramine, colestipol, or colesevelam, may decrease diarrhea caused by excess fecal bile acids (see Chapter 35). These products come in a variety of powder and pill formulations that may be taken one to three times daily before meals. Adverse effects include bloating, flatulence, constipation, and fecal impaction. In patients with diminished circulating bile acid pools, further removal of bile acids may lead to an exacerbation of fat malabsorption. Cholestyramine and colestipol bind a number of drugs and reduce their absorption; hence, they should not be given within 2 hours of other drugs. Colesevelam does not appear to have significant effects on absorption of other drugs.

OCTREOTIDE Somatostatin is a 14-amino-acid peptide that is released in the gastrointestinal tract and pancreas from paracrine cells, D cells, and enteric nerves as well as from the hypothalamus (see Chapter 37). Somatostatin is a key regulatory peptide that has many physiologic effects: 1. It inhibits the secretion of numerous hormones and transmitters, including gastrin, cholecystokinin, glucagon, growth hormone, insulin, secretin, pancreatic polypeptide, vasoactive intestinal peptide, and 5-HT. 2. It reduces intestinal fluid secretion and pancreatic secretion.

3. It slows gastrointestinal motility and inhibits gallbladder contraction.

4. It reduces portal and splanchnic blood flow.

5. It inhibits secretion of some anterior pituitary hormones.

The clinical usefulness of somatostatin is limited by its short half-life in the circulation (3 minutes) when it is administered by

intravenous injection. Octreotide is a synthetic octapeptide with actions similar to somatostatin. When administered intravenously, it has a serum half-life of 1.5 hours. It also may be administered by subcutaneous injection, resulting in a 6- to 12-hour duration of action. A longer-acting formulation is available for once-monthly depot intramuscular injection.

Clinical Uses 1. Inhibition of endocrine tumor effects—Two gastrointestinal neuroendocrine tumors (carcinoid, VIPoma) cause secretory diarrhea and systemic symptoms such as flushing and wheezing. For patients with advanced symptomatic tumors that cannot be completely removed by surgery, octreotide decreases secretory diarrhea and systemic symptoms through inhibition of hormonal secretion and may slow tumor progression.

2. Other causes of diarrhea—Octreotide inhibits intestinal secretion and has dose-related effects on bowel motility. In low doses (50 mcg subcutaneously), it stimulates motility, whereas at higher doses (eg, 100–250 mcg subcutaneously), it inhibits motility. Octreotide is effective in higher doses for the treatment of diarrhea due to vagotomy or dumping syndrome as well as for diarrhea caused by short bowel syndrome or AIDS. Octreotide has been used in low doses (50 mcg subcutaneously) to stimulate small bowel motility in patients with small bowel bacterial overgrowth or intestinal pseudo-obstruction secondary to scleroderma.

3. Other uses—Because it inhibits pancreatic secretion, octreotide may be of value in patients with pancreatic fistula. The role of octreotide in the treatment of pituitary tumors (eg, acromegaly) is discussed in Chapter 37. Octreotide is sometimes used in gastrointestinal bleeding (see below).

Adverse Effects Impaired pancreatic secretion may cause steatorrhea, which can lead to fat-soluble vitamin deficiency. Alterations in gastrointestinal motility cause nausea, abdominal pain, flatulence, and diarrhea. Because of inhibition of gallbladder contractility and alterations in fat absorption, long-term use of octreotide can cause formation of sludge or gallstones in over 50% of patients, which rarely results in the development of acute cholecystitis. Because octreotide alters the balance among insulin, glucagon, and growth hormone, hyperglycemia or, less frequently, hypoglycemia (usually mild) can occur. Prolonged treatment with octreotide may result in hypothyroidism. Octreotide also can cause bradycardia.

DRUGS USED IN THE TREATMENT OF IRRITABLE BOWEL SYNDROME IBS is an idiopathic chronic, relapsing disorder characterized by abdominal discomfort (pain, bloating, distention, or cramps) in association with alterations in bowel habits (diarrhea, constipation, or both). With episodes of abdominal pain or discomfort, patients note a change in the frequency or consistency of their bowel movements.

Pharmacologic therapies for IBS are directed at relieving abdominal pain and discomfort and improving bowel function. For patients with predominant diarrhea, antidiarrheal agents, especially loperamide, are helpful in reducing stool frequency and fecal urgency. For patients with predominant constipation, fiber supplements may lead to softening of stools and reduced straining; however, increased gas production may exacerbate bloating and abdominal discomfort. Consequently, osmotic laxatives, especially milk of magnesia, are commonly used to soften stools and promote increased stool frequency.

For chronic abdominal pain, low doses of tricyclic antidepressants (eg, amitriptyline or desipramine, 10–50 mg/d) appear to be helpful (see Chapter 30). At these doses, these agents have no effect on mood but may alter central processing of visceral afferent information.

The anticholinergic properties of these agents also may have effects on gastrointestinal motility and secretion, reducing stool frequency and liquidity. Finally, tricyclic antidepressants may alter receptors for enteric neurotransmitters such as serotonin, affecting visceral afferent sensation.

Several other agents are available that are specifically intended for the treatment of IBS.

ANTISPASMODICS (ANTICHOLINERGICS) Some agents are promoted as providing relief of abdominal pain or discomfort through antispasmodic actions. However, small or large bowel spasm has not been found to be an important cause of symptoms in patients with IBS. Antispasmodics work primarily through anticholinergic activities. Commonly used medications in this class include dicyclomine and hyoscyamine (see Chapter 8). These drugs inhibit muscarinic cholinergic receptors in the enteric plexus and on smooth muscle. The efficacy of antispasmodics for relief of abdominal symptoms has never been convincingly demonstrated. At low doses, they have minimal autonomic effects. However, at higher doses they exhibit significant additional anticholinergic effects, including dry mouth, visual disturbances, urinary retention, and constipation. For these reasons, antispasmodics are infrequently used.

SEROTONIN 5-HT3-RECEPTOR ANTAGONISTS 5-HT3 receptors in the gastrointestinal tract activate visceral afferent pain sensation via extrinsic sensory neurons from the gut to the spinal cord and central nervous system. Inhibition of afferent gastrointestinal 5-HT3 receptors may reduce unpleasant visceral afferent sensation, including nausea, bloating, and pain. Blockade of central 5-HT3 receptors also reduces the central response to visceral afferent stimulation. In addition, 5-HT3 -receptor blockade on the terminals of enteric cholinergic neurons inhibits colonic motility, especially in the left colon, increasing total colonic transit time.

Alosetron is a 5-HT3 antagonist that has been approved for the treatment of patients with severe IBS with diarrhea (Figure 62â&#x20AC;&#x201C;5).

Four other 5-HT3 antagonists (ondansetron, granisetron, dolasetron, and palonosetron) have been approved for the prevention and treatment of nausea and vomiting (see Antiemetics); however, their efficacy in the treatment of IBS has not been determined. The differences between these 5-HT3 antagonists that determine their pharmacodynamic effects have not been well studied.

FIGURE 62â&#x20AC;&#x201C;5 Chemical structure of serotonin; the 5-HT3 antagonists ondansetron, granisetron, dolasetron, and alosetron; and the 5HT4 partial agonist tegaserod.

Pharmacokinetics & Pharmacodynamics Alosetron is a highly potent and selective antagonist of the 5-HT3 receptor. It is rapidly absorbed from the gastrointestinal tract with a bioavailability of 50â&#x20AC;&#x201C;60% and has a plasma half-life of 1.5 hours but a much longer duration of effect. It undergoes extensive hepatic cytochrome P450 metabolism with renal excretion of most metabolites. Alosetron binds with higher affinity and dissociates more slowly from 5-HT3 receptors than other 5-HT3 antagonists, which may account for its long duration of action.

Clinical Uses

Alosetron is approved for the treatment of women with severe IBS in whom diarrhea is the predominant symptom (“diarrheapredominant IBS”). Its efficacy in men has not been established. In a dosage of 1 mg once or twice daily, it reduces IBS-related lower abdominal pain, cramps, urgency, and diarrhea. Approximately 50–60% of patients report adequate relief of pain and discomfort with alosetron compared with 30–40% of patients treated with placebo. It also leads to a reduction in the mean number of bowel movements per day and improvement in stool consistency. Alosetron has not been evaluated for the treatment of other causes of diarrhea.

Adverse Events In contrast to the excellent safety profile of other 5-HT3 -receptor antagonists, alosetron is associated with rare but serious gastrointestinal toxicity. Constipation occurs in up to 30% of patients with diarrhea-predominant IBS, requiring discontinuation of the drug in 10%. Serious complications of constipation requiring hospitalization or surgery have occurred in 1 of every 1000 patients. Episodes of ischemic colitis—some fatal—have been reported in up to 3 per 1000 patients. Given the seriousness of these adverse events, alosetron is restricted to women with severe diarrhea-predominant IBS who have not responded to conventional therapies and who have been educated about the relative risks and benefits.

Drug Interactions Despite being metabolized by a number of CYP enzymes, alosetron does not appear to have clinically significant interactions with other drugs.

CHLORIDE CHANNEL ACTIVATORS As discussed previously, lubiprostone is a prostanoic acid derivative that stimulates the type 2 chloride channel (ClC-2) in the small intestine. Lubiprostone is approved for the treatment of women with IBS with predominant constipation. Its efficacy for men with IBS is unproven. The approved dose for IBS is 8 mcg twice daily (compared with 24 mcg twice daily for chronic constipation). In clinical trials, lubiprostone resulted in modest clinical benefit—only 8% more patients than with placebo. Lubiprostone is listed as category C for pregnancy and should be avoided in women of child-bearing age.

Also discussed previously, linaclotide is a guanylyl cyclase-C agonist that leads to activation of the CFTR in the small intestine with stimulation of chloride-rich intestinal secretion. It is approved for treatment of adults with IBS with constipation at an approved dose of 290 mcg once daily (compared with 145 mcg once daily for chronic constipation). In clinical trials, up to 25% more patients treated with linaclotide than with placebo demonstrated significant clinical improvement. Linaclotide is listed as category C for pregnancy and is contraindicated for pediatric patients.

Due to their high cost and lack of information about long-term safety and efficacy, the role of these agents in the treatment of IBS with constipation is uncertain. Neither agent has been compared with other less expensive laxatives (eg, milk of magnesia).

ANTIEMETIC AGENTS Nausea and vomiting may be manifestations of a wide variety of conditions, including adverse effects from medications; systemic disorders or infections; pregnancy; vestibular dysfunction; central nervous system infection or increased pressure; peritonitis; hepatobiliary disorders; radiation or chemotherapy; and gastrointestinal obstruction, dysmotility, or infections.

PATHOPHYSIOLOGY The brainstem “vomiting center” is a loosely organized neuronal region within the lateral medullary reticular formation and coordinates the complex act of vomiting through interactions with cranial nerves VIII and X and neural networks in the nucleus tractus solitarius that control respiratory, salivatory, and vasomotor centers. High concentrations of muscarinic M 1 , histamine H1 , neurokinin 1 (NK1 ), and serotonin 5-HT3 receptors have been identified in the vomiting center (Figure 62–6).

FIGURE 62–6 Neurologic pathways involved in pathogenesis of nausea and vomiting (see text). (Adapted, with permission, from Krakauer EL et al: Case records of the Massachusetts General Hospital. N Engl J Med 2005;352:817. Copyright © 2005 Massachusetts Medical Society. Reprinted, with permission, from Massachusetts Medical Society.)

There are four important sources of afferent input to the vomiting center: 1. The “chemoreceptor trigger zone” or area postrema is located at the caudal end of the fourth ventricle. This is outside the blood-brain barrier and is accessible to emetogenic stimuli in the blood or cerebrospinal fluid. The chemoreceptor trigger zone is rich in dopamine D2 receptors and opioid receptors, and possibly serotonin 5-HT3 receptors and NK1 receptors.

2. The vestibular system is important in motion sickness via cranial nerve VIII. It is rich in muscarinic M1 and histamine H1 receptors.

3. Vagal and spinal afferent nerves from the gastrointestinal tract are rich in 5-HT3 receptors. Irritation of the gastrointestinal mucosa by chemotherapy, radiation therapy, distention, or acute infectious gastroenteritis leads to release of mucosal serotonin and activation of these receptors, which stimulate vagal afferent input to the vomiting center and chemoreceptor trigger zone.

4. The central nervous system plays a role in vomiting due to psychiatric disorders, stress, and anticipatory vomiting prior to cancer chemotherapy.

Identification of the different neurotransmitters involved with emesis has allowed development of a diverse group of antiemetic

agents that have affinity for various receptors. Combinations of antiemetic agents with different mechanisms of action are often used, especially in patients with vomiting due to chemotherapeutic agents.

SEROTONIN 5-HT3ANTAGONISTS Pharmacokinetics & Pharmacodynamics Selective 5-HT3 -receptor antagonists have potent antiemetic properties that are mediated in part through central 5-HT3 -receptor blockade in the vomiting center and chemoreceptor trigger zone but mainly through blockade of peripheral 5-HT3 receptors on extrinsic intestinal vagal and spinal afferent nerves. The anti-emetic action of these agents is restricted to emesis attributable to vagal stimulation (eg, postoperative) and chemotherapy; other emetic stimuli such as motion sickness are poorly controlled.

Four agents are available in the USA: ondansetron, granisetron, dolasetron, and palonosetron. (Tropisetron is available outside the USA.) The first three agents (ondansetron, granisetron, and dolasetron, Figure 62–5) have a serum half-life of 4–9 hours and may be administered once daily by oral or intravenous routes. All three drugs have comparable efficacy and tolerability when administered at equipotent doses. Palonosetron is a newer intravenous agent that has greater affinity for the 5-HT3 receptor and a long serum half-life of 40 hours. All four drugs undergo extensive hepatic metabolism and are eliminated by renal and hepatic excretion.

However, dose reduction is not required in geriatric patients or patients with renal insufficiency. For patients with hepatic insufficiency, dose reduction may be required with ondansetron.

5-HT3 -receptor antagonists do not inhibit dopamine or muscarinic receptors. They do not have effects on esophageal or gastric motility but may slow colonic transit.

Clinical Uses 1. Chemotherapy-induced nausea and vomiting—5-HT3 -receptor antagonists are the primary agents for the prevention of acute chemotherapy-induced nausea and emesis. When used alone, these drugs have little or no efficacy for the prevention of delayed nausea and vomiting (ie, occurring > 24 hours after chemotherapy). The drugs are most effective when given as a single dose by intravenous injection 30 minutes prior to administration of chemotherapy in the following doses: ondansetron, 8 mg; granisetron, 1 mg; dolasetron, 100 mg; or palonosetron, 0.25 mg. A single oral dose given 1 hour before chemotherapy may be equally effective in the following regimens: ondansetron 8 mg twice daily or 24 mg once; granisetron, 2 mg; dolasetron, 100 mg. Although 5-HT 3 -receptor antagonists are effective as single agents for the prevention of chemotherapy-induced nausea and vomiting, their efficacy is enhanced by combination therapy with a corticosteroid (dexamethasone) and NK1 -receptor antagonist (see below).

2. Postoperative and postradiation nausea and vomiting—5-HT3 -receptor antagonists are used to prevent or treat postoperative nausea and vomiting. Because of adverse effects and increased restrictions on the use of other antiemetic agents, 5-HT3 -receptor antagonists are increasingly used for this indication. They are also effective in the prevention and treatment of nausea and vomiting in patients undergoing radiation therapy to the whole body or abdomen.

Adverse Effects The 5-HT3 -receptor antagonists are well-tolerated agents with excellent safety profiles. The most commonly reported adverse effects are headache, dizziness, and constipation. All four agents cause a small but statistically significant prolongation of the QT interval, but this is most pronounced with dolasetron. Although cardiac arrhythmias have not been linked to dolasetron, it should not be administered to patients with prolonged QT or in conjunction with other medications that may prolong the QT interval (see Chapter 14).

Drug Interactions No significant drug interactions have been reported with 5-HT3 -receptor antagonists. All four agents undergo some metabolism by the hepatic cytochrome P450 system but they do not appear to affect the metabolism of other drugs. However, other drugs may reduce hepatic clearance of the 5-HT3 -receptor antagonists, altering their half-life.

CORTICOSTEROIDS Corticosteroids (dexamethasone, methylprednisolone) have antiemetic properties, but the basis for these effects is unknown. The pharmacology of this class of drugs is discussed in Chapter 39. These agents appear to enhance the efficacy of 5-HT3 -receptor antagonists for prevention of acute and delayed nausea and vomiting in patients receiving moderately to highly emetogenic chemotherapy

regimens. Although a number of corticosteroids have been used, dexamethasone, 8–20 mg intravenously before chemotherapy, followed by 8 mg/d orally for 2–4 days, is commonly administered.

NEUROKININ RECEPTOR ANTAGONISTS Neurokinin 1 (NK1 )-receptor antagonists have antiemetic properties that are mediated through central blockade in the area postrema.

Aprepitant (an oral formulation) is a highly selective NK1 -receptor antagonist that crosses the blood-brain barrier and occupies brain NK1 receptors. It has no affinity for serotonin, dopamine, or corticosteroid receptors. Fosaprepitant is an intravenous formulation that is converted within 30 minutes after infusion to aprepitant.

Pharmacokinetics The oral bioavailability of aprepitant is 65%, and the serum half-life is 12 hours. Aprepitant is metabolized by the liver, primarily by the CYP3A4 pathway.

Clinical Uses Aprepitant is used in combination with 5-HT3 -receptor antagonists and corticosteroids for the prevention of acute and delayed nausea and vomiting from highly emetogenic chemotherapeutic regimens. Combined therapy with aprepitant, a 5-HT3 -receptor antagonist, and dexamethasone prevents acute emesis in 80–90% of patients compared with less than 70% treated without aprepitant. Prevention of delayed emesis occurs in more than 70% of patients receiving combined therapy versus 30–50% treated without aprepitant. NK1 receptor antagonists may be administered for 3 days as follows: oral aprepitant 125 mg or intravenous fosaprepitant 115 mg given 1 hour before chemotherapy, followed by oral aprepitant 80 mg/d for 2 days after chemotherapy.

Adverse Effects & Drug Interactions Aprepitant may be associated with fatigue, dizziness, and diarrhea. The drug is metabolized by CYP3A4 and may inhibit the metabolism of other drugs metabolized by the CYP3A4 pathway. Several chemotherapeutic agents are metabolized by CYP3A4, including docetaxel, paclitaxel, etoposide, irinotecan, imatinib, vinblastine, and vincristine. Drugs that inhibit CYP3A4 metabolism may significantly increase aprepitant plasma levels (eg, ketoconazole, ciprofloxacin, clarithromycin, nefazodone, ritonavir, nelfinavir, verapamil, and quinidine). Aprepitant decreases the international normalized ratio (INR) in patients taking warfarin.

PHENOTHIAZINES & BUTYROPHENONES Phenothiazines are antipsychotic agents that can be used for their potent antiemetic and sedative properties (see Chapter 29). The antiemetic properties of phenothiazines are mediated through inhibition of dopamine and muscarinic receptors. Sedative properties are due to their antihistamine activity. The agents most commonly used as antiemetics are prochlorperazine, promethazine, and thiethylperazine.

Antipsychotic butyrophenones also possess antiemetic properties due to their central dopaminergic blockade (see Chapter 29). The main agent used is droperidol, which can be given by intramuscular or intravenous injection. In antiemetic doses, droperidol is extremely sedating. Previously, it was used extensively for postoperative nausea and vomiting, in conjunction with opiates and benzodiazepines for sedation for surgical and endoscopic procedures, for neuroleptanalgesia, and for induction and maintenance of general anesthesia.

Extrapyramidal effects and hypotension may occur. Droperidol may prolong the QT interval, rarely resulting in fatal episodes of ventricular tachycardia including torsades de pointes. Therefore, droperidol should not be used in patients with QT prolongation and should be used only in patients who have not responded adequately to alternative agents.

SUBSTITUTED BENZAMIDES Substituted benzamides include metoclopramide (discussed previously) and trimethobenzamide. Their primary mechanism of antiemetic action is believed to be dopamine-receptor blockade. Trimethobenzamide also has weak antihistaminic activity. For prevention and treatment of nausea and vomiting, metoclopramide may be given in the relatively high dosage of 10–20 mg orally or intravenously every 6 hours. The usual dose of trimethobenzamide is 300 mg orally, or 200 mg by intramuscular injection. The principal adverse effects of these central dopamine antagonists are extrapyramidal: restlessness, dystonias, and parkinsonian symptoms.

H1ANTIHISTAMINES & ANTICHOLINERGIC DRUGS The pharmacology of anticholinergic agents is discussed in Chapter 8 and that of H1 antihistaminic agents in Chapter 16. As single agents, these drugs have weak antiemetic activity, although they are particularly useful for the prevention or treatment of motion sickness. Their use may be limited by dizziness, sedation, confusion, dry mouth, cycloplegia, and urinary retention. Diphenhydramine and one of its salts, dimenhydrinate, are first-generation histamine H1 antagonists that also have significant anticholinergic properties.

Because of its sedating properties, diphenhydramine is commonly used in conjunction with other antiemetics for treatment of emesis due to chemotherapy. Meclizine is an H1 antihistaminic agent with minimal anticholinergic properties that also causes less sedation. It is used for the prevention of motion sickness and the treatment of vertigo due to labyrinth dysfunction.

Hyoscine (scopolamine), a prototypic muscarinic receptor antagonist, is one of the best agents for the prevention of motion sickness.

However, it has a very high incidence of anticholinergic effects when given orally or parenterally. It is better tolerated as a transdermal patch. Superiority to dimenhydrinate has not been proved.

BENZODIAZEPINES Benzodiazepines such as lorazepam or diazepam are used before the initiation of chemotherapy to reduce anticipatory vomiting or vomiting caused by anxiety. The pharmacology of these agents is presented in Chapter 22.

CANNABINOIDS Dronabinol is δ9 -tetrahydrocannabinol (THC), the major psychoactive chemical in marijuana (see Chapter 32). After oral ingestion, the drug is almost completely absorbed but undergoes significant first-pass hepatic metabolism. Its metabolites are excreted slowly over days to weeks in the feces and urine. Like crude marijuana, dronabinol is a psychoactive agent that is used medically as an appetite stimulant and as an antiemetic, but the mechanisms for these effects are not understood. Because of the availability of more effective agents, dronabinol now is uncommonly used for the prevention of chemotherapy-induced nausea and vomiting. Combination therapy with phenothiazines provides synergistic antiemetic action and appears to attenuate the adverse effects of both agents. Dronabinol is usually administered in a dosage of 5 mg/m2 just prior to chemotherapy and every 2–4 hours as needed. Adverse effects include euphoria, dysphoria, sedation, hallucinations, dry mouth, and increased appetite. It has some autonomic effects that may result in tachycardia, conjunctival injection, and orthostatic hypotension. Dronabinol has no significant drug-drug interactions but may potentiate the clinical effects of other psychoactive agents.

Nabilone is a closely related THC analog that has been available in other countries and is now approved for use in the USA.

DRUGS USED TO TREAT INFLAMMATORY BOWEL DISEASE IBD comprises two distinct disorders: ulcerative colitis and Crohn’s disease. The etiology and pathogenesis of these disorders remain unknown. For this reason, pharmacologic treatment of inflammatory bowel disorders often involves drugs that belong to different therapeutic classes and have different but nonspecific mechanisms of anti-inflammatory action. Drugs used in IBD are chosen on the basis of disease severity, responsiveness, and drug toxicity (Figure 62–7).

FIGURE 62–7 Therapeutic pyramid approach to inflammatory bowel diseases. Treatment choice is predicated on both the severity of the illness and the responsiveness to therapy. Agents at the bottom of the pyramid are less efficacious but carry a lower risk of serious adverse effects. Drugs may be used alone or in various combinations. Patients with mild disease may be treated with 5-aminosalicylates (with ulcerative colitis or Crohn’s colitis), topical corticosteroids (ulcerative colitis), antibiotics (Crohn’s colitis or Crohn’s perianal disease), or budesonide (Crohn’s ileitis). Patients with moderate disease or patients who fail initial therapy for mild disease may be treated with oral corticosteroids to promote disease remission; immunomodulators (azathioprine, mercaptopurine, methotrexate) to promote or maintain disease remission; or anti-TNF antibodies. Patients with moderate disease who fail other therapies or patients with severe disease may require intravenous corticosteroids, anti-TNF antibodies, or surgery. Natalizumab is reserved for patients with severe Crohn’s disease who have failed immunomodulators and TNF antagonists. Cyclosporine is used primarily for patients with severe ulcerative colitis who have failed a course of intravenous corticosteroids. TNF, tumor necrosis factor.

AMINOSALICYLATES Chemistry & Formulations Drugs that contain 5-aminosalicylic acid (5-ASA) have been used successfully for decades in the treatment of IBDs (Figure 62–8). 5ASA differs from salicylic acid only by the addition of an amino group at the 5 (meta) position. Aminosalicylates are believed to work topically (not systemically) in areas of diseased gastrointestinal mucosa. Up to 80% of unformulated, aqueous 5-ASA is absorbed from the small intestine and does not reach the distal small bowel or colon in appreciable quantities. To overcome the rapid absorption of 5ASA from the proximal small intestine, a number of formulations have been designed to deliver 5-ASA to various distal segments of the small bowel or the colon. These include sulfasalazine, olsalazine, balsalazide, and various forms of mesalamine.

FIGURE 62–8 Chemical structures and metabolism of aminosalicylates. Azo compounds (balsalazide, olsalazine, sulfasalazine) are converted by bacterial azoreductase to 5-aminosalicylic acid (mesalamine), the active therapeutic moiety.

1. Azo compounds—Sulfasalazine, balsalazide, and olsalazine contain 5-ASA bound by an azo (N=N) bond to an inert compound or to another 5-ASA molecule (Figure 62–8). In sulfasalazine, 5-ASA is bound to sulfapyridine; in balsalazide, 5-ASA is bound to 4aminobenzoyl-β-alanine; and in olsalazine, two 5-ASA molecules are bound together. The azo structure markedly reduces absorption of the parent drug from the small intestine. In the terminal ileum and colon, resident bacteria cleave the azo bond by means of an azoreductase enzyme, releasing the active 5-ASA. Consequently, high concentrations of active drug are made available in the terminal ileum or colon.

2. Mesalamine compounds—Other proprietary formulations have been designed that package 5-ASA itself in various ways to deliver it to different segments of the small or large bowel. These 5-ASA formulations are known generically as mesalamine. Pentasa is a mesalamine formulation that contains timed-release microgranules that release 5-ASA throughout the small intestine (Figure 62–9).

Asacol and Apriso have 5-ASA coated in a pH-sensitive resin that dissolves at pH 6-7 (the pH of the distal ileum and proximal colon).

Lialda also uses a pH-dependent resin that encases a multimatrix core. On dissolution of the pH-sensitive resin in the colon, water slowly penetrates its hydrophilic and lipophilic core, leading to slow release of mesalamine throughout the colon. 5-ASA also may be delivered in high concentrations to the rectum and sigmoid colon by means of enema formulations (Rowasa) or suppositories (Canasa).

FIGURE 62–9 Sites of 5-aminosalicylic acid (5-ASA) release from different formulations in the small and large intestines.

Pharmacokinetics & Pharmacodynamics Although unformulated 5-ASA is readily absorbed from the small intestine, absorption of 5-ASA from the colon is extremely low. In contrast, approximately 20–30% of 5-ASA from current oral mesalamine formulations is systemically absorbed in the small intestine.

Absorbed 5-ASA undergoes N-acetylation in the gut epithelium and liver to a metabolite that does not possess significant antiinflammatory activity. The acetylated metabolite is excreted by the kidneys.

Of the azo compounds, 10% of sulfasalazine and less than 1% of balsalazide are absorbed as native compounds. After azoreductase breakdown of sulfasalazine, over 85% of the carrier molecule sulfapyridine is absorbed from the colon. Sulfapyridine undergoes hepatic metabolism (including acetylation) followed by renal excretion. By contrast, after azoreductase breakdown of balsalazide, over 70% of the carrier peptide is recovered intact in the feces and only a small amount of systemic absorption occurs.

The mechanism of action of 5-ASA is not certain. The primary action of salicylate and other NSAIDs is due to blockade of prostaglandin synthesis by inhibition of cyclooxygenase. However, the aminosalicylates have variable effects on prostaglandin production.

It is thought that 5-ASA modulates inflammatory mediators derived from both the cyclooxygenase and lipoxygenase pathways. Other potential mechanisms of action of the 5-ASA drugs relate to their ability to interfere with the production of inflammatory cytokines. 5ASA inhibits the activity of nuclear factor-κB (NF-κB), an important transcription factor for proinflammatory cytokines. 5-ASA may also inhibit cellular functions of natural killer cells, mucosal lymphocytes, and macrophages, and it may scavenge reactive oxygen metabolites.

Clinical Uses 5-ASA drugs induce and maintain remission in ulcerative colitis and are considered to be the first-line agents for treatment of mild to moderate active ulcerative colitis. Their efficacy in Crohn’s disease is unproven, although many clinicians use 5-ASA agents as first-line therapy for mild to moderate disease involving the colon or distal ileum.

The effectiveness of 5-ASA therapy depends in part on achieving high drug concentration at the site of active disease. Thus, 5-ASA suppositories or enemas are useful in patients with ulcerative colitis or Crohn’s disease confined to the rectum (proctitis) or distal colon (proctosigmoiditis). In patients with ulcerative colitis or Crohn’s colitis that extends to the proximal colon, both the azo compounds and mesalamine formulations are useful. For the treatment of Crohn’s disease involving the small bowel, mesalamine compounds, which release 5-ASA in the small intestine, have a theoretic advantage over the azo compounds.

Adverse Effects Sulfasalazine has a high incidence of adverse effects, most of which are attributable to systemic effects of the sulfapyridine molecule.

Slow acetylators of sulfapyridine have more frequent and more severe adverse effects than fast acetylators. Up to 40% of patients cannot tolerate therapeutic doses of sulfasalazine. The most common problems are dose-related and include nausea, gastrointestinal upset, headaches, arthralgias, myalgias, bone marrow suppression, and malaise. Hypersensitivity to sulfapyridine (or, rarely, 5-ASA) can result in fever, exfoliative dermatitis, pancreatitis, pneumonitis, hemolytic anemia, pericarditis, or hepatitis. Sulfasalazine has also been associated with oligospermia, which reverses upon discontinuation of the drug. Sulfasalazine impairs folate absorption and processing; hence, dietary supplementation with 1 mg/d folic acid is recommended.

In contrast to sulfasalazine, other aminosalicylate formulations are well tolerated. In most clinical trials, the frequency of drug adverse events is similar to that in patients treated with placebo. For unclear reasons, olsalazine may stimulate a secretory diarrhea—which should not be confused with active IBD—in 10% of patients. Rare hypersensitivity reactions may occur with all aminosalicylates but are much less common than with sulfasalazine. Careful studies have documented subtle changes indicative of renal tubular damage in patients receiving high doses of aminosalicylates. Rare cases of interstitial nephritis are reported, particularly in association with high doses of mesalamine formulations; this may be attributable to the higher serum 5-ASA levels attained with these drugs. Sulfasalazine and other aminosalicylates rarely cause worsening of colitis, which may be misinterpreted as refractory colitis.

GLUCOCORTICOIDS Pharmacokinetics & Pharmacodynamics In gastrointestinal practice, prednisone and prednisolone are the most commonly used oral glucocorticoids. These drugs have an intermediate duration of biologic activity allowing once-daily dosing.

Hydrocortisone enemas, foam, or suppositories are used to maximize colonic tissue effects and minimize systemic absorption via topical treatment of active IBD in the rectum and sigmoid colon. Absorption of hydrocortisone is reduced with rectal administration, although 15–30% of the administered dosage is still absorbed.

Budesonide is a potent synthetic analog of prednisolone that has high affinity for the glucocorticoid receptor but is subject to rapid first-pass hepatic metabolism (in part by CYP3A4), resulting in low oral bioavailability. Two pH-controlled delayed-release oral formulations of budesonide are available that release the drug either in the distal ileum and colon (pH > 5.5, Entocort) or in the colon (pH > 7, Uceris), where it is absorbed. The bioavailability of controlled-release budesonide capsules is approximately 10%.

As in other tissues, glucocorticoids inhibit production of inflammatory cytokines (TNF-α, IL-1) and chemokines (IL-8); reduce expression of inflammatory cell adhesion molecules; and inhibit gene transcription of nitric oxide synthase, phospholipase A 2 , cyclooxygenase-2, and NF-κB.

Clinical Uses Glucocorticoids are commonly used in the treatment of patients with moderate to severe active IBD. Active disease is commonly treated with an initial oral dosage of 40–60 mg/d of prednisone or prednisolone. Higher doses have not been shown to be more efficacious but have significantly greater adverse effects. Once a patient responds to initial therapy (usually within 1–2 weeks), the dosage is tapered to minimize development of adverse effects. In severely ill patients, the drugs are usually administered intravenously.

For the treatment of IBD involving the rectum or sigmoid colon, rectally administered glucocorticoids are preferred because of their lower systemic absorption.

The oral controlled-release budesonide (9 mg/d) formulations described above are used in the treatment of mild to moderate Crohn’s disease involving the ileum and proximal colon (Entocort) and ulcerative colitis (Uceris). They are slightly less effective than prednisolone in achieving clinical remission but have significantly less adverse systemic effects.

Corticosteroids are not useful for maintaining disease remission. Other medications such as aminosalicylates or immunosuppressive agents should be used for this purpose.

Adverse Effects Oral controlled-release budesonide formulations are metabolized extensively in the liver by CYP3A4. Potent inhibitors of CYP3A4 can increase budesonide plasma levels several-fold, increasing the likelihood of adverse effects. General adverse effects of glucocorticoids are reviewed in Chapter 39.

PURINE ANALOGS: AZATHIOPRINE & 6-MERCAPTOPURINE Pharmacokinetics & Pharmacodynamics Azathioprine and 6-mercaptopurine (6-MP) are purine anti-metabolites that have immunosuppressive properties (see Chapters 54 and 55).

The bioavailability of azathioprine (80%) is superior to 6-MP (50%). After absorption azathioprine is rapidly converted by a nonenzymatic process to 6-MP. 6-Mercaptopurine subsequently undergoes a complex biotransformation via competing catabolic enzymes (xanthine oxidase and thiopurine methyltransferase) that produce inactive metabolites and anabolic pathways that produce active thioguanine nucleotides. Azathioprine and 6-MP have a serum half-life of less than 2 hours; however, the active 6-thioguanine nucleotides are concentrated in cells resulting in a prolonged half-life of days. The prolonged kinetics of 6-thioguanine nucleotide results

in a median delay of 17 weeks before onset of therapeutic benefit from oral azathioprine or 6-MP is observed in patients with IBD.

Clinical Uses Azathioprine and 6-MP are important agents in the induction and maintenance of remission of ulcerative colitis and Crohn’s disease.

Although the optimal dose is uncertain, most patients with normal thiopurine-S-methyltransferase (TPMT) activity (see below) are treated with 6-MP, 1–1.5 mg/kg/d, or azathioprine, 2–2.5 mg/kg/d. After 3–6 months of treatment, 50–60% of patients with active disease achieve remission. These agents help maintain remission in up to 80% of patients. Among patients who depend on long-term glucocorticoid therapy to control active disease, purine analogs allow dose reduction or elimination of steroids in the majority.

Adverse Effects Dose-related toxicities of azathioprine or 6-MP include nausea, vomiting, bone marrow depression (leading to leukopenia, macrocytosis, anemia, or thrombocytopenia), and hepatic toxicity. Routine laboratory monitoring with complete blood count and liver function tests is required in all patients. Leukopenia or elevations in liver chemistries usually respond to medication dose reduction. Severe leukopenia may predispose to opportunistic infections; leukopenia may respond to therapy with granulocyte stimulating factor. Catabolism of 6-MP

by TPMT is low in 11% and absent in 0.3% of the population, leading to increased production of active 6-thioguanine metabolites and increased risk of bone marrow depression. TPMT levels can be measured before initiating therapy. These drugs should not be administered to patients with no TPMT activity and should be initiated at lower doses in patients with intermediate activity.

Hypersensitivity reactions to azathioprine or 6-MP occur in 5% of patients. These include fever, rash, pancreatitis, diarrhea, and hepatitis.

As with transplant recipients receiving long-term 6-MP or azathioprine therapy, there appears to be an increased risk of lymphoma among patients with IBD. These drugs cross the placenta; however, there are many reports of successful pregnancies in women taking these agents, and the risk of teratogenicity appears to be small.

Drug Interactions Allopurinol markedly reduces xanthine oxide catabolism of the purine analogs, potentially increasing active 6-thioguanine nucleotides that may lead to severe leukopenia. Allopurinol should not be given to patients taking 6-MP or azathioprine except in carefully monitored situations.

METHOTREXATE Pharmacokinetics & Pharmacodynamics Methotrexate is another antimetabolite that has beneficial effects in a number of chronic inflammatory diseases, including Crohn’s disease and rheumatoid arthritis (see Chapter 36), and in cancer (see Chapter 54). Methotrexate may be given orally, subcutaneously, or intramuscularly. Reported oral bioavailability is 50–90% at doses used in chronic inflammatory diseases. Intramuscular and subcutaneous methotrexate exhibit nearly complete bioavailability.

The principal mechanism of action is inhibition of dihydrofolate reductase, an enzyme important in the production of thymidine and purines. At the high doses used for chemotherapy, methotrexate inhibits cellular proliferation. However, at the low doses used in the treatment of IBD (12–25 mg/wk), the antiproliferative effects may not be evident. Methotrexate may interfere with the inflammatory actions of interleukin-1. It may also stimulate increased release of adenosine, an endogenous anti-inflammatory autacoid. Methotrexate may also stimulate apoptosis and death of activated T lymphocytes.

Clinical Uses Methotrexate is used to induce and maintain remission in patients with Crohn’s disease. Its efficacy in ulcerative colitis is uncertain. To induce remission, patients are treated with 15–25 mg of methotrexate once weekly by subcutaneous injection. If a satisfactory response is achieved within 8–12 weeks, the dose is reduced to 15 mg/wk.

Adverse Effects At higher dosage, methotrexate may cause bone marrow depression, megaloblastic anemia, alopecia, and mucositis. At the doses used in the treatment of IBD, these events are uncommon but warrant dose reduction if they do occur. Folate supplementation reduces the risk of these events without impairing the anti-inflammatory action.

In patients with psoriasis treated with methotrexate, hepatic damage is common; however, among patients with IBD and rheumatoid arthritis, the risk is significantly lower. Renal insufficiency may increase risk of hepatic accumulation and toxicity.

ANTITUMOR NECROSIS FACTOR THERAPY Pharmacokinetics & Pharmacodynamics A dysregulation of the helper T cell type 1 (T H1) response and regulatory T cells (Tregs) is present in IBD, especially Crohn’s disease.

One of the key proinflammatory cytokines in IBD is tumor necrosis factor (TNF). TNF is produced by the innate immune system (eg, dendritic cells, macrophages), the adaptive immune system (especially TH1 cells), and nonimmune cells (fibroblasts, smooth muscle cells).

TNF exists in two biologically active forms: soluble TNF and membrane-bound TNF. The biologic activity of soluble and membranebound TNF is mediated by binding to TNF receptors (TNFR) that are present on some cells (especially TH1 cells, innate immune cells, and fibroblasts). Binding of TNF to TNFR initially activates components including NF-κB that stimulate transcription, growth, and expansion. Biologic actions ascribed to TNFR activation include release of proinflammatory cytokines from macrophages, T-cell activation and proliferation, fibroblast collagen production, up-regulation of endothelial adhesion molecules responsible for leukocyte migration, and stimulation of hepatic acute phase reactants. Activation of TNFR may later lead to apoptosis (programmed cell death) of activated cells.

Four monoclonal antibodies to human TNF are approved for the treatment of IBD: infliximab, adalimumab, golimumab, and certolizumab (Table 62–3). Infliximab, adalimumab, and golimumab are antibodies of the IgG1 subclass. Certolizumab is a recombinant antibody that contains an Fab fragment that is conjugated to polyethylene glycol (PEG) but lacks an Fc portion. The Fab portion of infliximab is a chimeric mouse-human antibody, but adalimumab, certolizumab, and golimumab are fully humanized. Infliximab is administered as an intravenous infusion. At therapeutic doses of 5–10 mg/kg, the half-life of infliximab is approximately 8–10 days, resulting in plasma disappearance of antibodies over 8–12 weeks. Adalimumab, golimumab, and certolizumab are administered by subcutaneous injection. Their half-lives are approximately 2 weeks.

TABLE 62–3 Anti-TNF antibodies used in inflammatory bowel disease.

All four agents bind to soluble and membrane-bound TNF with high affinity, preventing the cytokine from binding to its receptors.

Binding of all three antibodies to membrane-bound TNF also causes reverse signaling that suppresses cytokine release. When infliximab, adalimumab, or golimumab bind to membrane-bound TNF, the Fc portion of the human IgG1 region promotes antibody-mediated apoptosis, complement activation, and cellular cytotoxicity of activated T lymphocytes and macrophages. Certolizumab, without an Fc portion, lacks these properties.

Clinical Uses Infliximab, adalimumab, and certolizumab are approved for the acute and chronic treatment of patients with moderate to severe Crohnâ&#x20AC;&#x2122;s disease who have had an inadequate response to conventional therapies. Infliximab, adalimumab, and golimumab are approved for the acute and chronic treatment of moderate to severe ulcerative colitis. With induction therapy, these approved agents lead to symptomatic improvement in 60% and disease remission in 30% of patients with moderate to severe Crohnâ&#x20AC;&#x2122;s disease, including patients who have been dependent on glucocorticoids or who have not responded to 6-MP or methotrexate. The median time to clinical response is 2 weeks. Induction therapy is generally given as follows: infliximab 5 mg/kg intravenous infusion at 0, 2, and 6 weeks; adalimumab 160 mg (in divided doses) initially and 80 mg subcutaneous injection at 2 weeks; and certolizumab 400 mg subcutaneous injection at 0, 2, and 4 weeks. Patients who respond may be treated with chronic maintenance therapy, as follows: infliximab 5 mg/kg intravenous infusion every 8 weeks; adalimumab 40 mg subcutaneous injection every 2 weeks; certolizumab 400 mg subcutaneous injection every 4 weeks. With

chronic, regularly scheduled therapy, clinical response is maintained in more than 60% of patients and disease remission in 40%.

However, one-third of patients eventually lose response despite higher doses or more frequent injections. Loss of response in many patients may be due to the development of antibodies to the TNF antibody or to other mechanisms.

Infliximab is approved for the treatment of patients with moderate to severe ulcerative colitis who have had inadequate response to mesalamine or corticosteroids. After induction therapy of 5–10 mg/wk at 0, 2, and 6 weeks, 70% of patients have a clinical response and one third achieve a clinical remission. With continued maintenance infusions every 8 weeks, approximately 50% of patients have continued clinical response. Adalimumab and golimumab were recently approved for the treatment of moderate to severe ulcerative colitis but appear to be less effective than intravenous infliximab. After induction therapy, less than 55% of patients have a clinical response and less than 20% achieve remission. The reason why subcutaneous anti-TNF formulations are less effective than intravenous infliximab is uncertain.

Adverse Effects Serious adverse events occur in up to 6% of patients with anti-TNF therapy. The most important adverse effect of these drugs is infection due to suppression of the TH1 inflammatory response. This may lead to serious infections such as bacterial sepsis, tuberculosis, invasive fungal organisms, reactivation of hepatitis B, listeriosis, and other opportunistic infections. Reactivation of latent tuberculosis, with dissemination, has occurred. Before administering anti-TNF therapy, all patients must undergo testing with tuberculin skin tests or interferon gamma release assays. Prophylactic therapy for tuberculosis is warranted for patients with positive test results before beginning anti-TNF therapy. More common but usually less serious infections include upper respiratory infections (sinusitis, bronchitis, and pneumonia) and cellulitis. The risk of serious infections is increased markedly in patients taking concomitant corticosteroids.

Antibodies to the antibody (ATA) may develop with all four agents. These antibodies may attenuate or eliminate the clinical response and increase the likelihood of developing acute or delayed infusion or injection reactions. Antibody formation is much more likely in patients given episodic anti-TNF therapy than regular scheduled injections. In patients on chronic maintenance therapy, the prevalence of ATA with infliximab is 10%, with certolizumab 8%, and with adalimumab or golimumab 3%. Antibody development also is less likely in patients who receive concomitant therapy with immunomodulators (ie, 6-MP or methotrexate). Concomitant treatment with anti-TNF agents and immunomodulators may increase the risk of lymphoma.

Infliximab intravenous infusions result in acute adverse infusion reactions in up to 10% of patients, but discontinuation of the infusion for severe reactions is required in less than 2%. Infusion reactions are more common with the second or subsequent infusions than with the first. Early mild reactions include fever, headache, dizziness, urticaria, or mild cardiopulmonary symptoms that include chest pain, dyspnea, or hemodynamic instability. Reactions to subsequent infusions may be reduced with prophylactic administration of acetaminophen, diphenhydramine, or corticosteroids. Severe acute reactions include significant hypotension, shortness of breath, muscle spasms, and chest discomfort; such reactions may require treatment with oxygen, epinephrine, and corticosteroids.

A delayed serum sickness-like reaction may occur 1–2 weeks after anti-TNF therapy in 1% of patients. These reactions consist of myalgia, arthralgia, jaw tightness, fever, rash, urticaria, and edema and usually require discontinuation of that agent. Positive antinuclear antibodies and anti-double-stranded DNA develop in a small number of patients. Development of a lupus-like syndrome is rare and resolves after discontinuation of the drug.

Rare but serious adverse effects of all anti-TNF agents also include severe hepatic reactions leading to acute hepatic failure, demyelinating disorders, hematologic reactions, and new or worsened congestive heart failure in patients with underlying heart disease.

Anti-TNF agents may cause a variety of psoriatic skin rashes, which usually resolve after drug discontinuation.

Lymphoma appears to be increased in patients with untreated IBD. Anti-TNF agents may further increase the risk of lymphoma in this population, although the relative risk is uncertain. An increased number of cases of hepatosplenic T-cell lymphoma, a rare but usually fatal disease, have been noted in children and young adults, virtually all of whom have been on combined therapy with immunomodulators, anti-TNF agents, or corticosteroids.

ANTI-INTEGRIN THERAPY Integrins are a family of adhesion molecules on the surface of leukocytes that may interact with another class of adhesion molecules on the surface of the vascular endothelium known as selectins, allowing circulating leukocytes to adhere to the vascular endothelium and subsequently move through the vessel wall into the tissue. Integrins consist of heterodimers that contain two subunits, alpha and beta.

Natalizumab is a humanized IgG4 monoclonal antibody targeted against the α4 subunit, and thereby blocks several integrins on circulating inflammatory cells and thus prevents binding to the vascular adhesion molecules and subsequent migration into surrounding tissues.

Natalizumab has shown significant efficacy for a subset of patients with moderate to severe Crohn’s disease. Unfortunately, patients treated with natalizumab may develop progressive multifocal leukoencephalopathy (PML) due to reactivation of a human polyomavirus (JC virus), which is present in latent form in over 80% of adults. Patients who are positive for JC-virus antibody have a mean risk of PML of 3.9/1000 patients; however, the risk is markedly increased in patients treated for more than 24 months or receiving other

immunosuppressants. Natalizumab is currently approved through a carefully restricted program for patients with moderate to severe Crohn’s disease who have failed other therapies. The approved dosage is 300 mg every 4 weeks by intravenous infusion, and patients should not be on other immune suppressant agents. Approximately 50% of patients respond to initial therapy with natalizumab. Of patients with an initial response, long-term response is maintained in 60% and remission in over 40%. Other adverse effects include acute infusion reactions and a small risk of opportunistic infections.

PANCREATIC ENZYME SUPPLEMENTS Exocrine pancreatic insufficiency is most commonly caused by cystic fibrosis, chronic pancreatitis, or pancreatic resection. When secretion of pancreatic enzymes falls below 10% of normal, fat and protein digestion is impaired and can lead to steatorrhea, azotorrhea, vitamin malabsorption, and weight loss. Pancreatic enzyme supplements, which contain a mixture of amylase, lipase, and proteases, are the mainstay of treatment for pancreatic enzyme insufficiency. Two major types of preparations in use are pancreatin and pancrelipase. Pancreatin is an alcohol-derived extract of hog pancreas with relatively low concentrations of lipase and proteolytic enzymes, whereas pancrelipase is an enriched preparation. On a per-weight basis, pancrelipase has approximately 12 times the lipolytic activity and more than 4 times the proteolytic activity of pancreatin. Consequently, pancreatin is no longer in common clinical use. Only pancrelipase is discussed here.

Pancrelipase is available worldwide in both non-enteric-coated and enteric-coated preparations. Formulations are available in sizes containing varying amounts of lipase, amylase, and protease. However, manufacturers’ listings of enzyme content do not always reflect true enzymatic activity. Pancrelipase enzymes are rapidly and permanently inactivated by gastric acids. Viokace is a non-enteric-coated tablet that should be given concomitantly with acid suppression therapy (PPI or H2 antagonist) to reduce acid-mediated destruction within the stomach. Enteric-coated formulations are more commonly used because they do not require concomitant acid suppression therapy.

At present, five enteric-coasted, delayed-release formulations are approved for use (Creon, Pancreaze, Zenpep, Ultresa, and Pertyze).

Pancrelipase preparations are administered with each meal and snack. Enzyme activity may be listed in international units (IU) or USP units. One IU is equal to 2–3 USP units. Dosing should be individualized according to the age and weight of the patient, the degree of pancreatic insufficiency, and the amount of dietary fat intake. Therapy is initiated at a dose that provides 60,000–90,000 USP units (20–30,000 IU) of lipase activity in the prandial and postprandial period—a level that is sufficient to reduce steatorrhea to a clinically insignificant level in most cases. Suboptimal response to enteric-coated formulations may be due to poor mixing of granules with food or slow dissolution and release of enzymes. Gradual increase of dose, change to a different formulation, or addition of acid suppression therapy may improve response. For patients with feeding tubes, microspheres may be mixed with enteral feeding prior to administration.

Pancreatic enzyme supplements are well tolerated. The capsules should be swallowed, not chewed, because pancreatic enzymes may cause oropharyngeal mucositis. Excessive doses may cause diarrhea and abdominal pain. The high purine content of pancreas extracts may lead to hyperuricosuria and renal stones. Several cases of colonic strictures were reported in patients with cystic fibrosis who received high doses of pancrelipase with high lipase activity. These high-dose formulations have since been removed from the market.

GLUCAGON-LIKE PEPTIDE 2 ANALOG FOR SHORT-BOWEL SYNDROME Extensive surgical resection or disease of the small intestine may result in short-bowel syndrome with malabsorption of nutrients and fluids. Patients with less than 200 cm of small intestine (with or without colon resection) usually are dependent on partial or complete parenteral nutritional support to maintain hydration and nutrition. Teduglutide is a glucagon-like peptide 2 analog that binds to enteric neurons and endocrine cells, stimulating release of a number of trophic hormones (including insulin-like growth factor) that stimulate mucosal epithelial growth and enhance fluid absorption. In clinical trials, 54% of patients treated with teduglutide (0.05 mg/kg once daily by subcutaneous injection) reduced their need for parenteral support by at least 1 day/wk compared with 23% treated with placebo.

Teduglutide may be associated with an increased risk of neoplasia, including colorectal polyps.

BILE ACID THERAPY FOR GALLSTONES Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid that makes up less than 5% of the circulating bile salt pool in humans and a much higher percentage in bears. After oral administration, it is absorbed, conjugated in the liver with glycine or taurine, and excreted in the bile. Conjugated ursodiol undergoes extensive enterohepatic recirculation. The serum half-life is approximately 100 hours.

With long-term daily administration, ursodiol constitutes 30–50% of the circulating bile acid pool. A small amount of unabsorbed conjugated or unconjugated ursodiol passes into the colon, where it is either excreted or undergoes dehydroxylation by colonic bacteria to lithocholic acid, a substance with potential hepatic toxicity.

Pharmacodynamics

The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin, and cholesterol. Although prolonged ursodiol therapy expands the bile acid pool, this does not appear to be the principal mechanism of action for dissolution of gallstones.

Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion. Ursodiol also appears to stabilize hepatocyte canalicular membranes, possibly through a reduction in the concentration of other endogenous bile acids or through inhibition of immunemediated hepatocyte destruction.

Clinical Use Ursodiol is used for dissolution of small cholesterol gallstones in patients with symptomatic gallbladder disease who refuse cholecystectomy or who are poor surgical candidates. At a dosage of 10 mg/kg/d for 12–24 months, dissolution occurs in up to 50% of patients with small (< 5–10 mm) noncalcified gallstones. It is also effective for the prevention of gallstones in obese patients undergoing rapid weight loss therapy. Several trials demonstrate that ursodiol 13–15 mg/kg/d is helpful for patients with early-stage primary biliary cirrhosis, reducing liver function abnormalities and improving liver histology.

Adverse Effects Ursodiol is practically free of serious adverse effects. Bile salt-induced diarrhea is uncommon. Unlike its predecessor, chenodeoxycholate, ursodiol has not been associated with hepatotoxicity.

DRUGS USED TO TREAT VARICEAL HEMORRHAGE Portal hypertension most commonly occurs as a consequence of chronic liver disease. Portal hypertension is caused by increased blood flow within the portal venous system and increased resistance to portal flow within the liver. Splanchnic blood flow is increased in patients with cirrhosis due to low arteriolar resistance that is mediated by increased circulating vasodilators and decreased vascular sensitivity to vasoconstrictors. Intrahepatic vascular resistance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins as well as reversible vasoconstriction of hepatic sinusoids and venules. Among the consequences of portal hypertension are ascites, hepatic encephalopathy, and the development of portosystemic collaterals—especially gastric or esophageal varices. Varices can rupture, leading to massive upper gastrointestinal bleeding.

Several drugs are available that reduce portal pressures. These may be used in the short term for the treatment of active variceal hemorrhage or long term to reduce the risk of hemorrhage.

SOMATOSTATIN & OCTREOTIDE The pharmacology of octreotide is discussed above under Antidiarrheal Agents. In patients with cirrhosis and portal hypertension, intravenous somatostatin (250 mcg/h) or octreotide (50 mcg/h) reduces portal blood flow and variceal pressures; the mechanism by which they do so is poorly understood. They do not appear to induce direct contraction of vascular smooth muscle. Their activity may be mediated through inhibition of release of glucagon and other gut peptides that alter mesenteric blood flow. Although data from clinical trials are conflicting, these agents are probably effective in promoting initial hemostasis from bleeding esophageal varices. They are generally administered for 3–5 days.

VASOPRESSIN & TERLIPRESSIN Vasopressin (antidiuretic hormone) is a polypeptide hormone secreted by the hypothalamus and stored in the posterior pituitary. Its pharmacology is discussed in Chapters 17 and 37. Although its primary physiologic role is to maintain serum osmolality, it is also a potent arterial vasoconstrictor. When administered intravenously by continuous infusion, vasopressin causes splanchnic arterial vasoconstriction that leads to reduced splanchnic perfusion and lowered portal venous pressures. Before the advent of octreotide, vasopressin was commonly used to treat acute variceal hemorrhage. However, because of its high adverse-effect profile, it is no longer used for this purpose. In contrast, for patients with acute gastrointestinal bleeding from small bowel or large bowel vascular ectasias or diverticulosis, vasopressin may be infused—to promote vasospasm—into one of the branches of the superior or inferior mesenteric artery through an angiographically placed catheter. Adverse effects with systemic vasopressin are common. Systemic and peripheral vasoconstriction can lead to hypertension, myocardial ischemia or infarction, or mesenteric infarction. These effects may be reduced by coadministration of nitroglycerin, which may further reduce portal venous pressures (by reducing portohepatic vascular resistance) and may also reduce the coronary and peripheral vascular vasospasm caused by vasopressin. Other common adverse effects are nausea, abdominal cramps, and diarrhea (due to intestinal hyperactivity). Furthermore, the antidiuretic effects of vasopressin promote retention of free water, which can lead to hyponatremia, fluid retention, and pulmonary edema.

Terlipressin is a vasopressin analog that appears to have similar efficacy to vasopressin with fewer adverse effects. Although this

agent is available in other countries, it has never been approved for use in the USA.

BETA-RECEPTOR-BLOCKING DRUGS The pharmacology of β-receptor-blocking agents is discussed in Chapter 10. Beta-receptor antagonists reduce portal venous pressures via a decrease in portal venous inflow. This decrease is due to a decrease in cardiac output (β 1 blockade) and to splanchnic vasoconstriction (β2 blockade) caused by the unopposed effect of systemic catecholamines on α receptors. Thus, nonselective β blockers such as propranolol and nadolol are more effective than selective β1 blockers in reducing portal pressures. Among patients with cirrhosis and esophageal varices who have not previously had an episode of variceal hemorrhage, the incidence of bleeding among patients treated with nonselective β blockers is 15% compared with 25% in control groups. Among patients with a history of variceal hemorrhage, the likelihood of recurrent hemorrhage is 80% within 2 years. Nonselective β blockers significantly reduce the rate of recurrent bleeding, although a reduction in mortality is unproved.

SUMMARY Drugs Used Primarily for Gastrointestinal Conditions

PREPARATIONS AVAILABLE

REFERENCES Acid-Peptic Diseases Alhazzani W et al: Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: A systematic review and metaanalysis. Crit Care Med 2013; 41:693.

Bredenoord AJ et al: Gastro-oesophageal reflux disease. Lancet 2013;381(9881):1933.

Chen J et al: Recent safety concerns with proton pump inhibitors. J Clin Gastroenterol 2012;46:93.

Chen J et al: Pharmacodynamic impacts of proton pump inhibitors on the efficacy of clopidogrel in vivoâ&#x20AC;&#x201D;A systematic review. Clin Cardiol 2013;356:184.

Chu S: Gastric secretion. Curr Opin Gastroenterol 2012;9:636.

Gerson L: Proton pump inhibitors and potential interactions with clopidogrel: An update. Curr Gastroenterol Rep 2013;15:329.

Kate V et al: Sequential therapy versus standard triple-drug therapy for Helicobacter pylori eradication: A systematic review of recent evidence. Drugs 2013;73:815.

Malfertheiner P et al: Management of Helicobacter pylori infectionâ&#x20AC;&#x201D;T he Maastricht IV/Florence Consensus report. Gut 2012;61:646.

Medlock S et al: Co-prescription of gastroprotective agents and their efficacy in elderly patients taking nonsteroidal anti-inflammatory drugs: A systematic review of observational studies. Clin Gastroenterol Hepatol 2013;11:1259.

Neumann I et al: Comparison of different regimens of proton pump inhibitors for acute peptic ulcer bleeding. Cochrane Database Syst Rev 2013;12:CD007999.

Sigterman KE et al: Short-term treatment with proton pump inhibitors, H2-receptor antagonists, and prokinetics for gastro-oesophageal reflux disease-like symptoms and endoscopy negative reflux disease. Cochrane Database Syst Rev 2013;5:CD002095.

T ang RS et al: T herapeutic management of recurrent peptic ulcer disease. Drugs 2012;72:1605.

Yang YX et al: Safety of proton pump inhibitor exposure. Gastroenterology 2010;139:1115.

Motility Disorders Camilleri M et al: Clinical guideline: Management of gastroparesis. Am J Gastroenterol 2013;108:18.

Enweluzo C et al: Gastroparesis: A review of current and emerging treatment options. Clin Exp Gastroenterol 2013;6:161.

Farmer AD: Diabetic gastroparesis: Pathophysiology, evaluation and management. Br J Hosp Med 2012;73:451.

Laxatives Bharucha AE et al: American Gastroenterological Association Medical Position Statement on constipation. Gastroenterology 2013;144:211.

Brock C et al: Opioid-induced bowel dysfunction: Pathophysiology and management. Drugs 2012;72:1847.

Ehrenpresis ED et al: Renal risks of sodium phosphate tablets for colonoscopy preparation: A review of adverse drug reactions reported to the US Food and Drug Administration. Colorect Dis 2011;13:e270.

Fleming JA et al: Split-dose picosulfate, magnesium oxide, and citric solution markedly enhances colon cleansing before colonoscopy: A randomized, controlled trial.

Gastrointest Endosc 2012;75:537.

Ford AC et al: Laxatives for chronic constipation in adults. BMJ 2012;345:e6168.

Gonzalez-Martinez MA et al: Novel pharmacological therapies for the management of chronic constipation. J Clin Gastroenterol 2014;48:21.

Hoy SM: Sodium picosulfate/magnesium citrate: A review of its use as a colorectal cleanser. Drugs 2009;69:123.

Kilgore T W et al: Bowel preparation with split-dose polyethylene glycol before colonoscopy: A meta-analysis of randomized controlled trials. Gastrointest Endosc 2011;73:1240.

Linaclotide (Linzess) for constipation. Med Lett Drugs T her 2012;54:91.

Rex DK et al: A randomized clinical study comparing reduced-volume oral sulfate solution with standard 4-liter sulfate-free electrolyte lavage solution as preparation for colonoscopy. Gastrointest Endosc 2010;72:328.

Schey R et al: Lubiprostone for the treatment of adults with constipation and irritable bowel syndrome. Dig Dis Sci 2011;56:1619.

Antidiarrheal Agents Kent AJ: Pharmacologic management of diarrhea. Gastroenterol Clin N Am 2010;39:496.

Li Z et al: T reatment of chronic diarrhea. Best Pract Clin Gastroenterol 2012;26:677.

Odunsi-Shiyanbade ST et al: Effects of chenodeoxycholate and a bile acid sequestrant, colesevelam, on intestinal transit and bowel function. Clin Gastroenterol Hepatol 2010;8:159.

Drugs Used for Irritable Bowel Syndrome Chey WD et al: Linaclotide for irritable bowel syndrome with constipation: A 26-week randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. Am J Gastroenterol 2012;107:1702.

Vazquez RM et al: Linaclotide, a synthetic guanylate cyclase C agonist, for the treatment of functional gastrointestinal disorders associated with constipation. Expert Rev Gastroenterol Hepatol 2011;5:301.

Wilkins T et al: Diagnosis and management of IBS in adults. Am Fam Phys 2012;86:419.

Antiemetic Agents Basch E et al: Antiemetics: American Society of Clinical Oncology Clinical Practice Guideline update. J Clin Oncol 2011;29:4189.

Ettinger DS et al: Antiemesis. J Natl Canc Comp Netw 2012;10: 456.

Hasketh PJ: Chemotherapy-induced nausea and vomiting. N Engl J Med 2008;358:2482.

Le T P et al: Update on the management of postoperative nausea and vomiting and postdischarge nausea vomiting in ambulatory surgery. Anesthesiol Clin 2010;28:225.

Drugs Used for Inflammatory Bowel Disease Baumgart D et al: Crohn’s disease. Lancet 2012;380:1590.

Bernstein CN et al: World Gastroenterology Organization Practice Guidelines for the diagnosis and management of IBD in 2010. Inflamm Bowel Dis 2010;16:112.

Bloomgren G et al: Risk of natalizumab-associated progressive multifocal leukoencephalopathy. N Engl J Med 2012;366:20.

Cheifetz AS et al: Management of active Crohn disease. JAMA 2013;309:2150.

Columbel JF et al: Infliximab, azathioprine, or combination therapy for Crohn’s disease. N Engl J Med 2010;362:1383.

Etchevers MJ et al: Optimizing the use of tumor necrosis factor inhibitors in Crohn’s disease: A practical approach. Drugs 2010;70:190.

Ford AC et al: Efficacy of biological therapies in inflammatory bowel disease: A systematic review and meta-analysis. Am J Gastroenterol 2011;106:644.

Ford A et al: Efficacy of oral vs. topical, or combined oral and topical 5-aminosalicylates in ulcerative colitis: A systematic review and meta-analysis. Am J Gastroenterol 2012;107:167.

Ford A et al: Ulcerative colitis. BMJ 2013;346:f432.

Kornbluth A et al: Ulcerative colitis guidelines in adults: American College of Gastroenterology, Practice Parameters Committee. Am J Gastroenterol 2010;105:501.

Mowat C et al: Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571.

Ordas I: Ulcerative colitis. Lancet 2012;380:1606.

Pola S et al: Strategies for the care of adults hospitalized for active ulcerative colitis. Clin Gastroenterol Hepatol 2012;10:1315.

Prefontaine E et al: Azathioprine or 6-mercaptopurine for induction of remission in Crohn’s disease. Cochrane Database Syst Rev 2010;16:CD000545.

Sandborn WJ et al: Adalimumab induces and maintains clinical remission in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2012;142:257.

Sandborn WJ et al: Subcutaneous golimumab induces clinical response and remission in patients with moderate to severe ulcerative colitis. Gastroenterology 2014;146:85.

Sandborn WJ et al: Subcutaneous golimumab maintains clinical response in patients with moderate-to-severe ulcerative colitis. Gastroenterology 2014;146:96.

Pancreatic Enzyme Supplements Forsmark C: Management of chronic pancreatitis. Gastroenterology 2013; 144:1282.

Whitcomb DC et al: Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: A double-blind randomized trial. Am J Gastroenterol 2010;105:2276.

Wier HA et al: Pancreatic enzyme supplementation. Curr Opin Pediatr 2011; 23:541.

Bile Acids for Gallstone Therapy Hempfling W, Dilger K, Beuers U: Systematic review: Ursodeoxycholic acid—Adverse effects and drug interactions. Aliment Pharmacol T her 2003;18:963.

Drugs for Portal Hypertension Ahmed ME: T reatment of portal hypertension. World J Gastroenterol 2012;18:1166.

Garcia-T sao G et al: Management of varices and variceal hemorrhage in cirrhosis. N Engl J Med 2010;362:823.

Drugs for Short Bowel Syndrome Buchman AL: T eduglutide and short bowel syndrome: Every night without parenteral fluids is a good night. Gastroenterology 2012;143:1416.

Jeppesen PB et al: T eduglutide reduces need for parenteral support among patients with short bowel syndrome with intestinal failure. Gastroenterology 2012;143:1473.

CASE STUDY ANSWER The immediate goals of therapy are to improve this young woman’s symptoms of abdominal pain, diarrhea, weight loss, and fatigue.

Equally important goals are to reduce the intestinal inflammation in hopes of preventing progression to intestinal stenosis, fistulization, and need for surgery. One option now is to step up her therapy by giving her a slow, tapering course of systemic corticosteroids (eg, prednisone) for 8–12 weeks in order to quickly bring her symptoms and inflammation under control while also initiating therapy with an immunomodulator (eg, azathioprine or mercaptopurine) in hopes of achieving long-term disease remission. If satisfactory disease control is not achieved within 3–6 months, therapy with an anti-TNF agent would then be recommended. Alternatively, patients with moderate-to-severe Crohn’s disease who have failed mesalamine may be treated upfront with both an anti-TNF agent and immunomodulators, which achieves higher remission rates than either agent alone and may improve long-term outcomes.

CHAPTER

63 Therapeutic & Toxic Potential of Over-the-Counter Agents Robin L. Corelli, PharmD

CASE STUDY A 66-year-old man presents to his primary care provider for worsening shortness of breath, chest congestion, and symptoms of a severe cold (cough, rhinorrhea, nasal congestion, drowsiness) over the past week. His past medical history is significant for heart failure, hypertension, and hyperlipidemia. His current medications include metoprolol succinate 50 mg daily, lisinopril 20 mg daily, atorvastatin 20 mg daily, furosemide 40 mg daily, and potassium chloride 20 mEq daily. The patient reports excellent compliance with his prescribed medications but admits to taking several over-the-counter (OTC) medications over the past 5 days for his recent cold symptoms, including Alka-Seltzer Plus Cold Formula (2 tablets every 4 hours during the day), Sudafed (60 mg every 6 hours), and Advil PM (2 tablets at bedtime). His social history is significant for alcohol use (3–4 beers/night). His vital signs include the following: afebrile, blood pressure 172/94 mm Hg, pulse 84 bpm, respiratory rate 16/min. On physical examination an S3 gallop is heard; 3+ pitting edema is noted in his lower extremities, and a chest examination reveals inspiratory rales bilaterally. What medications do OTC “cold” preparations typically contain? Which of the OTC medications might have contributed to the patient’s current hypertension? Are any of these preparations implicated in the signs of heart failure?

In the USA, medications are divided by law into two classes: those restricted to sale by prescription only and those for which directions for safe use by the public can be written. The latter category constitutes the nonprescription or over-the-counter (OTC) medications.

This category does not include supplements (vitamins, minerals, herbals, and botanicals), which are subject to different regulatory requirements (see Chapter 64). In 2013, the American public spent approximately 33.1 billion on OTC products to medicate themselves for ailments ranging from acne to warts. These products contain approximately 800 active ingredients in various forms and combinations.

It is apparent that many OTC medications are no more than “me too” products advertised to the public in ways that suggest significant differences between them. For example, there are over 100 different systemic analgesic products, almost all of which contain aspirin, acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, or a combination of these agents as primary ingredients. They are made different from one another by the addition of questionable ingredients such as caffeine or antihistamines; by brand names chosen to suggest a specific use or strength (“women’s,” “migraine,” “arthritis,” “maximum”); or by special dosage formulations (enteric-coated tablets, geltabs, liquids, orally disintegrating strips and tablets, sustained-release products, powders, seltzers).

There is a price attached to all of these features, and in most cases a less expensive generic product can be equally effective. It is probably safe to assume that the public is generally overwhelmed and confused by the wide array of products presented and will probably use those that are most heavily advertised.

Over the past four decades the FDA has been engaged in a methodical review of OTC ingredients for both safety and efficacy.

There have been two major outcomes of this review: (1) Ingredients designated as ineffective or unsafe for their claimed therapeutic use are being eliminated from OTC product formulations (eg, antimuscarinic agents have been eliminated from OTC sleep aids, attapulgite and polycarbophil can no longer be marketed as OTC antidiarrheal products); and (2) agents previously available by prescription only have been made available for OTC use because they were judged by the review panel to be generally safe and effective for consumer use without medical supervision (Table 63–1). The prescription-to-OTC switch process has significantly enhanced and expanded selfcare options for US consumers. Indeed, more than 100 OTC active ingredients or dosages are on the market today that were available only by prescription less than 40 years ago. Some agents such as docosanol and the nicotine polacrilex lozenge have bypassed the prescription route altogether and have been released directly to the OTC market. Other OTC ingredients previously available in low doses only are now available in higher-strength or original prescription strength formulations. Examples of other prescription medications with the potential for future OTC reclassification include oral contraceptives, nicotine replacement therapy (oral inhaler, nasal spray) for smoking cessation, proton-pump inhibitors (pantoprazole) for heartburn, and second-generation nonsedating antihistamines (desloratadine, levocetirizine) for relief of allergy and cold symptoms. The frequency of prescription-to-OTC switches, while commonplace in the mid-

1990s, has largely declined over the past decade. The prescription-to-OTC reclassification process is both costly and rigorous and fewer prescription medications are appropriate candidates for a switch (eg, a consumer can self-diagnose and safely treat the condition). For example, the cholesterol-lowering agents lovastatin and pravastatin were denied OTC status on the basis that these agents could not be used safely and effectively in an OTC setting. The nonprescription drug advisory committee believed that diagnosis and ongoing management by a health care professional was necessary for the management of hyperlipidemia, a chronic, asymptomatic condition with potentially life-threatening consequences. In a similar recommendation, oral acyclovir for OTC use in the treatment of recurrent genital herpes was not approved because of concerns about misdiagnosis and inappropriate use leading to increased viral resistance.

TABLE 63â&#x20AC;&#x201C;1 Selected agents switched from prescription to OTC status by the Food and Drug Administration.

There are three reasons why it is essential for clinicians to be familiar with the OTC class of products. First, many OTC medications are effective in treating common ailments, and it is important to be able to help the patient select a safe, effective product. Because managed-care practices encourage clinicians to reduce costs, many will recommend effective OTC treatments to their patients, since these medications are rarely paid for by health plans (Table 63â&#x20AC;&#x201C;2). Second, many of the active ingredients contained in OTC medications may worsen existing medical conditions or interact with prescription medications. (See Chapter 66, Important Drug Interactions & Their Mechanisms.) Finally, the misuse or abuse of OTC products may actually produce significant medical complications.

Phenylpropanolamine, for example, a sympathomimetic previously found in many cold, allergy, and weight control products, was withdrawn from the US market by the FDA based on reports that the drug increased the risk of hemorrhagic stroke. Dextromethorphan, an antitussive found in many cough and cold preparations, has been increasingly abused in high doses (eg, > 5â&#x20AC;&#x201C;10 times the recommended antitussive dose) by adolescents as a hallucinogen. Although severe complications associated with dextromethorphan as a single agent in overdose are uncommon, many dextromethorphan-containing products are formulated with other ingredients (acetaminophen, antihistamines, and sympathomimetics) that can be fatal in overdose. Additionally, pseudoephedrine, a decongestant contained in numerous OTC cold preparations, has been used in the illicit manufacture of methamphetamine. A general awareness of these products and their formulations will enable clinicians to more fully appreciate the potential for OTC medication-related problems in their patients.

TABLE 63â&#x20AC;&#x201C;2 Ingredients of known efficacy for selected OTC classes.

Table 63â&#x20AC;&#x201C;2 lists examples of OTC products that may be used effectively to treat common medical problems. The selection of one ingredient over another may be important in patients with certain medical conditions or in patients taking other medications. These are discussed in detail in other chapters. The recommendations listed in Table 63â&#x20AC;&#x201C;2 are based on the efficacy of the ingredients and on the principles set forth in the following paragraphs.

1. Select the product that is simplest in formulation with regard to ingredients and dosage form. In general, single-ingredient products are preferred. Although some combination products contain effective doses of all ingredients, others contain therapeutic doses of some ingredients and subtherapeutic doses of others. Furthermore, there may be differing durations of action among the ingredients, and there is always a possibility that the clinician or patient is unaware of the presence of certain active ingredients in the product.

Acetaminophen, for example, is in many cough and cold preparations; a patient unaware of this may take separate doses of analgesic in addition to that contained in the cold preparation, potentially leading to hepatotoxicity.

2. Select a product that contains a therapeutically effective dose.

3. Consumers and providers should carefully read the “Drug Facts” label to determine which ingredients are appropriate based on the patient’s symptoms, underlying health conditions, and whatever is known about the medications the patient is already taking. This is critical because many products with the same brand name contain different ingredients that are labeled for different uses. For example, multiple products (with different active ingredients) carry the Allegra name including Allegra Allergy (fexofenadine), Allegra-D (fexofenadine and pseudoephedrine), and Allegra Anti-Itch Cream (allantoin and diphenhydramine). This marketing practice of “extending a brand name” across product lines, while legal, is confusing and can lead to medication errors.

4. Recommend a generic product if one is available.

5. Be wary of “gimmicks” or advertising claims of specific superiority over similar products.

6. For children, the dose, dosage form, and palatability of the product are prime considerations.

Certain ingredients in OTC products should be avoided or used with caution in selected patients because they may exacerbate existing medical problems or interact with other medications the patient is taking. Many of the more potent OTC ingredients are hidden in products where their presence would not ordinarily be expected (Table 63–3). Although OTC medications have standardized label formatting and content requirements that specify the indications for use, dosage, warnings, and active and inactive ingredients contained in the product, many consumers do not carefully read or comprehend this information. Lack of awareness of the ingredients in OTC products and the belief by many providers that OTC products are ineffective and harmless may cause diagnostic confusion and perhaps interfere with therapy. For example, innumerable OTC products, including analgesics and allergy, cough, and cold preparations, contain sympathomimetics. These agents should be avoided or used cautiously by type 1 diabetics and patients with hypertension, angina, or hyperthyroidism. Aspirin should not be used in children and adolescents for viral infections (with or without fever) because of an increased risk of Reye’s syndrome. Aspirin and other NSAIDs should be avoided by individuals with active peptic ulcer disease, certain platelet disorders, and patients taking oral anticoagulants. Cimetidine, an H2 -receptor antagonist, is a well-known inhibitor of hepatic drug metabolism and can increase the blood levels and toxicity of agents such as phenytoin, theophylline, and warfarin.

Overuse or misuse of OTC products may induce significant medical problems. A prime example is rebound congestion from the regular use of decongestant nasal sprays for more than 3 days. The improper and long-term use of some antacids (eg, aluminum hydroxide) may cause constipation and even impaction in elderly people, as well as hypophosphatemia. Laxative abuse can result in abdominal cramping and fluid and electrolyte disturbances. Insomnia, nervousness, and restlessness can result from the use of sympathomimetics or caffeine hidden in many OTC products (Table 63–3). The long-term use of some analgesics containing large amounts of caffeine may produce rebound headaches, and long-term use of analgesics has been associated with interstitial nephritis.

OTC products containing aspirin, other salicylates, acetaminophen, ibuprofen, or naproxen may increase the risk of hepatotoxicity and gastrointestinal hemorrhage in individuals who consume three or more alcoholic drinks daily. Recent evidence suggests the long-term use of certain NSAIDs may increase the risk of heart attack or stroke. Furthermore, acute ingestion of large amounts of acetaminophen by adults or children can cause serious, and often fatal, hepatotoxicity. Antihistamines may cause sedation or drowsiness, especially when taken concurrently with sedative-hypnotics, tranquilizers, alcohol, or other central nervous system depressants. Antihistamines and other substances contained in OTC topical and vaginal products may induce allergic reactions.

TABLE 63–3 Hidden ingredients in OTC products.

Finally, use of OTC cough and cold preparations in the pediatric population has been under scrutiny by the FDA based on a lack of efficacy data in children less than 12 years of age and reports of serious toxicity in children. Following a thorough review, the FDA recommends that OTC cough and cold agents (eg, products containing antitussives, expectorants, decongestants, and antihistamines) not be used in infants and children younger than 2 years due to serious and potentially life-threatening adverse events associated with accidental overdose including arrhythmias, hallucinations, and encephalopathy. Further safety reviews by the FDA regarding the use of these agents in children between the ages of 2 and 11 years are ongoing.

There are three major drug information sources for OTC products. Handbook of Nonprescription Drugs is the most comprehensive resource for OTC medications; it evaluates ingredients contained in major OTC drug classes and lists the ingredients included in many OTC products. Nonprescription Drug Therapy is an online reference that is updated monthly; it provides detailed OTC product information and patient counseling instructions. Physicians’ Desk Reference for Nonprescription Drugs , a compendium of manufacturers’ information regarding OTC products, is published annually but is somewhat incomplete with regard to the number of products included. Any health care provider who seeks more specific information regarding OTC products may find useful the references listed below.

REFERENCES Conca AJ, Worthen DR: Nonprescription drug abuse. J Pharm Pract 2012;25:13.

Consumer Healthcare Products Association website: http://www.chpa.org/.

Handbook of Nonprescription Drugs, 17th ed. American Pharmacists Association, 2011.

Nonprescription Drug Therapy. Facts and Comparisons Clinical eAnswers (online). Wolters Kluwer Health, 2014.

Physicians’ Desk Reference for Nonprescription Drugs, 35th ed. T homson Healthcare, 2014.

US Food and Drug Administration website. FDA Approved Drug Products: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm.

CASE STUDY ANSWER OTC cold medications typically contain antihistamines (eg, brompheniramine, chlorpheniramine, diphenhydramine), antitussives (eg, dextromethorphan), expectorants (eg, guaifenesin), and nasal decongestants (eg, phenylephrine, pseudoephedrine). Systemic nasal decongestants (contained in Alka-Seltzer and Sudafed) stimulate α 1 -adrenoceptors and may raise blood pressure through direct vasoconstrictor effects. Additionally, NSAIDs (such as ibuprofen, contained in Advil PM) increase blood pressure and may reduce the effectiveness of antihypertensive agents. NSAIDs may also exacerbate heart failure through increased fluid retention and elevated blood pressure. Alka-Seltzer cold preparations should be avoided in patients with heart failure due to the high sodium content, which can lead to fluid retention. The sodium content in one dose of Alka-Seltzer Plus cold medicine (948 mg/dose) provides more than half of the maximum recommended daily sodium allowance for patients with heart failure.

CHAPTER

64 Dietary Supplements & Herbal Medications* Cathi E. Dennehy, PharmD, & Candy Tsourounis, PharmD

CASE STUDY A 65-year-old man with a history of coronary artery disease, high cholesterol, type 2 diabetes, and hypertension presents with a question about a dietary supplement. He is in good health, exercises regularly, and eats a low-fat, low-salt diet. His most recent laboratory values show that his low-density lipoprotein (LDL) cholesterol is still slightly above goal at 120 mg/dL (goal < 100 mg/dL) and his hemoglobin A 1c is well controlled at 6%. His blood pressure is also well controlled. His medications include simvastatin, metformin, benazepril, and aspirin. He also regularly takes a vitamin B-complex supplement and coenzyme Q10. He asks you if taking a garlic supplement could help to bring his LDL cholesterol down to less than 100 mg/dL. What are two rationales for why he might be using a coenzyme Q10 supplement? Are there any supplements that could increase bleeding risk if taken with aspirin?

The medical use of plants in their natural and unprocessed form undoubtedly began when the first intelligent animals noticed that certain food plants altered particular body functions. While there is a great deal of historical information about the use of plant-based supplements, there is also much unreliable information from poorly designed clinical studies that do not account for randomization errors, confounders, and—most importantly—a placebo effect that can contribute 30–50% of the observed response. Since the literature surrounding dietary supplements is evolving, reputable evidence-based resources should be used to evaluate claims and guide treatment decisions. An unbiased and regularly updated compendium of basic and clinical reports regarding botanicals is Pharmacist’s Letter/Prescriber’s Letter Natural Medicines Comprehensive Database (see References). Another evidence-based resource is Natural Standard, which includes an international, multi-disciplinary collaborative website, http://www.naturalstandard.com. The recommendations in this database are limited by the quality of the existing research available for each dietary supplement ingredient.

(These two sources may be combined in the near future.) As a result, all statements regarding positive benefits should be regarded as preliminary and conclusions regarding safety should be considered tentative at this time.

For legal purposes, “dietary supplements” are distinguished from “prescription drugs” derived from plants (morphine, digitalis, atropine, etc) by virtue of being available without a prescription and, unlike “over-the-counter medications,” are legally considered dietary supplements rather than drugs. This distinction eliminates the need for proof of efficacy and safety prior to marketing and also places the burden of proof on the FDA to prove that a supplement is harmful before its use can be restricted or removed from the market.

Furthermore, marketed dietary supplements are not tested for dose-response relationships or toxicity and there is a lack of adequate testing for mutagenicity, carcinogenicity, and teratogenicity. Although manufacturers are prohibited from marketing unsafe or ineffective products, the FDA has met significant challenges from the supplement industry largely due to the strong lobbying effort by supplement manufacturers and the variability in interpretation of the Dietary Supplement Health and Education Act (DSHEA). The DSHEA defines dietary supplements as vitamins, minerals, herbs or other botanicals, amino acids or dietary supplements used to supplement the diet by increasing dietary intake, or concentrates, metabolites, constituents, extracts, or any combination of these ingredients. For the purposes of this chapter, plant-based substances and certain synthetic purified chemicals will be referred to as dietary supplements. Among the purified chemicals, glucosamine, coenzyme Q10, and melatonin are of significant pharmacologic interest.

This chapter provides some historical perspective and describes the evidence provided by randomized, double-blind, placebocontrolled trials, meta-analyses, and systematic reviews involving several of the most commonly used agents in this class. Ephedrine, the active principle in Ma-huang, is discussed in Chapter 9.

HISTORICAL & REGULATORY FACTORS Under the DSHEA, dietary supplements are not considered over-the-counter drugs in the USA but rather food supplements used for

health maintenance. Legally, dietary supplements are intended to supplement the diet, but consumers may use them in the same fashion as drugs and even use them in place of drugs or in combination with drugs.

In 1994, the U.S. Congress, influenced by growing “consumerism” as well as strong manufacturer lobbying efforts, passed the DSHEA. The DSHEA required the establishment of Good Manufacturing Practice (GMP) standards for the supplement industry; however, it was not until 2007 that the FDA issued a final rule on the proposed GMP standards. This 13-year delay allowed supplement manufacturers to self-regulate the manufacturing process and resulted in many instances of adulteration, misbranding, and contamination.

For example, a recent study using DNA barcoding to confirm botanical content evaluated 44 botanicals containing 30 plant species and found product substitutions in 32% of samples (see Newmaster reference). Therefore, much of the criticism regarding the dietary supplement industry involves problems with botanical misidentification, a lack of product purity, and variations in potency and purification, which continue to be problematic even with GMP standards in place. When the new GMP standards are met, dietary supplement manufacturers should be in compliance with this legislation. However, the FDA has limited resources to investigate and oversee compliance with manufacturing standards, particularly since many ingredient suppliers are based overseas. Furthermore, the dietary supplement ingredient supply chain is complex and federal regulators are not able to inspect all manufacturing facilities in a timely and efficient manner.

Because of the problems that resulted from self-regulation, another law, the Dietary Supplement and Non-Prescription Drug Consumer Protection Act, was approved in 2006. This law requires manufacturers, packers, or distributors of supplements to submit reports of serious adverse events to the FDA. Serious adverse events are defined as death, a life-threatening event, hospitalization, a persistent or significant disability or incapacity, congenital anomaly or birth defect, or an adverse event that requires medical or surgical intervention to prevent such outcomes based on reasonable medical judgment. These reports are intended to identify trends in adverse effects and would help to alert the public to safety issues.

CLINICAL ASPECTS OF THE USE OF BOTANICALS Many U.S. consumers have embraced the use of dietary supplements as a “natural” approach to their health care. Unfortunately, misconceptions regarding safety and efficacy of the agents are common, and the fact that a substance can be called “natural” does not of course guarantee its safety. In fact, botanicals may be inherently inert or toxic. If a manufacturer does not follow GMP this can also result in intentional or unintentional plant species substitutions (eg, misidentification), adulteration with pharmaceuticals, or contamination.

Adverse effects have been documented for a variety of dietary supplements; however, under-reporting of adverse effects is likely since consumers do not routinely report, and do not know how to report an adverse effect if they suspect that the event was caused by consumption of a supplement. Furthermore, chemical analysis is rarely performed on the products involved, including those products that are described in the literature as being linked to an adverse event. This leads to confusion about whether the primary ingredient or an adulterant caused the adverse effect. In some cases, the chemical constituents of the herb can clearly lead to toxicity. Some of the herbs that should be used cautiously or not at all are listed in Table 64–1.

TABLE 64–1 Various supplements and some associated risks.

An important risk factor in the use of dietary supplements is the lack of adequate testing for drug interactions. Since botanicals may contain hundreds of active and inactive ingredients, it is very difficult and costly to study potential drug interactions when they are combined with other medications. This may present significant risks to patients.

BOTANICAL SUBSTANCES ECHINACEA (ECHINACEA PURPUREA) Chemistry The three most widely used species of Echinacea are Echinacea purpurea, E pallida, and E angustifolia. The chemical constituents include flavonoids, lipophilic constituents (eg, alkamides, polyacetylenes), water-soluble polysaccharides, and water-soluble caffeoyl conjugates (eg, echinacoside, cichoric acid, caffeic acid). Within any marketed echinacea formulation, the relative amounts of these components are dependent upon the species used, the method of manufacture, and the plant parts used. E purpurea, the purple coneflower, has been the most widely studied in clinical trials. Although the active constituents of echinacea are not completely known, cichoric acid from E purpurea and echinacoside from E pallida and E angustifolia, as well as alkamides and polysaccharides, are most often noted as having immune-modulating properties. Most commercial formulations, however, are not standardized for any particular constituent.

Pharmacologic Effects 1. Immune modulation—The effect of echinacea on the immune system is controversial. In vivo human studies using commercially marketed formulations of E purpurea have shown increased phagocytosis, total circulating monocytes, neutrophils, and natural killer cells, indicative of general immune modulation. In vitro, a standardized ethanol extract of the aerial (above-ground) parts of E purpurea, known as Echinaforce, inhibited the rise in pro-inflammatory cytokines and interleukins-6 and -8, and also inhibited mucin secretion caused by exposure to rhinovirus type 1A in a 3D tissue model of human airway epithelium. This type of model is intended to mimic what would be seen in vivo. The extract had no effect on cytokine actions.

2. Anti-inflammatory effects—Certain echinacea constituents have demonstrated anti-inflammatory properties in vitro. Inhibition of cyclooxygenase, 5-lipoxygenase, and hyaluronidase may be involved. In animals, application of E purpurea prior to application of a topical irritant reduced both paw and ear edema. Despite these laboratory findings, randomized, controlled clinical trials involving echinacea for wound healing have not been performed in humans.

3. Antibacterial, antifungal, antiviral, and antioxidant effects—In vitro studies have reported some antibacterial, antifungal, antiviral, and antioxidant activity with echinacea constituents. For example, Echinaforce demonstrated virucidal activity (MIC100 < 1 μg/mL) against influenza and herpes simplex viruses and bactericidal activity against Streptococcus pyogenes, Haemophilus influenzae, and Legionella pneumophila in human bronchial cells. In vitro, Echinaforce inactivated both avian influenza virus (H5N1, H7N7) and swineorigin influenza virus (H1N1) at doses consistent with recommended oral consumption. The extract blocked key steps (ie, viral hemagglutination activity and neuraminidase activity in vitro) involved in early virus replication and cellular entry. It was less effective against intracellular virus. Newer in vitro research in human skin fibroblasts also suggests bactericidal activity and inhibition of secretion of inflammatory cytokines produced by Propionibacterium acnes with Echinaforce.

Clinical Trials Echinacea is most often used to enhance immune function in individuals who have colds and other respiratory tract infections. Two reviews have assessed the efficacy of echinacea for this primary indication. A review by the Cochrane Collaboration involved 24 randomized, double-blind trials with 33 comparisons of Echinacea mono-preparations and placebo. Trials were included if they involved echinacea for cold treatment or prevention, where the primary efficacy outcome was cold incidence in prevention trials and duration of symptoms in treatment trials. Overall, the review did not find significant evidence of benefit for Echinacea (among all species) in treating colds. Preparations made from the aerial parts of E purpurea plants and prepared as alcoholic extracts or pressed juices were discussed as possibly being preferred to other formulations for cold treatment in adults, but still having a weak overall treatment effect. In prevention trials, pooling results suggested a small relative risk reduction in development of 10–20%, but no statistically significant benefit within individual trials.

A separate meta-analysis involving 14 randomized, placebo-controlled trials of echinacea for cold treatment or prevention was published in Lancet. In this review, echinacea decreased the risk of developing clear signs and symptoms of a cold by 58% and decreased symptom duration by 1.25 days. This review, however, was confounded by the inclusion of four clinical trials involving multiingredient echinacea preparations, as well as three studies using rhinovirus inoculation versus natural cold development.

Echinacea has been used investigationally to enhance hematologic recovery following chemotherapy. It has also been used as an adjunct in the treatment of urinary tract and vaginal fungal infections. These indications require further research before they can be accepted in clinical practice. E purpurea is ineffective in treating recurrent genital herpes.

Adverse Effects Adverse effects with oral commercial formulations are minimal and most often include unpleasant taste, gastrointestinal upset, or rash. In one large clinical trial, pediatric patients using an oral echinacea product were significantly more likely to develop a rash than those taking placebo.

Drug Interactions & Precautions Until the role of echinacea in immune modulation is better defined, this agent should be avoided in patients with immune deficiency disorders (eg, AIDS, cancer), or autoimmune disorders (eg, multiple sclerosis, rheumatoid arthritis). While there are no reported drug interactions for echinacea, in theory, it should also be avoided in persons taking immunosuppressant medications (eg, organ transplant recipients).

Dosage It is recommended to follow the dosing on the package label, as there may be variations in dose based on the procedure used in product manufacture. Standardized preparations made from the aerial parts of E purpurea (Echinaforce, Echinaguard) as an alcoholic extract or fresh pressed juice may be preferred in adults for common cold treatment if taken within the first 24 hours of cold symptoms. It should not be used on a continuous basis for longer than 10–14 days.

GARLIC (ALLIUM SATIVUM) Chemistry The pharmacologic activity of garlic involves a variety of organosulfur compounds. Dried and powdered formulations contain many of the compounds found in raw garlic and will usually be standardized to allicin or alliin content. Allicin is responsible for the characteristic odor of garlic, and alliin is its chemical precursor. Dried powdered formulations are often enteric-coated to protect the enzyme allinase (the enzyme that converts alliin to allicin) from degradation by stomach acid. Aged garlic extract has also been studied in clinical trials, but to a lesser degree than dried, powdered garlic. Aged garlic extract contains no alliin or allicin and is odor-free. Its primary constituents are water-soluble organosulfur compounds, and packages may carry standardization to the compound S-allylcysteine.

Pharmacologic Effects 1. Cardiovascular effects—In vitro, allicin and related compounds inhibit HMG-CoA reductase, which is involved in cholesterol biosynthesis (see Chapter 35), and exhibit antioxidant properties. Several clinical trials have investigated the lipid-lowering potential of garlic. A meta-analysis by Reinhart and colleagues involved 29 randomized, double-blind, placebo-controlled trials and found a small but significant reduction in both total cholesterol (−0.19 mmol/L, 6 mg/dL) and triglycerides (−0.011 mmol/L, 1.1 mg/dL), but no effect on low- (LDL) or high-density lipoproteins (HDL). A more recent meta-analysis of 26 randomized, double-blind, placebo-controlled trials found a significant reduction in total cholesterol (−0.28 mmol/L, 9.3 mg/dL) for garlic compared with placebo. No impact on LDL or HDL was observed. Trials of longer duration (> 12 weeks) showed a greater reduction in total cholesterol and triglycerides as compared to trials of shorter duration (0–4 weeks), with garlic powder and aged garlic extract formulations having the greatest benefit.

Cumulatively, these data suggest a small but significant benefit of garlic in lowering total cholesterol and triglycerides. The lack of change in HDL and LDL indicate that garlic is unlikely to be clinically relevant, however, in benefiting patients with hyperlipidemia.

Clinical trials report antiplatelet effects (possibly through inhibition of thromboxane synthesis or stimulation of nitric oxide synthesis) following garlic ingestion. A majority of human studies also suggest enhancement of fibrinolytic activity. These effects in combination with antioxidant effects (eg, increased resistance to LDL oxidation) and reductions in total cholesterol might be beneficial in patients with atherosclerosis. A randomized, controlled trial among persons with advanced coronary artery disease who consumed dried powdered garlic for 4 years showed significant reductions in secondary markers (plaque accumulation in the carotid and femoral arteries) as compared with placebo, but primary end points (death, stroke, myocardial infarction) were not assessed.

Garlic constituents may affect blood vessel elasticity and blood pressure. Various mechanisms have been proposed. There have been a limited number of randomized, controlled trials in humans for this indication. Ten trials were included in a systematic review and metaanalysis that found no effect on systolic or diastolic pressure in patients without elevated systolic blood pressure but a significant reduction in systolic and diastolic pressure among the three trials involving patients with elevated systolic blood pressure. A Cochrane

review on the effect of garlic monotherapy for prevention of cardiovascular morbidity and mortality in hypertensive patients identified a small number of randomized, controlled trials for inclusion. Although the trials lacked outcomes to assess an impact on cardiovascular events, the review did identify a significant reduction in systolic and diastolic pressure compared with placebo. A separate Cochrane review of the effect of garlic on peripheral occlusive disease found insufficient support for this indication.

2. Endocrine effects—The effect of garlic on glucose homeostasis does not appear to be significant in persons with diabetes. Certain organosulfur constituents in garlic, however, have demonstrated hypoglycemic effects in nondiabetic animal models.

3. Antimicrobial effects—The antimicrobial effect of garlic has not been extensively studied in clinical trials. Allicin has been reported to have in vitro activity against some gram-positive and gram-negative bacteria as well as fungi (Candida albicans), protozoa (Entamoeba histolytica), and certain viruses. The primary mechanism involves the inhibition of thiol-containing enzymes needed by these microbes. Given the availability of safe and effective prescription antimicrobials, the usefulness of garlic in this area appears limited.

4. Antineoplastic effects—In rodent studies, garlic inhibits procarcinogens for colon, esophageal, lung, breast, and stomach cancer, possibly by detoxification of carcinogens and reduced carcinogen activation. Several epidemiologic case-control studies demonstrate a reduced incidence of stomach, esophageal, and colorectal cancers in persons with high dietary garlic consumption. Current anti-cancer studies are focused on specific organosulfur garlic compounds in in vivo animal models of cancer, and in vitro effects on human cancer cell lines.

Adverse Effects Following oral ingestion, adverse effects of garlic products may include nausea (6%), hypotension (1.3%), allergy (1.1%), and bleeding (rare). Breath and body odor have been reported with an incidence of 20–40% at recommended doses using enteric-coated powdered garlic formulations. Contact dermatitis may occur with the handling of raw garlic.

Drug Interactions & Precautions Because of reported antiplatelet effects, patients using anticlotting medications (eg, warfarin, aspirin, ibuprofen) should use garlic cautiously. Additional monitoring of blood pressure and signs and symptoms of bleeding is warranted. Garlic may reduce the bioavailability of saquinavir, an antiviral protease inhibitor, but it does not appear to affect the bioavailability of ritonavir.

Dosage Dried, powdered garlic products should be standardized to contain 1.3% alliin (the allicin precursor) or have an allicin-generating potential of 0.6%. Enteric-coated formulations are recommended to minimize degradation of the active substances. A daily dose of 600–900 mg/d of powdered garlic is most common. This is equivalent to one clove of raw garlic (2–4 g) per day. A garlic bulb can contain up to 1.8% alliin.

GINKGO (GINKGO BILOBA) Chemistry Ginkgo biloba extract is prepared from the leaves of the ginkgo tree. The most common formulation is prepared by concentrating 50 parts of the crude leaf to prepare one part of extract. The active constituents in ginkgo are flavone glycosides and terpenoids including ginkgolides A, B, C, J, and bilobalide.

Pharmacologic Effects 1. Cardiovascular effects—In animal models and some human studies, ginkgo has been shown to increase blood flow, reduce blood viscosity, and promote vasodilation, thus enhancing tissue perfusion. Enhancement of endogenous nitric oxide effects (see Chapter 19) and antagonism of platelet-activating factor have been observed in animal models.

Ginkgo biloba has been studied for its effects on mild to moderate occlusive peripheral arterial disease. Among 11 randomized, placebo-controlled studies involving 477 participants using standardized ginkgo leaf extract (EGb761) for up to 6 months, a nonsignificant trend toward improvements in pain-free walking distance (increase of 64.5 meters) was observed (p = .06). The authors concluded that the standardized extract lacked benefit for this indication.

The Ginkgo Evaluation of Memory (GEM) study and the recently published GuidAge study evaluated cardiovascular outcomes as

well as incidence and mean time to Alzheimer’s dementia associated with the long-term use of ginkgo for 5–6 years in approximately 3000 elderly (age 70 or older) adults with normal cognition or mild cognitive impairment. Daily use of 240 mg/d EGb761 did not affect the incidence of hypertension or reduce blood pressure among persons with hypertension or prehypertension. No significant effects in cardiovascular disease mortality, ischemic stroke or events, or hemorrhagic stroke were observed.

2. Metabolic effects—Antioxidant and radical-scavenging properties have been observed for the flavonoid fraction of ginkgo as well as some of the terpene constituents. In vitro, ginkgo has been reported to have superoxide dismutase-like activity and superoxide anion- and hydroxyl radical-scavenging properties. The flavonoid fraction has also been observed to have anti-apoptotic properties. In some studies, it has also demonstrated a protective effect in limiting free radical formation in animal models of ischemic injury and in reducing markers of oxidative stress in patients undergoing coronary artery bypass surgery.

3. Central nervous system effects—In aged animal models, chronic administration of ginkgo for 3–4 weeks led to modifications in central nervous system receptors and neurotransmitters. Receptor densities increased for muscarinic, α2 , and 5-HT1a receptors, and decreased for β adrenoceptors. Increased serum levels of acetylcholine and norepinephrine and enhanced synaptosomal reuptake of serotonin have also been reported. Additional effects include reduced corticosterone synthesis and inhibition of amyloid-beta fibril formation.

Ginkgo has been used to treat cerebral insufficiency and dementia of the Alzheimer type. The term cerebral insufficiency, however, includes a variety of manifestations ranging from poor concentration and confusion to anxiety and depression as well as physical complaints such as hearing loss and headache. For this reason, studies evaluating cerebral insufficiency tend to be more inclusive and difficult to assess than trials evaluating dementia. A meta-analysis of ginkgo for cognitive impairment or dementia was performed by the Cochrane Collaboration. They reviewed 36 randomized, double-blind, placebo-controlled trials ranging in length from 3 to 52 weeks.

Significant improvements in cognition and activities of daily living were observed at 12 but not 24 weeks. Significant improvements in clinical global improvement, however, were observed at 24 but not 12 weeks. The authors concluded that the effects of ginkgo in the treatment of cognitive impairment and dementia were unpredictable and unlikely to be clinically relevant.

A separate meta-analysis of nine randomized, double-blind trials (eight placebo-controlled and one comparative trial to donepezil) using EGb761 for 12–52 weeks limited inclusion criteria to patients with dementia of the Alzheimer, vascular, or mixed dementia type.

Significant improvements in cognition were observed for all dementia patients and significant improvements in cognition and activities of daily living were observed for patients with dementia of the Alzheimer type receiving ginkgo compared with placebo. This suggests that patients with a diagnosis of dementia are more likely to benefit than patients with more mild cognitive impairment.

In the GEM and GuidAge studies, the effects of gingko as a prophylactic agent to prevent progression to dementia were assessed.

No benefit was observed with 5–6 years of ginkgo treatment.

4. Miscellaneous effects—Ginkgo has been studied for its effects in allergic and asthmatic bronchoconstriction, short-term memory in healthy, nondemented adults, erectile dysfunction, tinnitus and hearing loss, and macular degeneration. There is insufficient evidence to warrant clinical use for any of these conditions.

Adverse Effects Adverse effects have been reported with a frequency comparable to that of placebo. These include nausea, headache, stomach upset, diarrhea, allergy, anxiety, and insomnia. A few case reports noted bleeding complications in patients using ginkgo. In a few of these cases, the patients were also using either aspirin or warfarin.

Drug Interactions & Precautions Ginkgo may have antiplatelet properties and should not be used in combination with antiplatelet or anticoagulant medications. Other single case reports noted virologic failure when ginkgo was combined with efavirenz, sedation when combined with trazodone, priapism when combined with risperidone, and seizure when combined with valproic acid and phenytoin; all warrant further pharmacokinetic studies before firm conclusions can be drawn. Seizures have been reported as a toxic effect of ginkgo, most likely related to seed contamination in the leaf formulations. Uncooked ginkgo seeds are epileptogenic due to the presence of ginkgotoxin. Ginkgo formulations should be avoided in individuals with preexisting seizure disorders.

Dosage Ginkgo biloba dried leaf extract is usually standardized to contain 24% flavone glycosides and 6% terpene lactones. The daily dose ranges from 120 to 240 mg of the dried extract in two or three divided doses.

GINSENG

Chemistry Ginseng may be derived from any of several species of the genus Panax. Of these, crude preparations or extracts of Panax ginseng, the Chinese or Korean variety, and P quinquefolium, the American variety, are most often available to consumers in the United States.

The active principles appear to be the triterpenoid saponin glycosides called ginsenosides or panaxosides, of which there are approximately 30 different types. It is recommended that commercial P ginseng formulations be standardized to contain 4–10% ginsenosides.

Other plant materials are commonly sold under the name ginseng but are not from Panax species. These include Siberian ginseng (Eleutherococcus senticosus) and Brazilian ginseng (Pfaffia paniculata). Of these, Siberian ginseng may be more widely available in the USA. Siberian ginseng contains eleutherosides but no ginsenosides. Currently, there is no recommended standardization for eleutheroside content in Siberian ginseng products.

Pharmacologic Effects An extensive literature exists on the potential pharmacologic effects of ginsenosides. Unfortunately, the studies differ widely in the species of Panax used, the ginsenosides studied, the degree of purification applied to the extracts, the animal species studied, the doses or concentrations involved, and the measurements used to evaluate the responses. Reported beneficial pharmacologic effects include modulation of immune function (induced mRNA expression for interleukins-2 and -1α, interferon-γ, and granulocyte-macrophage colonystimulating factor; activated B and T cells, natural killer cells, and macrophages). Central nervous system effects included increased proliferating ability of neural progenitors and increased central levels of acetylcholine, serotonin, norepinephrine, and dopamine in the cerebral cortex. Miscellaneous effects included antioxidant activity; anti-inflammatory effects (inhibited tumor necrosis factor-α, interleukin-1β, and vascular and intracellular cell adhesion molecules); antistress activity (ie, stimulated pituitary-adrenocortical system, agonist at glucocorticoid receptor); analgesia (inhibited substance P); vasoregulatory effects (increased endothelial nitric oxide, inhibited prostacyclin production); cardioprotective activity (reduced ventricular remodeling and cardiac hypertrophy in animal models of myocardial ischemia); antiplatelet activity; improved glucose homeostasis (reduced cell death in pancreatic beta cells; increased insulin release, number of insulin receptors, and insulin sensitivity); and anticancer properties (reduced tumor angiogenesis, increased tumor cell apoptosis). These extensive claims require careful replication.

Clinical Trials Ginseng is most often claimed to help improve physical and mental performance or to function as an “adaptogen,” an agent that helps the body to return to normal when exposed to stressful or noxious stimuli. However, the clinical trials evaluating ginseng for these indications have shown few if any benefits. Some randomized controlled trials evaluating “quality of life” and “cognition” have claimed significant benefits in some subscale measures of behavior, cognitive function, or quality of life but rarely in overall composite scores using P ginseng. Better results have been observed with P quinquefolium and P ginseng in lowering postprandial glucose indices in subjects with and without diabetes. This was the subject of a systematic review in which 15 studies (13 randomized and 2 nonrandomized) were evaluated. Nine of the studies reported significant reductions in blood glucose. Some randomized, placebo-controlled trials have reported immunomodulating benefits of P quinquefolium and P ginseng in preventing upper respiratory tract infections. Use of ginseng for 2–4 months in healthy seniors may reduce the risk of acquiring the common cold as well as the duration of symptoms. Because of heterogeneity in these trials, however, these findings are insufficient to recommend the use of ginseng for this indication. Preliminary studies also claim a non-organ-specific cancer preventive effect with long-term administration of P ginseng and alleviation of some cancer fatigue symptoms with administration of P quinquefolium versus placebo over a 2-month period. In summary, the strongest support for use of P ginseng or P quinquefolium currently relates to its effects in cold prevention, lowering postprandial glucose, nonspecific cancer prevention, and possible benefit in alleviating cancer-related fatigue.

Adverse Effects Vaginal bleeding and mastalgia have been described in case reports, suggesting possible estrogenic effects. Central nervous system stimulation (eg, insomnia, nervousness) and hypertension have been reported in patients using high doses (more than 3 g/d) of P ginseng.

Methylxanthines found in the ginseng plant may contribute to this effect. Vasoregulatory effects of ginseng are unlikely to be clinically significant.

Drug Interactions & Precautions Irritability, sleeplessness, and manic behavior have been reported in psychiatric patients using ginseng in combination with other medications (phenelzine, lithium, neuroleptics). Ginseng should be used cautiously in patients taking any psychiatric, estrogenic, or hypoglycemic medications. Ginseng has antiplatelet properties and should not be used in combination with warfarin. Cytokine stimulation

has been claimed for both P ginseng and P quinquefolium in vitro and in animal models. In a randomized, double-blind, placebocontrolled study, P ginseng significantly increased natural killer cell activity versus placebo with 8 and 12 weeks of use.

Immunocompromised individuals, those taking immune stimulants, and those with autoimmune disorders should use ginseng products with caution.

Dosage One to two grams per day of the crude P ginseng root or its equivalent is considered standard dosage. Two hundred milligrams of standardized P ginseng extract is equivalent to 1 g of the crude root. The trademarked preparation Ginsana has been used as a standardized extract in some clinical trials and is available in the USA.

MILK THISTLE (SILYBUM MARIANUM) Chemistry The fruit and seeds of the milk thistle plant contain a lipophilic mixture of flavonolignans known as silymarin. Silymarin comprises 2–3% of the dried herb and is composed of three primary isomers, silybin (also known as silybinin or silibinin), silychristin (silichristin), and silydianin (silidianin). Silybin is the most prevalent and potent of the three isomers and accounts for 50–70% of the silymarin complex.

Products should be standardized to contain 70–80% silymarin.

Pharmacologic Effects 1. Liver disease—In animal models, milk thistle purportedly limits hepatic injury associated with a variety of toxins, including Amanita mushrooms, galactosamine, carbon tetrachloride, acetaminophen, radiation, cold ischemia, and ethanol. In vitro studies and some in vivo studies indicate that silymarin reduces lipid peroxidation, scavenges free radicals, and enhances glutathione and superoxide dismutase levels. This may contribute to membrane stabilization and reduce toxin entry.

Milk thistle appears to have anti-inflammatory properties. In vitro, silybin strongly and noncompetitively inhibits lipoxygenase activity and reduces leukotriene formation. Inhibition of leukocyte migration has been observed in vivo and may be a factor when acute inflammation is present. Silymarin inhibits nuclear factor kappa B (NF-κB), an inflammatory response mediator. One of the most unusual mechanisms claimed for milk thistle involves an increase in RNA polymerase I activity in nonmalignant hepatocytes but not in hepatoma or other malignant cell lines. By increasing this enzyme’s activity, enhanced protein synthesis and cellular regeneration might occur in healthy but not malignant cells. In an animal model of cirrhosis, it reduced collagen accumulation, and in an in vitro model it reduced expression of the fibrogenic cytokine transforming growth factor-β. If confirmed, milk thistle may have a role in the treatment of hepatic fibrosis.

In animal models, silymarin has a dose-dependent stimulatory effect on bile flow that could be beneficial in cases of cholestasis. To date, however, there is insufficient evidence to warrant the use of milk thistle for these indications.

2. Chemotherapeutic effects—Preliminary in vitro and animal studies of the effects of silymarin and silybinin have been carried out with several cancer cell lines. In murine models of skin cancer, silybinin and silymarin were said to reduce tumor initiation and promotion.

Induction of apoptosis has also been reported using silymarin in a variety of malignant human cell lines (eg, melanoma, prostate, colon, leukemia cells, bladder transitional-cell papilloma cells, and hepatoma cells). Inhibition of cell growth and proliferation by inducing a G1 cell cycle arrest has also been claimed in cultured human breast and prostate cancer cell lines. The use of milk thistle in the clinical treatment of cancer has not yet been adequately studied but preliminary trials in patients undergoing chemotherapy show that it may improve liver function (ie, reduced liver transaminase concentrations in blood). There is insufficient data to support use in patients with cancer. The antioxidant potential of milk thistle should be taken into consideration prior to administration with chemotherapeutic agents that may be affected by antioxidant compounds.

3. Lactation—Historically, milk thistle has been used by herbalists and midwives to induce lactation in pregnant or postpartum women.

In female rats, milk thistle increases prolactin production. As such, it is possible that it could have an effect on human breast milk production. Clinical trial data are lacking, however, for this indication, as are safety data on nursing mothers and infants. Until further data become available, milk thistle should not be used for this indication.

Clinical Trials Milk thistle has been used to treat acute and chronic viral hepatitis, alcoholic liver disease, and toxin-induced liver injury in human patients. A systematic review of 13 randomized trials involving 915 patients with alcoholic liver disease or hepatitis B or C found no significant reductions in all-cause mortality, liver histopathology, or complications of liver disease with 6 months of use. A significant

reduction in liver-related mortality was claimed using the data from all the surveyed trials, but not when the data were limited to trials of better design and controls. It was concluded that the effects of milk thistle in improving liver function or mortality from liver disease are currently poorly substantiated. A recent multicenter, double-blind, placebo-controlled clinical trial in patients with hepatitis C refractory to interferon treatment failed to show a benefit with 24 weeks of milk thistle, 420 mg and 700 mg, on reduction of serum ALT levels. Milk thistle also had no effect on mean serum hepatitic C virus (HCV) RNA levels at 24 weeks. In contrast, the intravenous use of silybinin succinate has shown some benefit in reducing HCV RNA levels and alanine aminotransferase levels in patients with treatment-resistant hepatitis C infection. This suggests that formulation and oral bioavailability may influence treatment outcomes.

Although milk thistle has not been confirmed as an antidote following acute exposure to liver toxins in humans, intravenous silybinin is marketed and used in Europe (Legalon SIL) as an antidote in Amanita phalloides mushroom poisoning. This use is based on favorable outcomes reported in case-control studies.

Adverse Effects Milk thistle has rarely been reported to cause adverse effects when used at recommended doses. In clinical trials, the incidence of adverse effects (eg, gastrointestinal upset, dermatologic, headaches) was comparable to that of placebo. At high doses (> 1500 mg), it can have a laxative effect caused by stimulation of bile flow and secretion.

Drug Interactions, Precautions, & Dosage Milk thistle does not significantly alter the pharmacokinetics of other drugs transported by the P-glycoprotein transporter or metabolized by cytochrome enzymes. In a recent review, the impact of the herb was listed as “posing no risk for drug interactions in humans.”

Recommended dosage is 280–420 mg/d, calculated as silybin, in three divided doses.

ST. JOHN’S WORT (HYPERICUM PERFORATUM) Chemistry St. John’s wort, also known as hypericum, contains a variety of constituents that might contribute to its claimed pharmacologic activity in the treatment of depression. Hypericin, a marker of standardization for currently marketed products, was thought to be the primary antidepressant constituent. Recent attention has focused on hyperforin, but a combination of several compounds is probably involved.

Commercial formulations are usually prepared by soaking the dried chopped flowers in methanol to create a hydroalcoholic extract that is then dried.

Pharmacologic Effects 1. Antidepressant action—The hypericin fraction was initially reported to have MAO-A and -B inhibitor properties. Later studies found that the concentration required for this inhibition was higher than that achieved with recommended dosages. In vitro studies using the commercially formulated hydroalcoholic extract have shown inhibition of nerve terminal reuptake of serotonin, norepinephrine, and dopamine. While the hypericin constituent did not show reuptake inhibition for any of these systems, the hyperforin constituent did.

Chronic administration of the commercial extract has also been reported to significantly down-regulate the expression of cortical β adrenoceptors and up-regulate the expression of serotonin receptors (5-HT2 ) in a rodent model.

Other effects observed in vitro include sigma receptor binding using the hypericin fraction and GABA receptor binding using the commercial extract. Interleukin-6 production is also reduced in the presence of the extract. a. Clinical trials for depression—The most recent systematic review and meta-analysis involved 29 randomized, double-blind, controlled trials (18 compared St. John’s wort with placebo, 5 with tricyclic antidepressants, and 12 with selective serotonin reuptake inhibitors [SSRIs]). Only studies meeting defined classification criteria for major depression were included. St. John’s wort was reported to be more efficacious than placebo and equivalent to prescription reference treatments including the SSRIs for mild to moderate depression but with fewer side effects. Most trials used 900 mg/d of St. John’s wort for 4–12 weeks. Depression severity was mild to moderate in 19 trials, moderate to severe in 9 trials, and not stated in one trial. In a longer but uncontrolled trial, the use of the herb for up to 52 weeks was reported to reduce depression scores in patients with mild to moderate severity depression. These data and the mechanism of action data reported above suggest a potential role for St. John’s wort in relieving symptoms of mild to moderate depression. Due to the short study duration of these clinical trials, efficacy beyond 12 weeks still requires further study. b. Other mood-related conditions—St. John’s wort has been studied for several other indications related to mood, including premenstrual dysphoric disorder, climacteric complaints, somatoform disorders, and anxiety. These studies are too few in number, however, to draw any firm conclusions regarding efficacy.

2. Antiviral and anticarcinogenic effects—The hypericin constituent of St. John’s wort is photolabile and can be activated by exposure to certain wavelengths of visible or ultraviolet A light. Parenteral formulations of hypericin (photoactivated just before administration) have been used investigationally to treat HIV infection (given intravenously) and basal and squamous cell carcinoma (given by intralesional injection). In vitro, photoactivated hypericin inhibits a variety of enveloped and nonenveloped viruses as well as the growth of some neoplastic cells. Inhibition of protein kinase C and inhibition of singlet oxygen radical generation have been proposed as possible mechanisms. The latter could inhibit cell growth or cause cell apoptosis. These studies were carried out using the isolated hypericin constituent of St. John’s wort; the usual hydroalcoholic extract of St. John’s wort has not been studied for these indications and should not be recommended for patients with viral illness or cancer.

Adverse Effects Photosensitization is related to the hypericin and pseudohypericin constituents in St. John’s wort. Consumers should be instructed to wear sunscreen and eye protection while using this product when exposed to the sun. Hypomania, mania, and autonomic arousal have also been reported in patients using St. John’s wort.

Drug Interactions & Precautions Inhibition of reuptake of various amine transmitters has been highlighted as a potential mechanism of action for St. John’s wort. Drugs with similar mechanisms (ie, antidepressants, stimulants) should be used cautiously or avoided in patients using St. John’s wort due to the risk of serotonin syndrome (see Chapters 16 and 30). This herb may induce hepatic CYP enzymes (3A4, 2C9, 1A2) and the Pglycoprotein drug transporter. This has led to case reports of subtherapeutic levels of numerous drugs, including digoxin, birth control drugs (and subsequent pregnancy), cyclosporine, HIV protease and nonnucleoside reverse transcriptase inhibitors, warfarin, irinotecan, theophylline, and anticonvulsants.

Dosage The most common commercial formulation of St. John’s wort is the dried hydroalcoholic extract. Products should be standardized to 2– 5% hyperforin, although most still bear the older standardized marker of 0.3% hypericin. The recommended dosing for mild to moderate depression is 900 mg of the dried extract per day in three divided doses. Onset of effect may take 2–4 weeks. Long-term benefits beyond 12 weeks have not been studied.

SAW PALMETTO (SERENOA REPENS OR SABAL SERRULATA) Chemistry The active constituents in saw palmetto berries are not well defined. Phytosterols (eg, β-sitosterol), aliphatic alcohols, polyprenic compounds, and flavonoids are all present. Marketed preparations are dried lipophilic extracts that are generally standardized to contain 85–95% fatty acids and sterols.

Pharmacologic Effects Saw palmetto is most often promoted for the treatment of benign prostatic hyperplasia (BPH). Enzymatic conversion of testosterone to dihydrotestosterone (DHT) by 5α-reductase is inhibited by saw palmetto in vitro. Specifically, saw palmetto shows a noncompetitive inhibition of isoforms I and II of this enzyme, thereby reducing DHT production. In vitro, saw palmetto also inhibits the binding of DHT to androgen receptors. Additional effects observed in vitro include inhibition of prostatic growth factors, blockade of α 1 adrenoceptors, and inhibition of inflammatory mediators produced by the 5-lipoxygenase pathway.

The clinical pharmacology of saw palmetto in humans is not well defined. One week of treatment in healthy volunteers failed to influence 5α-reductase activity, DHT concentration, or testosterone concentration. Six months of treatment in patients with BPH also failed to affect prostate-specific antigen (PSA) levels, a marker that is typically reduced by enzymatic inhibition of 5α-reductase. In contrast, other researchers have reported a reduction in epidermal growth factor, DHT levels, and antagonist activity at the nuclear estrogen receptor in the prostate after 3 months of treatment with saw palmetto in patients with BPH.

Clinical Trials The most recent review involved 32 randomized controlled trials in 5666 men with symptoms consistent with BPH. Seventeen trials compared saw palmetto monotherapy with placebo and found no significant improvement in most urologic symptoms (eg, international prostate symptom scores, peak flow, prostate size).

Adverse Effects Adverse effects are reported with an incidence of 1–3%. The most common include abdominal pain, nausea, diarrhea, fatigue, headache, decreased libido, and rhinitis. Saw palmetto has been associated with a few rare case reports of pancreatitis, liver damage, and increased bleeding risk, but due to confounding factors, causality remains inconclusive. In comparison to tamsulosin and finasteride, saw palmetto was claimed to be less likely to affect sexual function (eg, ejaculation).

Drug Interactions, Precautions, & Dosage No drug-drug interactions have been reported for saw palmetto. Because saw palmetto has no effect on the PSA marker, it will not interfere with prostate cancer screening using this test. Recommended dosage of a standardized dried extract (containing 85–95% fatty acids and sterols) is 160 mg orally twice daily. The lack of positive results as noted in the review of randomized controlled studies cited above indicates that the use of saw palmetto in prostate disease cannot be recommended.

PURIFIED NUTRITIONAL SUPPLEMENTS COENZYME Q10 Coenzyme Q10, also known as CoQ, CoQ10, and ubiquinone, is found in the mitochondria of many organs, including the heart, kidney, liver, and skeletal muscle. After ingestion, the reduced form of coenzyme Q10, ubiquinol, predominates in the systemic circulation.

Coenzyme Q10 is a potent antioxidant and may have a role in maintaining healthy muscle function, although the clinical significance of this effect is unknown. Reduced serum levels have been reported in Parkinson’s disease.

Clinical Uses 1. Hypertension—In clinical trials, small but significant reductions in systolic and diastolic blood pressure were reported after 8–10 weeks of coenzyme Q10 supplementation. The exact mechanism is unknown but might be related to the antioxidant and vasodilating properties of coenzyme Q10. In three randomized, placebo-controlled trials, coenzyme Q10 was reported to significantly lower systolic and diastolic blood pressure by 11 mm Hg and 7 mm Hg, respectively, compared with no change in the placebo groups. However, an exaggerated treatment effect may have occurred as adequate randomization, blinding, and concealment of allocation have been questioned for these studies. Whether coenzyme Q10 can be used to lower blood pressure remains unclear.

2. Heart failure—Low endogenous coenzyme Q10 levels have been associated with worse heart failure outcomes, but this association is likely because low levels are a marker for more advanced heart failure, rather than a predictor of disease. Despite these findings, coenzyme Q10 is often advocated to improve heart muscle function in patients with heart failure. According to the most recent metaanalysis, coenzyme Q10 was shown to improve ejection fraction by 3.7% when used short term (2–28 weeks). It is unclear whether improvements in ejection fraction are applicable to all patients with heart failure, including those receiving the current standard of care for heart failure management. More research is required to assess the role of coenzyme Q10 in heart failure and its impact on disease severity, particularly with concomitant prescription medications.

3. Ischemic heart disease—The effects of coenzyme Q10 on coronary artery disease and chronic stable angina are modest but appear promising. A theoretical basis for such benefit could be metabolic protection of the ischemic myocardium. Double-blind, placebocontrolled trials have suggested that coenzyme Q10 supplementation improved a number of clinical measures in patients with a history of acute myocardial infarction (AMI). Improvements have been observed in lipoprotein (a), high-density lipoprotein cholesterol, exercise tolerance, and time to development of ischemic changes on the electrocardiogram during stress tests. In addition, very small reductions in cardiac deaths and rate of reinfarction in patients with previous AMI have been reported (absolute risk reduction 1.5%).

4. Prevention of statin-induced myopathy—Statins reduce cholesterol by inhibiting the HMG-CoA reductase enzyme (see Chapter 35). This enzyme is also required for synthesis of coenzyme Q10. Initiating statin therapy has been shown to reduce endogenous coenzyme Q10 levels, which may block steps in muscle cell energy generation, possibly leading to statin-related myopathy. It is unknown whether a reduction in intramuscular coenzyme Q10 levels leads to statin myopathy or if the myopathy causes cellular damage that reduces intramuscular coenzyme Q10 levels. In one of the largest studies, when rosuvastatin was used in patients with heart failure, there was no association between statin-induced low coenzyme Q10 levels and poorer heart failure outcomes. Furthermore, the study found no observable difference in the incidence of statin-induced myopathy regardless of endogenous coenzyme Q10 levels. More information is needed to determine which patients with statin-related myopathy might benefit from coenzyme Q10 supplementation, especially as it relates to the specific statin, the dose, and the duration of therapy.

Adverse Effects Coenzyme Q10 is well tolerated, rarely leading to any adverse effects at doses as high as 3000 mg/d. In clinical trials, gastrointestinal upset, including diarrhea, nausea, heartburn, and anorexia, has been reported with an incidence of less than 1%. Cases of maculopapular rash and thrombocytopenia have very rarely been observed. Other rare adverse effects include irritability, dizziness, and headache.

Drug Interactions Coenzyme Q10 shares a structural similarity with vitamin K, and an interaction has been observed between coenzyme Q10 and warfarin.

Coenzyme Q10 supplements may decrease the effects of warfarin therapy. This combination should be avoided or very carefully monitored.

Dosage As a dietary supplement, 30 mg/d of coenzyme Q10 is adequate to replace low endogenous levels. For cardiac effects, typical dosages are 100–600 mg/d given in two or three divided doses. These doses increase endogenous levels to 2–3 mcg/mL (normal for healthy adults, 0.7–1 mcg/mL).

GLUCOSAMINE Glucosamine is found in human tissue, is a substrate for the production of articular cartilage, and serves as a cartilage nutrient.

Glucosamine is commercially derived from crabs and other crustaceans. As a dietary supplement, glucosamine is primarily used for pain associated with knee osteoarthritis. Sulfate and hydrochloride forms are available, but recent research has shown the hydrochloride form to be ineffective.

Pharmacologic Effects & Clinical Uses Endogenous glucosamine is used for the production of glycosaminoglycans and other proteoglycans in articular cartilage. In osteoarthritis, the rate of production of new cartilage is exceeded by the rate of degradation of existing cartilage. Supplementation with glucosamine is thought to increase the supply of the necessary glycosaminoglycan building blocks, leading to better maintenance and strengthening of existing cartilage.

Many clinical trials have been conducted on the effects of both oral and intra-articular administration of glucosamine. Early studies reported significant improvements in overall mobility, range of motion, and strength in patients with osteoarthritis. More recent studies have reported mixed results, with both positive and negative outcomes. One of the largest and best-designed clinical trials, which compared glucosamine, chondroitin sulfate, the combination, celecoxib, and placebo, found no benefit for glucosamine therapy in mild to moderate disease. Unfortunately the investigators studied the glucosamine hydrochloride formulation, which has been shown to be inferior to the sulfate formulation. The formulation of glucosamine appears to play an important role with regard to efficacy and this may be a factor contributing to the variability observed across published studies. More research is needed to better define the ideal glucosamine formulation and patient populations that stand to benefit from glucosamine sulfate.

Adverse Effects Oral glucosamine sulfate is very well tolerated. In clinical trials, mild diarrhea, abdominal cramping, and nausea were occasionally reported. Cross allergenicity in people with shellfish allergies is a potential concern; however, this is unlikely if the formulation has been properly manufactured and purified.

Drug Interactions & Precautions Glucosamine sulfate may increase the international normalized ratio (INR) in patients taking warfarin, increasing the risk for bruising and bleeding. The mechanism is not well understood and may be dose-related as increases in INR have occurred when the glucosamine dose was increased. Until more is known, the combination should be avoided or very carefully monitored.

Dosage The oral dosage used most often in clinical trials is 500 mg three times daily or 1500 mg once daily. Glucosamine does not have direct analgesic effects, and improvements in function, if any, may not be observed for 1–2 months.

MELATONIN Melatonin, a serotonin derivative produced by the pineal gland and some other tissues (see also Chapter 16), is believed to be responsible for regulating sleep-wake cycles. Release coincides with darkness; it typically begins around 9 pm and lasts until about 4 am. Melatonin release is suppressed by daylight. Melatonin has also been studied for a number of other functions, including contraception, protection against endogenous oxidants, prevention of aging, treatment of depression, HIV infection, and a variety of cancers. Currently, melatonin is most often used to prevent jet lag and to induce sleep.

Pharmacologic Effects & Clinical Uses 1. Jet lag—Jet lag, a disturbance of the sleep-wake cycle, occurs when there is a disparity between the external time, ie, hours of daylight or darkness, and the traveler’s endogenous circadian clock (internal time). The internal time regulates not only daily sleep rhythms but also body temperature and many metabolic systems. The synchronization of the circadian clock relies on light as the most potent “zeitgeber” (time giver).

Jet lag is especially common among frequent travelers and airplane cabin crews. Typical symptoms of jet lag may include daytime drowsiness, insomnia, frequent awakenings, and gastrointestinal upset. Clinical studies of melatonin have reported subjective reduction in daytime fatigue, improved mood, and a quicker recovery time (return to normal sleep patterns, energy, and alertness). Although taking melatonin has not been shown to adjust circadian patterns of melatonin release, it may have a role in helping people fall asleep once they arrive at their new destination. When traveling across five or more time zones, jet lag symptoms are reduced when taking melatonin close to the target bedtime (10 PM to midnight) at the new destination. The benefit of melatonin is thought to be greater as more time zones are crossed. In addition, melatonin appears more effective for eastbound travel than for westward travel. Finally, maximizing exposure to daylight on arrival at the new destination can also aid in resetting the internal clock.

2. Insomnia—Melatonin has been studied in the treatment of various sleep disorders, including insomnia and delayed sleep-phase syndrome. It has been reported to improve sleep onset, duration, and quality when administered to healthy volunteers, suggesting a pharmacologic hypnotic effect. Melatonin has also been shown to increase rapid-eye-movement (REM) sleep. These observations have been applied to the development of ramelteon, a prescription hypnotic that is an agonist at melatonin receptors (see Chapter 22).

Clinical studies in patients with primary insomnia have shown that oral melatonin supplementation may alter sleep architecture.

Melatonin appears effective in some patients who develop insomnia from β blockers. Subjective and objective improvements in sleep quality and improvements in sleep onset and sleep duration have been reported. Specifically, melatonin taken at the desired bedtime, with bedroom lights off, has been shown to improve morning alertness and quality of sleep as compared with placebo. These effects have been observed in both young and older adults (18–80 years of age). Interestingly, baseline endogenous melatonin levels were not predictive of exogenous melatonin efficacy.

3. Female reproductive function—Melatonin receptors have been identified in ovarian granulosa cell membranes, and significant amounts of melatonin have been detected in follicular fluid. Melatonin has been associated with midcycle suppression of luteinizing hormone surge and secretion. This may result in partial inhibition of ovulation. Nightly doses of melatonin (75–300 mg) given with a progestin through days 1–21 of the menstrual cycle resulted in lower mean luteinizing hormone levels. Therefore, melatonin should not be used by women who are pregnant or attempting to conceive. Furthermore, melatonin supplementation may decrease prolactin release in women and therefore should be used cautiously or not at all while nursing.

4. Male reproductive function—In healthy men, chronic melatonin administration (≥ 6 months) decreased sperm quality, possibly by aromatase inhibition in the testes. However, when endogenous melatonin levels were measured in healthy men, high endogenous melatonin concentrations were associated with enhanced sperm quality and short-term in vitro exposure to melatonin improved sperm motility. Until more is known, melatonin should not be used by couples who are actively trying to conceive.

Adverse Effects Melatonin appears to be well tolerated and is often used in preference to over-the-counter “sleep-aid” drugs. Although melatonin is associated with few adverse effects, some next-day drowsiness has been reported as well as fatigue, dizziness, headache, and irritability.

Transient depressive symptoms and dysphoria have been reported rarely. Melatonin may affect blood pressure as both increases and decreases in blood pressure have been observed. Careful monitoring is recommended, particularly in patients initiating melatonin therapy while taking antihypertensive medications.

Drug Interactions Melatonin drug interactions have not been formally studied. Various studies, however, suggest that melatonin concentrations are altered by a variety of drugs, including nonsteroidal anti-inflammatory drugs, antidepressants, β-adrenoceptor agonists and antagonists,

scopolamine, and sodium valproate. The relevance of these effects is unknown. Melatonin is metabolized by CYP450 1A2 and may interact with other drugs that either inhibit or induce the 1A2 isoenzyme, including fluvoxamine. Melatonin may decrease prothrombin time and may theoretically decrease the effects of warfarin therapy. A dose-response relationship between the plasma concentration of melatonin and coagulation activity has been suggested according to one in vitro analysis. If combination therapy is desired, careful monitoring is recommended especially if melatonin is being used on a short-term basis. Melatonin may interact with nifedipine, possibly leading to increased blood pressure and heart rate. The exact mechanism is unknown.

Dosage 1. Jet lag—Daily doses of 0.5–5 mg appear to be equally effective for jet lag; however, the 5 mg dose resulted in a faster onset of sleep and better sleep quality than lower doses. The immediate-release formulation is preferred and should be given at the desired sleep time (10 PM–midnight) upon arrival at the new destination and for 1–3 nights after arrival. A dark room environment is important when taking melatonin and when possible, room lights should be turned off. The value of extended-release formulations remains unknown, as evidence suggests the short-acting, high-peak effect of the immediate-release formulation to be more effective. Exposure to daylight at the new time zone is also important to regulate the sleep-wake cycle.

2. Insomnia—Doses of 0.3–10 mg of the immediate-release formulation given orally once nightly have been used. The lowest effective dose should be used first and may be repeated in 30 minutes up to a maximum of 10–20 mg. Sustained-release formulations are effective and may be used but as noted above, may be inferior to immediate-release formulations. Sustained-release formulations are also more costly.

REFERENCES Agbabiaka T B et al: Serenoa repens (saw palmetto): A systematic review of adverse events. Drug Saf 2009;32:637.

Barnes J et al: Echinacea species (Echinacea angustifolia (DC.) Hell., Echinacea pallida (Nutt.) Nutt., Echinacea purpurea (L.) Moench): A review of their chemistry, pharmacology and clinical properties. Pharm Pharmacol 2005;57:929.

Birks J, Evans JG: Ginkgo biloba for cognitive impairment and dementia. Cochrane Database Syst Rev 2009;(1):CD003120.

Brattstrom A: Long term effects of St John’s wort (Hypericum perforatum) treatment: A 1 year safety study in mild to moderate depression. Phytomedicine 2009;16:277.

Brzezinski A et al: Effects of exogenous melatonin on sleep: A meta-analysis. Sleep Med Rev 2005;9:41.

Buck AC: Is there a scientific basis for the therapeutic effects of Serenoa repens in benign prostatic hyperplasia? Mechanisms of action. J Urol 2004;172:1792.

Butterweck V, Schmidt M: St John’s wort: Role of active compounds for its mechanism of action and efficacy. Wien Med Wochenschr 2007;157:356.

Capasso A: Antioxidant action and therapeutic efficacy of Allium sativum L. Molecules 2013;18:690.

Fotino AD, T hompson-Paul AM, Bazzano LA: Effect of coenzyme Q10 supplementation on heart failure: A meta-analysis. Am J Clin Nutr 2013;97:268.

Fried MW et al: Effect of silymarin (milk thistle) on liver disease in patients with chronic hepatitis C unsuccessfully treated with interferon therapy. JAMA 2012;308:274.

Herxheimer A, Petrie KJ: Melatonin for the prevention and treatment of jet lag. Cochrane Database Syst Rev 2002;(2):CD001520.

Ho MJ, Bellusci A, Wright JM: Blood pressure lowering efficacy of coenzyme Q10 for primary hypertension. Cochrane Database Syst Rev 2009;(4):CD007435.

Hudson JB: Applications of phytomedicine Echinacea purpurea (Purple Coneflower) in infectious diseases. J Biomed and Biotechnology 2012;2012:769896.

Izzo AA: Interactions between herbs and conventional drugs: Overview of the clinical data. Med Princ Pract 2012;21:404.

Jellin JM et al: Pharmacist’s Letter/Prescriber’s Letter Natural Medicines Comprehensive Database, 14th ed. T herapeutic Research Faculty, 2010.

Kang S, Min H: Ginseng, the immunity boost: Effects of Panax ginseng on the immune system. J Ginseng Res 2012;36:354.

Karsch-Völk M et al: Echinacea for preventing and treating the common cold. Cöchrane Database Syst. Rev 2014(2):CD000530.

Kim HJ, Kim P, Shin CY: A comprehensive review of the therapeutic and pharmacologic effects of ginseng and ginsenosides in central nervous system. J Ginseng Res 2013;37:8.

Linde K: St John’s wort—an overview. Forsch Komplementmed 2009;16:146.

Linde K et al: St. John’s wort for major depression. Cochrane Database Syst Rev 2008;(4):CD000448.

Loguercio C, Festi D: Silybin and the liver: From basic research to clinical practice. World J Gastroenterol 2011;17:2288.

Mengs U, Pohl RT , Mitchell T : Legalon SIL: T he antidote of choice in patients with acute hepatotoxicity from amatoxin poisoning. Curr Pharmaceut Biotechnol 2012;13:1964.

Natural Standard: http://www.naturalstandard.com. (Evidence-based compendium authored by academics, available to institutions.)

Newmaster SG et al: DNA barcoding detects contamination and substitution in North American herbal products. BMC Med 2013;11:222.

Nicolai SP et al.: Ginkgo biloba for intermittent claudication. Cochrane Database Syst Rev 2013;(6):CD006888.

Ramaswami R, Stebbing J: Ginseng: Panacea among herbal remedies? Lancet Oncol 2013;3:195.

Rambaldi A et al: Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases. Cochrane Database Syst Rev 2007;(4):CD003620.

Reinhart KM et al: Effects of garlic on blood pressure in patients with and without systolic hypertension: A meta-analysis. Ann Pharmacother 2008;42:1766.

Reinhart KM et al: T he impact of garlic on lipid parameters: A systematic review and meta-analysis. Nutr Res Rev 2009;22:39.

Scheer FAJL et al: Repeated melatonin supplementation improves sleep in hypertensive patients treated with beta-blockers: A randomized controlled trial. Sleep 2012;35:1395.

Schergis JL et al: Panax ginseng in randomized controlled trials: A systematic review. Phytother Res 2013;27:949.

Seida JK, Durec T , Kuhle S: North American (Panax quinquefolius) and Asian ginseng (Panax ginseng) preparations for prevention of the common cold in healthy adults: A systematic review. Evid Based Complement Alternat Med 2011;2011:282151.

Sharma M et al: Bactericidal and anti-inflammatory properties of a standardized Echinacea extract (Echinaforce): Dual actions against respiratory bacteria. Phytomedicine 2010;17:563.

Sharma M et al: T he efficacy of Echinacea in a 3-D tissue model of human airway epithelium. Phytother Res 2010;24:900.

Shi C et al: Ginkgo biloba extract in Alzheimer’s disease: From action mechanisms to medical practice. Int J Mol Sci 2010;11:107.

T acklind J et al: Serenoa repens for benign prostatic hyperplasia. Cochrane Database Syst Rev 2012;(12):CD001423.

Van Vijven JP et al: Symptomatic and chondroprotective treatment with collagen derivatives in osteoarthritis: A systematic review. Osteoarthritis Cartilage 2012;20:809.

Vellas B et al: Long term use of standardized ginkgo biloba extract for the prevention of Alzheimer’s disease (GuidAge): A randomized placebo-controlled trial. Lancet Neurol 2012;11:836.

Weinmann S et al: Effects of ginkgo biloba in dementia: Systematic review and meta-analysis. BMC Geriatr 2010;10:14.

Wu D et al: Efficacies of different preparations of glucosamine for the treatment of osteoarthritis: A meta-analysis of randomised, double-blind, placebo-controlled trials. Int J Clin Pract 2013;67:585.

Zeng T et al: A meta-analysis of randomized, double-blind, placebo-controlled trials for the effects of garlic on serum lipid profiles. J Sci Food Agric 2012;92:1892.

CASE STUDY ANSWER Garlic has not been shown to significantly lower LDL cholesterol. It has been shown to have a small but significant lowering effect on total cholesterol, but only when dietary controls were not in place. There is limited evidence to suggest that garlic may lower plaque burden in patients with coronary artery disease (CAD). It is advisable to monitor the patient’s blood pressure for 2 weeks after initiating a garlic supplement as he takes prescription medications for hypertension. He might be using coenzyme Q10 for CAD or hypertension, or because he takes simvastatin. Current literature does not support a reduced risk of statin-related myopathy. The data supporting benefits of coenzyme Q10 in patients with CAD are preliminary and limited to studies in persons with a previous myocardial infarction. Several dietary supplements reviewed in this chapter (garlic, ginkgo, and ginseng) have antiplatelet effects that could be additive with aspirin. If this patient were also taking warfarin, additional interactions could occur with coenzyme Q10 (vitamin K-like structure), St. John’s wort (cytochrome P450 1A2, 2C9, 3A4 inducer), and melatonin (in vitro decreased prothrombin time), leading to a decreased warfarin effect, or with glucosamine (increased international normalized ratio), leading to an increased warfarin effect.

_______________ * T he industry marketing these materials is replacing the terms “ herbal medication” and “ botanical medication” with the term “ dietary supplement” in order to avoid legal liability and added governmental regulation. For the purposes of this chapter, they are identical.

CHAPTER

65 Rational Prescribing & Prescription Writing Paul W. Lofholm, PharmD, & Bertram G. Katzung, MD, PhD

Once a patient with a clinical problem has been evaluated and a diagnosis has been reached, the practitioner can often select from a variety of therapeutic approaches. Medication, surgery, psychiatric treatment, radiation, physical therapy, health education, counseling, further consultation (second opinions), and no therapy are some of the options available. Of these options, drug therapy is by far the one most frequently chosen. In most cases, this requires the writing of a prescription. A written prescription is the prescriber’s order to prepare or dispense a specific treatment—usually medication—for a specific patient. When a patient comes for an office visit, the physician or other authorized health professional prescribes medications 67% of the time, and an average of one prescription is written per office visit because more than one prescription may be written at a single visit.

In this chapter, a plan for prescribing is presented. The physical form of the prescription, common prescribing errors, and legal requirements that govern various features of the prescribing process are then discussed. Finally, some of the social and economic factors involved in prescribing and drug use are described.

RATIONAL PRESCRIBING Like any other process in health care, writing a prescription should be based on a series of rational steps.

1. Make a specific diagnosis: Prescriptions based merely on a desire to satisfy the patient’s psychological need for some type of therapy are often unsatisfactory and may result in adverse effects. A specific diagnosis, even if it is tentative, is required to move to the next step. For example, in a patient with a probable diagnosis of rheumatoid arthritis, the diagnosis and the reasoning underlying it should be clear and should be shared with the patient.

2. Consider the pathophysiologic implications of the diagnosis: If the disorder is well understood, the prescriber is in a much better position to offer effective therapy. For example, increasing knowledge about the mediators of inflammation makes possible more effective use of nonsteroidal anti-inflammatory drugs (NSAIDs) and other agents used in rheumatoid arthritis. The patient should be provided with the appropriate level and amount of information about the pathophysiology. Many pharmacies, websites, and disease-oriented public and private agencies (eg, Arthritis Foundation, American Heart Association, American Cancer Society, etc) provide information sheets suitable for patients.

3. Select a specific therapeutic objective: A therapeutic objective should be chosen for each of the pathophysiologic processes defined in the preceding step. In a patient with rheumatoid arthritis, relief of pain by reduction of the inflammatory process is one of the major therapeutic goals that identifies the drug groups that should be considered. Arresting the course of the disease process in rheumatoid arthritis is a different therapeutic goal, which might lead to consideration of other drug groups and prescriptions.

4. Select a drug of choice: One or more drug groups will be suggested by each of the therapeutic goals specified in the preceding step. Selection of a drug of choice from among these groups follows from a consideration of the specific characteristics of the patient and the clinical presentation. For certain drugs, characteristics such as age, other diseases, and other drugs being taken (because of the risk of duplicative therapy or drug-drug interactions) are extremely important in determining the most suitable drug for management of the present complaint. In the example of the patient with probable rheumatoid arthritis, it would be important to know whether the patient has a history of aspirin intolerance or ulcer disease, whether the cost of medication is an especially important factor and the nature of the patient’s insurance coverage, and whether there is a need for once-daily dosing. Based on this information, a drug would probably be selected from the NSAID group. If the patient does not have ulcer disease but does have a need for low-cost treatment, ibuprofen or naproxen would be a rational choice.

5. Determine the appropriate dosing regimen: The dosing regimen is determined primarily by the pharmacokinetics of the drug in that patient. If the patient is known to have disease of the organs required for elimination of the drug selected, adjustment of the average regimen is needed. For a drug such as ibuprofen, which is eliminated mainly by the kidneys, renal function should be assessed. If renal function is normal, the half-life of ibuprofen (about 2 hours) requires administration three or four times daily. The

dose suggested in this book, drug handbooks, and the manufacturer’s literature is 400–800 mg four times daily.

6. Devise a plan for monitoring the drug’s action and determine an end point for therapy: The prescriber should be able to describe to the patient the kinds of drug effects that will be monitored and in what way, including laboratory tests (if necessary) and signs and symptoms that the patient should report. For conditions that call for a limited course of therapy (eg, most infections), the duration of therapy should be made clear so that the patient does not stop taking the drug prematurely and understands why the prescription probably need not be renewed. For the patient with rheumatoid arthritis, the need for prolonged—perhaps indefinite— therapy should be explained, including how to obtain refills. The prescriber should also specify any changes in the patient’s condition that would call for changes in therapy. For example, in the patient with rheumatoid arthritis, development of gastrointestinal bleeding would require an immediate change in drug therapy and a prompt workup of the bleeding. Major toxicities that require immediate attention should be explained clearly to the patient.

7. Plan a program of patient education: The prescriber and other members of the health team should be prepared to repeat, extend, and reinforce the information transmitted to the patient as often as necessary. The more toxic the drug prescribed, the greater the importance of this educational program. The importance of informing and involving the patient in each of the above steps must be recognized, as shown by experience with teratogenic drugs (see Chapter 59). Many pharmacies routinely provide this type of information with each prescription filled, but the prescriber must not assume that this will occur.

THE PRESCRIPTION Although a prescription can be written on any piece of paper (as long as all of the legal elements are present), it usually takes a specific form. A typical printed prescription form for outpatients is shown in Figure 65–1.

FIGURE 65–1 Common form of outpatient prescription. Circled numbers are explained in the text.

In the hospital setting, drugs are prescribed on a particular page of the patient’s hospital chart called the physician’s order sheet (POS) or chart order. The contents of that prescription are specified in the medical staff rules by the hospital’s Pharmacy and Therapeutics Committee. The patient’s name is typed or written on the form; therefore, the orders consist of the name and strength of the medication, the dose, the route and frequency of administration, the date, other pertinent information, and the signature of the prescriber. If the duration of therapy or the number of doses is not specified (which is often the case), the medication is continued until the prescriber discontinues the order or until it is terminated as a matter of policy routine, eg, a stop-order policy.

A typical chart order might be as follows: 3/12/14 10:30 a.m.

(1) Ampicillin 500 mg IV q6h 23times; 5 days (2) Aspirin 0.6 g per rectum q6h prn temp over 101 [Signe d] Jane t B. Doe , MD

Thus, the elements of the hospital chart order are equivalent to the central elements (5, 8–11, 15) of the outpatient prescription.

ELEMENTS OF THE PRESCRIPTION The first four elements (see circled numerals in Figure 65–1) of the outpatient prescription establish the identity of the prescriber: name, license classification (ie, professional degree), address, and office telephone number. Before dispensing a prescription, the pharmacist must establish the prescriber’s bona fides and should be able to contact the prescriber by telephone if any questions arise. Element [5] is the date on which the prescription was written. It should be near the top of the prescription form or at the beginning (left margin) of the chart order. Since the order has legal significance and usually has some temporal relationship to the date of the patient-prescriber interview, a pharmacist should refuse to fill a prescription without verification by telephone if too much time has elapsed since its writing.

Elements [6] and [7] identify the patient by name and address. The patient’s name and full address should be clearly spelled out.

The body of the prescription contains the elements [8] to [11] that specify the medication, the strength and quantity to be dispensed, the dosage, and complete directions for use. When writing the drug name (element [8]), either the brand name (proprietary name) or the generic name (nonproprietary name) may be used. Reasons for using one or the other are discussed below. The strength of the medication [9] should be written in metric units. However, the prescriber should be familiar with both systems now in use: metric and apothecary. For practical purposes, the following approximate conversions are useful: 1 grain (gr) = 0.065 grams (g), often rounded to 60 milligrams (mg) 15 gr = 1 g 1 ounce (oz) by volume = 30 milliliters (mL) 1 teaspoonful (tsp) = 5 mL 1 tablespoonful (tbsp) = 15 mL 1 quart (qt) = 1000 mL 1 minim = 1 drop (gtt) 20 drops = 1 mL 2.2 pounds (lb) = 1 kilogram (kg) The strength of a solution is usually expressed as the quantity of solute in sufficient solvent to make 100 mL; for instance, 20% potassium chloride solution is 20 grams of KCl per deciliter (g/dL) of final solution. Both the concentration and the volume should be explicitly written out.

The quantity of medication prescribed should reflect the anticipated duration of therapy, the cost, the need for continued contact with the clinic or physician, the potential for abuse, and the potential for toxicity or overdose. Consideration should be given also to the standard sizes in which the product is available and whether this is the initial prescription of the drug or a repeat prescription or refill. If 10 days of therapy are required to effectively cure a streptococcal infection, an appropriate quantity for the full course should be prescribed. Birth control pills are often prescribed for 1 year or until the next examination is due; however, some patients may not be able to afford a year’s supply at one time; therefore, a 3-month supply might be ordered, with refill instructions to renew three times or for 1 year (element [12]). Some third-party (insurance) plans limit the amount of medicine that can be dispensed—often to only one month’s supply. Finally, when first prescribing medications that are to be used for the treatment of a chronic disease, the initial quantity should be small, with refills for larger quantities. The purpose of beginning treatment with a small quantity of drug is to reduce the cost if the patient cannot tolerate it. Once it is determined that intolerance is not a problem, a larger quantity purchased less frequently is sometimes less expensive.

The directions for use (element [11]) must be both drug-specific and patient-specific. The simpler the directions, the better; and the fewer the number of doses (and drugs) per day, the better. Patient noncompliance (also known as nonadherence, failure to adhere to the

drug regimen) is a major cause of treatment failure. To help patients remember to take their medications, prescribers often give an instruction that medications be taken at or around mealtimes and at bedtime. However, it is important to inquire about the patient’s eating habits and other lifestyle patterns, because many patients do not eat three regularly spaced meals a day.

The instructions on how and when to take medications, the duration of therapy, and the purpose of the medication must be explained to each patient both by the prescriber and by the pharmacist. (Neither should assume that the other will do it.) Furthermore, the drug name, the purpose for which it is given, and the duration of therapy should be written on each label so that the drug may be identified easily in case of overdose. An instruction to “take as directed” may save the time it takes to write the orders out but often leads to noncompliance, patient confusion, and medication error. The directions for use must be clear and concise to prevent toxicity and to obtain the greatest benefits from therapy.

Although directions for use are no longer written in Latin, many Latin apothecary abbreviations (and some others included below) are still in use. Knowledge of these abbreviations is essential for the dispensing pharmacist and often useful for the prescriber. Some of the abbreviations still used are listed in Table 65–1.

TABLE 65–1 Abbreviations used in prescriptions and chart orders.

Note: It is always safer to write out the direction without abbreviating.

Elements [12] to [14] of the prescription include refill information, waiver of the requirement for childproof containers, and additional labeling instructions (eg, warnings such as “may cause drowsiness,” “do not drink alcohol”). Pharmacists put the name of the medication on the label unless directed otherwise by the prescriber, and some medications have the name of the drug stamped or imprinted on the tablet or capsule. Pharmacists must place the expiration date for the drug on the label. If the patient or prescriber does not request waiver of childproof containers, the pharmacist or dispenser must place the medication in such a container. Pharmacists may not refill a prescription medication without authorization from the prescriber. Prescribers may grant authorization to renew prescriptions at the time of writing the prescription or over the telephone or electronically. Elements [15] to [17] are the prescriber’s signature and other identification data such as National Provider Identification (NPI), Drug Enforcement Agency (DEA) number, or State License number.

PRESCRIBING ERRORS Unfortunately, prescribing errors are common. Several groups provide online information regarding practices designed to reduce or document such errors, eg, Institute for Safe Medication Practices (ISMP; http://www.ismp.org/) and National Coordinating Council for Medication Error Reporting and Prevention Program (MERP; http://www.nccmerp.org/aboutNCCMERP.html).

All prescription orders should be legible, unambiguous, dated (and timed in the case of a chart order), and signed clearly for optimal communication between prescriber, pharmacist, and nurse. Furthermore, a good prescription or chart order should contain sufficient information to permit the pharmacist or nurse to discover possible errors before the drug is dispensed or administered.

Certain types of prescribing errors are particularly common. These include errors involving omission of needed information; poor writing perhaps leading to errors of drug dose or timing; and prescription of drugs that are inappropriate for the specific situation.

OMISSION OF INFORMATION Errors of omission are common in hospital orders and may include instructions to “resume pre-op meds,” which assumes that a full and accurate record of the “pre-op meds” is available; “continue present IV fluids,” which fails to state exactly what fluids are to be given, in what volume, and over what time period; or “continue eye drops,” which omits mention of which eye is to be treated as well as the drug, concentration, and frequency of administration. Chart orders may also fail to discontinue a prior medication when a new one is begun; may fail to state whether a regular or long-acting form is to be used; may fail to specify a strength or notation for long-acting forms; or may authorize “as needed” (prn) use that fails to state what conditions will justify the need.

POOR PRESCRIPTION WRITING Poor prescription writing is traditionally exemplified by illegible handwriting. However, other types of poor writing are common and often more dangerous. One of the most important is the misplaced or ambiguous decimal point. Thus “.1” is easily misread as “1,” a tenfold overdose, if the decimal point is not unmistakably clear. This danger is easily avoided by always preceding the decimal point with a zero.

On the other hand, appending an unnecessary zero after a decimal point increases the risk of a tenfold overdose, because “1.0 mg” is easily misread as “10 mg,” whereas “1 mg” is not. The slash or virgule (“/”) was traditionally used as a substitute for a decimal point.

This should be abandoned because it is too easily misread as the numeral “1.” Similarly, the abbreviation “U” for units should never be used because “10U” is easily misread as “100”; the word “units” should always be written out. Doses in micrograms should always have this unit written out because the abbreviated form (“μg”) is very easily misread as “mg,” a 1000-fold overdose! Orders for drugs specifying only the number of dosage units and not the total dose required should not be filled if more than one size dosage unit exists for that drug. For example, ordering “one ampule of furosemide” is unacceptable because furosemide is available in ampules that contain 20, 40, or 100 mg of the drug. The abbreviation “OD” should be used (if at all) only to mean “the right eye”; it has been used for “every day” and has caused inappropriate administration of drugs into the eye. Similarly, “Q.D.” or “QD” should not be used because it is often read as “QID,” resulting in four daily doses instead of one. Acronyms and abbreviations such as “ASA” (aspirin), “5-ASA” (5aminosalicylic acid), “6MP” (6-mercaptopurine), etc, should not be used; drug names should be written out. Unclear handwriting can be lethal when drugs with similar names but very different effects are available, eg, acetazolamide and acetohexamide, methotrexate and metolazone. In this situation, errors are best avoided by noting the indication for the drug in the body of the prescription, eg, “acetazolamide, for glaucoma.”

INAPPROPRIATE DRUG PRESCRIPTIONS Prescribing an inappropriate drug for a particular patient often results from failure to recognize contraindications imposed by other diseases the patient may have, failure to obtain information about other drugs the patient is taking (including over-the-counter drugs), or failure to recognize possible physicochemical incompatibilities between drugs that may react with each other. Contraindications to drugs

in the presence of other diseases or pharmacokinetic characteristics are listed in the discussions of the drugs described in this book. The manufacturer’s package insert usually contains similar information. Some of the important drug interactions are listed in Chapter 66 of this book as well as in package inserts.

Physicochemical incompatibilities are of particular concern when parenteral administration is planned. For example, certain insulin preparations should not be mixed. Similarly, the simultaneous administration of antacids or products high in metal content may compromise the absorption of many drugs in the intestine, eg, tetracyclines. The package insert and the Handbook on Injectable Drugs (see References) are good sources for this information.

E-PRESCRIBING Electronic prescribing of prescriptions is gaining momentum in the USA. Congress has passed legislation to support this health care initiative. E-prescribing provides an electronic flow of information between the prescriber, intermediary, pharmacy, and health plan. The health plan can provide information on patient eligibility, formulary, benefits, costs, and sometimes, a medication history. The prescriber selects the medication, strength, dosage form, quantity, and directions for use and the prescription is transmitted to the pharmacy where the appropriate data fields are populated. The pharmacist reviews the order and, if appropriate, dispenses the prescription. The electronic system must be Health Insurance Portability and Accountability Act (HIPAA)-compliant, and there needs to be a business association agreement between the pharmacy and insurance plan involved.

Prescribers can obtain decision support information such as disease-drug and drug-drug interaction information or cost information prior to prescribing as part of the health plan information. Prescriptions can be clear in their writing, but pull-down drug lists can create new errors. Prescription renewals can be processed electronically and drug misuse or abuse may be identifiable. Theoretically, time to process prescription orders should be reduced and patients would have their medication ready when they arrive at the pharmacy.

The Drug Enforcement Administration has begun to issue tentative rules for e-prescribing of controlled substances. Currently, only registered prescribers can e-prescribe, and there will be several independent identification proofing sources required: a unique pin number, or retinal scan, or a finger print. The objective is to prevent drug diversion. Pharmacies currently can order controlled drugs via computer using a specific form once they are certified (Controlled Substances Ordering System).

COMPLIANCE Compliance (sometimes called adherence) is the extent to which patients follow treatment instructions. There are four types of noncompliance leading to medication errors and increased health care costs.

1. The patient fails to obtain the medication. Some studies suggest that one third of patients never have their prescriptions filled. Some patients leave the hospital without obtaining their discharge medications, whereas others leave the hospital without having their prehospitalization medications resumed. Some patients cannot afford the medications prescribed.

2. The patient fails to take the medication as prescribed. Examples include wrong dosage, wrong frequency of administration, improper timing or sequencing of administration, wrong route or technique of administration, or taking medication for the wrong purpose. This usually results from inadequate communication between the patient, the prescriber, and the pharmacist.

3. The patient prematurely discontinues the medication. This can occur, for instance, if the patient incorrectly assumes that the medication is no longer needed because the bottle is empty or symptomatic improvement has occurred.

4. The patient (or another person) takes medication inappropriately. For example, the patient may share a medication with others for any of several reasons.

Several factors encourage noncompliance. Some diseases cause no symptoms (eg, hypertension); patients with these diseases therefore have no symptoms to remind them to take their medications. Patients with painful conditions such as arthritis may continually change medications in the hope of finding a better one. Characteristics of the therapy itself can limit the degree of compliance; patients taking a drug once a day are much more likely to be compliant than those taking a drug four times a day. Various patient factors also play a role in compliance. Patients living alone are much less likely to be compliant than married patients of the same age. Packaging may also be a deterrent to compliance—elderly arthritic patients often have difficulty opening their medication containers. Lack of transportation as well as various cultural or personal beliefs about medications are likewise barriers to compliance.

Strategies for improving compliance include enhanced communication between the patient and health care team members; assessment of personal, social, and economic conditions (often reflected in the patient’s lifestyle); development of a routine for taking medications (eg, at mealtimes if the patient has regular meals); provision of systems to assist taking medications (ie, containers that separate drug doses by day of the week, or medication alarm clocks that remind patients to take their medications); and mailing of refill reminders by the pharmacist to patients taking drugs chronically. The patient who is likely to discontinue a medication because of a perceived drug-related problem should receive instruction about how to monitor and understand the effects of the medication.

Compliance can often be improved by enlisting the patient’s active participation in the treatment.

LEGAL FACTORS (USA) The United States government recognizes two classes of drugs: (1) over-the-counter (OTC) drugs and (2) those that require a prescription from a licensed prescriber (Rx Only). OTC drugs are those that can be safely self-administered by the layman for selflimiting conditions and for which appropriate labels can be written for lay comprehension (see Chapter 63). Half of all drug doses consumed by the American public are OTC drugs.

Physicians, dentists, podiatrists, and veterinarians—and, in many states, specialized pharmacists, nurses, physician’s assistants, and optometrists—are granted authority to prescribe dangerous drugs (those bearing the federal legend statement, “Rx Only”) on the basis of their training in diagnosis and treatment (see Box: Who May Prescribe?). Pharmacists are authorized to dispense prescriptions pursuant to a prescriber’s order provided that the medication order is appropriate and rational for the patient. Nurses are authorized to administer medications to patients subject to a prescriber’s order.

Because of the multiplicity of third-party payers (health insurers) and Medicare and Medicaid claimants, the concept of electronic processing of prescriptions (“e-prescribing”) has become urgent. (Further information about e-prescribing may be found at http://www.cms.gov/Medicare/E-Health/Eprescribing/.) To further standardize electronic prescription transmission and billing, the Centers for Medicare and Medicaid (CMS) issued regulations effective in 2008 requiring all US health care providers to obtain a National Provider Identification (NPI) number. This 10-digit identifier is issued by the National Plan and Provider Enumeration System (NPPES) at https://NPPES.cms.hhs.gov. The purpose of the NPI is to identify all health care transactions (and associated costs) incurred by a particular practitioner with a single number.

In addition to a health care provider’s unique identification number, some states require that prescriptions for controlled substances be written on tamper-resistant security prescription forms. The purpose of this legislation is to prevent forgeries and to tighten the control of prescription order forms.

The concept of a “secure” prescription form was expanded by the federal government in 2008 to all prescriptions written for Medicaid patients. Any prescription for a Medicaid patient must be written on a security form if the pharmacist is to be compensated for the prescription service. In turn, the use of “triplicate” prescription forms was eliminated and replaced with an online electronic transmission system whereby orders for Schedule II and Schedule III prescriptions are transmitted to a company that acts as a repository for these transactions. In California, it is called the CURES program (Controlled Substances Utilization Review and Evaluation System).

Additional information about CURES may be found at http://oag.ca.gov/cures-pdmp.

In the USA, prescription drugs are controlled by the FDA as described in 1. The federal legend statement as well as the package insert is part of the packaging requirements for all prescription drugs. The package insert is the official brochure setting forth the indications, contraindications, warnings, and dosing for the drug.

The prescriber, by writing and signing a prescription order, controls who may obtain prescription drugs. The pharmacist may purchase these drugs, but they may be dispensed only on the order of a legally qualified prescriber. Thus, a prescription is actually three things: the prescriber’s order in the patient’s chart, the written order to which the pharmacist refers when dispensing, and the patient’s medication container with a label affixed.

Whereas the federal government controls the drugs and their labeling and distribution, the state legislatures control who may prescribe drugs through their licensing boards, eg, the Board of Medical Examiners. Prescribers must pass examinations, pay fees, and— in the case of some states and some professions—meet other requirements for relicensure such as continuing education. If these requirements are met, the prescriber is licensed to order dispensing of drugs.

The federal government and the states further impose special restrictions on drugs according to their perceived potential for abuse (Table 65–2). Such drugs include opioids, hallucinogens, stimulants, depressants, and anabolic steroids. Special requirements must be met when these drugs are to be prescribed. The Controlled Drug Act requires prescribers and dispensers to register with the Drug Enforcement Agency (DEA), pay a fee, receive a personal registration number, and keep records of all controlled drugs prescribed or dispensed. Every time a controlled drug is prescribed, a valid DEA number must appear on the prescription blank.

TABLE 65–2 Classification of controlled substances. (See Inside Front Cover for examples.)

Who May Prescribe?

The right to prescribe drugs has traditionally been the responsibility of the physician, dentist, podiatrist, or veterinarian. Prescribing now includes—in a number of states and in varying degrees—pharmacists, nurse practitioners, nurse midwives, physician’s assistants, and optometrists (see below). In the future, physical therapists may be licensed to prescribe drugs relevant to their practice. The development of large health maintenance organizations has greatly strengthened this expansion of prescribing rights because it offers these extremely powerful economic bodies a way to reduce their expenses.

The primary organizations controlling the privilege of prescribing in the USA are the state boards, under the powers delegated to them by the state legislatures. Many state boards have attempted to reserve some measure of the primary responsibility for prescribing to physicians by requiring that the ancillary professional work with or under a physician according to a specific protocol.

In the state of California, this protocol must include a statement of the training, supervision, and documentation requirements of the arrangement and must specify referral requirements, limitations to the list of drugs that may be prescribed (ie, a formulary), and a method of evaluation by the supervising physician. The protocol must be in writing and must be periodically updated.

The following rules govern prescribing by non-physicians in the various states at the time of this writing: In almost all states, nurse practitioners (NPs) and physician assistants (PAs) may prescribe with or without physician supervision depending on the state. Likewise, optometrists may prescribe selected formulary drugs for ophthalmological indications.

Pharmacists can initiate prescriptions in three states: Montana, New Mexico, and North Carolina. They may practice with physicians in collaborative drug therapy management (CDTM) programs in 47 states—all except New York, Maine, Oklahoma, and Alabama. Pharmacists may prescribe controlled substances under physician supervision in California, Massachusetts, Montana, New Mexico, North Carolina, North Dakota, and Washington.

New Mexico grants prescribing authority to medical psychologists with advanced training.

Prescriptions for substances with a high potential for abuse (Schedule II drugs) cannot be refilled without a new prescription.

However, multiple prescriptions for the same drug may be written with instructions not to dispense before a certain date and up to a total of 90 days. Prescriptions for Schedules III, IV, and V can be refilled if ordered, but there is a five-refill maximum, and in no case may the prescription be refilled after 6 months from the date of writing. Schedule II drug orders may not be transmitted over the telephone, and some states require a tamper-resistant security prescription blank to reduce the chances for drug diversion.

These restrictive prescribing laws are intended to limit the amount of drugs of abuse that are made available to the public.

Unfortunately, the inconvenience occasioned by these laws—and an unwarranted fear by medical professionals themselves regarding the risk of patient tolerance and addiction—continues to hamper adequate treatment of patients with terminal conditions. This has been shown to be particularly true in children and elderly patients with cancer. There is no excuse for inadequate treatment of pain in a terminal patient; not only is addiction irrelevant in such a patient, it is actually uncommon in patients who are being treated for pain (see Chapter 31).

Some states have recognized the underutilization of pain medications in the treatment of pain associated with chronic and terminal conditions. California, for example, has enacted an “intractable pain treatment” act that reduces the difficulty of renewing prescriptions for opioids. Under the provisions of this act, upon receipt of a copy of the order from the prescriber, eg, by fax, a pharmacist may write a prescription for a Schedule II substance for a patient under hospice care or living in a skilled nursing facility or in cases in which the patient is expected to live less than 6 months, provided that the prescriber countersigns the order (by fax); the word “exemption” with

regulatory code number is written on a typical prescription, thus providing easier access for the terminally ill.

Labeled & Off-Labeled Uses of Drugs In the USA, the FDA approves a drug only for the specific uses proposed and documented by the manufacturer in its New Drug Application (see Chapter 1). These approved (labeled) uses or indications are set forth in the package insert that accompanies the drug.

For a variety of reasons, these labeled indications may not include all the conditions in which the drug might be useful. Therefore, a clinician may wish to prescribe the agent for some other, unapproved (off-label), clinical condition, often on the basis of adequate or even compelling scientific evidence. Federal laws governing FDA regulations and drug use place no restrictions on such unapproved use.* Even if the patient suffers injury from the drug, its use for an unlabeled purpose does not in itself constitute “malpractice.” However, the courts may consider the package insert labeling as a complete listing of the indications for which the drug is considered safe unless the clinician can show that other use is considered safe by competent expert testimony.

Drug Safety Surveillance Governmental drug-regulating agencies have responsibility for monitoring drug safety. In the USA, the FDA-sponsored Med Watch program collects data on safety and adverse drug effects (ADEs) through mandatory reporting by drug manufacturers and voluntary reporting by health care practitioners. Practitioners may submit reports on any suspected adverse drug (or medical device) effect using a simple form obtainable from http://www.fda.gov/medwatch/index.html. The FDA is expected to use these data to establish an adverse effect rate. It is not clear that the FDA has sufficient resources at present to carry out this mandate, but they are empowered to take further regulatory actions if deemed necessary. A similar vaccine reporting program is in place to monitor vaccine safety. The FDA home page can be found at http://www.fda.gov/default.htm.

The FDA has also increased requirements for labeling on drugs that carry special risks. Dispensers of medications are required to distribute “Med Guides” to patients when these medications are dispensed. These guides are generated by the manufacturers of the medications. In addition, pharmacists often provide patient educational materials that describe the drug, its use, adverse effects, storage requirements, methods of administration, what to do when a dose is missed, and the potential need for ongoing therapy.

SOCIOECONOMIC FACTORS Generic Prescribing Prescribing by generic name offers the pharmacist flexibility in selecting the particular drug product to fill the order and offers the patient a potential savings when there is price competition. For example, the brand name of a popular sedative is Valium, manufactured by Hoffmann-LaRoche. The generic (public nonproprietary) name of the same chemical substance adopted by United States Adopted Names (USAN) and approved by the FDA is diazepam. All diazepam drug products in the USA meet the pharmaceutical standards expressed in the United States Pharmacopeia (USP). However, there are several manufacturers, and prices vary greatly. For drugs in common use, the difference in cost between the trade-named product and generic products varies from less than twofold to more than 100-fold.

In most states and in most hospitals, pharmacists have the option of supplying a generically equivalent drug product even if a proprietary name has been specified in the order. If the prescriber wants a particular brand of drug product dispensed, handwritten instructions to “dispense as written” or words of similar meaning are required. Some government-subsidized health care programs and many third-party insurance payers require that pharmacists dispense the cheapest generically equivalent product in the inventory (generic substitution). However, the principles of drug product selection by private pharmacists do not permit substituting one therapeutic agent for another (therapeutic substitution); that is, dispensing trichlormethiazide for hydrochlorothiazide would not be permitted without the prescriber’s permission even though these two diuretics may be considered pharmacodynamically equivalent. Pharmacists within managed care organizations may follow different policies; see below.

It cannot be assumed that every generic drug product is as satisfactory as the trade-named product, although examples of unsatisfactory generics are rare. Bioavailability—the effective absorption of the drug product—varies between manufacturers and sometimes between different lots of a drug produced by the same manufacturer. In spite of the evidence, many practitioners avoid generic prescribing, thereby increasing medical costs. In the case of a very small number of drugs, which usually have a low therapeutic index, poor solubility, or a high ratio of inert ingredients to active drug content, a specific manufacturer’s product may give more consistent results. In the case of life-threatening diseases, the advantages of generic substitution may be outweighed by the clinical urgency so that the prescription should be filled as written.

In an effort to codify bioequivalence information, the FDA publishes Approved Drug Products with Therapeutic Equivalence Evaluations, with monthly supplements, commonly called “the Orange Book.” The book contains listings of multi-source products in one of two categories: Products given a code beginning with the letter “A” are considered bioequivalent to a reference standard formulation

of the same drug and to all other versions of that product with a similar “A” coding. Products not considered bioequivalent are coded “B.” Of the approximately 8000 products currently listed, 90% are coded “A.” Additional code letters and numerals are appended to the initial “A” or “B” and indicate the approved route of administration and other variables.

Mandatory drug product selection on the basis of price is common practice in the USA because third-party payers (insurance companies, health maintenance organizations, etc) enforce money-saving regulations. If outside a managed care organization, the prescriber can sometimes override these controls by writing “dispense as written” on a prescription that calls for a brand-named product.

However, in such cases, the patient may have to pay the difference between the dispensed product and the cheaper one.

Within most managed care organizations, formulary controls have been put in place that force the selection of less expensive medications whenever they are available. In a managed care environment, the prescriber often selects the drug group rather than a specific agent, and the pharmacist dispenses the formulary drug from that group. For example, if a prescriber in such an organization decides that a patient needs a thiazide diuretic, the pharmacist automatically dispenses the single thiazide diuretic carried on the organization’s formulary. As noted below, the choice of drugs for the organization’s formulary may change from time to time, depending on negotiation of prices and rebates with different manufacturers.

Other Cost Factors The private pharmacy bases its charges on the cost of the drug plus a fee for providing a professional service. Each time a prescription is dispensed, there is a fee. The prescriber controls the frequency of filling prescriptions by authorizing refills and specifying the quantity to be dispensed. However, for medications used for chronic illnesses, the quantity covered by insurance may be limited to the amount used in 1 month or 30 days. Thus, the prescriber can save the patient money by prescribing standard sizes (so that drugs do not have to be repackaged) and, when chronic treatment is involved, by ordering the largest quantity consistent with safety, expense, and third-party plan. Optimal prescribing for cost savings often involves consultation between the prescriber and the pharmacist. Because of continuing increases in the wholesale prices of drugs in the USA, prescription costs have risen dramatically over the past 3 decades; and from 1999 to 2009, the number of prescriptions purchased has increased 39% while the population grew 9% (see Box: The Cost of Prescriptions).

The Cost of Prescriptions The cost of prescriptions has risen dramatically in the last several decades. The average price for a single prescription in the USA in 2004 was $55. By 2006, this average cost had risen to $75. In the California Medicaid Sector, the average charge was over $80, with generic products being under $40 per prescription and brand-name products over $140. This rise is occasioned by new technology, marketing costs, and stockholder expectations. The pharmaceutical industry typically posts profits of 10–15% annually, whereas the retail business sector shows a 3% profit. The cost to the patient for many new drugs such as statins exceeds $1000 per year. The cost of some therapeutic antibody products (eg, MABs) is more than $10,000 per year. Pharmaceuticals tend to be the highest out-of-pocket health-related cost because other health care services are covered by health insurance, whereas prescriptions often are not, although this is changing.

Because of public and political pressure resulting from this problem, the US Congress enacted the Medicare Modernization Act in 2003 establishing the Medicare Part D plan. This voluntary prescription plan provides for partial payment by private medical insurance companies for some prescriptions for patients who are Medicare-eligible. Unfortunately, the complexity of the legislation and the resulting confusing insurance plans with gaps in coverage, formulary and quantity limits, and the favored economic treatment given the pharmaceutical industry, prevent this plan from solving the high drug cost problem.

High drug costs have caused payers and consumers alike to do without or seek alternative sources. Because most other governments, eg, Canada, have done a better job in controlling drug prices, the prices for the same drug are usually less in other countries than those in the United States. This fact has caused many U.S. citizens to purchase their drugs “off-shore” in a variety of countries for “personal use” in quantities up to a 3-month supply—at substantial savings, often as much as 50%. However, there is no assurance that these drugs are always what they are purported to be, or that they will be delivered in a timely manner, or that there is a traditional doctor-pharmacist-patient relationship and the safeguards that such a relationship offers.

Without a true universal health care program, the cost of drugs in the USA will continue to be subject to the negotiating power (or lack thereof) of the purchasing group-insurance company, hospital consortium, HMO, small retail pharmacy, etc, and will be driven primarily by the economic policies of the large manufacturers. In most companies, these policies favor executive compensation and stockholder dividends above the interests of consumers or employees. Thus far, only the US Veterans Administration system, the larger HMOs, and a few “big box” stores have proved strong enough to control costs through bulk purchases of drugs and serious negotiation of prices with manufacturers. Until new legislation gives other organizations the same power to negotiate, or pricing policies are made more equitable, no real solution to the drug cost problem can be expected.

REFERENCES

American Pharmacists Association and T he National Association of Chain Drug Stores: MT M in Pharmacy Practice, Core Elements v. 2, 2008.

Avorn J: Part “ D” for “ defective”—T he Medicare drug benefit chaos. N Engl J Med 2006;354:1339.

Bell D: A toolset for e-prescribing implementation. Rand Health, US AHRQ, 2011.

California Business and Professions Code, Chapter 9, Division 2, Pharmacy Law. Department of Consumer Affairs, Sacramento, California, 2011.

Graber MA, Easton-Carr R: Poverty and pain: Ethics and the lack of opioid pain medications in fixed-price, low-cost prescription plans. Ann Pharmacother 2008;42:1913.

Hendrickson R (editor): Remington’s Practice and Science of Pharmacy. Advanced Concepts Institute, 2005.

Institute for Safe Medication Practices-ISMP. http://www.ismp.org.

Jerome JB, Sagan P: T he USAN nomenclature system. JAMA 1975;232:294.

Kesselheim AS et al: Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: A systematic review and meta-analysis. JAMA 2008;300:2514.

Prescription drug costs. http://www.kaiseredu.org/Issue-Modules/Prescription-Drug-Costs/Background-Brief.aspx.

Schnipper JL et al: Role of pharmacist counseling in preventing adverse drug events after hospitalization. Arch Intern Med 2006;166:565.

Schumock GT et al: National trends in prescription drug expenditures and projections for 2014. Am J Health Syst Pharm. 2014 Mar 15;71:482 T rissel LA: Handbook on Injectable Drugs, 13th ed. American Society of Hospital Pharmacists, 2005. ( With supplements.)

_______________ * “ Once a product has been approved for marketing, a physician may prescribe it for uses or in treatment regimens or patient populations that are not included in the approved labeling. Such ‘unapproved’ or, more precisely, ‘unlabeled’ uses may be appropriate and rational in certain circumstances, and may, in fact, reflect approaches to drug therapy that have been extensively reported in medical literature.”—FDA Drug Bull 1982;12:4.

CHAPTER

66 Important Drug Interactions & Their Mechanisms John R. Horn, PharmD, FCCP

One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorized as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic (additive, synergistic, or antagonistic effects), or combined interactions. The general principles of pharmacokinetics are discussed in Chapters 3 and 4; the general principles of pharmacodynamics in Chapter 2.

Botanical medications (“herbals”) may interact with each other or with conventional drugs. Unfortunately, botanicals are much less well studied than other drugs, so information about their interactions is scanty. Pharmacodynamic herbal interactions are described in Chapter 64. Pharmacokinetic interactions that have been documented (eg, St. John’s wort) are listed in Table 66–1.

TABLE 66-1 Important drug interactions.

Knowledge of the mechanism by which a given drug interaction occurs is often clinically useful, since the mechanism may influence both the time course and the methods of circumventing the interaction. Some important drug interactions occur as a result of two or more mechanisms.

PREDICTABILITY OF DRUG INTERACTIONS The designations listed in Table 66â&#x20AC;&#x201C;1 are used here to estimate the predictability of the drug interactions. These estimates are intended to indicate simply whether or not the interaction will occur, and they do not always mean that the interaction is likely to produce an adverse effect. Whether or not the interaction occurs (precipitant drug produces a measurable change in the object drug) and produces an adverse effect depends on both patient- and drug-specific factors. Patient factors can include intrinsic drug clearance, genetics, gender, concurrent diseases, and diet. Drug-specific factors include dose, route of administration, drug formulation, and the sequence of drug administration. The most important factor that can mitigate the risk of patient harm is recognition by the prescriber of a potential interaction followed by appropriate action.

PHARMACOKINETIC MECHANISMS The gastrointestinal absorption of drugs may be affected by concurrent use of other agents that (1) have a large surface area upon which the drug can be adsorbed, (2) bind or chelate, (3) alter gastric pH, (4) alter gastrointestinal motility, or (5) affect transport proteins such as P-glycoprotein and organic anion transporters. One must distinguish between effects on absorption rate and effects on extent of absorption. A reduction in only the absorption rate of a drug is seldom clinically important, whereas a reduction in the extent of absorption is clinically important if it results in subtherapeutic serum concentrations.

The mechanisms by which drug interactions alter drug distribution include (1) competition for plasma protein binding, (2) displacement from tissue binding sites, and (3) alterations in local tissue barriers, eg, P-glycoprotein inhibition in the blood-brain barrier.

Although competition for plasma protein binding can increase the free concentration (and thus the effect) of the displaced drug in plasma, the increase will be transient owing to a compensatory increase in drug disposition. The clinical importance of protein binding displacement has been overemphasized; current evidence suggests that such interactions are unlikely to result in adverse effects.

Displacement from tissue binding sites would tend to transiently increase the blood concentration of the displaced drug.

The metabolism of drugs can be stimulated or inhibited by concurrent therapy, and the importance of the effect varies from negligible to dramatic. Drug metabolism primarily occurs in the liver and the wall of the small intestine, but other sites include plasma, lung, and kidney. Induction (stimulation) of cytochrome P450 isozymes in the liver and small intestine can be caused by drugs such as barbiturates, bosentan, carbamazepine, efavirenz, nevirapine, phenytoin, primidone, rifampin, rifabutin, and St. Johnâ&#x20AC;&#x2122;s wort. Enzyme inducers can also increase the activity of phase II metabolism such as glucuronidation. Enzyme induction does not take place quickly; maximal effects usually occur after 7â&#x20AC;&#x201C;10 days and require an equal or longer time to dissipate after the enzyme inducer is stopped.

Rifampin, however, may produce enzyme induction after only a few doses. Inhibition of metabolism generally takes place more quickly than enzyme induction and may begin as soon as sufficient tissue concentration of the inhibitor is achieved. However, if the half-life of the affected (object) drug is long, it may take a week or more (three to four half-lives) to reach a new steady-state serum concentration.

Drugs that may inhibit the cytochrome P450 metabolism of other drugs include amiodarone, androgens, atazanavir, chloramphenicol, cimetidine, ciprofloxacin, clarithromycin, cyclosporine, delavirdine, diltiazem, diphenhydramine, disulfiram, enoxacin, erythromycin, fluconazole, fluoxetine, fluvoxamine, furanocoumarins (substances in grapefruit juice), indinavir, isoniazid, itraconazole, ketoconazole, metronidazole, mexiletine, miconazole, omeprazole, paroxetine, quinidine, ritonavir, sulfamethizole, sulfamethoxazole, verapamil, voriconazole, zafirlukast, and zileuton.

The renal excretion of active drug can also be affected by concurrent drug therapy. The renal excretion of certain drugs that are weak acids or weak bases may be influenced by other drugs that affect urinary pH. This is due to changes in ionization of the drug, as described in 1 under Ionization of Weak Acids and Weak Bases; the Henderson-Hasselbalch Equation. For some drugs, active secretion into the renal tubules is an important elimination pathway. P-glycoprotein, organic anion transporters, and organic cation transporters are involved in active tubular secretion of some drugs, and inhibition of these transporters can inhibit renal elimination with attendant increase in serum drug concentrations. Drugs that are partially eliminated by P-glycoprotein include digoxin, cyclosporine, dabigatran, colchicine, daunorubicin, and tacrolimus. The plasma concentration of these drugs can be increased by inhibitors of P-glycoprotein including amiodarone, clarithromycin, erythromycin, ketoconazole, ritonavir, and quinidine.

PHARMACODYNAMIC MECHANISMS When drugs with similar pharmacologic effects are administered concurrently, an additive or synergistic response is usually seen. The two drugs may or may not act on the same receptor to produce such effects. In theory, drugs acting on the same receptor or process are usually additive, eg, benzodiazepines plus barbiturates. Drugs acting on different receptors or sequential processes may be synergistic, eg,

nitrates plus sildenafil or sulfonamides plus trimethoprim. Conversely, drugs with opposing pharmacologic effects may reduce the response to one or both drugs. Pharmacodynamic drug interactions are relatively common in clinical practice, but adverse effects can usually be minimized if one understands the pharmacology of the drugs involved. In this way, the interactions can be anticipated and appropriate counter-measures taken.

COMBINED TOXICITY The combined use of two or more drugs, each of which has toxic effects on the same organ, can greatly increase the likelihood of organ damage. For example, concurrent administration of two nephrotoxic drugs can produce kidney damage, even though the dose of either drug alone may have been insufficient to produce toxicity. Furthermore, some drugs can enhance the organ toxicity of another drug, even though the enhancing drug has no intrinsic toxic effect on that organ.

REFERENCES Boobis A et al: Drug interactions. Drug Metab Rev 2009;41:486.

DeGorter MK et al: Drug transporters in drug efficacy and toxicity. Annu Rev Pharmacol T oxicol 2012;52:249.

DuBuske LM: T he role of P-glycoprotein and organic anion-transporting polypeptides in drug interactions. Drug Saf 2005;28:789.

Hansten PD, Horn JR: Drug Interactions Analysis and Management. Facts & Comparisons. 2013. [Quarterly.]

Hansten PD, Horn JR: The Top 100 Drug Interactions. A Guide to Patient Management. H&H Publications, 2014.

Hillgren KM et al: Emerging transporters of clinical importance: An update from the international transporter consortium. Clin Pharmacol T her 2013;94:52.

Horn JR et al: Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41:674.

Hukkanen J: Induction of cytochrome P450 enzymes: A view on human in vivo findings. Expert Rev Clin Pharmacol 2012;5:569.

Juurlink DN et al: Drug-drug interactions among elderly patients hospitalized for drug toxicity. JAMA 2003;289:1652.

Leucuta SE, Vlase L: Pharmacokinetics and metabolic drug interactions. Curr Clin Pharmacol 2006;1:5.

Lin JH, Yamazaki M: Role of P-glycoprotein in pharmacokinetics: Clinical implications. Clin Pharmacokinet 2003;42:59.

Pelkonen O et al: Inhibition and induction of human cytochrome P450 enzymes: Current status. Arch T oxicol 2008;82:667.

Roberts JA, et al: T he clinical relevance of plasma protein binding changes. Clin Pharmacokinet 2013;52:1.

T atro DS (editor): Drug Interaction Facts. Facts & Comparisons. 2011. [ Quarterly.]

T helen K, Dressman JB: Cytochrome P540-mediated metabolism in the human gut wall. J Pharm Pharmacol 2009;61:541.

Williamson EM: Drug interactions between herbal and prescription medicines. Drug Saf 2003;26:1075.

Appendix: Vaccines, Immune Globulins, & Other Complex Biologic Products Harry W. Lampiris, MD, & Daniel S. Maddix, PharmD

Vaccines and related biologic products constitute an important group of agents that bridge the disciplines of microbiology, infectious diseases, immunology, and immunopharmacology. A list of the most important preparations is provided here. The reader who requires more complete information is referred to the sources listed at the end of this appendix.

ACTIVE IMMUNIZATION Active immunization consists of the administration of antigen to the host to induce formation of antibodies and cell-mediated immunity.

Immunization is practiced to induce protection against many infectious agents and may utilize either inactivated (killed) materials or live attenuated agents (Table Aâ&#x20AC;&#x201C;1). Desirable features of the ideal immunogen include complete prevention of disease, prevention of the carrier state, production of prolonged immunity with a minimum of immunizations, absence of toxicity, and suitability for mass immunization (eg, cheap and easy to administer). Active immunization is generally preferable to passive immunizationâ&#x20AC;&#x201D;in most cases because higher antibody levels are sustained for longer periods of time, requiring less frequent immunization, and in some cases because of the development of concurrent cell-mediated immunity. However, active immunization requires time to develop and is therefore generally inactive at the time of a specific exposure (eg, for parenteral exposure to hepatitis B, concurrent hepatitis B IgG [passive antibodies] and active immunization are given to prevent illness).

TABLE Aâ&#x20AC;&#x201C;1 Materials commonly used for active immunization in the United States.1

Current recommendations for routine active immunization of children are given in Table Aâ&#x20AC;&#x201C;2.

TABLE Aâ&#x20AC;&#x201C;2 Recommended routine childhood immunization schedule.

PASSIVE IMMUNIZATION Passive immunization consists of transfer of immunity to a host using preformed immunologic products. From a practical standpoint, only immunoglobulins have been used for passive immunization, because passive administration of cellular components of the immune system has been technically difficult and associated with graft-versus-host reactions. Products of the cellular immune system (eg, interferons) have also been used in the therapy of a wide variety of hematologic and infectious diseases (see Chapter 55).

Passive immunization with antibodies may be accomplished with either animal or human immunoglobulins in varying degrees of purity.

These may contain relatively high titers of antibodies directed against a specific antigen or, as is true for pooled immune globulin, may simply contain antibodies found in most of the population. Passive immunization is useful for (1) individuals unable to form antibodies (eg, congenital agammaglobulinemia); (2) prevention of disease when time does not permit active immunization (eg, postexposure); (3) for treatment of certain diseases normally prevented by immunization (eg, tetanus); and (4) for treatment of conditions for which active immunization is unavailable or impractical (eg, snakebite).

Complications from administration of human immunoglobulins are rare. The injections may be moderately painful and rarely a sterile abscess may occur at the injection site. Transient hypotension and pruritus occasionally occur with the administration of intravenous immune globulin (IVIG) products, but generally are mild. Individuals with certain immunoglobulin deficiency states (IgA deficiency, etc) may occasionally develop hypersensitivity reactions to immune globulin that may limit therapy. Conventional immune globulin contains aggregates of IgG; it will cause severe reactions if given intravenously. However, if the passively administered antibodies are derived from animal sera, hypersensitivity reactions ranging from anaphylaxis to serum sickness may occur. Highly purified immunoglobulins, especially from rodents or lagomorphs, are the least likely to cause reactions. To avoid anaphylactic reactions, tests for hypersensitivity to the animal serum must be performed. If an alternative preparation is not available and administration of the specific antibody is deemed essential, desensitization can be carried out.

Antibodies derived from human serum not only avoid the risk of hypersensitivity reactions but also have a much longer half-life in humans (about 23 days for IgG antibodies) than those from animal sources (5â&#x20AC;&#x201C;7 days or less). Consequently, much smaller doses of human antibody can be administered to provide therapeutic concentrations for several weeks. These advantages point to the desirability of using human antibodies for passive protection whenever possible. Materials available for passive immunization are summarized in Table Aâ&#x20AC;&#x201C;3.

TABLE Aâ&#x20AC;&#x201C;3 Materials available for passive immunization.1

LEGAL LIABILITY FOR UNTOWARD REACTIONS It is the physician’s responsibility to inform the patient of the risk of immunization and to use vaccines and antisera in an appropriate manner. This may require skin testing to assess the risk of an untoward reaction. Some of the risks previously described are, however, currently unavoidable; on balance, the patient and society are clearly better off accepting the risks for routinely administered immunogens (eg, influenza and tetanus vaccines).

Manufacturers should be held legally accountable for failure to adhere to existing standards for production of biologicals. However, in the present litigious atmosphere of the USA, the filing of large liability claims by the statistically inevitable victims of good public health practice has caused many manufacturers to abandon efforts to develop and produce low-profit but medically valuable therapeutic agents such as vaccines. Since the use and sale of these products are subject to careful review and approval by government bodies such as the Surgeon General’s Advisory Committee on Immunization Practices and the FDA, “strict product liability” (liability without fault) may be an inappropriate legal standard to apply when rare reactions to biologicals, produced and administered according to government guidelines, are involved.

RECOMMENDED IMMUNIZATION OF ADULTS FOR TRAVEL Every adult, whether traveling or not, should be immunized with tetanus toxoid and should also be fully immunized against poliomyelitis, measles (for those born after 1956), and diphtheria. In addition, every traveler must fulfill the immunization requirements of the health authorities of the countries to be visited. These are listed in Health Information for International Travel, available from the Superintendent of Documents, United States Government Printing Office, Washington, DC 20402. A useful website is http://wwwnc.cdc.gov/travel/. The Medical Letter on Drugs and Therapeutics also offers periodically updated recommendations for international travelers (see Treatment Guidelines from The Medical Letter, 2012;10:45). Immunizations received in preparation for travel should be recorded on the International Certificate of Immunization. Note: Smallpox vaccination is not recommended or required for travel in any country.

REFERENCES Ada G: Vaccines and vaccination. N Engl J Med 2001;345:1042.

Advice for travelers. T reat Guidel Med Lett 2012;10:45.

Avery RK: Immunizations in adult immunocompromised patients: Which to use and which to avoid. Cleve Clin J Med 2001;68:337.

CDC websites: http://www.cdc.gov/vaccines/ and http://wwwnc.cdc.gov/travel/ Centers for Disease Control and Prevention: Advisory Committee on Immunization Practices (ACIP) recommended immunization schedules for persons aged 0 through 18 years and adults aged 19 years and older—United States, 2013. MMWR Morb Mortal Wkly Rep 2013:62(Suppl 1):1.

Dennehy PH: Active immunization in the United States: Developments over the past decade. Clin Micro Rev 2001;14:872.

Gardner P, Peter G: Vaccine recommendations: Challenges and controversies. Infect Dis Clin North Am 2001;15:1.

Gardner P et al: Guidelines for quality standards for immunization. Clin Infect Dis 2002;35:503.

General recommendations on immunization. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2011;60(2):1.

Hill DR et al: T he practice of travel medicine: Guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2006;43:1499.

Keller MA, Stiehm ER: Passive immunity in prevention and treatment of infectious diseases. Clin Microbiol Rev 2000;13:602.

Pickering LK et al: Immunization programs for infants, children, adolescents, and adults: Clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis 2009;49:817.

Zumula A et al: T ravel medicine. Infect Dis Clin North Am 2012;26:575.

Index

Please note that index links point to page beginnings from the print edition. Locations are approximate in e-readers, and you may need to page down one or more times after clicking a link to get to the indexed material.

Note: In this index, the letters “b,” “f,” and “t” denote text box, figures, and tables, respectively.

A Abacavir, 842, 843t, 845 HLA polymorphisms in hypersensitivity reactions to, 77t, 79t, 83, 83t, 84f Abarelix, 654–655 Abatacept, 625–626, 962 Abbreviations, prescriptions, and chart order, 1111t ABC (ATP-binding cassette) family, 8 ABCG5 mutation, 607 ABCG8 mutation, 607 Abciximab, 585f, 596, 963 Abiraterone adrenocortical antagonist actions of, 681f, 693 antiandrogen actions of, 720, 721t for prostate cancer, 942 Abortion, eicosanoids for, 324–325 Absence seizures, 415. See also Seizures Absorption, 7 extent of, 47, 47f, 47t percutaneous, 1033, 1034f rate of, 47f, 48 on target concentration, 51–52 Abstinence syndrome, 537 Abuse, drug. See Drugs of abuse Acamprosate, for alcoholism, 392, 394t, 395t Acarbose, 738–739, 738t, 743t Acceptable daily intake (ADI), 972 Accumulation, drug, 46–47, 46f Accumulation factor, 47 Acebutolol, 160t, 162. See also β-receptor antagonist drugs for hypertension, 179 Acetaldehyde, metabolism of, 385f, 386 Acetaminophen, 65f, 634, 639t metabolism to toxic products of, 63, 65f poisoning management for, 65f, 1006–1007, 1007t preparations of, available, 639t safety of, case study on, 56, 73 Acetazolamide, 255–256, 255t, 267t for epilepsy, 414

Acetohexamide, 733–735, 743t. See also Sulfonylureas Acetylator, slow, 68 Acetylcholine (ACh). See also Neuromuscular blocking drugs in CNS, 362f, 364t, 366 functions of, 92t structure of, 107, 107f, 457f Acetylcholine-blocking drugs, for parkinsonism, 481, 481t, 487t Acetylcholinesterase (AChE), 92 cholinomimetics on, 106f, 107 Acetylcholinesterase inhibitors, 5 for Alzheimer’s disease, 117 Acidosis, metabolic hyperchloremic from carbonic anhydrase inhibitors, 255t, 256 from potassium-sparing diuretics, 261 hypokalemic from loop diuretics, 258 from thiazide diuretics, 260 Acid-peptic disease, 1052 Acid-peptic disease drugs, 1052–1061, 1079t intragastric acidity–reducing agents, 1052–1060, 1079t acid secretion in, physiology of, 1052–1053, 1053f antacids, 1053–1054 H2 -receptor antagonists, 1054–1056 proton-pump inhibitors, 1056–1060 mucosal protective agents bismuth compounds, 1061 mechanisms of, 1060 prostaglandin analogs, 1060–1061 sucralfate, 1060 Acid reducers, OTC H2 -antagonists, 1087t proton-pump inhibitors, 1087t Acid secretion, gastrointestinal, 1052–1053, 1053f Acid, weak examples of, 10t ionization of, 9 Acitretin, for psoriasis, 1043 Aclidinium, for COPD, 344, 349 Acne preparations antibacterial, 1036–1037 azelaic acid, 1042–1043 benzoyl peroxide, 1042 brimonidine, 1043 isotretinoin, 1042 OTC, 1087t retinoic acid derivatives, 1041–1042 Acquired immunodeficiency syndrome (AIDS), 954. See also Human immunodeficiency virus (HIV) Acromegaly, 648

dopamine agonists for, 656 Action potential–prolonging drugs (class 3), for arrhythmia, 239–241, 246t amiodarone, 235t, 236t, 239–240, 246t dofetilide, 235t, 236t, 241, 246t dronedarone, 235t, 236t, 240, 246t ibutilide, 235t, 236t, 241, 246t preparations, available, 247t sotalol, 235t, 236t, 240–241, 246t Action potentials cardiac, sodium channels in, 227–228, 227f resting potentials on, 228–229, 228f Activated charcoal, 1006 Activated partial thromboplastin time (aPTT, PTT), 588, 589 Activator. See also Antagonist; specific types allosteric, 5, 6f chloride channel, 1064, 1067–1068 tissue plasminogen, 587, 587f, 595 Active immunization, 1133 routine childhood, recommended schedule for, 1133, 1137t Activin in ovary, 708 in testis, 716 Acute colonic pseudo-obstruction, 1062 Acute coronary syndrome, 191–192 vasodilators for, 205 Acute dystonic reactions, from antipsychotics, 500–501 Acute heart failure. See also Heart failure treatment of, 220 Acute kidney injury, from diuretics, 249, 269 Acute lymphoblastic leukemia (ALL), childhood, 939 Acute mountain sickness, carbonic anhydrase inhibitors for, 255t, 256 Acute myelogenous leukemia (AML), 939, 944 Acute myocardial infarction from female hormonal contraceptives, 711 thrombolytics for, 594–595, 594b Acute renal failure, from potassium-sparing diuretics, 262 Acyclovir for HSV and VZV, 836–837, 837f, 838t topical dermatologic, 1039 Adalimumab for inflammatory bowel disease, 1075–1076, 1075t for psoriasis, 1044 for rheumatic disorders, 629, 630f Adapalene, for acne, 1042 Adaptive immune system, 947–950, 948f, 949f, 951f Addiction. See also Drugs of abuse animal models of, 553 clinical pharmacology of, 564 cocaine, 552, 566

definition of, 531 dopamine hypothesis of, 555b dopamine transporter in, 553, 554f, 556t as maladaptive learning, 555–557, 556f, 556t nicotine, 560–561 opioid, 543 receptors in, 553, 556f Gio protein-coupled, 553, 554f, 556f ionotropic, 553, 554f, 556f, 556t relapse in, 555–556 Addison’s disease case study of, 680, 695 corticosteroids for, 686–687 Adefovir dipivoxil, for hepatitis B, 857–858 Adenohypophysis, 643, 644f Adenosine for arrhythmia, 235t, 236t, 242–243, 247t in central nervous system, 368 on kidney, 254 vasodilator actions of, 203b Adenosine deaminase (ADA) deficiency, 953–954 Adenosine triphosphate (ATP) in central nervous system, 368 functions of, 92t Adenylyl cyclase, activation and inhibition of, 135, 136f Adherence, 1112–1113 Adjuvant chemotherapy, 920 Administration. See also specific drugs alternative routes of, first-pass effect in, 47t, 48 rate of, 51 Adrenal androgens, 692 Adrenal cortex, angiotensin II on, 297 Adrenal steroid inhibitors mineralocorticoid antagonists, 694 preparations, available, 695t synthesis inhibitors and glucocorticoid antagonists, 692–694 Adrenergic fibers, 88f, 90 Adrenergic neuron-blocking agents guanethidine, 175t, 177–178, 187t reserpine, 175t, 178, 187t Adrenergic neurons, 92, 93f, 94f cotransmitters in, 92t, 96 Adrenergic transmission, 92–96, 93f–95f Adrenoceptor, 96, 97t, 134–138 alpha, 134f, 135, 135t beta, 135–136, 135t, 136f biased agonists at, 137, 138b definition of, 96 desensitization of, 137

dopamine, 135t, 136–137 polymorphisms of, 138 regulation of, 137 selectivity and affinities of, 137, 137t structure of, 134, 134f Adrenoceptor antagonist drugs, 133–168, 150t. See also Sympathomimetic drugs alpha-receptor, 152–158, 166t, 167t (See also α adrenoreceptor antagonists) beta-receptor, 158–166, 166t–167t (See also β-receptor antagonist drugs) thyroid, 672 Adrenocortical antagonists, 692–694 mineralocorticoid antagonists, 694 preparations, available, 695t synthesis inhibitors and glucocorticoid antagonists abiraterone, 681f, 693 aminoglutethimide, 692–693, 692f etomidate, 693 ketoconazole, 692f, 693 metyrapone, 692f, 693 mifepristone (RU-486), 693–694 mitotane, 692f, 694 trilostane, 693 Adrenocortical insufficiency, corticosteroids for acute, 687 chronic (Addison’s disease), 686–687 Adrenocorticosteroids, 680–692. See also specific types classification of, 680 corticosteroids, synthetic, 686–692 (See also Corticosteroids, synthetic) glucocorticoids, naturally occurring, 681–685 (See also Glucocorticoids, naturally occurring) structures and properties of, 680, 681f Adrenocorticotropic hormone (ACTH), 644–645, 644f, 645t vs. adrenocortical steroids, 690 diagnostic uses of, 646t Adrenomedullin (AM), 307–308 Adverse drug event (ADE), 18 Adverse drug reaction (ADR), 18 African trypanosomiasis drugs antiprotozoal, 901–905, 901t–903t (See also Antiprotozoal drugs) benznidazole, 903t, 904 eflornithin, 901t, 904 melarsoprol, 901t, 904 pentamidine, 901–903, 901t suramine, 901t, 904 Afterload, 212f, 213 Age in drug metabolism, 69 on physiologic function, 1025, 1025f Age-related macular degeneration drugs, in elderly, 1030 with Alzheimer’s and hypertension, 1024, 1032 Aging

androgens and anabolic steroids for, 718 molecular basis of, 1024 pharmacology in, 1024–1032 (See also Geriatric pharmacology) Agitation, antipsychotics for, 498. See also Antipsychotic agents Agomelatine, 281b Agonist, 5, 6f. See also specific types biased, 137 at beta receptors, 138b binding molecule inhibition by, 5 definition of, 3, 20 drugs as mediators of, 20 full, 5, 6f inverse, 5–6, 6f partial, 5–6, 6f, 24–25, 25f receptor binding of, concentration-effect curves and, 21, 22f Agonist-antagonist property, mixed, 24–25, 25f Agranulocytosis, from antipsychotics, 501 Air pollutants, 973–976 carbon monoxide, 974–975, 974t nitrogen oxides, 974t, 975–976 ozone and other oxides, 974t, 976 permissible exposure limit values of, 974t sources of, 973–974 sulfur dioxide, 974t, 975 Akathisia from antipsychotics, 500–501 tardive, 485 Akinesia, end-of-dose, 476 ALA photodynamic therapy, 1048 Albendazole, for helminths, 908–910, 909t Albiglutide, 739 Albumin concentration, in protein binding, 53 Albuterol, 150t. See also Sympathomimetic drugs for asthma, 340, 348–349, 352t structure of, 339f Alcohol abuse, 384–385. See also Ethanol ionotropic receptors in, 561–562 in OTC agents, 1092t pharmacology of, 561 treatment of, 391–392, 394t, 395t, 562, 565t Alcohol dehydrogenase inhibitor, for methanol poisoning, 393, 394t Alcohol dehydrogenase pathway, 385, 385f Alcohols, 384–395, 394t for antisepsis and disinfection, 867t, 868 drug interactions of, 390, 1119t ethanol (ethyl alcohol), 384–392 (See also Ethanol) ethylene glycol, 393–394, 394t isopropyl alcohol, 392 methanol, 392–393, 393f, 394t

Alcohol use disorder, 384. See also Ethanol drugs for, 394t, 395t Aldehydes, 869–970 Aldosterone, 691 Aldosterone antagonists, 221t for heart failure, 223t Aldosteronism, corticosteroids for, 687–688 Alefacept, 962 for psoriasis, 1043–1044 Alemtuzumab, 960 Alendronate for bone metastases and hypercalcemia, 764t for osteoporosis, 754b, 762, 764t for Paget’s disease of bone, 763 Alfentanil, 545, 549t. See also Opioid agonists Alfuzosin, 156 Alirocumab, 614 Aliskiren for heart failure, 217 for hypertension, 188t, 189t on renin-angiotensin system, 295f, 297f, 299 on vasoactive peptides, 309t Alitretinoin, dermatologic, 1050 Alkaloids, cholinomimetic, 107, 108f. See also specific types Alkalosis, metabolic, carbonic anhydrase inhibitors for, 255t, 256 Alkylating agents, 922–927 adverse effects of, 924, 925f bendamustine, 925, 926t dacarbazine, 925, 926t mechanism of action of, 923, 924f nitrosoureas, 923f, 924 platinum analogs, 925–927, 926t procarbazine, 924–925, 926t resistance to, 923–924 structures of, 922–923, 923f Allele, 75t Allele frequency, 75t Allergic rhinoconjunctivitis, cromolyn and nedocromil for, 345, 352t Allergy preparations, OTC, 1087t Allium sativum, 1097–1098 Allopurinol for angina pectoris, 204 drug interactions of, 1119t for gout, 636–637, 637f for hypercalciuria, 763 Allosteric activator, 5, 6f Allosteric inhibitor, 5, 6f Allosteric modulators negative, 24

positive, 24 Allylamines dermatologic topical, 1037 terbinafine, 833t topical antifungal, 832, 833t Almorexant, 378b Aloe, 1064 Alogliptan, 740, 744t Alosetron chemical structure of, 1067f for irritable bowel syndrome, 1066–1067, 1067f Alpha1 -acid glycoprotein concentration, 53 α1 adrenoceptor activation of, 134, 134f cardiovascular system activation by, 141, 142t, 143f, 144f α1 -selective adrenoceptor agonists, 150t α1 -selective adrenoreceptor antagonists, for hypertension, 175t, 180, 189t α2 adrenoreceptor antagonists, 158 α2 adrenoreceptors, cardiovascular system activation by, 141 α2 -selective adrenoceptor agonists, 145, 150t. See also Sympathomimetic drugs, direct-acting α2 -selective adrenoreceptor antagonists, 158 α adrenoreceptor, 96, 97t, 134f, 135, 135t affinities of, 137, 137t α adrenoreceptor antagonists, 152–158, 166t. See also α adrenoreceptor antagonists clinical pharmacology of, 156–158 α2 antagonist applications, 158 erectile dysfunction, 158 hypertension, chronic, 157 hypertensive emergencies, 157 peripheral vascular disease, 157 pheochromocytoma, 156–157, 157f urinary obstruction, 157 drugs alfuzosin, 156 chlorpromazine and haloperidol, 156 doxazosin, 155, 155t ergotamine and dihydroergotamine, 156 indoramin, 156 labetalol and carvedilol, 156 phenoxybenzamine, 155, 155t phentolamine, 155, 155t prazosin, 155, 155t silodosin, 156 tamsulosin, 155–156, 155t terazosin, 155, 155t trazodone, 156 urapidil, 156 yohimbine, 156 for hypertension, 180, 188t

pharmacologic effects of cardiovascular, 153, 153f, 154f other, 153 preparations of, available, 167t structure and mechanism of action in, 152–153, 153f α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid, 363 α-glucosidase inhibitors, 738–739, 738t, 743t α-linolenic acids, on arachidonic acid metabolism, 328 α methyldopa, 150t. See also Sympathomimetic drugs α-synuclein, 473 Alprazolam, 382t. See also Benzodiazepines structure of, 370f for tremor, 483 Alprostadil (PGE1 ), 315 for erectile dysfunction, 197b, 326 for patent ductus arteriosus, 326–327 structure of, 325f Altepase, 595 Alternative health care, history of, 3 Aluminum hydroxide, 1054 Alveolar-venous partial pressure difference, 425–426, 426f Alveolar ventilation, 423–424, 424f Alvimopan, 548, 549t laxative action of, 1064 Alzheimer’s disease, 1027–1029, 1028f, 1029t epidemiology of, 1027 mechanisms of, 1027–1028, 1028f prevention and treatment of, 1028–1029, 1029t Alzheimer’s disease drugs antipsychotics, 498 (See also Antipsychotic agents) in elderly, 1027–1029, 1028f, 1029t with hypertension and age-related macular degeneration, 1024, 1032 tacrine, 117 Amantadine for influenza, 862 for parkinsonism, 480 Ambrisentan, 304–305, 306b, 310t. See also Endothelin inhibitors Amebiasis drugs, 898–901 dioxanide furoate, 899t, 900, 900f emetine and dehydroemetine, 899t, 901 iodoquinol, 899–900, 899t, 900f metronidazole and tinidazole, 898–899, 899t, 900f paromomycin sulfate, 899t, 900–901, 900f preparations, available, 905t for specific forms, 898 Amenorrhea, estrogens for, 702 American trypanosomiasis drugs benznidazole, 901t, 904 nifurimox, 903t, 904

Amikacin, 800f, 804, 805t for tuberculosis, 816t, 820 Amiloride for diuresis, 260–262, 260f, 261t, 267t drug interactions of, 1129t Amine primary, 9 quaternary, 9 reversible protonation of, 9–10 secondary, 9 tertiary, 9 Amine hypothesis, for depression, 511, 512–514, 513f Amino acid neurotransmitters, CNS, 363–366. See also specific types GABA and glycine, 363–366, 364t glutamate, 363, 364t, 365f Aminocaproic acid (EACA) for coagulation disorders, 587f, 599–600 for fibrolysis, 587, 587f Aminoglutethimide, 692–693, 692f Aminoglycosides, 799–805, 805t adverse effects of, 802 amikacin, 800f, 804 clinical uses of, 802 gentamicin, 800f, 803 mechanism of action of, 799–800, 801f mechanisms of resistance of, 800 neomycin and kanamycin, 804–805 netilmicin, 800f, 804 pharmacokinetics and once-daily dosing of, 800–802 physical and chemical properties of, 799, 800f preparations of, available, 806t streptomycin, 800f, 802–803 tobramycin, 800f, 804 Aminolevulinic acid, for actinic keratoses, 1048 Aminopenicillins. See also Penicillins clinical uses of, 775 Aminosalicylates, for inflammatory bowel disease, 1071–1073, 1072f, 1080t adverse effects of, 1073 chemistry and formulations of, 1071–1072, 1072f clinical uses of, 1073 pharmacokinetics and pharmacodynamics of, 1072–1073 5-Aminosalicylic acid (5-ASA), for inflammatory bowel disease, 1071–1073, 1072f, 1080t Aminosalicylic acid (PAS), for tuberculosis, 816t, 820 Amiodarone, for arrhythmia, 235t, 236t, 239–240, 246t Amiodarone-induced thyrotoxicosis, 676 Amitriptyline, for migraine headache prophylaxis, 285 Amlodipine for angina pectoris, 202 (See also Calcium channel blockers) for hypertension, 175t, 183

Ammonium chloride, for methamphetamine intoxication, 1, 19 Ammonium compounds, quaternary, 869 Amnesia, in anesthesia, 427b Amobarbital, 382t. See also Barbiturates Amodiaquine, for malaria, 888f, 889t, 891 Amoxapine, 528t. See also Antidepressant agents; Tetracyclic agents Amoxicillin, rash from, 769, 787 AMPA, CNS, 363 AMPA receptors, CNS, 363 Amphetamines, 140f, 146. See also specific types abuse of, 556t, 557 biogenic amine binding in, 563–564, 563f noradrenergic transmitter release by, 94 poisoning management for, 1007–1008 structure of, 140f Amphotericin B, 825–828, 833t adverse effects of, 827–828 antifungal activity and clinical uses of, 827 chemistry and pharmacokinetics of, 825–826, 826t dermatologic topical, 1038 lipid formulations of, 826b, 826t mechanisms of action and resistance to, 826–827, 826f preparations of, available, 834t AMP kinase activation, 614 Amplification, 34 Amylin, 723, 724t Amyl nitrite, for angina pectoris, 191, 193–199, 199t, 206t. See also Nitrates and nitrites, for angina pectoris Amyloid beta (Aβ) peptide, 1027 Anabolic steroids. See also Androgens and anabolic steroids abuse of, in sports, 718 preparations of, available, 717t, 721t Anacetrapib, 614 Anakinra, 632, 966 Analgesia in general anesthesia, 428 opioids for, 533t, 540–541 (See also Opioid agonists) Analgesics. See also Opioids; specific types acetaminophen, 65f, 634, 639t disease-modifying antirheumatic drugs, 625–633, 639t in elderly, 1027 gout agents, 635–638, 639t ketorolac, 621t, 634 nonsteroidal antiinflammatory drugs, 619–625, 621t, 639t novel targets for, ion channels and, 538b opioid agonists, 544–547, 549t (See also Opioid agonists) OTC, 1088t preparations of, available, 639t tramadol, 634 Analytic epidemiologic studies, 14b

Anaphylaxis histamine in, 275 sympathomimetics for, 148–149 Anastrozole, 714–715 for breast cancer, 941 Androgen receptor inhibitors, 719f, 720, 721t Androgen replacement therapy, in men, 717–718, 717t Androgens adrenal, 692 ovarian, 707–708 Androgens and anabolic steroids, 716–719. See also specific types adverse effects of, 718–719 clinical uses of aging, 718 androgen replacement therapy, in men, 717–718, 717t androgen steroid and androgen abuse, sports, 718 anemia, 718 growth stimulators, 718 gynecologic disorders, 718 osteoporosis, 718 protein anabolic agents, 718 contraindications and cautions with, 719 mechanism of action of, 717 metabolism of, 716 pharmacologic effects of, 717 physiologic effects of, 716–717 preparations of, 717, 717t, 721t synthesis of, 681f, 698f, 716 synthetic steroids with androgenic and anabolic action in, 717, 717t Androgen steroid abuse, in sports, 718 Androgen suppression, 719, 719f, 721t Androstenedione metabolism of, 716 synthesis of, 716 in women, 707–708 Anemia drugs, 567–576. See also specific agents androgens and anabolic steroids, 718 folic acid, 574–576, 575b, 575f iron, 568–572, 569f, 569t preparations, available, 583t vitamin B12 , 572–574, 573f Anemias. See also specific types nutritional, 570–571, 570f, 581t–582t pernicious, 570t, 574 (See also Vitamin B12 deficiency) Anesthesia amnesia in, 427b balanced, 421, 430 consciousness in, 427b with hypertension and coronary artery disease, 421, 439

immobility in, 427b minimum alveolar concentration in, 425t, 427, 427b monitored anesthesia care in, 421, 422b opioids for, 541 primary effects of, 421 sedation in, 422b surgical, 428 Anesthetics, general, 421–439. See also specific types inhaled, 422–427 intravenous, 430–438 mechanism of action of, 421–422 preparations of, available, 438t Anesthetics, inhaled, 422–430 pharmacodynamics of cardiovascular effects, 428 cerebral effects, 427–428 renal and hepatic effects, 429 respiratory effects, 428–429 uterine smooth muscle effects, 429 pharmacokinetics of, 422–427 elimination in, 425t, 426–427 structures of, 424f uptake and distribution in, 422–426, 423f–426f, 425t potency of, 425t, 426, 427b targets of, putative, 422, 423f toxicity of, 429–430 volatile vs. gaseous, 422 Anesthetics, intravenous, 430–438 balanced anesthesia in, 421, 430 barbiturates, 423f, 431t, 432f, 433–434 benzodiazepines, 432f, 434–435 current clinical practice in, 438 dexmedetomidine, 431t, 437–438 etomidate, 431f, 431t, 435–436 fospropofol, 433 fundamentals of, 430 ketamine, 431f, 431t, 436–437 opioid analgesics, 438 propofol, 430–433, 431f, 431t sedative-hypnotics, 376 Anesthetics, local, 440–453 chemistry of, 440–441, 442f clinical pharmacology of, 446–450 clinical block characteristics in, 446–448 injection sites for, 446, 447f lipid resuscitation in, 450b toxicity of, 444f, 448–450 commonly used, 442t, 443t, 450–452, 453t articaine, 442t, 450–451

benzocaine, 442t, 451 bupivacaine, 442t, 443t, 451, 453t chloroprocaine, 451, 453t cocaine, 442t, 451, 453t EMLA, 452 etidocaine, 451 levobupivacaine, 451 lidocaine, 442t, 443t, 451, 453t mepivacaine, 442t, 443t, 452 prilocaine, 443t, 452, 453t ropivacaine, 442t, 443t, 452, 453t future developments in reduced toxicity and greater selectivity in, 452 sustained-release formulations in, 452 historical development of, 441b in OTC agents, 1092t pharmacodynamics of mechanism of action in, 443f, 444–445 neuronal factors affecting block in, 446 structure-activity characteristics in, 445 pharmacokinetics of, 441–444 absorption in, 443, 444f distribution in, 443 metabolism and excretion in, 443–444, 443t structure and properties in, 442t, 443t preparations of, available, 454t Angina of effort, vasodilators for, 204–205, 205f, 205t Angina pectoris, 191–194 definition of, 191 etiology of, 191 pathophysiology of, 192–194 coronary blood flow and myocardial oxygen supply in, 192 myocardial oxygen demand in, 192, 192t vascular tone in, 192–193, 192t, 193f, 194f treatment of (See also specific agents) vasodilators in, 191–208, 206t–207t (See also Vasodilators, for angina pectoris) types of classic, 191 effort, 191 unstable, 191–192 vasospastic, 191 variant, ergot alkaloids for diagnosis of, 289 Angioedema, hereditary, kinins in, 301 Angiotensin, 294–297 biosynthesis of, 294–297, 295f angiotensinase in, 297 angiotensin I in, 295f, 296 converting enzyme in, 296–297, 297f renin in, 294

renin release in, control of, 295–296, 296f renin-angiotensin system inhibition by, 298–299 on renin release, 295 Angiotensin antagonists, 221t Angiotensinase, 297 Angiotensin-converting enzyme (ACE), in angiotensin biosynthesis, 296–297, 297f Angiotensin-converting enzyme inhibitors (ACEIs). See also specific types for heart failure, 209, 217, 221t, 223 chronic, 219 preparations of, available, 223t for hypertension, 175t, 184–185, 188t, 189t immediate effects of, 48–49, 49f preparations of, available, 189t on renin-angiotensin system, 298 on vasoactive peptides, 309t Angiotensin I, 295f, 296 Angiotensin II on adrenal cortex and kidney, 297 on blood pressure, 297 on cell growth, 297–298 on central nervous system, 297 Angiotensin II inhibitors, for hypertension, 184–185 Angiotensin inhibitors, 172, 183–185 angiotensin-converting enzyme inhibitors, 175t, 184–185, 188t, 189t angiotensin receptor blockers, 175t, 185, 188t, 189t, 298–299 mechanisms and sites of action of, 183–184, 184f Angiotensin receptor, 298 for heart failure treatment, 217 Angiotensin receptor blockers (ARBs) for heart failure, 221t chronic, 219 preparations, available, 223t for hypertension, 175t, 185, 188t, 189t on renin-angiotensin system, 298–299 on vasoactive peptides, 309t Anidulafungin, 831, 833t Anion inhibitors, thyroid, 671 Antacids drug interactions of, 1119t OTC, 1088t preparations of, available, 1081t Antagonism in antimicrobial drug, 882 chemical, 25 physiologic, 25–26 Antagonist. See also specific types chemical, 3 competitive, 23–24, 23f definition of, 3, 20–21

drugs as mediators of, 20–21 inverse, 6, 7f irreversible, 23f, 24 neutral, 6 noncompetitive, 23f, 24 pharmacologic, 5, 6f Antagonist-precipitated withdrawal, 543 Anterior pituitary hormones, 644–656, 658t–660t. See also Pituitary hormones, anterior Anthelmintic drugs, 908–916 Anthracyclines, 932t, 934–935 Anthraquinone derivative laxatives, 1064 Antiandrogens, 719–720, 721t receptor inhibitors, 719f, 720, 721t steroid precursor conversion to androgens in, inhibitors of, 719f, 720, 721t steroid synthesis inhibitors, 719–720, 719f, 721t Antiarrhythmic agents, 232–248. See also specific agents action potential–prolonging drugs (class 3), 239–241, 246t amiodarone, 235t, 236t, 239–240, 246t dofetilide, 235t, 236t, 241, 246t dronedarone, 235t, 236t, 240, 246t ibutilide, 235t, 236t, 241, 246t sotalol, 235t, 236t, 240–241, 246t beta-adrenoceptor–blocking drugs (class 2), 239, 246t calcium channel–blocking drugs (class 4), 241–242, 247t diltiazem, 235t, 236t, 241–242, 247t verapamil, 235t, 236t, 241–242, 247t chloride channel drugs, 244 classification and overview of, 233, 235t, 246t–247t clinical use of for atrial fibrillation, 245b benefits and risks in, 244–245 conduct of therapy in, 245 pretreatment evaluation in, 244 in elderly, 1029–1030 mechanisms of action of, 228f, 232–233, 234f miscellaneous adenosine, 235t, 236t, 242–243, 247t ivabradine, 243 magnesium, 243, 247t potassium, 243, 247t ranolazine, 243 preparations of, available, 247t sodium channel-blocking drugs, class 1, 233–239, 235t, 236t, 246t class 1A disopyramide, 235t, 236–237, 236t, 246t procainamide, 233–235, 235t, 236t, 246t quinidine, 235–236, 235t, 236t, 246t class 1B lidocaine, 235t, 236t, 237–238, 237f, 246t

mexiletine, 235t, 236t, 238, 246t class 1C flecainide, 235t, 236t, 238, 246t moricizine, 235t, 236t, 239, 246t propafenone, 235t, 236t, 238–239, 246t Antiatherogenesis, nitric oxide for, 332, 333f Antibacterial agents, topical dermatologic for acne clindamycin, 1036 dapsone, 1036–1037 erythromycin, 1036 metronidazole, 1036 sodium sulfacetamide, 1036 bacitracin and gramicidin, 1035 fundamentals of, 1035 mupirocin, 1035 neomycin and gentamicin, 1036 polymyxin B sulfate, 1035–1036 retapamulin, 1035 Antibiotic resistance, 767 Antibiotics. See also Antimicrobial agents; specific types antitumor anthracyclines, 932t, 934–935 bleomycin, 932t, 935 mitomycin, 932t, 935 for malaria clindamycin, 890t, 897 doxycycline, 889t, 890t, 897 spiramycin, 897 Antibodies, 947, 950, 951f Antibodies, immunosuppressive, 958–960 antilymphocyte and antithymocyte, 959 chimeric molecules, 959 development of, 958–959 hyperimmune immunoglobulins, 960 immune globulin intravenous, 959 Rh0 (D) immune globulin micro-dose, 959–960 Anticholinergic agents. See also specific agents antiemetic properties of, 1070 for irritable bowel syndrome, 1066 poisoning management for, 1007t, 1008 Anticoagulants, 587–594, 600t. See also specific drugs oral, drug interactions of, 1119t–1120t pharmacology of, basic, 590–594 direct factor Xa inhibitors, oral, 592–593 direct thrombin inhibitors oral, 593–594 parenteral, 593 indirect thrombin inhibitors, heparin, 587–590, 588f

warfarin and other coumarins, 590–592 Anticonvulsants. See also Antiseizure drugs sedative-hypnotics, 376–377 Antidepressant agents, 510–530, 528t. See also specific agents chemistry and subgroups of, 515–517 5-HT2 receptor modulators, 516 monoamine oxidase inhibitors, 517 selective serotonin reuptake inhibitors, 514, 515f serotonin-norepinephrine reuptake inhibitors selective serotonin-norepinephrine reuptake inhibitors, 514 tricyclic antidepressants, 515, 516f tetracyclics, 516–517, 517f unicyclic, 516–517, 517f clinical pharmacology of, 521–527 adverse effects of 5-HT receptor modulators, 525 MAO inhibitors, 525 SNRIs and tricyclic antidepressants, 525 SSRIs, 524–525 tetracyclic and unicyclic agents, 525 clinical indications in anxiety disorders, 522 depression, 521–522 eating disorders, 523 other uses, 523 pain disorders, 522 premenstrual dysphoric disorder, 522 smoking cessation, 522 dosing of, 524, 524t drug interactions in 5-HT receptor modulators, 526–527 MAO inhibitors, 527 SNRIs and tricyclic antidepressants, 526 SSRIs, 526, 526t tetracyclics and unicyclic, 526t, 527 overdose in, 525–526 selection of, 523 drug interactions of heterocyclic antidepressants, 1121t tricyclic antidepressants, 1121t in elderly, 520t, 1027 indications for, 510 on NET, 93 non-depression uses of, 511 pathophysiology of depression and, 511–514, 511f, 513f pharmacodynamics of, 519–521 5-HT receptor modulators, 520t, 521 MAO inhibitors, 520t, 521 SNRIs, 520, 520t

SSRIs, 519–520, 520t tetracyclic and unicyclic agents, 520t, 521 tricyclic antidepressants, 520, 520t pharmacokinetics of 5-HT receptor modulators, 518t, 519 MAO inhibitors, 518t, 519 SNRIs, 518, 518t SSRIs, 517–518, 518t tetracyclic and unicyclic agents, 518t, 519 tricyclic antidepressants, 518t, 519 poisoning management for, 1007t, 1008 poisoning with, treating, 1008 preparations of, available, 529t prevalence of use of, 510–511 tricyclic (See Tricyclic antidepressants [TCAs] Antidiabetic agents, oral, 733–742, 743t–744t. See also specific agents α-glucosidase inhibitors, 738–739, 738t, 743t bromocriptine, 741, 744t categories of, 733 colesevelam hydrochloride, 741, 744t combination, for type 2 diabetes, 741–742, 741f drugs lowering glucose by tissue actions, 736–738 biguanides, 736–737, 743t thiazolidinedones, 737–738, 737t, 743t glucose absorption agents, 738–739 incretin mimics and action prolongers dipeptidyl peptidase-4 inhibitors, 740, 744t glucagon-like peptide-1 and, 739 glucagon-like peptide-1 receptor agonists, 739–740, 743t pramliintide, 740–741, 744t sodium-glucose co-transporter 2 (SGLT2) inhibitors, 740, 744t sulfonylurea receptor binders, 733–736 D-phenylalanine derivatives, 734, 735t, 736, 736t, 743t meglitinide analogs, 734, 736t, 743t sulfonylureas, 733–734, 733t, 734t, 743t Antidiarrheal agents bile salt–binding resins, 1065 colloidal bismuth compounds, 1065 octreotide, 1065–1066 opioid agonists, 1065 opioids for, 541 OTC, 1088t use of, 1065, 1079t Antidiuretic hormone (ADH). See Vasopressin Antidotes, specific, 1006, 1007t Antiemetic agents, 1068–1071, 1080t benzodiazepines, 1070 cannabinoids, 1071, 1080t corticosteroids, 1069

H1 antihistamines and anticholinergic drugs, 1070 mechanisms of action of, 1068–1069, 1068f neurokinin receptor antagonists, 1069–1070 phenothiazines and butyrophenones, 1070 serotonin 5-HT3 -antagonists, 1069, 1080t, 1081t substituted benzamides, 1070 Antiepileptics, 396–420. See also Antiseizure drugs Antifolate drugs, 807–810. See also specific drugs DNA gyrase inhibitors, 810–812, 813t methotrexate, 927–928, 928t pemetrexed, 928–929, 928t pralatrexate, 928t, 929 preparations, available, 813t sulfonamides, 807–809, 813t trimethoprim and trimethoprim-sulfamethoxazole mixtures, 809–810, 813t Antifungal agents, 825–834, 833t, 834t. See also specific types Antifungal agents, dermatologic oral azole derivatives, 1038 griseofulvin, 1038–1039 terbinafine, 1039 topical allylamines, 1037 azole derivatives, 1037 butenafine, 1037 ciclopirox olamine, 1037 nystatin and amphotericin B, 1038 tolnaftate, 1037–1038 Antifungal agents, OTC preparations topical, 1089t vaginal, 1089t Antifungal agents, systemic, 825–831 allylamine, 832, 833t amphotericin B, 825–828, 833t azoles, 828–831, 833t drug interactions of, 1121t–1122t echinocandins, 831, 833t flucytosine, 827f, 828, 833t oral, for mucocutaneous infections griseofulvin, 832 terbinafine, 832, 833t Antifungal agents, topical allylamines, 832, 833t azoles, 832 nystatin, 832 Antigen-presenting cells (APCs), 947, 948f albendazole, 908–910, 909t bithionol, 909t, 910 diethylcarbazine citrate, 909t, 910–911

ivermectin, 909t, 911–912 mebendazole, 909t, 912 metrifonate, 909t, 912–913 niclosamide, 909t, 913 oxamniquine, 909t, 913–914 piperazine, 909t, 914 praziquantel, 909t, 914–915 preparations, available, 909t, 916 pyrantel pamoate, 909t, 915–916 thiabendazole, 909t, 916 Antihemophilic factor (AHF), 596t Antihepatitis agents, 856–861, 856t hepatitis B adefovir dipivoxil, 857–858 entecavir, 858 fundamentals of, 857 lamivudine, 858 telbivudine, 858 tenofovir, 858 hepatitis C, 859–861 fundamentals of, 859 new and investigational, 861 polymerase inhibitors, 859 protease inhibitors, 859, 860f boceprevir, 856t, 859–860 simeprevir, 860 sofosbuvir, 856t, 859 telaprevir, 856t, 860–861 ribavirin, 861 interferon alfa, 856–857, 856t, 863t Antihistamines, in OTC agents, 1092t Antihypertensive agents, 169–190, 187t–188t. See also specific types with Alzheimer’s and age-related macular degeneration treatment, 1024, 1032 angiotensin inhibitors, 172, 183–185 angiotensin-converting enzyme inhibitors, 175t, 184–185, 188t, 189t angiotensin receptor blockers, 175t, 185, 188t, 189t mechanisms and sites of action of, 183–184, 184f categories of, 171–172, 172f clinical pharmacology of, 185–187 chronic hypertension, alpha-receptor antagonists, 157 general, 185–186 hypertensive emergencies, 187 outpatient therapy, 186 diuretics, 171, 172–174, 187t mechanisms of action and hemodynamic effects of, 173 toxicity of, 174 use of, 173–174, 175t in elderly, 1029 hypertension and blood pressure regulation by, 169–171, 170f, 171f (See also Hypertension)

preparations of, available, 189t sites of action of, 171, 172f sympathoplegics, 172, 172f, 174–180 adrenergic neuron-blocking agents guanethidine, 175t, 177–178, 187t reserpine, 175t, 178, 187t alpha-adrenoceptor blockers, other, 180 beta-adrenoceptor blocking agents, 175t, 178–180 (See also β-receptor antagonist drugs) esmolol, 180 centrally acting, 175–177, 175t, 187t clonidine, 175t, 176–177 guanabenz and guanfacine, 176 methyldopa, 175t, 176 preparations of, 189t ganglion-blocking agents, 177 prazosin and other α1 blockers, 175t, 180 vasodilators, 174f, 175t, 180–183, 188t calcium channel blockers, 175t, 183, 189t diazoxide, 182–183, 188t direct, 172 fenoldopam, 183, 188t hydralazine, 175t, 181 mechanisms and sites of action of, 180, 181t minoxidil, 175t, 181 preparations, available, 188t, 189t sodium nitroprusside, 171f, 182, 188t Anti-IgE monoclonal antibodies, for asthma, 346, 350, 352t Anti-inflammatory agents. See also specific types dermatologic, 1044–1046 corticosteroids, topical, 1044–1046, 1045t, 1046t tar compounds, 1046 in elderly, 1030 topical, OTC, 1089t Anti-influenza agents, 861–862 amantadine and rimantadine, 862 investigational, 862 oseltamivir and zanamivir, 861–862 Anti-integrin therapy, for inflammatory bowel disease, 1076–1077 Antilymphocyte globulin (ALT), 959 Antimetabolites, 927–931 antifolates methotrexate, 927–928, 928t pemetrexed, 928–929, 928t pralatrexate, 928t, 929 deoxycytidine analogs cytarabine, 928t, 929–930 gemcitabine, 928t, 930 development of, 927 fluoropyrimidines

5-fluorouracil, 928t, 929 capecitabine, 928t, 929 purine antagonists 6-thiopurines, 928t, 930–931, 931f cladribine, 928t, 931 fludarabine, 928t, 931 Antimicrobial agents, 767, 767f, 873–882. See also specific agents and types development of, 873 drug combinations of antagonism in, 882 rationale for, 881 synergism in, 881–882 drug toxicity management for, 876t–877t, 880–881 in elderly, 1030 eliminating misuse of, 767 empiric therapy with, 874–875, 876t–878t approach to, 874 choice of, 874–875 microbiology etiology in, 876t–877t site of infection in, 878t etiologic agent and indications for, 873–874 with infections of known etiology, 875–880 Antimicrobial prophylaxis nonsurgical, 883, 884t NRC wound classification criteria and, 883b surgical, 882–883, 883t Antimuscarinic drugs. See Muscarinic receptor blockers (antagonists) Antimycobacterial drugs, 815–824, 823t atypical mycobacteria, 821–822, 822t leprosy clofazimine, 823 dapsone and other sulfone, 822 rifampin, 822–823, 823t tuberculosis, 815–821 (See also Tuberculosis drugs) Antineoplastic agents. See Cancer chemotherapy; specific cancers Antiphospholipid antibody syndrome, 597 Antiplatelet agents, 595–597, 600t aspirin, 595, 596 cilostazol, 597 dipyridamole, 596–597 GP IIb/IIIa antagonists, 585f, 596 thienopyridines, 595–596 Antiprotozoal drugs, 886–907 African trypanosomiasis and other protozoal infections, 901t–903t nitazoxanide, 903 other trypanosomiasis and leishmaniasis drugs amphotericin, 902t, 904–905 benzinidazole, 903t, 904 eflornithine, 901t, 904

melarsoprol, 901t, 904 miltefosine, 905 need for, 903–904 nifurtimox, 903t, 904 paromomycin, 902t, 905 suramin, 901t, 904 visceral leishmaniasis drug combinations in, 905 pentamidine, 901–903, 901t–902t sodium stibogluconate, 900f, 902t, 903 amebiasis, 898–901 malaria, 886–898 preparations, available, 905t Antipruritic agents doxepin, 1048–1049 pramoxine, 1049 Antipsychotic agents, 490–502, 507t. See also specific agents bipolar disorder agents, newer, 508t chemical structures of atypical antipsychotics, 493f, 494, 494t butyrophenone derivatives, 493f, 494, 494t glutamatergic antipsychotics, 494–495 molindone, 493f, 494 phenothiazine derivative, 492f, 493–494, 494t pimozide, 493f, 494 thioxanthene derivatives, 492f, 494, 494t clinical pharmacology of, 497–502 adverse reactions to, 497t, 500–502 benefits and limitations in, 502 dosage of, 499, 500t drug choice in, 498–499, 499t drug combinations in, 500 drug interactions in, 502 indications for nonpsychiatric, 498 psychiatric, 497–498 maintenance treatment in, 500 overdoses of, 502 parenteral preparations of, 500 in elderly, 520t, 1027 history of, 490 lithium and other mood stabilizers, 502–507, 508t pharmacodynamics of, 495–497 cardiovascular effects, 497 differences in, by drug, 494t, 496–497, 497t dopamine receptors and their effects, 495–496, 496f dopaminergic systems, 495 electroencephalographic effects, 497 endocrine effects, 497 psychological effects, 497

pharmacokinetics of, 495 poisoning management for, 1008 preparations of, available, 508t Antipyretics, OTC, 1088t Antiretroviral agents, 842–856. See also specific types drug–drug interactions of two-drug combinations of, 847t entry inhibitors, 854–855 fundamentals of, 842 integrase strand transfer inhibitors, 855–856 nonnucleoside reverse transcriptase inhibitors, 849–851 nucleoside and nucleotide reverse transcriptase inhibitors, 842–849, 843t–845t in pregnancy, 848t protease inhibitors, 851–854 Antiseborrhea agents, 1049t, 1049 Antiseizure drugs, 396–420, 418t–419t chemistry of, 397, 398f clinical pharmacology of, 414–417 epilepsy management in, 415–417 generalized seizures, 415–416 infantile spasms, 415, 416 partial seizures and generalized tonic-clonic seizures, 415 status epilepticus, 416–417 seizure classification in generalized, 414–415 partial (focal), 414 therapeutic strategy in, 415, 416t developmental, 417 development of, initial, 396–397, 398f, 399f for epilepsy management acetazolamide, 414 benzodiazepines, 413–414, 418t for generalized seizures, 411–413 ethosuximide, 218t, 411 oxazolidinediones, 413 phensuximide and methsuximide, 412 valproic acid and sodium valproate, 401f, 412–413, 419t molecular targets for at excitatory, glutamatergic synapse, 397, 398f at inhibitory, GABAergic synapse, 397, 399f for partial seizures and generalized tonic-clonic seizures, 400–411 carbamazepine, 401f, 402–403, 418t eslicarbazine, 404, 418t ezogabine (retigabine), 408 felbamate, 405–406 gabapentin and pregabalin, 406, 419t lacosamide, 406–407 lamotrigine, 407, 419t levetiracetam, 407–408, 419t mephenytoin, ethotoin, and phenacemide, 402

oxcarbazepine, 403–404, 418t perampanel, 398f, 408, 419t phenobarbital, 404, 418t phenytoin, 400–402, 400f, 401f, 418t primidone, 404–405, 405f, 418t retigabine, 408, 419t rufinamide, 409, 419t stiripentol, 409 tiagabine, 409–410, 419t topiramate, 410, 419t vigabatrin, 410–411, 419t zonisamide, 411, 419t pharmacokinetics of, 397–399, 398f, 399f preparations, available, 420t structure of, 400f toxicology of suicidality in, 417 teratogenicity in, 417 withdrawal in, 417 Antisense oligonucleotides (ANOs), therapeutic, 2 Antisepsis, 867t Antiseptics. See Disinfectants and antiseptics; specific types Antispasmodics (anticholinergics), for irritable bowel syndrome, 1066 Antithrombin (AT), 586, 587–588, 588f Antithrombotics, 597, 598t, 600t nitric oxide, 332, 333f Antithymocyte globulin (ATG), 959 Antithyroid drugs, 669–678, 677t basic pharmacology of, 669–672 adrenoceptor-blocking agents, 672 anion inhibitors, 671 iodides, 671–672, 677t radioactive iodine, 672, 677t thioamides, 670–671, 671f, 677t clinical pharmacology of, 674–677 hyperthyroidism, 674–676 (See also Hyperthyroidism) nontoxic goiter, 676 thyroid neoplasms, 676–677 for Graves’ disease, 674, 675 preparations of, available, 678t Antitrichogenic agents, 1049 Antitumor antibiotics anthracyclines, 932t, 934–935 bleomycin, 932t, 935 mitomycin, 932t, 935 Antitumor monoclonal antibodies, 960–961 Anti–tumor necrosis factor (anti-TNF) therapy, for inflammatory bowel disease, 1075–1076, 1075t, 1080t Antitussives opioid, 547, 549t, 550t

OTC, 1089t Antivenoms, 960 Antiviral agents, 835–864. See also specific types antihepatitis, 856–861, 856t anti-influenza, 861–862 antiretroviral, 842–856 entry inhibitors, 854–855 fundamentals of, 842 integrase strand transfer inhibitors, 855–856 nonnucleoside reverse transcriptase inhibitors, 849–851 nucleoside and nucleotide reverse transcriptase inhibitors, 842–849, 843t–845t protease inhibitors, 851–854 cytomegalovirus, 839–842 herpes simplex virus and varicella-zoster virus, 836–839 history of, 835 imiquimod, 863 interferons, 862, 863t palivizumab, 863 preparations of, available, 863t–864t ribavirin, 862–863 topical, 1039 viral replication and, 835–836, 836f Anxiety performance, β-receptor antagonists for, 165 sedative-hypnotics for, 378 Apixaban, 592–593 Apo B-100 synthesis antisense inhibition, 614 Apocrine sweat glands, adrenoreceptors in, 143 Apolipoprotein B-100, 602, 604f familial ligand-defective, 605t, 607 Apomorphine (hydrochloride), for parkinsonism, 480–481, 487t

Apraclonidine, 150t. See also Sympathomimetic drugs Aprepitant, 306, 310t, 1069–1070, 1080t. See also Substance P antagonists Apriso, for inflammatory bowel disease, 1071–1073, 1072f Aprotinin, 301, 309t, 600 Aquaporin-2 (AQP2), 253, 253f Aquaretics, 251t, 262, 267t, 268t Aqueous diffusion, 7–8, 8f Arachidonic acid (AA), 313–314, 314f dietary manipulation of metabolism of, 328 prostanoid mediators from, 619, 622f Arcitumomab, 961 Area under the blood concentration-time curve, 47, 47f Area under the curve (AUC), 45 Argatroban, 593 Arginine vasopressin. See Vasopressin; Vasopressin receptor agonists Aripiprazole. See also Antipsychotic agents for psychosis, 493f, 494, 507t for tics, 485 Arizona bark scorpion antivenom, 960 Aromatic hydrocarbons, 977–978 Aromatic (4)-hydroxylation, 65 Arrestins, adrenoceptor affinity of, 137 Arrhythmias, cardiac β-receptor antagonists for, 164 mechanisms of, 229–233 impulse conduction disturbances in, 230–232, 231f–233f impulse formation disturbances in, 229–230, 231f molecular and genetic basis of, 229b, 230t, 231f, 233f pathophysiology of, 224, 225f treatment of drugs in, 232–248 nonpharmacologic therapy in, 242b Arsenic, 991–993 forms of intoxication with acute inorganic, 992 arsine gas, 993 chronic inorganic, 992–993, 993f history and epidemiology of, 991 pharmacodynamics of, 992 pharmacokinetics of, 988t, 991 Artemether, for malaria, 891–892 Artemisinins, for malaria, 888f, 889t, 890t, 891–892 Arterial dilators, for heart failure, 222t Arterial thrombosis, 597 Artesunate-amodiaquine, for malaria, 891, 891t Artesunate, for malaria, 890t, 891–892 Artesunate-suladoxine-pyrimethamine, for malaria, 891, 891t Articaine, 442t, 450–451. See also Anesthetics, local Asacol, for inflammatory bowel disease, 1071–1073, 1072f

Asbestos, 984 Ascariasis drugs. See also Anthelmintic drugs albendazole, 908–909, 909t mebendazole, 912 piperazine, 914 pyrantel pamoate, 915–916 Asenapine, 494 Asparaginase, 938–939 Aspart, 723–733, 743t. See also Insulin Aspirin, 621, 621t, 622f antiplatelet effects of, 595 resistance to, 596 drug interactions of, 1130t for dysmenorrhea, 326 for heart attack and stroke prevention, 327 for inflammation, 328 in OTC agents, 1092t for peripheral artery disease and intermittent claudication, 206 poisoning management for, 1008–1009 Asthma clinical features and severity of, 336–337 forms of, 337 pathogenesis of, 337–338, 337f phenotypes of, 347–348, 347f prevalence of, 336 respiratory infection on, 336, 354 Asthma drugs, 336–354, 352t. See also specific drugs anti-IgE monoclonal antibodies, 346, 352t antimuscarinics, 342–344, 343f asthma pathophysiology in, 337–338, 337f clinical pharmacology of, 348–351 acute asthma management, 350 anti-IgE monoclonal antibody, 350 anti-inflammatory therapies, other, 350 bronchodilators, 348–349 corticosteroids, 349–350 leukotriene antagonists, 350 muscarinic antagonists, 349 corticosteroids inhaled, 344–345, 352t systemic, 344–345, 352t cromolyn and nedocromil, 345, 352t future directions in, 347–348, 347f leukotriene antagonists, 345–346, 346f, 352t methylxanthines, 341–342, 341f, 352t preparations of, available, 353t for prevention, 350–351 sympathomimetic agents, 338–340, 339f, 352t β2 -selective, 340

toxicities of, 340 Atazanavir, 843t, 851–852 Atenolol, 160t, 161. See also β-receptor antagonist drugs for angina pectoris, 206t for hypertension, 175t, 179 structure of, 159f Atherogenesis, 602–603 nitric oxide prophylaxis against, 332, 333f Athetosis, 472, 485 Atomexitine, 147 Atonic seizures, 415. See also Seizures Atorvastatin, 608–610, 609f, 616t Atosiban, 657, 660t for preterm labor, 202 Atovaquone, for malaria, 888f, 895–896 Atovaquone-proguanil, for malaria, 889t Atracurium. See also Neuromuscular blocking drugs pharmacokinetics of, 458 properties of, 459t structure of, 457f Atrial fibrillation antiarrhythmic agents for, 245b electrocardiogram of, 232f with left ventricular dysfunction, 224, 248 Atrial flutter, ECG of, 232f Atrial natriuretic peptide (ANP), 302–303, 302f on kidney, 254–255 mechanism of action of, 27–28 Atrioventricular (AV) node, 224, 225f Atropine, 121–129. See also Muscarinic receptor blockers actions of, 342 chemistry and pharmacokinetics in, 121–122, 122f, 123f for cholinergic poisoning, 128 clinical pharmacology of, 126–129 discovery of, 342 intoxication with, 117 pharmacodynamics of, 122–126 pharmacology of, 121–126, 121–129 structure of, 121, 122f Autacoids, renal adenosine, 254 peptides, 254–255 prostaglandins, 254 Autoclaving, 871 Autoimmune disorders. See also specific types immunosuppressive therapy for, 964 Autoimmune (type II) drug reactions, 950–951, 967 Autoimmunity, 952–953 Autologous stem cell transplantation, G-CSF for, 579–580

Automatisms, 414 Autonomic failure, pure, case study on, 133, 151 Autonomic motor nerves, 88f Autonomic nervous system (ANS), 87–90 anatomy of, 88–90, 88f, 89f divisions of parasympathetic, 88–89, 88f somatic, 87 sympathetic, 88–89, 88f enteric nervous system in, 89–90, 89f ergotropic, 97 functions of, 87 on immune function, 87 trophotropic, 97 Autonomic pharmacology, 87–104. See also specific agents autonomic nervous system in, 87–90 (See also Autonomic nervous system (ANS)) in eye, 101b, 103f functional organization of, 96–101 cardiovascular function integration in, 97–99, 99f central integration in, 89f, 96–97, 98t direct effects on organ systems of, 97, 98t postsynaptic regulation in, 100–101, 101f presynaptic regulation in, 99–100, 100t functions of, general, 87–88 neurotransmitter chemistry in, 88f, 90–96 adrenergic transmission in, 92–96, 93f–95f cholinergic and noradrenergic fibers in, 88f, 90 cholinergic transmission in, 90–92, 91f, 92t cotransmitters in, 90 cotransmitters in cholinergic and adrenergic nerves in, 92t, 96 nonadrenergic, noncholinergic neurons in, 89f, 92t, 96 pharmacologic modification of autonomic function in, 101–102, 102t receptors in, 96, 97t Autonomic receptors, 96, 97t Autonomic synapses, 90 Autonomic transmission, drugs on, 101, 102t Autoplex, 599 Autoreceptors, 100, 100t Autosomal dominant hypophosphatemia, 762 Autosomal dominant polycystic kidney disease, ADH antagonists for, 263 Autosomal recessive hypercholesterolemia (ARH), 607 AV nodal block, 230–232, 231f Azapropazone, 625 Azathioprine antirheumatic actions of, 626 for immunosuppression, 957 for inflammatory bowel disease, 1074 TPMT on metabolism of, 81 Azelaic acid, 1042–1043

Azithromycin, 793, 797t Azoles, 828–831, 833t adverse effects and drug interactions of, 830 chemistry and pharmacokinetics of, 828–829, 829f, 829t clinical uses of, 830 dermatologic oral, 1038 topical, 1037 drug interactions of, 1121t–1122t fluconazole, 829f, 829t, 830 itraconazole, 829f, 829t, 830, 833t ketoconazole, 829f, 829t, 830, 833t mechanisms of action and resistance to, 829–830 posaconazole, 829t, 831 preparations of, available, 834t topical, 832 voriconazole, 829f, 829t, 830 Aztreonam, 770f, 780, 785t B B1 receptor antagonists, 301 B2 receptor agonists, 302 B2 receptor antagonists, 301 Bacitracin, 773f, 783–784 topical dermatologic, 1035 Baclofen for dependence and addiction, 564 spasmolytic actions of, 466–467, 466f, 469t Bacterial cell wall, penicillins on, 771, 771f Bactericidal activity, vs. bacteriostatic, 879, 879t Bacteriostatic activity, vs. bactericidal, 879, 879t Bagging, 562 Balanced anesthesia, 421, 430 Balanced polyethylene glycol, 1063–1064 Ballismus, 472, 485 Balsalazide, for inflammatory bowel disease, 1071–1073, 1072f Bambuterol, for asthma, 340 Bapineuzumab, for Alzheimer’s disease, 1029 Barbiturates, 382t for anesthesia, 423f, 431t, 432f, 433–434 chemical classification of, 370, 371f clinical pharmacology of, 378–379, 378t dose-response curves for, 369, 370f drug interactions of, 1122t neuropharmacology of, 375 pharmacodynamics of, 374–377 biotransformation in, 373 pharmacokinetics of absorption and distribution in, 374

biodisposition in, factors in, 374 excretion in, 374 structure of, 371f Baroreceptor, renal, on renin release, 295 Baroreflex, postural, 171, 171f Bartter’s syndrome, 326 Bases, weak definition of, 9 examples of, 10t ionization of, 9–10 trapping of, 9, 10f Basic research, 14b Basiliximab, 962 Bazedoxifne, 713, 714f BCNU (carmustine), 923f, 924 Beclomethasone (dipropionate), 686–692, 686t. See also Corticosteroids, inhaled (aerosol) for asthma, 344–345, 352t Bedaquiline, for tuberculosis, 816t, 821 Beef tapeworm drugs niclosamide, 913 praziquantel, 915 Belimumab, 633 Benazepril, for hypertension, 175t, 184–185 Benign hereditary chorea, 485 Benign prostate hyperplasia (BPH), alpha-receptor antagonists for, 157 Benzalkonium chloride, 869 Benzamides, substituted, 1070 Benzathine penicillin, 774–775. See also Penicillins Benzene, 977 Benzene hexachlorides, 978–979, 978t, 981f Benzinidazole, for trypanosomiasis and leishmaniasis, 903t, 904 Benzocaine, 442t, 451. See also Anesthetics, local in OTC agents, 1092t Benzodiazepine antagonists, 377–378, 382t Benzodiazepines, 382t abuse of, 556t for anesthesia, 432f, 434–435 antiemetic properties of, 1070 binding site ligands of, 375 chemical classification of, 369–370, 370f clinical pharmacology of, 378–379, 378t dose-reponse curves for, 369, 370f for epilepsy, 413–414, 418t for ethanol withdrawal, acute, 394t, 562, 565t ionotropic receptors in, 561 pharmacodynamics of, 374–377 biotransformation in, 372–373, 373f, 373t pharmacokinetics of absorption and distribution in, 374

biodisposition in, 374 excretion in, 374 structure of, 370f Benzoic acid, 871 Benzomorphans, mixed receptor actions of, 547 Benzophenones, in sunscreen, 1041 Benzoyl peroxide, 1042 Benztropine mesylate, for parkinsonism, 481, 481t, 487t Benzyl alcohol, ectoparasiticidal action of, 1040 o-Benzyl-p-chlorophenol, 869 Bepridil, for angina pectoris, 201. See also Calcium channel blockers Berinert, 301, 309t. See also Kinin inhibitors on vasoactive peptides, 309t Beryllium, 985 β1 -selective agonists, 96, 97t, 137t, 145, 145f, 150t structure of, 145f β2 -selective agonists, 150t, 352t for asthma, 340 preparations of, available, 353t structure of, 145f β3 -selective agonists, 150t β adrenoceptor, 135–136, 135t, 136f affinities of, 137, 137t cardiovascular system activation by, 141–142, 142t, 143f β-arrestin, 31, 32f Beta blockers. See β-receptor antagonist drugs β-receptor agonist drugs, for heart failure, 222t β-receptor antagonist drugs for angina pectoris, 191, 203, 206t with nitrates, 205, 205t for arrhythmia, 239, 246t, 247t choice of, 165 clinical pharmacology of, 163–165 cardiac arrhythmias, 164 cardiovascular disorders, other, 164 glaucoma, 164 heart failure, 164 hypertension, 163 hyperthyroidism, 164 ischemic heart disease, 163–164, 163f, 164f misc., 165 neurologic diseases, 164–165 drug interactions of, 1122t–1123t for heart failure, 217–218 chronic, 219 dobutamine, 216 preparations of, available, 223t for hypertension, 175t, 178–180, 188t esmolol, 180

labetalol, carvedilol, and nebivolol, 175t, 179–180, 188t metoprolol and atenolol, 175t, 179 nadolol, carteolol, betaxolol, and bisoprolol, 175t, 179 pindolol, acebutolol, and penbutolol, 175t, 179 propranolol, 175t, 178–179 for hyperthyroidism, 672, 675, 676, 677t as inverse agonists, 158 pharmacodynamics of, 159–161 on cardiovascular system, 159, 160f on eye, 160 for glaucoma, 161b, 162t metabolic and endocrine effects in, 161 non–beta-blockade effects in, 160t, 161 on respiratory tract, 159–160 pharmacokinetics of, 158, 160t poisoning management for, 1007t, 1009 preparations of, available, 167t for hypertension, 189t specific agents in, 160t, 161–163 structure of, 158, 159f toxicity of, clinical, 165–166 for variceal hemorrhage, 1078 β-selective agonists, 137t, 145–146, 145f Beta-lactamase assay, 875 Beta-lactamase inhibitors, 780–781, 780f Beta-lactam compounds, 769–781, 784t–785t. See also specific types beta-lactamase inhibitors, 780–781, 780f carbapenems, 770f, 781, 785t cephalosporins and cephamycins, 770f, 776–780, 785t monobactams, 770f, 780, 785t penicillins, 769–776, 784t preparations, available, 786t Betamethasone, 683f, 686–692, 686t. See also Corticosteroids, synthetic Betaxolol, 160t, 162. See also β-receptor antagonist drugs for hypertension, 179 Bethanechol, 107, 107f, 119t Bethanidine, 177 Bevacizumab, 937t, 938, 960 Bexarotene, dermatologic, 1050 Bezafibrate, 610 Bezold-Jarisch reflex, 281 Biased agonists, 137 at β receptors, 138b BIBP3226, 310t. See also Neuropeptide Y antagonists Bicalutamide, 719f, 720 for prostate cancer, 942 Biguanides, 736–737, 743t BIIE0246, 310t. See also Neuropeptide Y antagonists Bile acid–binding resins, 613, 616t

drug interactions of, 1123t with ezetimibe, niacin, and reductase inhibitors, 615 with fibric acid derivatives, 615 with HMG CoA reductase inhibitors, 615 with niacin, 615 Bile acid sequestrants for diabetes mellitus, 741, 744t for dyslipidemia, 616t Bile acid therapy for gallstones, 1077–1078, 1080t, 1081t Bile salt–binding resins, for diarrhea, 1065 Bimatoprost for glaucoma, 328 ophthalmic, 1049 Binding sites, inert, 7 Bioaccumulation, 974b Bioavailability, 47–48 extent of absorption in, 47, 47f, 47t first-pass elimination in, 43t–44t, 47–48 rate of absorption in, 47f, 48 Biologic agents, for psoriasis alefacept, 1043–1044 fumaric acid esters, 1044 TNF inhibitors, 1044 ustekinumab, 1044 Biological License Application (BLA), 17 Biologics, for inflammation, 619 Biomagnification, 974b Biotransformation, drug, 56–73 commensal gut microbiota in, 69 in drug disposition, 57, 57f drug metabolism in clinical relevance of, 64–71 to toxic products, 63, 65f in liver, 57–58 liver P450 enzymes in, 59–61, 62t necessity for, 56–57 phase I reactions in, 57, 57f microsomal mixed function oxidase system and, 58–59, 58f phase II reactions in, 57, 57f, 62–63, 63f, 64t Biperiden, for parkinsonism, 481, 481t, 487t Bipolar affective disorder history of, 502–503 nature of, 503 pathophysiology of, 502–503 Bipolar affective disorder drugs, 503–508 antipsychotics, 498 carbamazepine, 507, 508t lamotrigine, 507, 508t lithium, 503–506, 504–505, 508t

preparations, available, 508t valproic acid, 506, 508t Bipyridines, for heart failure, 216, 222t Bipyridyl herbicides, 981f, 982 Bisacodyl, 1064 Bismuth compounds, colloidal, for diarrhea, 1065 Bismuth subcitrate potassium, for gastric mucosa protection, 1061 Bismuth subsalicylate, for gastric mucosa protection, 1061 Bisoprolol. See also β-receptor antagonist drugs for heart failure, 218, 219, 221t for hypertension, 179 Bisphosphonates on bone homeostasis, 754–755, 755f, 765t for bone metastases, 764t for hypercalcemia, 757, 764t for osteoporosis, 754b, 762, 764t for Paget’s disease of bone, 763 Bitabarbital, 382t. See also Barbiturates Bithionol, 909t, 910 Bitopertin, 494–495 Bivalrudin, 593 Bleach, household, 869 Bleomycin, 932t, 935 Blind, single vs double, 14 Block, heart, 230–232, 231f Blood–brain barrier, 356–357 Blood clotting factors, 585, 586f, 586t Blood concentration-time curve, 47, 47f Blood:gas partition coefficient, 424, 425f, 425t Blood pressure angiotensin II on, 297 contraceptives on, female hormonal, 709 methamphetamine on, 87, 104 Blood pressure regulation, 169–171 normal, 170–171, 170f postural baroreflex in, 171, 171f renal response to decreased blood pressure in, 171 Blood schizonticides, 886, 887f B lymphocytes, 950 Boceprevir, for hepatitis C, 856t, 859–860 Bonds covalent, 3–4 drug–receptor, 3–4 electrostatic, 4 hydrophobic, 4 Bone marrow transplantation immunosuppressive therapy for, 963–964 immune globulin, intravenous for, 1138t Bone mineral homeostasis

1,25-dihydroxyvitamin D in, 748, 749f calcitonin in, 748, 749f calcium and phosphate in, 747, 748f Bone mineral homeostasis drugs, 747–764, 764t clinical pharmacology of, 756–764 calcium levels in, abnormal serum hypercalcemia, 757–758 hypocalcemia, 758–759 enteric oxaluria, 764 mineral-regulating hormone uses in, 759–764 chronic kidney disease, 760–761 hereditary vitamin D–resistant rickets, 762–763 hyperparathyroidism, primary, 759 hypoparathyroidism, 759 idiopathic hypercalciuria, 763 intestinal osteodystrophy, 761 nephrotic syndrome, 763 nutritional rickets, 762 osteoporosis, 761–762, 761f pseudovitamin D deficiency rickets, 762 tumor-induced osteomalacia, 762 vitamin D deficiency/insufficiency, nutritional, 759–760 X-linked and autosomal dominant hypophosphatemia, 762 Paget’s disease of bone, 763–764 phosphate levels in, abnormal serum hyperphosphatemia, 759 hypophosphatemia, 759 presentation in, 756–757 hormonal regulators, principle, 748–753 fibroblast growth factor 23, 752–753, 752t parathyroid hormone, 748–751, 748f, 749f, 752t PTH, FGF23, and vitamin D interaction in, 752–753 vitamin D, 750f, 751–752, 751t, 752t hormonal regulators, secondary calcitonin, 753 estrogens, 753–754 glucocorticoids, 753 nonhormonal regulators, 754–756 bisphosphonates, 754–755, 755f, 764t calcimimetics, 756 denosumab, 755 fluoride, 756 plicamycin, 756 strontium ranelate, 756 thiazide diuretics, 756 pharmacology of, 747–748, 748f preparations of, available, 765t vitamin D in, 748, 748f, 764t Bopindolol, 162. See also β-receptor antagonist drugs

Bortezomib, for multiple myeloma, 941 Bosentan, 304–305, 306b, 310t. See also Endothelin inhibitors for heart failure, 217 Bosutinib, 936 Botanical pesticides, 980, 981f Botanicals. See Herbal medications Botulinum toxin, 92 spasmolytic actions of, 468 Botulism antitoxin heptavalent equine, Types A-G, 1138t Botulism immune globulin, 1138t Botulism toxin immunization for, 1138t Bradycardic drugs. See also specific drugs for angina pectoris, 204 BRAF inhibitors, for melanoma, 1049–1050 Brain cancer, chemotherapy for, 944 Brain-derived neurotrophic factor (BDNF), in depression, 511–512, 511f Brain natriuretic peptide (BNP), 302–303, 302f on kidney, 254–255 Breakthroughs, drug, 10 Breast cancer chemotherapy for stage I & II, 941–942 stage III & IV, 942 from female hormonal contraceptives, 711 Brentuximab vedotin, 961–962 Brimonidine, 150t. See also Sympathomimetic drugs for acne, 1043 Brinzolamide, 255–256, 255t, 267t for glaucoma, 255 Brivaracetam, 407, 417 Bromocriptine, 150t, 286–289, 291t. See also Ergot alkaloids; Sympathomimetic drugs for diabetes mellitus, 741, 744t as dopamine agonist, 655–656 for hyperprolactinemia, 289 for Parkinson’s disease, 478, 487t Bronchial smooth muscle, adrenoreceptors in, 142 Bronchodilators. See also specific types for asthma, 348–349 Brugia malayi, diethylcarbamazine citrate for, 910–911 Brugia timori, diethylcarbamazine citrate for, 910–911 Bucindolol, 162 Budesonide. See also Corticosteroids, inhaled (aerosol) for asthma, 344–345, 352t for inflammatory bowel disease, 1073 Bulk-forming laxatives, 1063, 1081t Bumetanide, for diuresis, 257–259, 257t, 258t, 267t Bundle branch nodal block, 230–232, 231f–233f Bupivacaine, 442t, 443t, 451, 453t. See also Anesthetics, local

cardiotoxicity of, 441b, 449 lipid resuscitation for reversal of, 449, 450b historical development of, 441b Buprenorphine mixed receptor actions of, 546–547, 549t for opioid addiction, 558, 565t Bupropion for depression, 528t chemistry of, 516–517, 517f clinical pharmacology of adverse effects in, 525 drug interactions in, 526t, 527 pharmacodynamics of, 520t, 521 pharmacokinetics of, 518t, 519 preparations of, available, 529t for nicotine abuse, 561 poisoning/overdose of seizure management in, 1001, 1012 treatment of, 1008 Buserelin, 652–654, 715 Buspirone, 282, 371, 379t, 382t. See also Serotonin (5-HT) receptor agonists Busulfan, 923f. See also Alkylating agents Butenafine, 1037 Butorphanol, mixed receptor actions of, 547 Butoxamine, 163. See also β-receptor antagonist drugs Butyrophenone derivatives, for psychosis, 494, 494t, 507t.

Butyrophenones, 490–502, 492f, 507t. See also Antipsychotic agents antiemetic properties of, 1070 structure of, 492f Butyrylcholinesterase (BCHE), 68 cholinesterase inhibitors on, 107 genetic polymorphisms in, 67t, 68 BZ site, GABAA receptor, 374 C C6, 130–131, 130f. See also Ganglion blockers Cabazitaxel, 933 Cabergoline, 655–656, 656f. See also Dopamine agonists; Ergot alkaloids for hyperprolactinemia, 289 Cadmium, 985 Cadmium fume fever, 985 Caffeine for asthma, 341–342 diuretic actions of, 257 in OTC agents, 1092t structure of, 341f Calcimimetics on bone homeostasis, 756 for hyperparathyroidism, 759 Calcineurin inhibitors

cyclosporine, 955 tacrolimus, 955 Calcipotriene, 764t. See also Vitamin D for bone homeostasis, 751, 751t for psoriasis, 1033, 1043, 1051 Calcipotriol, for bone homeostasis, 751, 751t Calcitonin on bone homeostasis, 748, 749f, 753 for hypercalcemia, 757, 764t for osteoporosis, 762, 764t for Paget’s disease of bone, 763 Calcitonin gene-related peptide (CGRP), 92t, 283, 307, 310t Calcitriol for bone homeostasis, 764t (See also Vitamin D) for chronic kidney disease, 760 for psoriasis, 1033, 1043, 1051 for rickets hereditary vitamin D-resistant, 762–763 for pseudovitamin D deficiency, 762 Calcium abnormal serum levels of hypercalcemia, 757–758 hypocalcemia, 758–759 for bone, 764t, 765t on bone homeostasis, 747, 748f for enteric oxaluria, 764 for hyperphosphatemia, 759 for hypocalcemia, 758 in membrane electrical activity, 225–226, 226f Calcium carbonate, antacid actions of, 1054 Calcium channel blockers for angina pectoris, 191, 199–203, 206t calcium channels in, voltage-activated, 199t chemistry and pharmacokinetics of, 200, 200f, 200t clinical use of, 202–203 discovery and history of, 199–200 mechanism of clinical effects of, 202 nitrates with, 205, 205t pharmacodynamics of, 200t, 201–202 preparations of, available, 208t toxicity of, 202 for arrhythmia, 241–242, 247t diltiazem, 235t, 236t, 241–242, 247t verapamil, 235t, 236t, 241–242, 247t drug interactions of, 1123t for heart failure, chronic, 219 Calcium channel blockers (Cont.): for hypertension, 175t, 183, 189t for migraine headache prophylaxis, 285

poisoning management for, 1007t, 1009 preparations of, available, 247t on smooth muscle contraction, 192–193, 193f Calcium channels, voltage-activated, 199t Calcium ion (Ca2+), 30 as second messenger, 33–34, 33f Calcium oxalate stones, 764 Calcium receptor agonists, 764t for hyperparathyroidism, 759, 764t preparations of, available, 765t cAMP (cyclic adenosine-3’,5’-monophosphate), 30 on renin release, 295, 296f Camptothecins, 932t, 934 Canagliflozin, 256–257, 267t, 268t for diabetes mellitus, 740, 744t Canakinumab, 632, 962, 966 Cancer. See also specific types causes of, 918–919 epidemiology of, 918 from female hormonal contraceptives, 711 treatment modalities for, 919–920 Cancer chemotherapy, 918–945. See also specific drugs adjuvant, 920 alkylating agents, 922–927 antimetabolites, 927–931 (See also Antimetabolites) antimicrobial agents, 767, 767f antitumor antibiotics anthracyclines, 932t, 934–935 bleomycin, 932t, 935 mitomycin, 932t, 935 asparaginase, 938–939 cell cycle kinetics and anti-cancer effect in, 920–921, 920f, 921f, 921t clinical pharmacology of, 939–944 brain cancer, 944 breast cancer stage I & II, 941–942 stage III & IV, 942 fundamentals of, 939 gastrointestinal cancers, 942–943 leukemia, acute adult, 939 childhood, 939 leukemia, chronic lymphocytic, 940 myelogenous, 939–940 lymphoma Hodgkin’s, 940 non-Hodgkin’s, 940–941 malignant melanoma, 944

multiple myeloma, 941 ovarian cancer, 943 prostate cancer, 942 secondary malignancies, 944 testicular cancer, 944 dermatologic alitretinoin, 1050 bexarotene, 1050 romidepsin, 1050–1051 vismodegib, 1050–1051 vorinostat, 1050–1051 dosage factors in, 922 drug combinations in, 921–922 drug resistance in, 922 growth factor receptor inhibitors, 936–938, 937t imatinib and other tyrosine kinase inhibitors, 936, 937t natural product drugs, 931–934, 932t camptothecins, 932t, 934 epidophyllotoxins, 932t, 934 taxanes and other anti-microtubule drugs, 932t, 933–934 vinca alkaloids, 931–933, 932t neoadjuvant, 919–920 primary induction, 919 Candesartan for heart failure, 217 for hypertension, 185 on vasoactive peptides, 309t Canglifozin, 256–257, 267t Cannabinoid receptor inverse agonist, 565t Cannabinoids, 556t, 557–558 antiemetic properties of, 1071, 1080t Gio protein–coupled receptor activation by, 556t, 558–559, 560f Capacity-limited elimination, 45–46 Capacity-limited protein binding, 53 Capecitabine, 928t, 929 dihydropyrimidine dehydrogenase on, 78t, 80 Capreomycin, for tuberculosis, 816t, 820 Capromab pendetide, 962 Capsaicin, 96 Capsaicin receptors (TRPV1, TRPA1), 538b Captopril for heart failure, 217 for hypertension, 175t, 184–185, 188t on renin-angiotensin system, 298 on vasoactive peptides, 309t Carbachol, 107, 107f, 119t Carbamate pesticides, 980, 980t Carbamazepine, 508t for bipolar disorder, 507, 508t

drug interactions of, 1123t–1124t for seizures, 401f, 402–403, 418t Carbamic acids, 113–114, 113f Carbapenems, 770f, 781, 785t Carbaryl, 113, 113f Carbidopa, 474f, 487t. See also Parkinsonism Carbidopa-levodopa, parkinsonism, 474f, 476, 487t Carbimazole, 670–671, 671f Carbonic anhydrase inhibitors, 255–256, 255t, 267t, 268t Carbon monoxide, 974–975, 974t poisoning management for, 1007t, 1009, 1010t Carbon tetrachloride, 977–978 Carboplatin, 925–927, 926t Carboprost tromethamine for abortion, 324–325 structure of, 325f Carboxypenicillins, 775. See also Penicillins Cardiac arrhythmias. See Arrhythmias, cardiac Cardiac cell membrane, active, 227–228, 227f Cardiac contractility modulation therapy for chronic heart failure on, 220 normal control of, 210, 211f Cardiac glycosides. See also Digitalis; Digoxin; specific types for heart failure, 214–217, 215f, 216f, 221t Cardiac muscle sarcomere, 210, 211f Cardiac performance, 213, 213f Cardiac resynchronization, for chronic heart failure, 220 Cardiac rhythm electrophysiology, normal, 224–229 active cell membrane in, 227–228, 227f ionic basis of membrane electrical activity in, 225–227, 226f nodes and conduction in, 224, 225f potassium effects in, 227b resting potentials on action potentials in, 228–229, 228f Cardiovascular system autonomic integration of, 97–99, 99f contraceptives on, female hormonal, 709 kinins on, 300 Cardioverter-debrillator, implantable, 242b Carfilzomib, for multiple myeloma, 941 Cariprazine, 494 Carmustine (BCNU), 923f, 924 Carperitide, 303. See also Natriuretic peptides for heart failure, 217 on vasoactive peptides, 310t Carperitide (ANP), on kidney, 254 Carprofen, 625 Carrier molecules, special, 8, 8f Carteolol, 160t, 162. See also β-receptor antagonist drugs for hypertension, 179

Carvedilol, 156, 160t, 162–163. See also β-receptor antagonist drugs dissociation constants and enantiomers of, 4, 4t for heart failure, 218, 219, 221t for hypertension, 179–180 Cascara, 1064 Case-control epidemiologic studies, 14b Case reports, 14b Case series, 14b Case studies acetaminophen safety, 56, 73 Addison’s disease, 680, 695 alcohol poisoning, acute, 385, 395 amoxicillin, rash from, 769, 787 anesthesia with hypertension and coronary artery disease, 421, 439 antiseizure drugs, 396, 420 asthma, respiratory infection on, 336, 354 atrial fibrillation and left ventricular dysfunction, 224, 248 autonomic failure, pure, 133, 151 bupropion overdose, seizure management in, 1001, 1012 Clostridium difficile, treatment and antisepsis with, 865, 872 cocaine addiction, 552, 566 cold medications, hypertension from, 1084, 1093 colorectal cancer stage III, chemotherapy for, 918, 939 community-acquired pneumonia and meningitis, cephalosporin and vancomycin for, 769, 787 coronary artery disease with hyperlipidemia, angina treatment in, 191, 208 Crohn’s disease treatment, 1052, 1083 deep venous thrombosis, heparin for pulmonary embolism from, 584, 601 dihydropyrimidine dehydrogenase enzyme deficiency, 918, 939 diuretics, acute kidney injury from chronic use of, 249, 269 epilepsy (seizures), 396, 420 falciparum malaria treatment, 886, 907 fluoxetine for depression, CYP450 and pharmacodynamic interactions of, 510, 530 growth hormone deficiency, 643, 662 heart failure, diuretics and ACE for, 209, 223 HIV and tuberculosis, antimycobacterial drugs for, 815, 824 HIV plus HBV treatment, in alcoholic smoker on methadone, 835, 864 hyperlipidemia treatment, 602, 617 hypertension, 169, 190 with Alzheimer’s and age-related macular degeneration, 1024, 1032 renin-angiotensin system suppression for, 294, 312 irinotecan pharmacogenomics, 74, 86 lead, chelation for, 995, 1000 megaloblastic anemia, vitamin B12 deficiency, 567, 583 meningitis, 873, 885 methamphetamine ammonium chloride for intoxication with, 1, 19 on blood pressure, 87, 104 mucormycosis, 825, 834 muscle relaxants, for emergency trauma surgery, 455, 471

opioids for trauma with COPD, 531, 551 organophosphate cholinesterase inhibitor poisoning, 105, 120 osteoporosis, 747, 766 premature ovarian failure, hormone replacement therapy for, 696, 722 psoriasis, corticosteroids + calcipotriene/calcitriol + coal tar shampoo for, 1033, 1051 rheumatoid arthritis, 618, 641 Rh negative in labor, immunotherapy for, 946, 969 urinary frequency and incontinence after prostatectomy, 121, 132 urinary tract infection, antibiotic choice in, 807, 814 verapamil vs. propranolol, 20, 40 Caspofungin, 831, 833t Catatonic schizophrenia, antipsychotics for, 497. See also Antipsychotic agents Catecholamine receptors agonists binding to, 135, 136f structure of, 140f Catecholamine reuptake inhibitors, 139f, 147 Catecholamines. See also specific types biosynthesis of, 92, 94f endogenous, 142t, 143f, 144–145 metabolism of, 94–96, 95f Catechol-O-methyltransferase (COMT), 139 catecholamine metabolism by, 95f Catechol-O-methyltransferase (COMT) inhibitors, for parkinsonism, 479–480, 487t Cathartics, for toxin elimination, 1006 Catumaxomab, 960–961 Causal prophylactic drugs, for malaria, 886 CB1 receptors, brain, 365t, 368 CD8 T lymphocytes, 948f, 950 Celecoxib, 621t, 623 Celiprolol, 160t, 162. See also β-receptor antagonist drugs Cell-mediated immunity, 947 Cell wall, bacterial, penicillins on, 771, 771f Central integration, autonomic, 89f, 96–97, 98t Central nervous system (CNS), 87, 355–362 angiotensin II on, 297 brain cellular organization in hierarchical systems in, 361, 361f nonspecific or diffuse neuronal systems in, 361–362, 362f contraceptives on, female hormonal, 709 fundamentals of, 355 ion channels and neurotransmitter receptors in, 357–358, 357f natural toxins for, 358b, 358t organization of blood–brain barrier, 356–357 neuroglia, 356, 356f neurons, 356, 356f sites of drug action in, 359–361, 360f sympathomimetics on, 144 synapses and synaptic potential in, 358–359, 359f

Central nervous system (CNS) drugs. in elderly, 1027–1029 Alzheimer’s disease, 1027–1029, 1028f, 1029t analgesics, 1027 antipsychotics and antidepressants, 520t, 1027 sedative-hypnotics, 1027 Central nervous system (CNS) neurotransmitters, 362–368 acetylcholine, 362f, 364t, 366 amino acid, 363–366 GABA and glycine, 363–366, 364t glutamate, 363, 364t, 365f endocannabinoids, 365t, 367–368 monoamine 5-hydroxytryptamine, 362f, 364t, 367 dopamine, 362f, 364t, 366 histamine, 364t, 367 norepinephrine, 362f, 364t, 366–367 neuropeptides, 367 nitric oxide, 368 opioid peptides, 365t orexins, 365t, 367 purine, 368 tachykinins, 365t Cephalosporins, 770f, 776–780, 785t adverse effects of, 779–780 chemistry and structure of, 770f, 776, 776f dosing of, 777t first-generation, 776–778, 776f, 777t fourth-generation, 776f, 777t, 779 for methicillin-resistant staphylococci, 776f, 777t, 779 preparations, available, 786t second-generation, 776f, 777t, 778 third-generation, 776f, 777t, 778–779 Cephamycin, 778 Cerebral insufficiency, senile, ergot alkaloids for, 289 Certolizumab for inflammatory bowel disease, 1075–1076, 1075t for rheumatic disorders, 629–630, 630f Cestode drugs. See also Anthelmintic drugs praziquantel, 914 Cetirizine, 275–278, 290t. See also H1 -receptor antagonists CETP inhibition, 614 Cetrorelix, 654–655 Cetuximab, 936–938, 937t, 961 Cevimeline, 119t CFTR gene, 244b CFTR mutations, 244b cGMP, on renin release, 295, 296f Chagas disease drugs

benznidazole, 901t, 904 nifurimox, 903t, 904 Charcoal, activated, 1006 Chart orders, 1109. See also Prescriptions abbreviations in, 1111t errors of omission in, 1111 Chelators, 995–999. See also specific types deferoxamine, 996f, 998 desferasirox, 998 dimercaprol, 990–991, 992, 994, 996, 996f edetate calcium disodium, 990–991, 995f, 997 penicillamine, 996f, 998 pharmacology of, 995, 995f preparations, available, 999t Prussian blue, 998–999 succimer, 990–991, 993, 994–995, 996–997, 996f unithiol, 992–995, 997–998 Chemical antagonism, 25 Chemical antagonist, 3.

Chemical transmission. See also Neurotransmitters, CNS in endocrine system, 87–88 in nervous vs. endocrine system, 87–88 Chemoattractant cytokines (chemokines), 947 Chemokines, 947 Chemoreceptor reflex, 281 Chemoreceptor trigger zone, 1068, 1068f Chemotherapy, cancer, 918–945 Chemotherapy-induced nausea and vomiting, serotonin 5-HT3 -receptor antagonists for, 1069, 1080t, 1081t Chemotherapy-induced neutropenia, G-CSF for, 579, 579f, 581t Chimeric molecules, 959 Chirality, 4 Chloral hydrate, 371f Chlorambucil, 922–927, 923f. See also Alkylating agents Chloramphenicol, 795–796, 797t drug interactions of, 1124t Chlordiazepoxide, 382t. See also Benzodiazepines for ethanol withdrawal, acute, 394t structure of, 370f Chlorhexidine, 867t, 868 Chloride channel CFTR, 244b in cystic fibrosis, 245 GABA receptor complex versatility in, 374, 374f, 376b Chloride channel activators for irritable bowel syndrome, 1067–1068 laxatives, 1064 Chloride channel drugs for arrhythmia, 244 preparations of, available, 247t

Chloride (Cl-), in membrane electrical activity, 225–226, 226f Chlorine, 869 2-Chlorodeoxyadenosine (cladribine), 928t, 931 Chloroform, 977–978 methyl, 977–978 Chlorophenothane (DDT), 978–979, 978t, 981f Chlorophenoxy herbicides, 980–981, 981f Chloroprocaine, 451, 453t. See also Anesthetics, local Chloroquine, 626, 887–891, 889t adverse effects of, 890–891 antimalarial action and resistance to, 887 chemistry and pharmacokinetics of, 887, 888f clinical uses of amebic liver abscess, 890 chemoprophylaxis, 889t, 890 treatment, 889–890, 889t, 890t contraindications and cautions with, 891 for malaria, 887–891, 889t, 890t Chlorothiazide, 259–260, 259f, 267t Chlorotrianisene, 699, 699f. See also Estrogens Chlorpheniramine, 275–278, 290t. See also H1 -receptor antagonists Chlorpromazine, 156. See also Antipsychotic agents for psychosis, 492f, 493–494, 494t, 507t Chlorpropamide, 733–735, 734f, 743t. See also Sulfonylureas Chlorthalidone, 259–260, 259f, 267t Cholecalciferol. See also Vitamin D for bone homeostasis, 764t Cholecystokinin (CCK), 92t Cholesterol α-hydroxylase, 607 Cholesterol guidelines, current, 605t Cholesterol, in cell membrane, 826 Cholesteryl esters, 602 Cholesteryl ester storage disease, 605t, 607 Cholestyramine, 613, 616t for diarrhea, 1065 Choline acetyltransferase (ChAT), 90, 91f Choline esters, 107, 107f, 108f, 108t Choline esters, direct-acting, 119t Cholinergic fibers, 88f, 90 Cholinergic junction, 90–92, 91f Cholinergic nerves, cotransmitters in, 92t, 96 Cholinergic poisoning, muscarinic receptor blockers for, 128–129 Cholinergic transmission, 90–92, 91f, 92t Cholinesterase inhibitors absorption, distribution, and metabolism of, 113–114, 114f, 114t for Alzheimer’s disease, 1028 durations of action of, 114t intermediate-acting, 119t mechanism of action of, 114–115

mode of action of, 91f, 106f, 107 pharmacodynamics of, 114–115 poisoning with case study of, 105, 120 management of, 1007t, 1009–1010 short-acting, 119t structure of, 113, 113f therapeutic uses of, 114t toxicity of, 118 Cholinesterase regenerators, 128–129, 131t, 132t Choline transporter (CHT), 90, 91f Cholinoceptor-blocking drugs, 121–132, 131t ganglion-blocking drug pharmacology in, 130–131 muscarinic receptor blockers, 121–129 clinical pharmacology of, 126–129 pharmacology of, 121–126 preparations of, available, 132t subgroups of, 121 Cholinoceptors, 92, 96, 97t. See also Muscarinic (M) receptors; Nicotinic (N) receptor definition of, 96 subtypes and characteristics of, 105–106, 106t Cholinomimetic agents, prokinetic activity of, 1062 Cholinomimetics, 105–120. See also specific types classification of, 105 clinical pharmacology of, 115–118, 119t, 120t clinical uses in antimuscarinic drug intoxication, 117 CNS, 117 eye, 103f, 116 GI and urinary tracts, 116 heart, 117 neuromuscular junction, 109f, 116–117 toxicity in cholinesterase inhibitors, 118 muscarinic stimulants, direct-acting, 117 nicotinic stimulants, direct-acting, 117–118 mode of action of, 91f, 106f, 107 spectrum of action of, 88f, 101f, 105–107, 106f, 106t Cholinomimetics, direct-acting, 107–113, 119t chemistry and pharmacokinetics of, 107, 107f, 108f, 108t mode of action of, 91f, 106f, 107 pharmacodynamics of, 106t, 108–113 mechanism of action in, 106t, 108–110, 109f organ system effects in, 110–113, 110t, 111f cardiovascular system, 99f, 110–111, 110t, 111f, 196f CNS, 108f, 112 eye, 110 gastrointestinal tract, 111–112 genitourinary tract, 112

neuromuscular junction, 106t, 109f, 112–113 PNS, 101f, 108f, 112 respiratory system, 111 secretory glands, 112 preparations of, available, 120t Cholinomimetics, indirect-acting, 113–115, 119t chemistry and pharmacokinetics of, 113–114, 113f, 114f, 114t mode of action of, 91f, 106f, 107 pharmacodynamics of, 110t, 114–115, 460f, 461f preparations of, available, 120t Cholinoreceptor stimulants, 105. See also Cholinomimetics CHOP, for non-Hodgkin’s lymphoma, 940 Chorea, 472 benign hereditary, 485 Huntington’s disease, 483–484, 484f, 487t Christmas disease, 598–599, 598t Christmas factor, 596t Chronic kidney disease, 760–761 Chronic lymphocytic leukemia (CLL), 940 immunization for, 1138t Chronic myelogenous leukemia (CML), 939–940 Chronic obstructive pulmonary disorder (COPD) muscarinic receptor blockers for, 123f, 127 opioids for trauma with, 531, 551 treatment of, 351 Chrousos syndrome, corticosteroids for, 687 Chylomicronemia, primary, 605–606, 605t Chylomicrons, 603 Ciclesonide, for asthma, 345 Ciclopirox olamine, dermatologic topical, 1037 Cidofovir, for cytomegalovirus, 840t, 841–842 Cilastatin, 781 Cilostazol, 597 for peripheral artery disease and intermittent claudication, 206 Cimetidine, 278, 290t, 1054–1056. See also H2 -receptor antagonists drug interactions of, 1124t Cinacalcet on bone homeostasis, 756 for hyperparathyroidism, 759, 764t Cinchonism, 893 Cinryze, 301, 309t. See also Kinin inhibitors on vasoactive peptides, 309t Ciprofloxacin, for tuberculosis, 816t Cirrhosis, hepatic, diuretics for, 265 Cisapride, 285 drug interactions of, 1124t–1125t Cisatracurium. See also Neuromuscular blocking drugs pharmacokinetics of, 458 properties of, 459t, 469t

Cisplatin, 925–927, 926t Citalopram, 528t. See also Selective serotonin reuptake inhibitors (SSRIs) poisoning with, treating, 1008 Cladribine, 928t, 931 Clarithromycin, 792f, 793, 797t Classic angina, 191 Claudication, intermittent, 205–206, 208t Clavulanic acid, 780–781, 780f Clearance (CL), 42–46. See also specific drugs capacity-limited elimination in, 45–46 for drug concentration measurement interpretation, 53 flow-dependent elimination in, 46 initial predictions of, 54 rate of elimination in, 45 revising individual estimates of, 54 on target concentration, 52 total systemic, 45 Clevidipine, for hypertension, 183 Clindamycin, 794, 797t, 798t for acne, 1036 for malaria, 890t, 897 Clinical trials, 15–17 confounding factors in, 14–15 controlled, 2 IND & NDA, 12f, 15–17 phase 1, 16 phase 2, 16 phase 3, 17 phase 4, 17 randomized controlled trails, 15b Clobazam, for seizures, 414, 418t Clofazimine, 823 Clomiphene, 699f, 713, 714f, 715–716 Clonazepam, 382t. See also Benzodiazepines for restless legs syndrome, 486 for seizures, 413–414, 418t Clonidine, 145, 150t. See also Sympathomimetic drugs for hypertension, 175t, 176–177 for tics, 485, 487t Clonorchiasis, praziquantel for, 914 Clopidogrel antiplatelet effects of, 596 CYP2C19 on metabolism of, 78t, 80 for peripheral artery disease and intermittent claudication, 206 Clorazepate, 382t. See also Benzodiazepines Clorazepate dipotassium, for seizures, 414 Clostridium difficile, treatment and antisepsis with, 865, 872 Clotrimazole-betamethasone dipropionate cream, 1037 Clotrimazole, topical, 832

dermatologic, 1037 Clotting factors, 585, 586f, 586t Clotting prevention agents, 597, 600t arterial thrombosis, 597 venous thrombosis, 597 Clozapine, 493f, 494, 507t Club drugs, 563 Coagulation estrogens on, 701 mechanisms of, 584–585 Coagulation cascade, 585–587, 585f fibrinolysis in, 587, 587f fundamentals of, 585, 586f, 586t tissue factor-VIIa complex in, 585–587, 586f Coagulation disorder drugs, 584–600. anticoagulants, 587–594, 600t antiplatelet agents, 595–597, 600t aspirin, 595, 596 cilostazol, 597 dipyridamole, 596–597 GP IIb/IIIa antagonists, 585f, 596 thienopyridines, 595–596 antithrombotics, 597, 600t factor VIIa, recombinant, 598t, 599, 600t fibrinolytic inhibitors, 598t, 599–600, 600t fibrinolytics, 587f, 594–595, 600t plasma fractions, 598–599, 598t, 600t serine protease inhibitors, 600 vitamin K for bleeding disorders, 590f, 597–598, 598t Coal tar shampoo, for scalp psoriasis, 1033, 1051 Cobicistat, 847 Cocaine, 139f, 442t, 451, 453t. See also Anesthetics, local abuse of, 556t, 557 addiction to, 552, 566 biogenic amine binding in, 562–563, 563f clinical uses of, 147 on dopamine transporter, 562–563, 563f historical development of, 441b on NET, 93 Cockroft-Gault formula, 1026 Codeine, 545–546, 549t. See also Opioid agonists antitussive, 547, 549t CYP2D6 activity on metabolism of, 78t, 79–80 Gio protein-coupled receptor activation by, 556t, 558, 560f Coding single nucleotide polymorphisms (cSNPs), 75t Coenzyme Q10, 1103–1104 Cognitive remediation, for schizophrenia, 502 Cohort epidemiologic studies, 14b Colchicine, drug interactions of, 1125t

Cold medications, hypertension from, 1084, 1093 “Cold” preparations, OTC, 1087t Colesevelam, 613, 616t for diarrhea, 1065 Colesevelam hydrochloride, for diabetes mellitus, 741, 744t Colestipol, 613, 616t for diarrhea, 1065 Collecting tubule system, 250f, 252–254, 253f Colloidal bismuth compounds, for diarrhea, 1065 Colonic pseudo-obstruction, acute, 1062 Colorectal cancer chemotherapy case study of, 918, 939 dihydropyrimidine dehydrogenase enzyme deficiency on, 939 Coma, nonketotic hyperosmolar, 724 Combined toxicity, of drug interactions, 1131 Commensal gut microbiota, 69 Community-acquired pneumonia, cephalosporin and vancomycin for, 769, 787 Competitive antagonists, 23–24, 23f Competitive inhibitor, 5, 6f Complementary medicine, 3 Complex partial seizure, 414 Compliance, 1112–1113 Compound 48/80, 272 Compound optimization, 12–13 Concentration-dependent killing, 801, 879 Concentration-effect curves, receptor binding of agonists on, 21, 22f Concentration measurements, drug interpretation of clearance in, 53 dosing history in, 53 initial predictions in, 54 revising individual estimates of, 54 timing of samples for measurement of, 53–54 volume of distribution in, 54 on pharmacologic effects, 20, 21–26 (See also Dose, on pharmacologic effects) Conductance, 226 potassium on, 227b Conduction, heart, 224, 225f Conflicts of interest, 17–18 Confounding factors, in clinical trials, 14–15 Congenital adrenal hyperplasia, corticosteroids for, 687 Conivaptan, 302, 658, 660t for diuresis, 263, 268t for heart failure, 220 on vasoactive peptides, 310t Conjugates, drug, 62–63, 63f, 64t Consciousness, in anesthesia, 427b Conscious sedation, 422b Constitutive activity, 5, 21

Contact hypersensitivity, 952 Context-sensitive half-time, 432, 432f Continuing medical education (CME), 18 Continuous subcutaneous insulin infusion (CSII) devices, 730–731 Contraception, hormonal, in women, 708–713 adverse effects of, 710–711 beneficial effects of, 712–713 clinical uses of, 710 contraindications and cautions with, 712 emergency, OTC, 1090t monophasic, biphasic, and triphasic, 708 pharmacologic effects of, 708–710 blood, 709 breast, 709 carbohydrate metabolism, 709 cardiovascular system, 709 CNS, 709 endocrine functions, 709 lipid metabolism, 709 liver, 709 mechanism of action of, 708 ovary, 708 skin, 709 uterus, 708–709 physiologic effects of, 704t, 705, 705f, 706t–707t postcoital contraceptives, 712, 712t preparations of, 706t–707t, 708 progestin-only contraception, 712 types of, 708 Contractility, cardiac, 213, 213f Controlled clinical trial, 2 Controlled ovarian stimulation GnRH for, 653 gonadotropins for, 650–651, 651f Controlled substances, 1113–1114, 1114t Conus, 358b Conversions, for prescriptions, 1110 Converting enzyme, in angiotensin biosynthesis, 296–297, 297f Convulsions, neuromuscular blockers for, 465 Coplanar biphenyls, 983 Copy number variations (CNVs), 75t Coral snake antivenom, 1139t Coral snake hyperimmune globulin, 960 Coronary artery disease (CAD) angina pectoris from, 191 with hyperlipidemia, angina treatment for, 191, 208 hypertension and, anesthesia with, 421, 439 myxedema and, 673 treatment of, 204

Coronary blood flow, 192 Coronary steal, 203b Corticosteroids antiemetic properties of, 1069 for asthma, 344–345, 352t clinical uses of, 349–350 on eicosanoid synthesis, 323 for gout, 638 for immunosuppression, 954–955, 954t for rheumatoid arthritis, 633 Corticosteroids, inhaled (aerosol) for asthma, 344–345, 352t clinical uses of, 349–350 preparations of, available, 353t Corticosteroids, synthetic, 686–692 adrenal androgens, 692 clinical pharmacology of, 686–691 adrenocortical hypo- and hyperfunction aldosteronism, 687–688 Chrousos syndrome, 687 congenital adrenal hyperplasia, 687 Cushing’s syndrome, 687 adrenocortical insufficiency acute, 687 chronic (Addison’s disease), 686–687 contraindications and cautions in, 690 diagnostic uses in, 688 drug selection and dosage in, 690–691 fetal lung maturation, 688 nonadrenal disorders, 688–689, 689t toxicity in, 689–690 mineralocorticoids aldosterone, 691 deoxycorticosterone, 691–692 fludrocortisone, 692 pharmacodynamics of, 686, 686t pharmacokinetics of, 683f, 686, 686t preparations of, available, 695t Corticosteroids, topical, 1044–1046, 1045t, 1046t adverse effects of, 1046 chemistry and pharmacokinetics of, 1044–1046, 1045t dermatologic, 1044–1046, 1045t, 1046t for psoriasis, 1033, 1051 Corticotropin-releasing hormone (CRH), 645, 645t Cortisol, 681–685, 695t. See also Glucocorticoids, naturally occurring Cortisone, 686–692, 686t. See also Corticosteroids, synthetic Cost, prescription, 1116, 1116b Cotransmitters, 90 autonomic, 90

in cholinergic and adrenergic nerves, 92t, 96 Coupling definition of, 22 receptor-effector, and spare receptors, 21–23, 22f Covalent bonds, 3–4 COX-1, 314–315, 315f COX-2, 314–315, 315f COX-2 inhibitors nonselective, 623–625 azapropazone, 625 carprofen, 625 diclofenac, 620f, 621t, 623 diflunisal, 621t, 623 etodolac, 621t, 623 flurbiprofen, 620f, 621t, 623 ibuprofen, 620f, 621t, 623–624 indomethacin, 620f, 621t, 624 ketoprofen, 621t, 624 meclofenamate, 625 nabumetone, 620f, 621t, 624 naproxen, 620f, 621t, 624 oxaprozin, 621t, 624 piroxicam, 620f, 621t, 624–625 sulindac, 621t, 625 tenoxicam, 625 tolmetin, 620f, 621t, 625 selective, 621–623, 621t adverse effects of, 619–620 celecoxib, 621t, 623 meloxicam, 621t, 623 COX inhibitors for Bartter’s syndrome, 326 for ductus arteriosus delayed closure, 327 C-peptide, 724–725, 724f Cretinism, 667, 672t Crofelemer, 1064 for arrhythmia, 244 Crohn’s disease helper T cell type 1 dysregulation in, 1075 treatment of, 1052, 1083 Cromolyn, 275 for allergic rhinoconjunctivitis, 345 for asthma, 345, 350, 352t Crotalidae polyvalent immune Fab antivenom, 1139t Crotamiton, ectoparasiticidal action of, 1040 Cryoablation, for cardiac arrhythmias, 242b Cryoprecipitate, 599 Cryptosporidium parvum, nitazoxanide for, 903 C-type natriuretic peptide (CNP), 302–303, 302f

on kidney, 254 Cumulative effects, 49 Cushing’s syndrome, corticosteroids for, 687 Cutaneous larva migrans drugs. See also Anthelmintic drugs albendazole, 909t, 910 thiabendazole, 916 Cyanide, poisoning management for, 1007t, 1010, 1010t Cyanocobalamin, for vitamin B12 deficiency, 572, 574, 581t Cyclic adenosine monophosphate (cAMP), 31–33, 33f in bronchodilation, 338, 339f Cyclic guanosine monophosphate (cGMP), 34, 333f Cyclic ureides, 418t. See also specific drugs Cyclobenzaprine, 469t Cyclodienes, 978–979, 978t, 981f Cyclooxygenases, 314–316, 315f Cyclopentolate, 131t. See also Muscarinic receptor blockers Cyclophosphamide, 922–927, 923f. See also Alkylating agents antirheumatic actions of, 626 for immunosuppression, 957 metabolism of, 924, 925f Cycloplegia, from atropine, 124–125, 124f Cycloserine, 773f, 784 for tuberculosis, 816t, 820 Cyclospasm, 101b Cyclosporine (cyclosporin A, CSA) antirheumatic actions of, 626–627 drug interactions of, 1125t for immunosuppression, 955 CYP2B6, 62t, 63f, 66t, 68 CYP2C9, 62t, 63f, 66t, 67 polygenic effects in, 77t, 79t, 85 CYP2C19, 62t, 63f, 65, 66t pharmacogenomics of, 76t, 78t, 80 CYP2D6, 62t, 63f, 65, 66t–67t pharmacogenomics of, 75–80, 76t, 78t CYP3A5, 63f, 67t, 68 Cyproheptadine, 285 Cyproterenone, 719f, 720 Cyproterenone acetate, 719f, 720 for contraception in men, 721 Cysticercosis, praziquantel for, 914 Cystic fibrosis chloride channels in, 245 heart and, 244b Cytarabine (ara-C), for immunosuppression, 928t, 929–930, 958 Cytisine, for nicotine abuse, 561, 565t Cytochrome P450-derived metabolites, 323 Cytochrome P450 oxidoreductase (POR, CYP), 58, 60t–61t Cytokine inhibitors, 966

Cytokine receptors, 28, 29f Cytokines, 964–966, 965t Cytomegalovirus (CMV) agents, 839–842 cidofovir, 840t, 841–842 cytomegalovirus immune globulin, 1138t foscarnet, 840t, 841 fundamentals of, 839–840 ganciclovir, 840–841, 840t valganciclovir, 840t, 841 Cytomegalovirus immune globulin, 1138t Cytopenia agents, 567–583 anemia agents, 567–576, 581t–583t hematopoietic growth factors, 576–581, 582t preparations, available, 583t Cytotoxic agents, immunosuppressive azathioprine, 957 cyclophosphamide, 957 hydroxychloroquine, 958 methotrexate, vincristine, and cytarabine, 958 pentostatin, 958 pyrimidine synthase inhibitors, 957–958 vinblastine, 958 D D3 , for bone homeostasis, 764t Dabigatran etexilate mesylate, 593–594 Dabrafenib, for melanoma, 944, 1050 Dacarbazine, 925, 926t Dacilizumab, 962 Dalbavancin, 782, 785t Dalteparin, 587–590, 588f. See also Heparin Danazol, 714 Dantrolene for malignant hyperthermia, 429, 468 spasmolytic actions of, 466f, 467–468, 469t Dapagliflozin, 256–257, 267t, 268t for diabetes mellitus, 740, 744t Dapsone, 822 for acne, 1036–1037

Daptomycin, 783, 783f, 784f, 785t Darbepoetin alfa, 577–578, 577t, 582t Darifenacin, 131t. See also Muscarinic receptor blockers for urinary disorders, 128 Darunavir, 843t, 852 Dasatinib, 936 Data, missing, 15 Datura, 121. See also Atropine; Muscarinic receptor blockers Daunorubicin, 932t, 934–935 DDT (chlorophenothane), 978–979, 978t, 981f Debrisoquin, 177 Debrisoquin-sparteine oxidation, 65 Decongestants, OTC systemic, 1090t topical, 1089t Decontamination, 867t of poisoned patient, 1005–1006 Deep sedation, 422b. See also Anesthetics, general Deep venous thrombosis (DVT) from female hormonal contraceptives, 711 heparin for pulmonary embolism from, 584, 601 thrombolytics for, 595 Deferasirox, for iron overload, 572, 581t Deferoxamine, 996f, 998 for iron overload, 572, 581t for iron toxicity, acute, 572 Definitive therapy, antimicrobial, 874 Degarelix, 654–655 Degree of spareness, 22f, 23 Dehydroemetine, for amebiasis, 899t, 901 Dehydroepiandrosterone (DHEA), 716 Dehydroepiandrosterone sulfate (DHEAS), 716 Delavirdine, 843t, 849 Delayed afterdepolarizations (DADs), 214, 230, 231f Delayed effects, 46f, 49 Delayed-type hypersensitivity (DTH), 951–952, 953f Delirium tremens, 388 management of, 391 sedative-hypnotics for, 379 Delta opioid receptors, 531, 532t Denervation supersensitivity, 100 Denosumab, 963 on bone homeostasis, 755 for osteoporosis, 750, 754b, 762, 764t Deoxycorticosterone (DOC), 691–692 Deoxycytidine analogs cytarabine, 928t, 929–930 gemcitabine, 928t, 930 Dependence, physical, 553–555

alcohol (ethanol), 384, 388 benzodiazepine, 561 clinical pharmacology of, 564 definition of, 531, 537 opioid, 537, 542, 543 sedative-hypnotics, 377 tolerance in, 553–554 withdrawal from, 554–555 sedative-hypnotics for, 379 Depression acute bipolar, antipsychotics for, 498 from female hormonal contraceptives, 711 major depressive disorder, 505, 510–514 (See also Major depressive disorder (MDD)) pathophysiology of, 511–514 integration of hypotheses on, 514 monoamine hypothesis in, 511, 512–514, 513f neuroendocrine factors in, 514 neurotrophic hypothesis in, 511–512, 511f recurrent, lithium for, 505 unipolar, antipsychotics for, 498 Dermatologic pharmacology, 1033–1051 acne preparations azelaic acid, 1042–1043 benzoyl peroxide, 1042 brimonidine, 1043 isotretinoin, 1042 retinoic acid derivatives, 1041–1042 antibacterial agents, topical bacitracin and gramicidin, 1035 fundamentals of, 1035 mupirocin, 1035 neomycin and gentamicin, 1036 polymyxin B sulfate, 1035–1036 retapamulin, 1035 antibacterial agents, topical acne clindamycin, 1036 dapsone, 1036–1037 erythromycin, 1036 metronidazole, 1036 sodium sulfacetamide, 1036 antifungal agents, oral azole derivatives, 1038 griseofulvin, 1038–1039 terbinafine, 1039 antifungal agents, topical allylamines, 1037 azole derivatives, 1037 butenafine, 1037 ciclopirox olamine, 1037

nystatin and amphotericin B, 1038 tolnaftate, 1037–1038 anti-inflammatory agents, 1044–1046 corticosteroids, topical, 1044–1046, 1045t, 1046t tar compounds, 1046 antineoplastic agents alitretinoin, 1050 bexarotene, 1050 romidepsin, 1050–1051 vismodegib, 1050–1051 vorinostat, 1050–1051 antipruritic agents doxepin, 1048–1049 pramoxine, 1049 antiseborrhea agents, 1049t, 1049 antiviral agents, topical, 1039 dermatologic vehicles, 1033–1034 drug reactions, 1033, 1035t ectoparasiticides benzyl alcohol, 1040 crotamiton, 1040 ivermectin, 1040 lindane, 1040 malathion, 1040 permethrin, 1039–1040 spinosad, 1040 sulfur, 1040 immunomodulators imiquimod, 1039 tacrolimus and picrolimus, 1039 keratolytic and destructive agents aminolevulinic acid, 1048 fluorouracil, 1048 ingenol mebutate, 1048 NSAIDs, 1048 podophyllum resin and podofilox, 1047–1048 propylene glycol, 1047 salicylic acid, 1046–1047 sinecatechins, 1048 urea, 1047 melanoma agents, 1050 BRAF inhibitors, 1050 iplimumab, 1050 pegylated interferon, 1050 other agents, 1050t, 1051 percutaneous absorption in, 1033, 1034f pharmacology response in, variables in, 1033 pigmentation agents, 1040–1041 hydroquinone, monobenzone, and mequinol, 1040–1041

trioxsalen and methoxsalen, 1041 psoriasis drugs acitretin, 1043 biologic agents alefacept, 1043–1044 fumaric acid esters, 1044 TNF inhibitors, 1044 ustekinumab, 1044 calcipotriene and calcitriol, 1043 tazarotene, 1043 sunscreens, 1041 trichogenic and antitrichogenic agents bimatoprost, 1049 eflornithine, 1049 finasteride, 1049 minoxidil, 1049 Dermatologic vehicles, 1033–1034 Desensitization, 31, 32f of adrenoreceptors, 137

by G protein–coupled receptor kinases, 137 heterologous, 137 homologous, 137 membrane, by muscle relaxants, 460f, 461 Desferasirox, 998 Desflurane, 422–430. See also Anesthetics, inhaled properties of, 425t structure of, 424f Design, rational drug, 4 Desloratadine, 275–278, 290t. See also H1 -receptor antagonists Desmopressin, 657–658, 660t for diuresis, 262 structure of, 657f Desmopressin acetate, 598t, 599 Desmthyldiazepam, 370f Desogestrel, 703–704, 704t, 705f. See also Progestins Desoxycorticosterone acetate, 686–692, 686t. See also Corticosteroids, synthetic Destructive agents, dermatologic, 1047–1048. See also Keratolytic and destructive agents, dermatologic Desvenlafaxine, 528t. See also Serotonin-norepinephrine reuptake inhibitors (SNRIs) Determir, 723–733, 743t. See also Insulin Development and regulation, drug, 10–18 breakthroughs in, 10 drug discovery in, 11–12, 12f drug screening in, 12–13 human evaluation in, 13–18 adverse drug reactions in, 18 clinical trials in confounding factors in, 14–15 IND & NDA, 15–17 conflicts of interest in, 17–18

Food & Drug Administration in, 15 guidelines for, 13 legislation on, 15, 16t orphan drugs and rare diseases in, 18 types of evidence in, 14b–15b new drug development in, 11, 12f safety and toxicity testing in, preclinical, 13, 13t Dexamethasone, 686–692, 686t. See also Corticosteroids, synthetic antiemetic properties of, 1069 Dexamethasone suppression test, 688 Dexfenfluramine, 283 Dexlansoprazole, 1056–1060. See also proton-pump inhibitors (PPIs) Dexmedetomidine, 145, 150, 150t. See also Sympathomimetic drugs for anesthesia, 431t, 437–438 Dexrazoxane, 935 Dextromethorphan abuse of, 557 antitussive, 547, 549t Diabetes insipidus diuretics for, 266 nephrogenic from ADH antagonists, 263 from lithium, 506 Diabetes mellitus definition of, 723 types of gestational, 724 other, 723 type 1, 723–724 type 2, 724 Diabetes mellitus treatment glucagon, 742 glycemic control, 731, 732b insulin, 723–733, 724t, 743t (See also Insulin) oral antidiabetic agents, 733–742, 743t–744t (See also Antidiabetic agents, oral) Diabetic ketoacidosis, 724 insulin for, 731 Diacetylmonoxime (DAM), 128–129 Diacylglycerol (DAG), 33–34, 33f, 134f, 135, 135t Dialysis, for poisoning, 1005t, 1006 Diarrhea, 1065, 1088t. See also Antidiarrheal agents Diastereomers, 4, 4t Diastolic heart failure, 209 vs. systolic heart failure, 218t treatment of, 220 Diazepam, 382t. See also Benzodiazepines for ethanol withdrawal, acute, 394t for seizures, 413–414, 418t spasmolytic actions of, 466, 466f, 469t

structure of, 370f Diazoxide, for hypertension, 182–183, 188t Dibenzomethanes, in sunscreen, 1041 Dibucaine number, 458 2,4-Dichlorophenoxyacetic acid (2,4-D), 980–981, 981f Diclegis, 275–278, 290t. See also H1 -receptor antagonists Diclofenac, 620f, 621t, 623. See also Nonsteroidal antiinflammatory drugs (NSAIDs) for actinic keratoses, 1048 Dicyclomine, for irritable bowel syndrome, 1066 Didanosine, 843t, 845–847, 846f Dietary supplements, 1103–1106 Diethylcarbazine citrate, 909t, 910–911 Diethylstilbestrol, 699, 699f. See also Estrogens Diet, in drug metabolism, 69 Difenoxin, 546. See also Opioid agonists Diffusible second messengers, CNS, 357f, 358 Diffusion aqueous, 7–8, 8f lipid, 8, 8f Diflunisal, 621t, 623 DiGeorge’s syndrome, 953 Digitalis antibody, for heart failure, 223t Digitalis, for heart failure, 214–216, 215f, 215t chronic, 219–220 drug interactions of, 1126t preparations of, available, 223t Digitalis glycosides, drug interactions of, 1126t Digoxin drug interactions of, 1126t for heart failure, 221t chronic, 219–220 mechanism of action of, 210 poisoning management for, 1007t, 1010–1011 toxicity of, 220 Digoxin immune fab, 220 Dihydroartemisinin, for malaria, 891–892 Dihydroartemisinin-piperaquine, for malaria, 891, 891t Dihydrocodeine, 545–546, 549t. See also Opioid agonists Dihydroergotamine, 156 Dihydropyridines. See also Calcium channel blockers; specific types for angina pectoris, 191, 199–203, 206t (See also Calcium channel blockers; Calcium channel blockers, for angina pectoris) for hypertension, 175t, 183 Dihydropyrimidine dehydrogenase (DPD, DPYD) deficiency of, 929, 939 pharmacogenomics of, 76t, 78t, 80 Dihydrotestosterone, synthesis of, 716 Dihydroxyphenylalanine (DOPA), 474f 1,25-Dihydroxyvitamin D (1,25(OH)2D), on bone homeostasis, 748, 749f Diiodotyrosine (DIT), 664, 664f

Diltiazem. See also Calcium channel blockers for angina pectoris, 191, 199–203, 206t (See also Calcium channel blockers, for angina pectoris) for arrhythmia, 235t, 236t, 241–242, 247t on double product, 204–205, 205f for hypertension, 175t, 183 Dimenhydrinate, antiemetic properties of, 1070 Dimercaprol (2,3-dimercaptopropanol, VAL), 996, 996f for arsenic poisoning, 992 for lead poisoning, 990–991 for mercury poisoning, acute, 994 Dimercaptopropanesulfonic acid (DMPS), 997–998. See Unithiol Dimercaptosuccinic acid (DMSA), 996–997.See Succimer Dimerization, 27 Dimethisterone, 703–704, 704t, 705f. See also Progestins Dimethylbenzene (xylene), 978 Dimethyl fumarate (DFMF), 958 Dinoprostone (PGE2 , PGF2α), 315 for abortion, 324 for labor, 325–326 for labor induction, 326 structure of, 325f Dioxanide furoate, for amebiasis, 899t, 900, 900f Dioxins, 983 Dipeptidyl peptidase-4 (DPP-4) inhibitors, 740, 744t Diphenhydramine, 275–278, 290t. See also H1 -receptor antagonists antiemetic properties of, 1070 Diphenoxylate, 546. See also Opioid agonists for diarrhea, 1065 Diphenylhydantoin, 400-402. See also Phenytoin Diphenylmethane derivative laxatives, 1064 Diphtheria vaccines diphtheria antitoxin, equine, 1138t diphtheria tetanus acellular pertussis (DTaP), 1134t tetanus-diphtheria (Td, DT), 1136t tetanus, diphtheria, pertussis (Tdap), 1136t Diphyllobothrium latum niclosamide for, 913 praziquantel for, 915 Dipyridamole, 596–597 vasodilator actions of, 203b Direct factor Xa inhibitors, oral, 592–593 Direct thrombin inhibitors oral, 593–594 parenteral, 593 Direct vasodilators, for hypertension, 172 Discovery, drug, 11–12, 12f Disease-modifying antirheumatic drugs (DMARDs), 625–633 abatacept, 625–626 azathioprine, 626

belimumab, 633 chloroquine and hydroxychloroquine, 626 combination therapy, 633 cyclophosphamide, 626 cyclosporine, 626–627 fundamentals of, 625 glucocorticoid drugs, 633 for inflammation, 619 interleukin-1 inhibitors adverse effects of, 633 anakinra, 632 canakinumab, 632 mechanism of action of, 632 rilonacept, 632–633 leflunomide, 627 methotrexate, 627 mycophenolate mofetil, 628 preparations of, available, 639t rituximab, 628 sulfasalazine, 628 TNF-α-blocking agents, 629–631 adalimumab, 629, 630f adverse effects of, 631 certolizumab, 629–630, 630f etanercept, 630, 630f golimumab, 630f, 631 infliximab, 630f, 631 structures of, 630f tocilizumab, 629 tofacitinib, 631–632 Disinfectants and antiseptics, 867–871 alcohols, 867t, 868 aldehydes, 869–970 chlorhexidine, 867t, 868 definitions of, 867t forms of, available, 872t fundamentals of, 867–868 halogens chlorine, 869 iodine, 868 iodophors, 868–869 phenolics, 869 heavy metals, 871 peroxygen compounds, 870–871 preservatives, 871 quaternary ammonium compounds, 869 superoxidized water, 870 Disinfection, 867t Disopyramide, for arrhythmia, 235t, 236–237, 236t, 246t

Disseminated intravascular coagulation (DIC), 587 Distal convoluted tubule (DCT), 250f, 252, 252f Distribution, drug, 7. See also specific drugs drug interactions on, 1118 models of, 42, 45f Disulfiram for alcoholism, 392, 394t, 395t drug interactions of, 1126t Diuresis, forced, for poisoning, 1006 Diuretics, 249–269, 267t–268t adenosine A1 -receptor antagonists, 257 antidiuretic hormone agonists, 262 antidiuretic hormone antagonists, 263, 268t aquaretics, 251t, 262, 267t, 268t carbonic anhydrase inhibitors, 255–256, 255t, 267t clinical pharmacology of, 264–266 edematous states, 264–266 edema, idiopathic, 265–266 general, 264 heart failure, 264–265 hepatic cirrhosis, 265 kidney disease and renal failure, 265 nonedematous states diabetes insipidus, 266 hypercalcemia, 266 hypertension, 266 nephrolithiasis, 266 combinations loop and thiazide agents, 263–264 potassium-sparing with loop or thiazide diuretics, 264 potassium-sparing with proximal tubule diuretics, 264 fundamentals of, 249 for heart failure, 209, 217, 221t, 223 acute, 220 chronic, 219 preparations of, available, 223t for hypertension, 171, 172–174, 175t, 187t mechanisms of action and hemodynamic effects of, 173 toxicity of, 174 use of, 173–174, 175t kidney injury from, acute, 249, 269 loop, 257–259, 257f, 257t, 258t, 267t, 268t osmotic, 251t, 262, 267t, 268t potassium-sparing, 260–262, 260f, 261t, 267t drug interactions of, 1129t preparations of, available, 268t with proximal tubule diuretics, 264 preparations of, available, 268t, 269t renal tubule transport and, 249–255 (See also Renal tubule transport mechanisms)

sodium glucose cotransporter 2 (SGLT2) inhibitors, 256–257, 267t, 268t thiazide, 259-260. See also Thiazide diuretics DNA guanine, alkylation of, 923, 924f DNA gyrase inhibitors, 810–812, 811f, 812t, 813t Dobutamine, 137t, 145, 145f, 150t. See also Sympathomimetic drugs for cardiac stress test, 148 for heart failure, 216, 222t acute, 220 structure of, 145f Docetaxel, 932t, 933 Docosanol, for HSV and VZV, 838t, 839 Docusate, 1063 Dofetilide, for arrhythmia, 235t, 236t, 241, 246t Dolasetron antiemetic properties of, 1069 chemical structure of, 1067f Dolutegravir, 843t, 855 Domperidone, prokinetic activity of, 1062–1063 Donepizil, for Alzheimer’s disease, 1028 Dopamine (DA), 474 biosynthesis of, 94f in CNS, 362f, 364t, 366 in depression, 512–513, 513f functions of, 92t, 145 for heart failure, 222t acute, 220 hypothalamic, 645, 645t metabolism of, 95f in parkinsonism, 473, 474f structure of, 140f Dopamine agonists, 655–656 clinical pharmacology of acromegaly, 656 hyperprolactinemia, 655, 656f lactation, physiologic, 655–656 pharmacokinetics of, 655 preparations of, available, 661t Dopamine hypothesis of addiction, 555b of schizophrenia, 491 Dopamine receptor, 96, 97t, 135t, 136–137, 474, 495–496, 496f in addiction, 553, 555b, 556f affinities of, 137, 137t on cardiovascular system, 142 in CNS, 366 effects of, 495–496, 496f Dopamine receptor agonists, 150t for diabetes mellitus, 741, 744t dopamine1 , 150t

dopamine2 , 150t for Parkinson’s disease, 147, 477–479, 487t adverse effects of, 478–479 bromocriptine, 478, 487t mechanism of action of, 477–478, 477f pergolide, 478 pharmacologic strategies for, 474, 477, 477f pramipexole, 478, 487t ropinrole, 478, 487t rotigotine, 478 for prolactinemia, 147 Dopamine receptor antagonists, for psychosis, 495 Dopamine reinforcement, in addiction, 531–532 Dopaminergic neurons, in parkinsonism, 473, 474f Dopamine system, mesolimbic, in addiction, 553 Dopamine transporter (DAT, SLC6A3), 95b in addiction, 553, 554f, 556t cocaine on, 562–563, 563f Doripenem, 770f, 781, 785t Dorzolamide, 255–256, 255t, 267t for glaucoma, 255 Dose. See also specific drugs clinical response and, 35–39 in patients, 35–37 graded dose–response relations in, 35–36, 35f quantal dose–effect curves in, 36–37, 36f shape of dose–response curves in, 35f, 36 selectivity and beneficial vs. toxic effects in, 38–39 variation in drug responsiveness in, 37–38 history of, for drug concentration measurement interpretation, 53 loading, 45f, 50–51, 51f maintenance, 50, 50b, 51f on pharmacologic effects, 20, 21–26 chemical antagonism in, 25 competitive and irreversible antagonists in, 23–24, 23f complexity of, 21 concentration-effect curves and receptor binding of agonists in, 21, 22f partial agonists in, 24–25, 25f physiologic antagonism in, 25–26 receptor-effector coupling and spare receptors in, 21–23, 22f surface area, age, and weight in calculation of, 1022, 1022t Dose axis, 35, 35f Dose–concentration effect, 41, 42f. See also Pharmacokinetics, pharmacodynamics Dose–effect curves, quantal, 36–37, 36f Dose–response curves graded relations in, 35–36, 35f shape of, 35f, 36 Double-burst stimulation, 462 Down-regulation, 28

Doxazosin, 155, 155t. See also Adrenoceptor antagonist drugs for hypertension, 180 Doxepin, antipruritic uses of, 1048–1049 Doxercalciferol for bone homeostasis, 751, 751t, 764t (See also Vitamin D) for chronic kidney disease, 760 Doxorubicin, 932t, 934–935 Doxycycline, for malaria, 889t, 890t, 897 Doxylamine, 275–278, 290t. See also H1 -receptor antagonists D-phenylalanine derivatives, 735–736, 736f, 743t Dronabinol, 1071, 1080t as cannabinoid agonist, 559 Dronedarone, for arrhythmia, 235t, 236t, 240, 246t Droperidol, 1070 Drospirenone, 694 Droxidopa, for orthostatic hypotension, 148 Drug action, duration of, 6–7 Drug–body interactions, 5–10 pharmacodynamic principles in, 5–7 agonists in, 5, 6f agonists inhibiting binding molecules in, 5 agonists, partial agonists and inverse agonists in, 5–6, 6f antagonists in, pharmacologic, 5, 6f drug-receptor interaction types in, 5 duration of drug action in, 6–7 receptors and inert binding sites in, 7 pharmacokinetic principles in, 7–10 Fick’s law of diffusion in, 8–9 Henderson-Hasselbalch equation in, 9–10, 10t permeation in, 7–8, 8f, 9t Drug conjugates, 62–63, 63f, 64t Drug escalation, in cancer chemotherapy, 922 Drug groups, 10 Drug interactions, 1118–1131, 1119t–1130t. from biotransformation, 58 combined toxicity in, 1131 in drug metabolism, 69–71, 70t pharmacodynamic mechanisms of, 1131 predictability of, pharmacokinetic mechanisms in, 1118, 1131 Drug reactions dermatologic, 1033, 1035t H1 -receptor antagonists, 277–278 hypersensitivity, 77t, 79t, 83–84, 83t, 84f Drug–receptor bonds, 3–4 Drug-receptor interactions, 5 Drug responsiveness idiosyncratic, 36 quantitative variations in, 37 variation in, 37–38

Drug safety surveillance, 1115 Drug screening, 12–13 Drugs of abuse, 552–566, 565t biogenic amines, drugs binding to transporters of, 562–564, 563f amphetamines, 563–564, 563f cocaine, 562–563, 563f ecstasy (MDMA), 556t, 564, 565t classes of, mechanistic, 556t clinical pharmacology of, 564 Gio protein–coupled receptors, drugs activating, 558–560, 560f cannabinoids, 556t, 558–559, 560f gamma-hydroxybutyric acid, 556t, 559, 560f LSD, mescaline, and psilocybin, 556t, 559–560 opioids, 556t, 558, 560f ionotropic receptors, drugs mediating effects via, 560–562 alcohol, 561–562 benzodiazepines, 561 inhalants, 562 ketamine and phencyclidine, 562 nicotine, 560–561 neurobiology of, 552–558 addiction in dopamine hypothesis of, 555b gambling and shopping, compulsive, 557 as maladaptive learning, 555–557, 556f, 556t animal models of, 553 dependence vs. addiction in, 552 dopamine reinforcement in, 552–553 nonaddictive, 556t, 557–558 tolerance, 553–554 withdrawal, 554–555 nonaddictive, 556t, 557–558 d-Tubocurarine, 456, 459t Ductus arteriosus delayed closure, COX inhibitors for, 327 Ductus deferens, alpha receptors in, 143 Duloxetine, 147, 528t. See also Serotonin-norepinephrine reuptake inhibitors (SNRIs) Duration of drug action, 6–7 of exposure, 973 Dutasteride, 720, 721t Dynorphins, 532, 532t Dysbetalipoproteinemia, familial, 605t, 606 Dyskinesias drug-induced, 485 from levodopa, 476 tardive, 485 from antipsychotics, 501 Dyslipidemia, 602–617 atherogenesis from, 602

hypercholesterolemias, primary ABCG5 and ABCG8 mutations, 607 autosomal recessive hypercholesterolemia, 607 cholesterol α-hydroxylase, 607 cholesteryl ester storage disease, 605t, 607 familial combined hyperlipoproteinemia, 605t, 607 familial hypercholesterolemia, 605t, 606–607, 607f familial ligand-defective apolipoprotein B-100, 605t, 607 HDL deficiency, 607–608 Lp(a) hyperlipoproteinemia, 605t, 607 PCSK9 mutations, 607 hyperlipidemia drugs, 608–615, 616t (See also Hyperlipidemia drugs) hyperlipoproteinemias, 603–608, 605t, 606t dietary management, 608 pathophysiology of, 603–608 hypertriglyceridemias, primary, 605–606, 606t lipid guidelines, blood, 604, 605t lipoproteins in, 602 Dysmenorrhea, estrogens for, 702 Dysmorphogenesis, from antipsychotics in pregnancy, 502 Dyspepsia, nonulcer H2 -receptor antagonists for, 1056 metoclopramide and domperidone for, 1062 proton-pump inhibitors for, 1059 Dysphoria, 538 Dystonia, 472, 485 acute, from antipsychotics, 500–501 tardive, 485 E Early afterdepolarizations (EADs), 230, 231f Ecallantide, 301, 309t. See also Kinin inhibitors on vasoactive peptides, 309t Ecamsule, in sunscreen, 1041 Echinacea (Echinacea purpurea), 1095–1097 Echinocandins caspofungin, 831, 833t preparations, available, 834t Echinococcus albendazole for, 909–910, 909t praziquantel for, 915 Echothiophate, 119t. See also Organophosphate cholinesterase inhibitors Econazole, dermatologic, 1037 Ecotoxicology, 972 Ecstasy (MDMA), 556t, 564 acamprosate for dependence on, 565t Ectoparasiticides benzyl alcohol, 1040 crotamiton, 1040 ivermectin, 1040

lindane, 1040 malathion, 1040 permethrin, 1039–1040 spinosad, 1040 sulfur, 1040 Eculizumab, 963 Edema estrogens on, 701 idiopathic, diuretics for, 265–266 Edetate calcium disodium (ethyelenediaminetetraacetic acid, EDTA), 990–991, 995f, 997 Edoxaban, 592–593 Edrophonium, 119t for myasthenia gravis, 116 for neuromuscular blockade reversal, 465 structure of, 113, 113f Efavirenz, 843t, 850 Effective dose, median (ED50 ), 36, 36f Efficacy intrinsic, 5–6 maximal, 35f, 36 practical, 36 Effort angina, 191 Eflornithine topical, 1049 for trypanosomiasis and leishmaniasis, 901t, 904 Eicosanoid receptors, 318–320, 318f, 319t Eicosanoids, 313–327 arachidonic acid and other polyunsaturated precursors, 313–314, 314f dietary manipulation of metabolism of, 328 clinical pharmacology of, 324–328 blood, 327 cardiovascular system, 326–327 gastrointestinal system, 327 history and fundamentals of, 324 immune system, 327–328 renal system, 326 reproductive system female, 324–326 male, 326 respiratory system, 327 structures of, 325f mechanisms and effects of, 318–323 in lipoxgenase and cytochrome P450-derived metabolites, 323 in prostaglandins and thromboxanes, 320–323 receptor mechanisms in, 318–320, 318f, 319t NSAIDs on synthesis of, 323–324 preparations of, available, 328t synthesis of, 314–317, 316f expoxygenase products, 317

inhibition of, 323–324 isoeicosanoids, 317 lipoxygenase products, 316–317, 316f prostaglandin endoperoxide synthase products, 314–316, 315f Eldecalcitol for bone homeostasis, 751, 751t for osteoporosis, 754b Elderly, pharmacology in, 1024–1032.

Electrocardiograms, normal sinus rhythm, 232f Electrochemical gradient, potassium on, 227b Electrophysiology, of normal cardiac rhythm, 224–229 Electrostatic bonds, 4 Elimination, 7. See also Clearance (CL) capacity-limited, 45–46 first-pass, 43t–44t, 47–48 flow-dependent, 46 models of, 42, 45f rate of, 45 time course of, 46f Elimination enhancement, for poisoned patient dialysis, 1005t, 1006 forced diuresis, 1006 urinary PH manipulation, 1006 Elixirs, 1020 Eltrombopag, 577t, 580–581, 581t Elvitegravir, 843t, 855 Emergency contraceptives, OTC, 1090t Emergency trauma surgery, muscle relaxant for, 455, 471 Emesis pathophysiology of, 1068–1069, 1068f for toxin elimination, 1006 Emetine, for amebiasis, 899t, 901 EMLA, 452. See also Anesthetics, local Empagliflozin, 740 Empiric therapy, antimicrobial, 874–875, 876t–878t. approach to, 874 choice of, 874–875 microbiology etiology in, 876t–877t site of infection in, 878t Emtricitabine, 843t, 847 Enalapril. See also Angiotensin-converting enzyme inhibitors (ACEIs) for heart failure, chronic, 219 for hypertension, 184–185 immediate effects of, 48–49, 49f on renin-angiotensin system, 298 on vasoactive peptides, 309t Enantiomers, dissociation constants of, 4, 4t Endocannabinoids, 365t, 367–368 Endocrine disruptors, 984

Endocrine dysfunction, on drug metabolism, 71 Endocrine glands, kinins on, 300–301 Endocrine system. See also specific organs and disorders chemical transmission in, 87–88 Endocytosis, 8, 8f End-of-dose akinesia, 476 Endogenous catecholamines, 142t, 143f, 144–145. See also specific types Endogenous opioid peptides, 532, 532t.

Endometriosis, gonadotropin-releasing hormone agonists for, 653 Endometrium, estrogens on, 700 Endomorphins, 532 Endorphins, 532, 532t Endothelial-derived relaxing factor (EDRF), 329 Endothelin inhibitors, 304–305, 310t Endothelin receptors (ETA, ETB), 304 Endothelins, 303–305 actions of, 304, 305f biosynthesis, structure, and clearance of, 303–304, 304f physiologic and pathologic roles of, 304–305 Endothelium-derived hyperpolarizing factors, 317 Endotracheal intubation, neuromuscular blockers for, 465 Enflurane, 422–430. See also Anesthetics, inhaled properties of, 425t structure of, 424f Enfuvirtide, 843t, 854 Enkephalins, 92t, 532, 532t Enoxaparin, 587–590, 588f. See also Heparin Entacapone for parkinsonism, 479–480, 487t structure of, 474f Entecavir, for hepatitis B, 858 Enteric nervous system (ENS), 89–90, 89f nonadrenergic, noncholinergic neurons in, 96 physiology of, 1061–1062, 1062f Enteric oxaluria, 764 Enterochromaffin-like (ECL) cells, 1053, 1053f Entry inhibitors, 854–855 enfuvirtide, 843t, 854 fundamentals of, 854 maraviroc, 844t, 854–855 Environmental factors cancer from, 918 in drug metabolism, 69 Environmental pollutants, 982–984 asbestos, 984 coplanar biphenyls, 983 endocrine disruptors, 984 perfluorinated compounds (PFCs), 983–984 polybrominated biphenyl esters (PBDEs), 983

polybrominated biphenyls (PBBs), 983 polychlorinated biphenyls (PCBs), 982–983 polychlorinated dibenzofurans (PCDFs), 983 polychlorinated dibenzo-p-dioxins (PCDDs, dioxins), 983 Environmental toxicology, 972 Enzalutamide, 719f, 720 Enzyme genetic variations, 75–82 other enzymes in, G6PD, 81–82, 82t phase I enzymes in, 75–80, 76t–79t phase II enzymes in, 76t–79t, 80–81 Enzyme induction in cytochrome P450 system, 59, 62t drugs in, 69–70, 70t Enzyme inhibition in cytochrome P450 system, 59–61, 62t drugs in, 70–71, 70t Enzymes. See also specific types as drug receptors, 21 Ephedrine, 140f, 146 for asthma, 339 noradrenergic transmitter release by, 94 structure of, 140f Epidemiologic studies analytic, 14b case-control, 14b cohort, 14b Epidermal growth factor (EGF), 27–28, 28f Epidermal growth factor (EGF) receptor, 28, 28f Epidermal growth factor receptor (EGFR) inhibitors, 936–938, 937t Epidophyllotoxins, 932t, 934 Epilepsy (seizures) case study on, 396, 420 drug development for, 396–397, 398f, 399f drugs for management of, 415–417 acetazolamide, 414 benzodiazepines, 413–414 generalized seizures, 415–416 infantile spasms, 415, 416 partial seizures and generalized tonic-clonic seizures, 415 seizures, 396–420 (See also Antiseizure drugs) status epilepticus, 416–417 prevalence of, 396 seizure classification in, 396, 397t Epinephrine biosynthesis of, 94f cardiovascular responses to, 142t functions of, 142t, 143f, 144–145 metabolism of, 94–96, 95f structure of, 140f

Epinephrine therapy for anaphylaxis, 148–149 for asthma, 338–339, 352t for cardiac arrest, 148 Epirubicin, 935 Epithelial Na channel (ENaC), 253, 253f Eplerenone, 221t, 694. See also Aldosterone antagonists; Diuretics for diuresis, 260–262, 261t, 267t drug interactions of, 1129t for heart failure, 217 Epoetin alfa, 577–578, 577t, 582t Epoprostenol (PGI2 analog), 315–316 for pulmonary hypertension, 326 structure of, 325f Epothilone-D, for Alzheimer’s disease, 1029 Epoxide hydrolases (EHs), 63, 64t Epoxyeicosatrienoic acid (EET), 317 effects of, 323 e-prescribing, 1112, 1113 Eprosartan for hypertension, 185 on vasoactive peptides, 309t Eptifilbatide, 585f, 596 Erectile dysfunction alpha-receptor antagonists for, 158 drugs for, 197b, 208t Erection, penile, nitric oxide in, 334 Ergoecalciferol. See also Vitamin D for bone homeostasis, 764t Ergoline, 286 Ergonovine, 286–289, 291t. See also Ergot alkaloids Ergosterol, 826 Ergot alkaloids, 286–289, 291t accidental ingestion of, 286 chemistry and pharmacokinetics of, 286, 287f, 287t clinical pharmacology of hyperprolactinemia, 289 migraine, 289 postpartum hemorrhage, 289 senile cerebral insufficiency, 289 variant angina diagnosis, 289 origins of, 286 pharmacodynamics of, 286–288, 287t, 288f preparations of, available, 291t Ergotamine, 156, 286–289, 291t Ergotism, 286, 287 Ergotropic nervous system, 97 Eribulin, 933–934 Erlotinib, 937t, 938

Errors prescribing, 1110–1111 Ertapenem, 770f, 781, 785t Erythema nodosum leprosum, 822 Erythromycin, 792–793, 797t for acne, 1036 prokinetic activity of, 1063 Erythropoietin (rHuEPO, EPO), 577–578, 577t, 582t, 965t Escalation, drug, in cancer chemotherapy, 922 Escitalopram, 528t. See also Selective serotonin reuptake inhibitors (SSRIs) Eslicarbazine (acetate), for seizures, 404, 418t Esmolol, 160t, 163. See also β-receptor antagonist drugs for arrhythmia, 239, 246t for hypertension, 180 Esomeprazole, 1056–1060. See also proton-pump inhibitors (PPIs) Esotropia, accommodative, cholinomimetics for, 116 Essential tremor, 482 Estazolam, 382t. See also Benzodiazepines Estradiol. See also Estrogens natural, 681f, 699, 699f synthetic, 699, 699f Estriol natural, 681f, 699, 699f synthetic, 699, 699f (See also Estrogens) Estrogen agonists, 713, 714f Estrogen and progesterone inhibitors and antagonists, 713–715 anastrozole, 714–715 danazol, 714 fadrozole, 715 fulvestrant, 715 GnRH and analogs, 715 letrozole, 715 mifepristone, 713–714 tamoxifen and related partial agonist estrogens, 713, 714f Estrogen receptors, 684f, 699–700 Estrogen response elements (EREs), 700 Estrogens, 697–703. See also specific types adverse effects of, 702–703 on bone homeostasis, 753–754 clinical uses of hypogonadism, primary, 701 ovulation suppression, 702 postmenopausal hormonal therapy, 701–702 contraindications to, 703 drug interactions of, 1126t natural, 698, 698f pharmacokinetics of, 699 physiologic effects of, 699–701 blood coagulation, 701 edema, 701

endometrial, 700 female maturation, 700 mechanism of action in, 684f, 699–700 metabolic and cardiovascular, 700–701 progesterone receptor synthesis, 701 stress system, 701 sympathetic nervous system, 701 preparations and dosages of, 700t, 703, 721t synthetic, 699, 699f types of, 697–698 Estrone. See also Estrogens natural, 681f, 699, 699f synthetic, 699, 699f Eszopiclone, 382t. See also Hypnotics, newer chemical classification of, 370–371, 371f Etanercept for psoriasis, 1044 for rheumatic disorders, 630, 630f Ethacrynic acid, for diuresis, 257–259, 257f, 257t, 258t, 267t Ethambutol, for tuberculosis, 816t, 818, 823t Ethanol, 370, 384–395, 394t. See also Sedative-hypnotic drugs alcohol use disorder with, 384 drugs for, 394t, 395t for antisepsis and disinfection, 867t, 868 clinical pharmacology of, 390–392 acute alcohol intoxication, 390–391 alcoholism, 391–392, 394t, 395t alcohol withdrawal syndrome, 391, 391f, 394t, 395t, 562, 565t dependence on, 384, 388 drug interactions of, 390, 1119t in OTC agents, 1092t pharmacodynamics of, 386–390 in acute consumption, 386, 386t alcohol-drug interactions in, 390 animal research on, 387b in chronic consumption, 386–390 cancer risk, 390 cardiovascular system, 389 endocrine system and electrolyte balance, 389 fetal alcohol syndrome, 389 immune system, 390 liver and GI tract, 387–388 nervous system, 388 pharmacokinetics of acetaldehyde metabolism in, 385f, 386 alcohol dehydrogenase pathway in, 385, 385f microsomal ethanol-oxidizing system in, 385, 385f poisoning management for, 1011 poisoning with, acute, case study on, 385, 395

prevalence of consumption of, 384 tolerance and dependence on, 384, 388 withdrawal syndrome management for, 391 drugs in, 394t, 395t, 562, 565t time course of, 391f Ethinyl estradiol, 699, 699f. See also Estrogens Ethionamide, for tuberculosis, 816t, 819–820 Ethosuximide, for seizures, 218t, 411 Ethotoin, for seizures, 402 Ethyl alcohol. See Ethanol Ethylene glycol, 393–394, 394t poisoning management for, 1007t, 1011 Ethylene oxide, 871 Ethynodiol diacetate, 703–704, 704t. See also Progestins Etidocaine, 451. See also Anesthetics, local Etidronate, on bone homeostasis, 754–755, 755f Etodolac, 621t, 623 Etomidate, 693 for anesthesia, 431f, 431t, 435–436 Etoposide, 932t, 934 Etravirine, 843t, 850 Euphoria, 538 Eutectic mixture of local anesthetics (EMLA), 452 Evacetrapib, 614 Everolimus, 955–956 Evidence, types of, 14b–15b Evolocumab, 614 Excitatory postsynaptic potential (EPSP), 100–101, 101f, 358f, 359 Excitement, in general anesthesia, 428 Exenatide, 739–740, 743t Exocrine glands, kinins on, 300–301 Exocrine pancreatic insufficiency, 1077 Exocytosis, 8, 8f Expectorants, OTC, 1090t Experimental physiology, history of, 2 Exposure duration of, 973 intensity of, 973 quantity of, 973 routes of, 973 Expoxygenase products, 317 Extensive metabolizer (EM), 65, 75t Extraction ratio (ER) first-pass effect and, 43t–44t, 47f, 48 formula for, 47 Extrinsic factor, 572 Eye autonomic pharmacology of, 101b, 103f β receptors in, 142

Ezetimibe, 613–614, 616t with bile-acid binding resins, niacin, and reductase inhibitors, 615 with reductase inhibitors, 615 Ezogabine, for seizures, 408, 419t F Factor V deficiency, 598t Factor V Leiden mutation, 587, 597 Factor VII deficiency, 598t Factor VIIa, recombinant, 598t, 599, 600t for warfarin reversal, 592 Factor VIII deficiency, 598–599, 598t Factor IX deficiency, 598–599, 598t Factor Xa inhibitors, oral direct, 592–593 Factor XIII deficiency, 598t Fadrozole, 715 Falciparum malaria treatment, 886, 907. See also Malaria drugs Famciclovir for HSV and VZV, 838t, 839 topical dermatologic, 1039 Familial combined hyperlipoproteinemia, 605t, 607 Familial combined hypertriglyceridemia, 605t, 606 Familial dysbetalipoproteinemia, 605t, 606 Familial hypercholesterolemia, 605t, 606–607, 607f Familial hypertriglyceridemia, 605t, 606 Familial hypoalphalipoproteinemia, 607–608 Familial ligand-defective apolipoprotein B-100, 605t, 607 Famotidine, 278, 290t, 1054–1056. See also H2 -receptor antagonists Fansidar, for malaria, 896–897 Fasidotrilat, 303, 310t. See also Vasopeptidase inhibitors Fasudil for angina pectoris, 204 for pulmonary hypertension, 306b FDA, Food & Drug Administration, 15 Febuxostat, 637–638 Feedback pathways, brain, 361 Feed-forward pathways, brain, 361 FEIBA, 599 Felbamate, for seizures, 405–406 Felodipine, for hypertension, 183 Female maturation, estrogens on, 700 Fenofibrate, 610–612, 611f, 616t with reductase inhibitors, 615 Fenoldopam, 150t. See also Sympathomimetic drugs for hypertension, 147, 183, 188t Fentanyl, 545, 549t. See also Opioid agonists transdermal patch, 542 Ferric carboxymaltose, for iron-deficiency anemia, 572, 581t Ferric hexacyanoferrate, 998–999 Ferrous fumarate, 572, 572t, 581t

Ferrous gluconate, 572, 572t, 581t Ferrous sulfate, 572, 572t, 581t Ferumoxytol, 572, 581t Fesoterodine. See also Muscarinic receptor blockers for urinary disorders, 128 Fetal alcohol syndrome, 389 Fetal development, critical periods of, 1015, 1015f Fetal drug metabolism, 1014. See also Pregnancy pharmacology Fexofenadine, 275–278, 290t. See also H1 -receptor antagonists Fibrates, 610–612, 611f, 616t with bile-acid binding resins, 615 Fibric acid derivatives, 610–612, 611f with bile-acid binding resins, 615 Fibrinogen, 596t Fibrinolysis, 587, 587f Fibrinolytic inhibitors, 587f, 598t, 599–600, 600t Fibrinolytics, for coagulation disorders, 594–595, 600t Fibrin-stabilizing factor, 596t Fibroblast growth factor 23 (FGF23) for bone homeostasis, 752–753 on bone homeostasis, 747–748, 748f on gut, bone, and kidney, 752t Fibroids, uterine, gonadotropin-releasing hormone agonists for, 653 Fick’s law of diffusion, 8–9 Fidaxomicin, 866, 871t Filgrastim, 577t, 578–580, 579f, 581t Finasteride antiandrogenic actions of, 719f, 720, 721t dermatologic use of, 1049 Fingolimod hydrochloride (FH), 958 First-in-human studies, 14b First-pass effect definition of, 58 extraction ratio and, 43t–44t, 47f, 48 intestinal metabolism in, 58 routes of administration in, alternative, 47t, 48 First-pass elimination, 43t–44t, 47–48 Fish tapeworm drugs niclosamide, 913 praziquantel, 915 5-aminosalicylic acid (5-ASA), for inflammatory bowel disease, 1071–1073, 1072f, 1080t 5-fluorouracil (5-FU), 928t, 929 for actinic keratoses, multiple, 1048 dihydropyrimidine dehydrogenase on, 78t, 80 5-HT1D/1B agonists, 283–285, 284f, 285t 5-HT3 -antagonists, antiemetics, 1069, 1080t, 1081t 5-HT receptor modulators, for depression, 528t. See also Antidepressant agents chemistry of, 516 clinical pharmacology of

adverse effects in, 525 drug interactions in, 526–527 pharmacodynamics of, 520t, 521 pharmacokinetics of, 518t, 519 preparations of, available, 529t 5-Hydroxytryptamine, 279–285 5-LOX, 316, 316f 5-LOX-activating protein (FLAP), 316, 316f 5-LOX inhibitors, 324 Flavin monooxygenase, 68 Flecainide, for arrhythmia, 235t, 236t, 238, 246t Flexible regulation, 34 Flow-dependent elimination, 46 Flucloxacillin, HLA polymorphisms in hypersensitivity reactions to, 83–84, 83t, 84f Fluconazole, 829f, 829t, 830 dermatologic, 1038 Flucytosine, 827f, 828, 833t Fludarabine, 928t, 931 Fludrocortisone, 686–692, 686t, 692. See also Corticosteroids, synthetic Fluke infections niclosamide for, 913 praziquantel for, 915 Flumazenil, 375, 377–378, 382t. See also Benzodiazepine antagonists Flunarizine, for migraine headache prophylaxis, 285 Flunisolide, 686–692, 686t. See also Corticosteroids, inhaled (aerosol); Corticosteroids, synthetic for asthma, 344–345, 352t Fluocinonide, topical, 1044–1046, 1045t, 1046t Fluoride, on bone homeostasis, 756 Fluoropyrimidines capecitabine, 928t, 929 5-fluorouracil, 928t, 929 Fluoroquinolones, 810–812, 813t adverse effects of, 812 antibacterial activity of, 811, 811f, 812t chemistry of, 810, 811f clinical uses of, 812 mechanism of action of, 811 pharmacokinetics of, 812, 812t preparations of, available, 813t resistance of, 811 for tuberculosis, 820–821 5-Fluorouracil (5-FU), 928t, 929 for actinic keratoses, multiple, 1048 dihydropyrimidine dehydrogenase on, 78t, 80 Fluoxetine for depression, 528t CYP450 and pharmacodynamic interactions of, 510, 530 poisoning with, treating, 1008 serotonergic action of, 285

Fluoxymesterone, 716–719, 717t. See also Androgens and anabolic steroids Fluphenazine for Huntington’s disease, 484, 487t for psychosis, 490–502, 492f, 507t (See also Antipsychotic agents) Fluprednisolone, 686–692, 686t. See also Corticosteroids, synthetic Flurazepam, 370f, 382t. See also Benzodiazepines Flurbiprofen, 620f, 621t, 623. See also Nonsteroidal antiinflammatory drugs (NSAIDs) Flutamide, 719f, 720 for prostate cancer, 942 Fluticasone. See also Corticosteroids, inhaled (aerosol) for asthma, 344–345, 352t Fluvastatin, 608–610, 609f, 616t Fluvoxamine, 528t Focal seizures, 414 Folacin, 582t. See also Folic acid Folate antagonists, 807–810. See also specific types DNA gyrase inhibitors, 810–812, 813t preparations, available, 813t sulfonamides, 807–809, 813t Folate deficiency, 570t, 574, 576 Folate synthesis inhibitors, for malaria, 896–897 fansidar, 896–897 proguanil, 888f, 889t, 890t, 896–897 pyrimethamine, 888f, 889t, 896 sulfadoxine, 888f, 896–897 sulfadoxine-pyrimethamine, 889t Folic acid, 574–576, 575b, 575f, 582t chemistry of, 574–575, 575f clinical pharmacology of, 576 in hematopoiesis, 568 pharmacodynamics of, 573f, 576 pharmacokinetics of, 573f, 575–576 preparations of, available, 583t public health dilemma of, 575b Folic acid deficiency, 574, 576, 582t Follicles, 696–697 Follicle-simulating hormone (FSH), 644–645, 644f, 645t chemistry and pharmacokinetics of, 650 in ovarian function, 696 pharmacodynamics of, 650 on testis, 716 Fomepizole, for methanol poisoning, 393, 394t Fondaparinux, 587–590, 588f. See also Heparin Food & Drug Administration (FDA), 15, 16t on prescribing, 1113 Forced diuresis, for poisoning, 1006 Formaldehyde, 869–870 Formalin, 870 Formoterol, for asthma, 340, 352t

Fosamprenavir, 844t, 852 Fosaprepitant, 306, 310t, 1069–1070. See also Substance P antagonists Foscarnet, for cytomegalovirus, 840t, 841 Fosfomycin, 773f, 783 Fosinopril, for hypertension, 184–185 Fosphenytoin, for seizures, 418t Fospropofol, for anesthesia, 433 Fresh-frozen plasma, for warfarin reversal, 592 Full agonists, 5, 6f Fulvestrant, 715 Fumaric acid esters, for psoriasis, 1044 Fungal meningitis, iatrogenic, 831b Furosemide, 221t. See also Diuretics for diuresis, 257–259, 257f, 257t, 258t, 267t for heart failure acute, 220 chronic, 219 Fusion proteins, 90, 91f. See also specific types G G6PD, pharmacogenomics of, 81–82, 82t GABA. See Gamma (γ)-aminobutyric acid (GABA) GABAA receptor, molecular pharmacology of, 374–375, 374f GABAergic synapse, inhibitory, antiseizure drugs at, 397, 399f Gabapentin for analgesia, on ion channels, 538b for seizures, 406, 419t spasmolytic actions of, 467 for tremor, 483 GABA receptor agonists, 375 GABA receptor antagonists, 375 GABA receptor inverse agonists, 375 GABA receptors chloride channel versatility of, 374, 374f, 376b in CNS, 361, 366 heterogeneity and pharmacologic selectivity of, 375b in Huntington’s disease, 483 Galanin, 92t Galantamine, for Alzheimer’s disease, 1028 Gallium nitrate, for hypercalcemia, 757 Gallstones, bile acid therapy for, 1077–1078, 1080t, 1081t Gametocides, malaria, 886 Gamma (γ)-aminobutyric acid (GABA) in brain, 361 in CNS, 363–366, 364t functions of, 92t neuropharmacology of, 375 Gamma-delta T (γδT), 947 Gamma (γ)-hydroxybutyric acid (GHB) abuse of, 556f

Gio protein–coupled receptor activation by, 556t, 559, 560f targets of, 556f Ganaxolone, 417 Ganciclovir, for cytomegalovirus, 840–841, 840t Ganglion blockers. See also specific types on cardiovascular response to phenylephrine, 141, 144f chemistry and pharmacokinetics of, 130, 130f clinical applications of, 131, 131t for hypertension, 177, 189t pharmacodynamics of, 130 pharmacology of, 130–131 preparations of, available, 132t toxicity of, 131, 131t Ganirelix, 654–655 Gantacurium. See also Neuromuscular blocking drugs pharmacokinetics of, 458 Garlic (Allium sativum), 1097–1098 Gases, toxic, poisoning management for, 1007t, 1009, 1010t Gastric lavage, for toxin elimination, 1006 Gastrinoma, proton-pump inhibitors for, 1059 Gastrin (CCK-B) receptors, 1052–1053, 1053f Gastrin-releasing peptide (GRP), 92t Gastritis, stress-related, prevention of H2 -receptor antagonists for, 1056 proton-pump inhibitors for, 1056 Gastroesophageal reflux disease (GERD) H2 -receptor antagonists for, 1055 metoclopramide for, 1062 proton-pump inhibitors for, 1058 Gastrointestinal cancers, chemotherapy for, 942–943 Gastrointestinal disease drugs, 1052–1083, 1079t–1080t. See also specific types acid-peptic diseases, 1052–1061, 1079t antidiarrheals, 1065–1066, 1079t antiemetics, 1068–1071, 1080t bile acid therapy for gallstones, 1077–1078, 1080t gastrointestinal motility stimulators, 1061–1063, 1079t glucagon-like peptide 2 analog for short-bowel syndrome, 1077 inflammatory bowel disease, 1071–1077, 1080t irritable bowel syndrome, 1066–1068, 1079t laxatives, 1063–1065, 1079t pancreatic enzyme supplements, 1077, 1080t preparations, available, 1081t variceal hemorrhage, 1078, 1080t Gastrointestinal motility, enteric nervous system in, 89–90, 1061–1062, 1062f Gastrointestinal motility stimulators, 1061–1063, 1079t cholinomimetic agents, 1062 macrolides, 1063 mechanism of action of, 1061–1062, 1062f metoclopramide and domperidone, 1062–1063

preparations, available, 1081t Gemcitabine, 928t, 930 Gemfibrozil, 610–612, 611f, 616t Gender, in drug metabolism, 69 “Gene-active” receptors, 26–27 General anesthetics. See Anesthetics, general Generalized seizures, 414–415. See also Antiseizure drugs; Seizures antiseizure drugs for, 411–413 ethosuximide, 218t, 411 oxazolidinediones, 413 phensuximide and methsuximide, 412 valproic acid and sodium valproate, 401f, 412–413, 419t clinical pharmacology of epilepsy management in, 415–416 Generalized tonic-clonic seizures, 414, 415. See also Antiseizure drugs; Seizures antiseizure drugs for, 401–411 (See also Antiseizure drugs) clinical pharmacology of epilepsy management in, 415 Generic prescribing, 1115–1116 Generic product, 17 Genetic factors, in drug metabolism, 64–69, 75–82 pharmacogenetic testing in drug therapy, 69 phase I enzyme polymorphisms in, 63f, 64–68, 66t–67t, 68f, 76t, 78t phase II enzyme polymorphisms in, 68–69 Genitourinary system, adrenoreceptors in, 142–143 Genomic medicine, 74 Gentamicin, 800f, 803, 805t topical dermatologic, 1036 Geriatric pharmacology, 1024–1032 adverse drug reactions, 1031 androgens and anabolic steroids, 718 anti-inflammatory drugs, 1030 antimicrobial therapy, 1030 cardiovascular drugs antiarrhythmics, 1029–1030 antihypertensives, 1029 positive inotropes, 1029 central nervous system drugs, 1027–1029 Alzheimer’s disease, 1027–1029, 1028f, 1029t analgesics, 1027 antipsychotics and antidepressants, 520t, 1027 sedative-hypnotics, 1027 drug taking errors from physical disability in, 1031 expense of, 1031 fundamentals of, 1024–1025 nonadherence to, 1031 ophthalmic drugs glaucoma, 1030 macular degeneration, age-related, 1030 pharmacologic changes, 1025–1027, 1025f behavior and lifestyle, 1026–1027

pharmacodynamics, 1026 pharmacokinetics, 1025–1026, 1025t, 1026t principles for, 1031–1032 Gestational diabetes mellitus, 724 Ghrelin, 723, 724t Giardiasis drugs. See also Amebiasis drugs nitazoxanide, 903 Gigantism, 648 Gilles de la Tourette’s syndrome, 472–473, 484–485, 487t antipsychotics for, 498 Ginkgo (Ginkgo biloba), 1098–1099 Ginseng, 1099–1100 Gio protein–coupled receptors in addiction, 553, 554f, 556f drugs activating, 558–560, 560f cannabinoids, 556t, 558–559, 560f gamma-hydroxybutyric acid, 556t, 559, 560f LSD, mescaline, and psilocybin, 556t, 559–560 Glargine, 723–733, 743t. See also Insulin Glatiramer acetate (GA), 958 Glaucoma drugs, 161b, 162t β-receptor antagonists, 164 carbonic anhydrase inhibitors, 255, 255t cholinomimetics, 116 in elderly, 1030 letanoprost and related agents, 328 Glia, 356, 356f Gliclazide, 733–735, 743t. See also Sulfonylureas Glimepiride, 733–735, 734f, 735, 743t. See also Sulfonylureas Glipizide, 733–735, 743t. See also Sulfonylureas Glucagon, 723, 724t for hypoglycemia in diabetes mellitus, 742 Glucagon-like peptide-1 (GLP-1), 739 Glucagon-like peptide-1 (GLP-1) receptor agonists, 739–740, 743t Glucagon-like peptide 2 analog, for short-bowel syndrome, 1077 Glucocorticoid antagonists, 692–694 Glucocorticoid receptor (GR) forms and interactions of, 682–684, 684f genes for, 682 Glucocorticoid receptor elements (GREs), 682 Glucocorticoid resistance, primary generalized, corticosteroids for, 687 Glucocorticoids. See also Corticosteroids; binding of, 27, 27f on bone homeostasis, 753 for gout, 638 for hypercalcemia, 758 for immunosuppression, 954–955, 954t for inflammation, 619 for inflammatory bowel disease, 1073

for rheumatoid arthritis, 633 Glucocorticoids, naturally occurring, 681–685 pharmacodynamics of antiinflammatory and immunosuppressive, 685 catabolic and antianabolic, 685 mechanism of action in, 682–684, 684f metabolic, 684–685 physiologic, 684 pharmacokinetics of, 681–682, 682f biosynthetic pathways in, 681, 681f circadian secretion in, 681, 682f preparations of, available, 695t structures of, 683f Glucosamine, 1104 Glucose 6-phosphate (G6PD) deficiency, 81–82, 82t Glucose absorption agents, 738–739 Glucose, for alcohol intoxication, acute, 390 Glucose transporters, 726, 726t Glulisine, 723–733, 743t. See also Insulin Glutamate in brain, 361 in CNS, 363, 364t, 365f in depression, 512–514 Glutamate hypothesis, of schizophrenia, 492 Glutamate receptor agonists, metabotropic, 494–495 Glutamatergic antipsychotics, 494–495 Glutamatergic synapse, excitatory, antiseizure drugs at, 397, 398f Glutaraldehyde, 869–870 Glutathione transferases (GSTs), 63, 63f, 64t genetic polymorphisms in, 67t, 69 Glutethimide, 371f Glyburide, 733–735, 734f, 735, 743t. See also Sulfonylureas Glycemic control, for diabetes mellitus, 731, 732b. See also Insulin Glycerin suppository, 1063 Glycine in brain, 361 in CNS, 363–366, 364t spasmolytic actions of, 467 Glycopeptide antibiotics, 781–782, 785t dalbavancin, 782, 785t teicoplanin, 782, 785t telavancin, 782, 785t vancomycin, 773f, 781–782, 785t Glycoprotein concentration, alpha1 -acid, 53 Glycopyrrolate, 131t. See also Muscarinic receptor blockers Glycosides, cardiac. See also Digitalis; Digoxin drug interactions of, 1126t for heart failure, 214–217, 215f, 216f, 221t Glyphosate, 981–982, 981f

Glypizide, 734f, 735 GnRH receptor antagonists, 654–655 Goiter nontoxic, 676 toxic multinodular, 675 toxic uninodular, 675 Goldman-Hodgkin-Katz equation, 227 Golimumab for inflammatory bowel disease, 1075–1076, 1075t for rheumatic disorders, 630f, 631 Gompertzian model, 920–921 Gonadal hormones and inhibitors, 696–722. ovarian, 696–716, 721t for contraception in women, 708–713 preparations of, available, 721t testicular, 716–721 androgens and anabolic steroids, 716–719, 717t, 721t androgen suppression, 719, 719f, 721t antiandrogens, 719–720, 721t contraception in men, chemical, 720–721 preparations, 717, 717t, 721t Gonadarche, 696 Gonadorelin, 652–654. See also Gonadotropin-releasing hormone (GnRH) Gonadotropin-releasing hormone (GnRH), 645, 645t, 652–654, 715 actions of, 652 chemistry and pharmacokinetics of, 652 clinical pharmacology of, 653–654 in ovarian function, 696 pharmacodynamics of, 652–653 toxicity of, 654 uses of, 652 Gonadotropin-releasing hormone (GnRH) agonists, 652–654 Gonadotropin-releasing hormone (GnRH) analogs, for contraception in men, 721 Gonadotropin-releasing hormone (GnRH) antagonists, 654–655 Gonadotropins, 649–652. chemistry and pharmacokinetics of, 649–650 clinical pharmacology of, 650–651, 651f pharmacodynamics of, 650 preparations of, available, 661t toxicity and contraindications to, 652 Goserelin, 652–654 Goserelin agonists, for prostate cancer, 942 Gossypol, for contraception in men, 721 Gout, 634f, 635 Gout agents, 635–638 allopurinol, 636–637, 637f colchicine, 635–636, 635f mechanism of action of, 634f, 635 febuxostat, 637–638

glucocorticoids, 638 interleukin-1 inhibitors, 638 NSAIDs, 636 pegloticase, 638 preparations of, available, 639t uricosuric agents, 635f, 636 GP IIb/IIIa antagonists, 585f, 596 G protein–coupled receptor (GPCR), 30, 30f, 31f, 31t in addiction, 553, 554f, 556f, 556t adrenoceptors as, 134, 134f phosphorylation in regulation of, 31, 32f G protein–coupled receptor kinases (GRKs), 31, 32f desensitization by, 137 G proteins, 30, 30f, 31f, 31t Graded dose–response relations, 35–36, 35f Gramicidin, 1035 Grand mal seizures. See Generalized tonic-clonic seizures; Seizures Granisetron antiemetic properties of, 1069 chemical structure of, 1067f Granulocyte colony-stimulating factor (G-CSF), 577t, 578–580, 579f, 581t, 965t Granulocyte macrophage colony-stimulating factor (GM-CSF), 577t, 578–580, 579f, 581t, 965t, 966 Graves’ disease, 674–675. See also Hyperthyroidism neonatal, 676 Griseofulvin, 832 dermatologic, 1038–1039 Groups, drug, 10 Growth factor receptor inhibitors, 936–938, 937t bevacizumab, 937t, 938 cetuximab and panitumumab, 936–938, 937t erlotinib, 937t, 938 pazopanib, 937t, 938 sorafenib, 937t, 938 sunitinib, 937t, 938 ziv-aflibercept, 937t, 938

Growth factors, hematopoietic, 576–581, 582t Growth hormone (GH), 644–648, 644f, 645t, 658t chemistry and pharmacokinetics of, 646 clinical pharmacology of, 647t AIDS, 647 anti-aging, 647 growth hormone deficiency, 646–647 short bowel syndrome, 647 short-stature pediatric patients, 647 pharmacodynamics of, 646 toxicity and contraindications to, 648 Growth hormone antagonists, 648–649 fundamentals of, 648 pegvisomant, 649 somatostatin analogs, 648–649, 648f Growth hormone deficiency, 646–647 case study on, 643, 662 Growth hormone-releasing hormone (GHRH), 645, 645t Growth stimulators, androgens and anabolic steroids as, 718 Guanabenz, 145, 150t. See also Sympathomimetic drugs for hypertension, 176 Guanadrel, 177 Guanethidine, for hypertension, 175t, 177–178, 187t Guanfacine, 145, 150t. See also Sympathomimetic drugs for hypertension, 176 for tics, 485, 487t Guedel’s signs, 428 Gut microbiota, commensal, 69 Gynecologic disorders, androgens and anabolic steroids for, 718 Gynecomastia, from potassium-sparing diuretics, 261–262 H H1 antihistamines, antiemetic properties of, 1070 H1 -receptor antagonists, 275–278, 290t chemistry and pharmacokinetics of, 275, 276f, 277t clinical pharmacology of, 277–278 pharmacodynamics of, 275–276, 277t H2 -receptor antagonists, 278, 290t, 1054–1056. See also specific types adverse effects of, 1056 chemistry and pharmacokinetics of, 1054, 1054t clinical comparisons of, 1054t clinical uses of, 1055–1056 drug interactions of, 1056 OTC, 1087t pharmacodynamics of, 1054t, 1055, 1055f preparations of, available, 1081t prevalence of use of, 1054 H3 -receptor antagonists, 278–279 H4 -receptor antagonists, 278–279

Haemophilus influenzae type b conjugate (Hib) vaccine, 1134t Hageman defect, 598t Hageman factor, 596t Hair growth stimulants, OTC, 1090t Half-life (t1/2 ), 45f, 46, 46f on target concentration, 52 Half-time, context-sensitive, 432, 432f Halofantrine, for malaria, 888f, 889t, 897–898 Halogenated aliphatic hydrocarbons, 976–977 Halogens chlorine, 869 iodine, 868 iodophors, 868–869 phenolics, 869 Haloperidol, 156 chemical structure of, 492f, 494, 494t for Huntington’s disease, 484, 487t for psychosis, 494, 494t, 507t for tics, 485, 487t Halothane, 422–430. See also Anesthetics, inhaled properties of, 425t structure of, 424f Halothane hepatitis, 429–430 Hand hygiene, 868 Haplotypes, 75t, 138 Hardy-Weinberg equilibrium, 75t Hashimoto’s thyroiditis hypothyroidism from, 665, 672–673, 672t nontoxic goiter from, 676 subacute thyroiditis from, 675 Hashish, 559. See also Cannabinoids Gio protein–coupled receptor activation by, 556t, 559, 560f Hazard, 972 HDL deficiency, 607–608 Head lice treatment, OTC, 1091t Heart block, 230–232, 231f–233f Heart failure, 209–213 angiotensin-converting enzyme, 209, 223 beta-receptor antagonists for, 164 cardiac performance pathophysiology in, 213, 213f chronic, classification and treatment of, 218t diastolic, 209 diuretics for, 209, 223, 264–265 pathophysiology of, 209, 212–213, 212f systolic, 209 systolic vs. diastolic, 218t Heart failure treatment, 213–223, 221t–222t cardiac contractility control in, normal, 210, 211f clinical pharmacology of, 218–220

for acute heart failure, 220 for chronic heart failure, 218–220, 218t ACE inhibitors and ARBs, 219 beta blockers and ion channel blockers, 219 cardiac contractility modulation therapy, 220 cardiac resynchronization, 220 digitalis, 219–220 sodium removal, 219 vasodilators, 219 for diastolic heart failure, 220 non-inotropic ACE inhibitors, 217 angiotensin receptor blockers, 217 beta-adrenoceptor blockers, 217–218 diuretics, 217 positive inotropes, 214–217 beta-adrenoceptor agonists, 216 bipyridines, 216 digitalis, 214–216, 215f, 215t, 223t investigational, 216–217 istaroxime, 216 levosimendan, 216 omecamtiv mecarbil, 216–217 preparations of, available, 223t systolic vs. diastolic, 218t therapies in, 209–210, 210t Heavy metals, 871, 987–995 arsenic, 988t, 991–993, 993f chelators for, 995–999, 999t lead, 987–991, 988t mercury, 988t, 993–995 poisoning management for, 1011 Helminth infections, 908 drugs for, 908–916, 909t Hematopoiesis, 567–568 Hematopoietic growth factors, 576–581, 582t clinical uses of, 577t endogenous, 568 erythropoietin, 577–578, 577t, 581t fundamentals of, 576–577 megakaryocyte growth factors, 580–581, 581t myeloid growth factors (G-CSF, GM-CSF), 577t, 578–580, 579f, 581t preparations of, available, 583t Hemochromatosis, 572, 581t Hemodialysis, for poisoning, 1005t, 1006 Hemophilia A, 598–599, 598t Hemophilia B, 598–599, 598t Hemophilia C, 598t Hemorrhage, postpartum, ergot alkaloids for, 289

Henbane, 121–122. See also Muscarinic receptor blockers Henderson-Hasselbalch equation, 9–10, 10t for local anesthetics, 440 Heparin, 587–590, 588f administration and dosage of, 589 chemistry and mechanism of action of, 587–588, 588f contraindications to, 589 monitoring effect of, 588 for pulmonary embolism, case study of, 584, 601 reversal of action of, 590 toxicity of, 588–589 Heparin-induced thrombocytopenia (HIT), 589 Hepatic disease. See also specific types on drug metabolism, 71 Hepatitis drugs for, 856–861, 856t (See also Antihepatitis agents) halothane, 429–430 Hepatitis A vaccine, 1134t Hepatitis B immune globulin (HBIG), 1138t Hepatitis B vaccine, 1134t Hepatitis B virus (HBV) treatment, with HIV in alcoholic smoker on methadone, 835, 864 Hepatitis C virus (HCV) life cycle, 859, 860f Hepoxillins, 317 Herbal medications, 1094–1103 clinical aspects of, 1095 echinacea, 1095–1097 garlic, 1097–1098 ginkgo, 1098–1099 ginseng, 1099–1100 historical and regulatory facts on, 1095 history of, 1094 literature on, 1094 milk thistle, 1100–1101 saw palmetto, 1102–1103 St. John’s wort, 1101–1102 toxicity of, 3 Herbicides, 980–982 bipyridyl (paraquat), 981f, 982 chlorophenoxy (2,4-D, 2,4,5-T), 980–981, 981f glyphosate, 981–982, 981f Hereditary angioedema, kinins in, 301 Hereditary vitamin D–resistant rickets, 762–763 Heroin, 544. See also Opioid agonists Gio protein–coupled receptor activation by, 556t, 558, 560f Herpes simplex virus (HSV) agents, 836–839 acyclovir, 836–837, 837f, 838t docosanol, 838t, 839 famciclovir, 838t, 839 penciclovir, 837f, 838t, 839

trifluridine, 837f, 838t, 839 valacyclovir, 837–839, 838t valomaciclovir, 839 20-HETE, 317, 323 12(R)-HETE, effects of, 323 12(S)-HETE, effects of, 323 Heterologous desensitization, 137 Heteroreceptors, 100, 100t Hexachlorocyclohexane, ectoparasiticidal action of, 1040 Hexachlorophene, 869 Hexamethonium (C6), 130–131, 130f. See also Ganglion blockers High-density lipoprotein (HDL), 602, 603–604, 604f High-extraction drugs, 46 High-molecular-weight (HMW) heparin, 587–590, 588f. See also Heparin Hirsutism, estrogens for, 702 Hirudin, 593 His-Purkinje system, 224, 225f Histamine and histamine agonists, 271–275 chemistry and pharmacokinetics of, 272 clinical uses of, 275 in CNS, 364t, 367 history of, 271–272 pharmacodynamics of, 272–274 storage and release of, 272 Histamine receptor antagonists, 275–279, 290t H1 -receptor, 275–278 chemistry and pharmacokinetics of, 275, 276f, 277t clinical pharmacology of, 277–278 pharmacodynamics of, 275–276, 277t H2 -receptor, 278 H3 - and H4 -receptor, 279 preparations of, available, 291t Histamine receptors, 272–273, 273t H2 parietal cell, 1052–1053, 1053f Histrelin, 652–654 HIV. See Human immunodeficiency virus (HIV) HLA polymorphisms, in hypersensitivity reactions, 77t, 79t, 83–84, 83t, 84f HMG-CoA reductase, 604f HMG-CoA reductase inhibitors with bile-acid binding resins, 615 competitive, 608–610, 609f, 616t drug interactions of, 1126t–1127t with ezetimibe, 615 with fenofibrate, 615 with niacin, 615 sites of action of, 607, 607f HMG-coenzyme A (CoA) reductase inhibitors, OATP1B1 on, 79t, 82–83 Homatropine, 131t. See also Muscarinic receptor blockers Homeostatic responses, for cardiovascular function, 99, 99f

Homologous desensitization, 137 Hookworm drugs. See also Anthelmintic drugs albendazole, 908–909, 909t mebendazole, 912 Hormone replacement therapy (HRT). See also Gonadal hormones and inhibitors postmenopausal, estrogens for, 701–702 for premature ovarian failure, 696, 722 Hormones, 3. See also specific types and disorders Hormone secretion, catecholamines on, 143–144 Horner’s syndrome, 149b Host factors, in antimicrobial choice, 874 Household bleach, 869 5-HT1D/1B agonists, 283–285, 284f, 285t 5-HT3 -antagonists, antiemetics, 1069, 1080t, 1081t Huffing, 562 Human chorionic gonadotropin (hCG) chemistry and pharmacokinetics of, 650 for male infertility, 651 pharmacodynamics of, 650 Human immunodeficiency virus (HIV) AIDS from, 954 life cycle of, 842, 846f treatment of in children, immune globulin intravenous, 1138t with HBV in alcoholic smoker on methadone, 835, 864 retroviral agents in, 842–856 (See also Retroviral agents) with tuberculosis, antimycobacterial drugs for, 815, 824 Human menopausal gonadotropin (hMG), 649–650. See also Gonadotropins for male infertility, 651 Human papillomavirus (HPV) vaccine, 1134t Humoral immunity, 947 Huntington’s disease, 483–484, 484f, 487t Hydatid disease drugs. See also Anthelmintic drugs albendazole, 909–910, 909t praziquantel, 915 Hydralazine for heart failure, 219, 222t for hypertension, 175t, 181 Hydrocarbons aromatic, 977–978 halogenated aliphatic, 976–977 inhalants, ionotropic receptors in, 562 Hydrochlorothiazide, 221t, 259–260, 259f, 267t. See also Diuretics for hypercalciuria, 763 Hydrocodone, 545–546, 549t. See also Opioid agonists Hydrocortisone natural, 681–685 (See also Glucocorticoids, naturally occurring) preparations, available, 695t synthetic, 686–692, 686t

topical, 1044–1046, 1045t, 1046t Hydroeicosatetraenoic acid. See HETE Hydrogen cyanide, poisoning management for, 1007t, 1010, 1010t Hydrogen peroxide, 870–871 Hydromorphone, 544, 549t. See also Opioid agonists Hydrophobic bonds, 4 Hydroquinone, for pigmentation disorders, 1040–1041 Hydroxocobalamin, for vitamin B12 deficiency, 572, 574, 581t Hydroxychloroquine for immunosuppression, 958 for rheumatoid arthritis, 626 Hydroxyprogesterone, 705f Hydroxyprogesterone caproate, 703–704, 704t. See also Progestins 5-Hydroxytryptamine. See Serotonin (5-HT) Hydroxyurea, sickle cell disease and, 568b Hymenolepis nana, praziquantel for, 915 Hyoscine, 121–122. See also Muscarinic receptor blockers action of, 124–125, 124f antiemetic properties of, 1070 Hyoscyamine, 121, 131t. See also Atropine; Muscarinic receptor blockers for irritable bowel syndrome, 1066 Hyperalgesia, opioid-induced, 537 Hypercalcemia, 757–758 diuretics for, 266 Hypercalciuria, idiopathic, 763 Hyperchloremic metabolic acidosis from carbonic anhydrase inhibitors, 255t, 256 from potassium-sparing diuretics, 261 Hypercholesterolemias, primary ABCG5 and ABCG8 mutations, 607 autosomal recessive hypercholesterolemia, 607 cholesterol α-hydroxylase, 607 cholesteryl ester storage disease, 605t, 607 dietary management for, 608 familial combined hyperlipoproteinemia, 605t, 607 familial hypercholesterolemia, 605t, 606–607, 607f familial ligand-defective apolipoprotein B-100, 605t, 607 HDL deficiency, 607–608 Lp(a) hyperlipoproteinemia, 605t, 607 PCSK9, 607 Hyperglycemia from antipsychotics, 501 from thiazide diuretics, 260 Hyperhidrosis, antimuscarinics for, 129 Hypericum perforatum, 1101–1102 Hyperimmune immunoglobulins, 960 Hyperkalemia, 227b from mannitol, 262 from neuromuscular blockers, 463

from potassium-sparing diuretics, 261 Hyperlipidemia, 603-608. See also Hyperlipoproteinemias from antipsychotics, 501 coronary artery disease with, angina treatment in, 191, 208 from thiazide diuretics, 260 Hyperlipidemia drugs, 608–615, 616t bile acid-binding resins, 613, 616t combinations fibric acid derivatives and bile-acid binding resins, 615 HMG CoA reductase inhibitors and bile-acid binding resins, 615 niacin and bile-acid binding resins, 615 niacin and reductase inhibitors, 615 reductase inhibitors and ezetimibe, 615 reductase inhibitors and fenofibrate, 615 resins, ezetimibe, niacin, and reductase inhibitors, 615 use of, 614 fibric acid derivatives, 610–612, 611f HMG-CoA reductase inhibitors, competitive, 608–610, 609f, 616t intestinal sterol absorption inhibitors, 613–614, 616t newer agents AMP kinase activation, 614 apo B-100 synthesis antisense inhibition, 614 CETP inhibition, 614 microsomal triglyceride transfer protein inhibitor, 614 PCSK9 inhibition, 614 niacin, 612, 616t Hyperlipoproteinemias, 603–608, 605t, 606t combined hyperlipidemia treatment, case study of, 602, 617 definition of, 602 dietary management, 608 pathophysiology of, 603–608 lipoprotein metabolism in, normal, 603–604, 604f secondary, 608 Hypernatremia, from mannitol, 262 Hyperosmolar hyperglycemic syndrome (HHS), insulin for, 731–732 Hyperparathyroidism, primary, 759 Hyperphosphatemia, 759 Hyperprolactinemia from antipsychotics, 501 dopamine agonists for, 655, 656f ergot alkaloids for, 289 Hyperreactive, 36 Hypersecretory conditions, proton-pump inhibitors for, 1059 Hypersensitivity reactions, 36, 950–952, 952f drug-induced, 77t, 79t, 83–84, 83t, 84f type I, 950, 951f, 966–967 type II, 950–951, 967 type III, 951, 952f, 967 type IV (delayed-type), 951–952, 953f

Hypertension, 169–171 agents for, 169-190 β-receptor antagonists for, 163 case study on, 169, 190 from cold medications, 1084, 1093 coronary artery disease and, anesthesia with, 421, 439 diagnosis and classification of, 169–170, 170t diuretics for, 266 essential, 170 etiology of, 170 portal, 1078 pulmonary eicosanoids for, 326 nitric oxide for, 334 preparations for, available, 311t treatment of, 306b renin-angiotensin system suppression for, 294, 312 resistant, polypharmacy and, 173b secondary, 170 Hypertensive emergencies, 187 alpha-receptor antagonists for, 157 Hyperthermia, malignant, 282t from anesthetics, 429, 464 dantrolene for, 429, 468 from succinylcholine, 429, 464 Hyperthermic syndromes, 282b, 282t Hyperthyroidism, 674–676 amiodarone-induced thyrotoxicosis, 676 β-receptor antagonists for, 164 dermopathy, 676 Graves' disease, 674–675 neonatal, 676 manifestations of, 670t ophthalmopathy, 675–676 subacute thyroiditis, 675 subclinical, 676 thyroid storm, 675 thyrotoxicosis in pregnancy, 676 toxic multinodular goiter, 675 toxic uninodular goiter, 675 Hypertriglyceridemia familial, 605t, 606 primary, 605–606, 606t chylomicronemia, primary, 605–606, 605t familial combined hypertriglyceridemia, 605t, 606 familial dysbetalipoproteinemia, 605t, 606 familial hypertriglyceridemia, 605t, 606 fundamentals of, 605 secondary, 606t

Hyperuricemia, 635 from loop diuretics, 258 from thiazide diuretics, 260 treatment of (See Gout agents) Hypnotics, 369 newer, 382t (See also Sedative-hypnotic drugs; specific types) clinical pharmacology of, 378–379, 378t pharmacodynamics of, 374–377 pharmacokinetics of absorption and distribution, 374 biodisposition, 374 biotransformation, 373–374, 373t excretion, 374 sedative-hypnotics, 376 Hypoalphalipoproteinemia, familial, 607–608 Hypocalcemia, 758–759 Hypofibrinogenemia, 598t Hypogonadism, primary, estrogens for, 701 Hypokalemia, 227b Hypokalemic metabolic acidosis from loop diuretics, 258 from thiazide diuretics, 260 Hypomagnesemia, from loop diuretics, 258 Hyponatremia from mannitol, 262 from thiazide diuretics, 260 Hypoparathyroidism, 759 Hypophosphatemia, 759 autosomal dominant, 762 X-linked, 762 Hyporeactive, 36 Hypotension, renal response to, 171 Hypothalamic-pituitary endocrine system, 643, 644f Hypothalamic-pituitary-thyroid axis, 665, 667f Hypothalamus, 643, 644f hormones and receptors of, 644–645, 644f, 645t Hypothyroidism, 672–674 congenital (cretinism), 667, 672t drug-induced, 668t, 672t, 674 on drug metabolism, 71 etiology and pathogenesis of, 672–673, 672t management of, 673–675 manifestations of, 667, 670t, 672 myxedema and coronary artery disease, 673 myxedema coma, 673 pregnancy and, 673–674 subclinical, 674 Hypoxic respiratory failure, newborn, nitric oxide for, 334 I

Ibandronate on bone homeostasis, 754–755, 755f, 764t for bone metastases and hypercalcemia, 764t for osteoporosis, 754b, 762, 764t Ibritumomab tiuxetan, 962 Ibuprofen, 620f, 621t, 623–624. See also Nonsteroidal antiinflammatory drugs (NSAIDs) on eicosanoid synthesis, 323–324 Ibutilide, for arrhythmia, 235t, 236t, 241, 246t Icatibant, 301, 309t. See also Kinin inhibitors on vasoactive peptides, 309t Idarubicin, 932t, 935 Idiopathic hypercalciuria, 763 Idiopathic short stature, 647 growth hormone for, 647 Idiopathic thrombocytic purpura (ITP), immune globulin intravenous for, 1138t Idiosyncratic drug response, 36 Idrocilamide, spasmolytic actions of, 467 IFNL3 (IL-28B), 77t, 79t, 84–85 Ifosfamide, 922–927. See also Alkylating agents IGF-I agonist, 648, 658t IL-28B, 77t, 79t, 84–85 Iloprost (PGI2 analog), 315–316 for pulmonary hypertension, 326 structure of, 325f Imatinib, 936, 937t Imidazoline receptor, clonidine binding to, 176 Imipenem, 770f, 781, 785t Imipramine, 528t. See also Muscarinic receptor blockers; Tricyclic antidepressants (TCAs) for urinary disorders, 128 Imiquimod, 863, 1039 Immediate (type I) drug allergy, 950, 951f, 966–967 Immediate effects, 48–49, 49f Immobility, in anesthesia, 427b Immune function, autonomic nervous system on, 87 Immune globulin (IM) for measles, 1138t for rubella, 1139t Immune globulin intravenous (IGIV), 959 for bone marrow transplantation, 1138t for chronic lymphocytic leukemia, 1138t complications of, 1133 for hepatitis A, 1138t for hepatitis B, 1138t for HIV-infected children, 1138t for idiopathic thrombocytic purpura, 1138t for immunodeficiency disorders, primary, 1138t for Kawasaki disease, 1138t for rabies, 1138t Immune response, 619

Immune system, 946–954 abnormal immune responses in, 950–954 autoimmunity, 952–953 hypersensitivity, 950–952, 952f immunodeficiency, 953–954 genetic variations on function of, 83–85 drug-induced hypersensitivity reactions, 77t, 79t, 83–84, 83t, 84f IFNL3 (IL-28B), 77t, 79t, 84–85 normal immune responses in, 946–950 adaptive immune system, 947–950, 948f, 949f, 951f innate immune system, 946–947 Immunization, 1133–1140. See also specific vaccines active, 1133, 1134t–1136t routine childhood, recommended schedule for, 1133, 1137t passive, 1133, 1137, 1138t–1139t for travelers, 1139–1140 untoward reactions to, legal liability for, 1137–1139 Immunodeficiency, 953–954. See also specific types primary disorders of, immune globulin intravenous for, 1138t Immunoglobulins hyperimmune, 960 human, complications of, 1133 Immunomodulators, therapeutic, 964–966 cytokine inhibitors, 966 cytokines, 964–966, 965t dermatologic imiquimod, 1039 tacrolimus and picrolimus, 1039 Immunomodulatory derivatives of thalidomide (IMiDs), 956–957 Immunopharmacology, 946–969 immune system in, 946–954 immunologic drug reactions and drug allergy, 966–967 autoimmune (type II) drug reactions, 950–951, 967 immediate (type I) drug allergy, 950, 951f, 966–967 serum sickness and vasculitis (type III) reactions, 951, 952f, 967 types of, 966 immunomodulation therapy, 964–966 immunosuppressive therapy, 954–963 clinical uses of, 963–964 preparations of, available, 968t Immunosuppressive therapy, 954–963 calcineurin inhibitors cyclosporine, 955 tacrolimus, 955 clinical uses of, 954t, 963–964 autoimmune disorders, 964 organ and bone marrow transplantation, 963–964 cytotoxic agents azathioprine, 957

cyclophosphamide, 957 hydroxychloroquine, 958 methotrexate, vincristine, and cytarabine, 958 pentostatin, 958 pyrimidine synthase inhibitors, 957–958 vinblastine, 958 dimethyl fumarate, 958 fingolimod hydrochloride, 958 glatiramer acetate, 958 glucocorticoids, 954–955, 954t immunosuppressive antibodies, 958–960 antilymphocyte and antithymocyte antibodies, 959 chimeric molecules, 959 development of, 958–959 hyperimmune immunoglobulins, 960 immune globulin intravenous, 959 Rh0 (D) immune globulin micro-dose, 959–960 monoclonal antibodies, 960–962 abciximab, 963 antitumor, 960–961 delivering isotopics and toxins to tumors, 961–962 denosumab, 963 eculizumab, 963 immunosuppressants and anti-inflammatory agents, 962–963, 962f palivizumab, 963 pegatinib, 963 ranibizumab, 963 raxibacumab, 963 mycophenolate mofetil, 956 proliferation signal inhibitors, 955–956 thalidomide, 956–957 Implantable cardioverter-defibrillator (ICD), for cardiac arrhythmias, 242b Inamrinone, for heart failure, 222t Incertohypothalamic pathway, 495 Incontinence, urinary, after prostatectomy, 121, 132 Incretin, agents mimicking and prolonging action of dipeptidyl peptidase-4 inhibitors, 740, 744t glucagon-like peptide-1 and, 739 glucagon-like peptide-1 receptor agonists, 739–740 IND, 12f, 17 Indacaterol for asthma, 340 for COPD, 148 Indinavir, 844t, 852 Indirect thrombin inhibitors, 587–590, 588f. See also Heparin Indomethacin, 624. See also Nonsteroidal anti-inflammatory drugs (NSAIDs) on eicosanoid synthesis, 323–324 structure and properties of, 620f, 621t Indoramin, 156

Inert binding sites, 7 Infantile spasms, 415. See also Seizures drugs for, 416 Infant pharmacology, 1016–1020 Infertility drugs female, gonadotropin-releasing hormone, 653 male gonadotropin-releasing hormone, 653 hCG and hMG, 651 Inflammation, 946, 948f aspirin for, 328 chronic, 619 kinins in, 301 NSAIDs on, 619 therapeutic strategies for, 619 (See also Analgesics) Inflammatory bowel disease (IBD) drugs, 1071–1077, 1080t. See also specific agents aminosalicylates, 1071–1073, 1072f, 1080t antiintegrin therapy, 1076–1077 antitumor necrosis factor therapy, 1075–1076, 1075t glucocorticoids, 1073, 1080t methotrexate, 1074, 1080t purine analogs, 1074, 1080t therapeutic pyramid for, 1071, 1071f Infliximab for inflammatory bowel disease, 1075–1076, 1075t, 1080t for psoriasis, 1044 for rheumatic disorders, 630f, 631 Influenza agents, 861–862 amantadine and rimantadine, 862 investigational, 862 oseltamivir and zanamivir, 861–862 Influenza vaccines Haemophilus influenzae type b conjugate (Hib), 1134t inactivated, 1135t live attenuated, 1135t Ingenol mebutate, for actinic keratoses, 1048 Inhalants, ionotropic receptors in, 562 Inhibin in ovary, 708 in testis, 716 Inhibitors. See also Antagonist; specific types acetylcholinesterase, 5 allosteric, 5, 6f competitive, 5, 6f suicide, 61 Inhibitory postsynaptic potential (IPSP), 100, 101f, 358f, 359 Innate immune system, 946–947 Inositol-1,4,5-trisphosphate (IP3, InsP3), 33–34, 33f, 134f, 135, 135t Inotropes, positive

in elderly, 1029 for heart failure, 214–217 acute, 220 beta-adrenoceptor agonists, 216 bipyridines, 216 digitalis, 214–216, 215f, 215t, 223t investigational, 216–217 istaroxime, 216 levosimendan, 216 omecamtiv mecarbil, 216–217 Insecticides organophosphates, 113–114, 114f thiophosphates, 114, 114f Insertions/deletion (indel), 75t Insomnia drugs OTC, 1091t sedative-hypnotics, 379 Inspired concentration, 422–423 Institutional review board (IRB), 16 Insulin, 723–733, 724t, 743t chemistry of, 724–725, 724f circulating, 725 complications of cancer, 733 hypoglycemia, 723–733 immunopathology, 733 lipodystrophy, injection-site, 733 concentration of, 730 degradation of, 725 preparations of, available, 728–730, 729t intermediate- and long-acting, 279t, 728f, 729–730 mixtures of insulins, 728t, 730 rapid-acting, 724f, 728–729, 729f, 729t short-acting, 279t, 728f, 729 types and durations of action, 728, 729f, 729t production of, 730 regulation of release of, 733, 733t secretion of, 725, 725f on targets, 726–727, 727f treatment with, 731 for diabetic ketoacidosis, 731 for hyperosmolar hyperglycemic syndrome, 731–732 regimens for, 731 tyrosine kinase receptors for, 27 Insulin delivery systems continuous subcutaneous infusion devices, 730–731 portable pen injectors, 730 standard, 730 Insulin pumps, 730–731

Insulin receptor, 726, 726f, 726t Insulin secretagogues meglitinide analogs, 734, 736t, 743t sulfonylureas, 733–735, 743t (See also Sulfonylureas) Integrase strand transfer inhibitors (INSIs), 855–856 dolutegravir, 843t, 855 elvitegravir, 843t, 855 fundamentals of, 855 raltegravir, 844t, 855–856 Integrins, 1076 Intensity of exposure, 973 Intention tremor, 483 Intercalated cells, 253, 253f Interferon-α, 964–965, 965t for hepatitis, 856–857, 856t, 863t Interferon-β, 964–965, 965t Interferon-γ, 964–965, 965t Interferon, pegylated for melanoma, 1050 preparations of, available, 863t with ribavirin, 79t, 84–85 Interferons, 964–965, 965t for condylomata acuminata, 862 preparations of, available, 862, 863t Interleukin-1α, 632 Interleukin-1 inhibitors adverse effects of, 633 for gout, 638 mechanism of action of, 632 for rheumatoid arthritis anakinra, 632 canakinumab, 632 rilonacept, 632–633 Interleukin-11 (IL-11), 580–581, 581t Interleukins, 965–966, 965t Intermediate-density lipoproteins (IDLs), 602 Intermittent claudication, 205–206, 208t International normalized ratio (INR), 591 Interval reduction, in cancer chemotherapy, 922 Intestinal fluke infections, niclosamide for, 913 Intestinal metabolism, in first-pass effect, 58 Intestinal osteodystrophy, 761 Intestinal sterol absorption inhibitors, 613–614, 616t Intracellular receptors, for lipid-soluble agents, 26–27, 27f Intravenous immunoglobulins (IVIG), 959. See Immune globulin intravenous (IGIV) Intrinsic efficacy, 5–6 Intrinsic factor, 572 Intubation, endotracheal, neuromuscular blockers for, 465 Inverse agonists, 5, 23, 375

β-receptor antagonist drugs as, 158 Inverse antagonists, 6, 7f Investigational New Drug (IND), 12f, 15 Iodide metabolism of, 663 organification of, 664, 664f Iodides, 671–672, 677t Iodine bactericidal, 868 radioactive (131 I, RAI), 672, 677t Iodism, 672 Iodophors, 868–869 Iodoquinol, for amebiasis, 899–900, 899t, 900f Ion channels. See also specific types in addiction, 553, 554f, 556t in central nervous system, 357–358, 357f natural toxins for, 358b, 358t ligand-gated, 28–29, 29f novel analgesic targets and, 538b voltage-gated, 29 Ionization constants, 9, 10t Ionization, of weak acids and bases, 9–10 Ionotropic receptors, drugs mediating effects via, 560–562. See also specific drugs alcohol, 561–562 benzodiazepines, 561 inhalants, 562 ketamine and phencyclidine, 561 nicotine, 560–561 Ionotropic receptors, in addiction, 553, 554f, 556f, 556t Ions. See also specific types in membrane electrical activity, 225–227, 226f Ipecac syrup, 1006 Iplimumab, for melanoma, 944, 1050 Ipratropium (bromide). See also Muscarinic receptor blockers (antagonists) for asthma, 342–344 for COPD, 127 Irbesartan for hypertension, 185 on vasoactive peptides, 309t Irinotecan, 932t, 934 pharmacogenomics of, case study on, 74, 86 UGT1A1 on metabolism of, 74, 76t, 78t, 81, 86 Iron, 568–572, 569f, 569t clinical pharmacology of, 570–572, 570f indications in, 570–571, 570t oral iron therapy, 571, 571t parental iron therapy, 571–572, 571t toxicity of, 572 contraceptives on, female hormonal, 709

drug interactions of, 1127t in hematopoiesis, 568 pharmacokinetics of, 568–570, 569f, 569t pharmacology of, 568 poisoning management for, 1011 preparations of, available, 583t toxicity of, clinical, 572, 581t Iron-deficiency anemia, 570, 570t drugs for, 568–572, 569f, 569t Iron dextran, for iron-deficiency anemia, 572, 581t Iron overload, 572, 581t Iron sucrose complex, for iron-deficiency anemia, 572, 581t Irreversible antagonists, 23f, 24 Irrigation, whole bowel, for iron toxicity, 572 Irritable bowel syndrome, 1066 Irritable bowel syndrome drugs, 1066–1068, 1079t antispasmodics, 1066 chloride channel activators, 1067–1068 serotonin 5-HT3 -receptor antagonists, 1066–1067, 1067f, 1079t, 1081t Ischemic heart disease β-receptor antagonists for, 163–164, 163f, 164f epidemiology of, 191 Islet amyloid, 740, 744t Islet amyloid polypeptide (IAPP), 723, 724t Islet amyloid polypeptide (IAPP) analogs, 740–741, 744t Isoeicosanoids, 317 Isoflurane, 422–430. See also Anesthetics, inhaled properties of, 425t structure of, 424f Isoniazid phase II activation of, 57, 57f for tuberculosis, 816–817, 816t, 823t Isopropyl alcohol (isopropanol) for antisepsis and disinfection, 867t, 868 ingestion of, 392 Isoprostanes, 317 Isoproterenol, 142t, 143f, 145. See also Sympathomimetic drugs, direct-acting for asthma, 339–340, 352t cardiovascular responses to, 142t structure of, 140f, 339f Isosorbide dinitrate for angina pectoris, 191, 193–199, 199t, 206t for heart failure, 222t Isosorbide dinitrate/hydralazine (BiDil), for heart failure, 219 Isosorbide mononitrate, for angina pectoris, 191, 193–199, 199t, 206t. See also Nitrates and nitrites, for angina pectoris Isotretinoin, 1042 Isoxazolyl penicillins, 775 Isradipine, for hypertension, 183 Istaroxime, for heart failure, 216

Itraconazole, 829f, 829t, 830, 833t dermatologic, 1038 Ivabradine for angina pectoris, 204 for arrhythmia, 243 for heart failure, chronic, 219 Ivacaftor, for arrhythmia, 244 Ivermectin ectoparasiticidal action of, 1040 for helminths, 909t, 911–912 Ixabepilone, 933 J JAK/STAT receptors, in anterior pituitary and hypothalamus, 644 Janus-kinase (JAK) family, 28, 29f Jerking, myoclonic, 415. See also Seizures Jimson-weed, 121. See also Atropine; Muscarinic receptor blockers Jod-Basedow phenomenon, 672 K Kainate receptors, CNS, 363 Kainic acid (KA), CNS, 363 Kallikrein inhibitors, 311t Kallikrein-kinin system, 299–300, 300f drugs affecting, 301–302, 309t Kallikreins, 299 Kanamycin, 804–805 for tuberculosis, 820 Kappa opioid receptors, 531, 532t Kawasaki disease, immune globulin intravenous for, 1138t Keratolytic and destructive agents, dermatologic aminolevulinic acid, 1048 fluorouracil, 1048 ingenol mebutate, 1048 NSAIDs, 1048 podophyllum resin and podofilox, 1047–1048 propylene glycol, 1047 salicylic acid, 1046–1047 sinecatechins, 1048 urea, 1047 Ketamine abuse of, 556t, 557 for analgesia, on ion channels, 538b for anesthesia, 431f, 431t, 436–437 for depression, 514 enantiomers of, 4, 4t ionotropic receptors in, 562 Ketanserin, 285–286, 290t. See also Serotonin (5-HT) receptor antagonists Ketoacidosis, diabetic, 724 insulin for, 731

Ketoconazole adrenocortical antagonist action of, 692f, 693 as antiandrogen, 719–720, 719f as antifungal, 829f, 829t, 830, 833t dermatologic, topical, 1037 topical, 832, 833t Ketolides, 794, 797t, 798t Ketones (inhalants), ionotropic receptors in, 562 Ketoprofen, 621t, 624 Ketorolac, 621t, 634 Kidney angiotensin II on, 297 nephron segments and functions in, 251t tubule transport mechanisms in, 249–255 (See also Renal tubule transport mechanisms) Kidney disease. See also specific types chronic, 760–761 from diuretics, 249, 269 diuretics for, 265 Kidney excretion, manipulation of, 9, 10f Kidney stones from carbonic anhydrase inhibitors, 255t, 256 from potassium-sparing diuretics, 262 Kininase II, in angiotensin biosynthesis, 296–297, 297f Kinin inhibitors, 301–302, 309t preparations of, available, 311t on vasoactive peptides, 309t Kininogens, 299–300 Kinins, 299–301 biosynthesis of kallikreins in, 299, 300f kininogens in, 299–300, 300f formation and metabolism of, 300, 300f physiologic and pathologic effects of on cardiovascular system, 300 on endocrine and exocrine glands, 300–301 in hereditary angioedema, 301 in inflammation and pain, 301 L Labeled uses of drugs, 1115 Labetalol, 156, 160t, 162. See also β-receptor antagonist drugs for hypertension, 179–180, 188t structure of, 159f Lacosamide, for seizures, 406–407 Lactation pharmacology of, 1020–1022, 1021t physiologic, dopamine agonists for, 655–656 postpartum stimulation of, domperidone for, 1062 Lactulose, 1063 Lamivudine, 844t, 847–848

for hepatitis B, 858 Lamotrigine, 508t for bipolar disorder, 507, 508t for seizures, 407, 419t Lanaclotide, 1064 Lanreotide, 649 Lansoprazole, 1056–1060. See also proton-pump inhibitors (PPIs) Lanthanum carbonate, for hyperphosphatemia, 759 L-asparagine amidohydrolase, 938–939 Latanoprost (PGF2α derivative), 315, 328 Latrodectus mactans antivenin, equine, 1138t Laxatives, 1063–1065, 1079t bulk-forming, 1063 chloride channel activators, 1064 opioid receptor antagonists, 1064 osmotic balanced polyethylene glycol, 1063–1064 nonabsorbable sugars or salts, 1063 OTC, 1090t preparations, available, 1081t serotonin 5-HT4 -receptor agonists, 1064–1065 stimulant, 1064 stool surfactant agents, 1063 LCAT, 607–608 Lead, 987–991 chelation for, 995, 1000 epidemiology of, 987 inorganic lead poisoning, 988t, 990 organolead poisoning, 990 pharmacodynamics of, 988–990 pharmacokinetics of, 987–988, 988t treatment of inorganic lead poisoning, 990–991 organolead poisoning, 991 Lead compound, 13 Lebrikizumab, for asthma, 348 Lecithin:cholesterol acyltransferase deficiency (LCAT), 607–608 Leflunomide, 627 for immunosuppression, 957–958 Left ventricular dysfunction, atrial fibrillation with, 224, 248 Legislation, U.S. drug, 15, 16t Leiomyomata, uterine, gonadotropin-releasing hormone agonists for, 653 Leishmaniasis drugs, 901–905, 901t–903t. See also Antiprotozoal drugs nitazoxanide, 903 pentamidine, 901–903, 902t preparations, available, 905t sodium stibogluconate, 900f, 902t, 903 visceral amphotericin, 904–905

drug combinations, 905 miltefosine, 905 paromomycin, 905 Lenalidomide for immunosuppression, 955–956 for multiple myeloma, 941 Lennox-Gastaut syndrome seizure drugs clobazam, 414 felbamate, 406 lamotrigine, 407, 419t rufinamide, 409, 419t topiramate, 410, 419t Lenograstim, 578–580, 579f Lepirudin, 593 Leprosy drugs clofazimine, 823 dapsone and other sulfone, 822 rifampin, 822–823, 823t Lethal dose median (LD50 ), 13, 36, 36f minimum, 13 Letrozole, 715 Leukemia chemotherapy acute adult, 939 childhood, 939 chronic lymphocytic, 940 myelogenous, 939–940 Leukotriene B4 (LTB4 ), 323 Leukotriene, biosynthesis of, 316–317, 316f Leukotriene C4 (LTC4 ), 316–317, 316f effects of, 323 Leukotriene D4 (LTD4 ), 316f, 317 effects of, 323 Leukotriene receptor antagonists for asthma, 327, 345–346, 346f, 350, 352t preparations of, available, 353t Leuprolide, 652–654 Leuprolide agonists, for prostate cancer, 942 Levalbuterol, for asthma, 340 Levetiracetam, for seizures, 407–408, 419t Levobunolol, 160t, 162. See also β-receptor antagonist drugs Levobupivacaine, 451. See also Anesthetics, local Levodopa, 147, 474–477, 487t adverse effects of, 476–477 chemistry of, 474, 474f clinical use of, 475–476 contraindications to, 477

drug holidays from, 477 drug interactions of, 477, 1127t mechanism of action of, 474 pharmacokinetics of, 474–475, 475f for prolactinemia, 147 Levomilnacipran, 528t. See also Serotonin-norepinephrine reuptake inhibitors (SNRIs) Levopropoxyphene, antitussive, 547, 549t Levorphanol, 545. See also Opioid agonists Levosimendan on calcium sensitivity, 210 for heart failure, 216, 220 Levothyroxine (T4 ), 666–669, 677t. See also Thyroid drugs Lewy bodies, in parkinsonism, 473 Lialda, for inflammatory bowel disease, 1072–1073, 1072f Lice treatment, OTC, 1091t Lidocaine, 442t, 443t, 451, 453t. See also Anesthetics, local for arrhythmia, 235t, 236t, 237–238, 237f, 246t historical development of, 441b on ion channels, 538b Ligand-gated channels, 28–29, 29f in central nervous system, 357, 357f Ligand-regulated transmembrane enzymes, 27–28, 28f Linaclotide, for irritable bowel syndrome, 1068 Linagliptin, 740, 744t Lindane, ectoparasiticidal action of, 1040 Linezolid, 796, 797t, 798t for tuberculosis, 816t, 821 Linkage disequilibrium, 75t Linoleic acids, on arachidonic acid metabolism, 328 Liothyronine (T3 ), 666–669, 677t. See also Thyroid drugs Lipid blood levels of, guidelines, 604, 605t diffusion of, 8, 8f metabolism of, female hormonal contraceptives on, 709 Lipid:aqueous partition coefficient, 8 Lipid resuscitation, 450b Lipid-soluble agents, intracellular receptors for, 26–27, 27f Lipoprotein, 602 high-density, 602, 603–604, 604f structure of, 603 synthesis and catabolism of, 603–604 types of, 602 very-low-density, 602, 603, 604f Lipoprotein (a) (Lp[a]), 602, 603 Lipoprotein disorders, 604, 605t, 606t.

Lipoprotein lipase (LPL), 603 Lipoxgenase (LOX) effects of, 323 products of, 316–317, 316f

Lipoxins, 317 Lipoxygenase (LOX), 316, 316f Liraglutide, 739–740, 743t Lispo, 723–733, 743t. See also Insulin Lithium, 502–507, 508t bipolar affective disorder and, 502–503 clinical pharmacology of, 504–507 for acute major depression, 505 adverse effects and complications of, 505–506 for bipolar affective disorder, 504–505 drug interactions in, 505 maintenance treatment in, 505 monitoring treatment in, 505 overdoses of, 506 for recurrent depression, 505 for schizoaffective disorder, 505 for schizophrenia, 505 drug interactions of, 1127t pharmacodynamics of, 503–504, 504f, 504t pharmacokinetics of, 503, 503t Liver biotransformation in, 57–58 contraceptives on, female hormonal, 709 Liver disease. See also Hepatitis; specific types on drug metabolism, 71, 71t L-Norgesterel. See Progestins Loading dose, 45f, 50–51, 51f Loa loa, diethylcarbamazine citrate for, 910–911 Lobeline, 107, 108f Local circuit neurons, 361, 361f Log-kill hypothesis, 920, 920f Lomitapide, 614 Lomustine, 923f, 924 Long QT syndrome molecular and genetic basis of, 229b, 230t, 231f torsade de pointes in, 229b, 233f Long-term potentiation (LTP), 363 Loop diuretics, 221t, 257–259, 257f, 257t, 258t, 267t. See also Diuretics kidney injury from, acute, 249, 269 with potassium-sparing diuretics, 264 preparations of, available, 268t with thiazide diuretics, 263–264 Loop of Henle, 250f, 252, 252f Loperamide, 546. See also Opioid agonists for diarrhea, 1065 Lopinavir, 844t, 852 Loratadine, 275–278, 290t. See also H1 -receptor antagonists Lorazepam, 382t. See also Benzodiazepines for ethanol withdrawal, 394t, 562, 565t

for seizures, 413–414, 418t structure of, 370f Lorcaserin, 283–285, 284f, 285t, 290t for obesity, 283b, 284t Losartan. See also Angiotensin receptor blockers (ARBs) for heart failure, 217, 219, 221t for hypertension, 175t, 185, 188t on renin-angiotensin system, 298–299 Lovastatin, 608–610, 609f, 616t Low-density lipoproteins (LDLs), 602, 603, 604f Low-molecular-weight (LMW) heparin, 587–590, 588f 5-LOX, 316, 316f 5-LOX-activating protein (FLAP), 316, 316f Loxapine, 493f 5-LOX inhibitors, 324 Lp(a) hyperlipoproteinemia, 605t, 607 Lp(a) lipoprotein, 602, 603 Lubiprostone, 1064 for irritable bowel syndrome, 1067–1068 Lugol’s solution, 671–672, 677t for Graves’ disease, neonatal, 676 Lumefantrine, for malaria, 888f, 889t, 890t, 898 Lung maturation, fetal, corticosteroids for, 688 Luteinizing hormone (LH), 644–645, 644f, 645t chemistry and pharmacokinetics of, 650 diagnosis of responsiveness of, GnRH in, 653 in ovarian function, 696 pharmacodynamics of, 650 Lymphoma chemotherapy Hodgkin’s, 940 non-Hodgkin’s, 940–941 Lynestrenol, 703–704, 704t. See also Progestins Lysergic acid diethylamide (LSD), 286–289, 291t, 556t, 557. See also Ergot alkaloids Gio protein–coupled receptor activation by, 556t, 559–560 M Macitentan, 304–305, 306b, 310t. See also Endothelin inhibitors Macrolides, 792–794, 797t azithromycin, 793, 797t clarithromycin, 792f, 793, 797t drug interactions of, 1128t erythromycin, 792–793, 797t ketolides, 794, 797t preparations of, available, 798t prokinetic activity of, 1063 Macrophage colony-stimulating factor, 965t Macula densa, on renin release, 295 Macular degeneration, age-related, drugs for, in elderly, 1030 with Alzheimer’s and hypertension, 1024, 1032 Magnesium citrate, 1063

Magnesium, for arrhythmia, 243, 247t Magnesium hydroxide, 1063 antacid actions of, 1054 Maintenance dose, 50, 50b, 51f Major depressive disorder (MDD), 510–514 characteristics of, 510 drugs for antidepressants, 510–530, 528t lithium, 505 pathophysiology of, 511–514 integration of hypotheses on, 514 monoamine hypothesis in, 511, 512–514, 513f neuroendocrine factors in, 514 neurotrophic hypothesis in, 511–512, 511f Major histocompatibility complex (MHC) molecules, 947–950, 948f Malaria drugs, 886–898 amodiaquine, 888f, 889t, 891 antibiotics clindamycin, 890t, 897 doxycycline, 889t, 890t, 897 spiramycin, 897 artemsinins, 888f, 889t, 890t, 891–892 artesunate, 890t, 891–892 artesunate-amodiaquine, 891, 891t artesunate-suladoxine-pyrimethamine, 891, 891t atovaquone, 888f, 895–896 atovaquone-proguanil, 889t case study on, 886, 907 chemical structure of, 888f chemoprophylaxis and treatment of, 886–887, 889t–891t chloroquine, 887–891, 889t, 890t (See also Chloroquine) classification of, 886 dihydroartemisinin-piperaquine, 891, 891t folate synthesis inhibitors, 896–897 fansidar, 896–897 proguanil, 888f, 889t, 890t, 896–897 pyrimethamine, 888f, 889t, 896 sulfadoxine, 888f, 896–897 sulfadoxine-pyrimethamine, 889t halofantrine, 888f, 889t, 897–898 lumefantrine, 888f, 889t, 890t, 898 major, 888f, 889t malarone, 889t, 890t, 895–896 mefloquine, 888f, 890t, 893–894 piperaquine, 888f, 889t, 891, 891t preparations of, available, 905t for prevention in travelers, 889t primaquine, 888f, 889t, 890t, 894–895 quinine and quinidine, 888f, 889t, 890t, 892–893

for treatment, 890t, 891t Malaria life cycle, 886, 887f Malarone, 895–896 for malaria, 889t, 890t, 895–896 Malathion, 119t. See also Organophosphate cholinesterase inhibitors ectoparasiticidal action of, 1040 Malignant hyperthermia, 282t from anesthetics, 429, 464 dantrolene for, 429, 468 from succinylcholine, 429, 464 Malignant melanoma, chemotherapy for, 944 Mannitol, for diuresis, 251t, 262, 267t, 268t Maprotiline, 528t. See also Antidepressant agents; Tetracyclic agents Maraviroc, 844t, 854–855 Marfan syndrome, 298 Marijuana, 556t, 557–558 Gio protein–coupled receptor activation by, 556t, 558–559, 560f Marinobufagenin, 214 Mast cell stabilizers, for asthma, 345, 352t Materia medica, 2 Maturation, female, estrogens on, 700 Maximal efficacy, 35f, 35 Maximal electroshock (MES) test, 397 Maximum effect, on target concentration, 52 MDMA, 556t, 564 acamprosate for dependence on, 565t Mean arterial pressure, autonomic regulation of, 97–99, 99f Measles, immune globulin for, 1138t Measles-mumps rubella (MMR) vaccine, 1135t Mebendazole, 909t, 912 Mecamylamine, 130–131, 130f. See also Ganglion blockers Mecasermin, 648, 658t Mechlorethamine, 922–927, 923f. See also Alkylating agents Meclinertant, 310t. See also Neurotensin antagonists Meclizine, antiemetic properties of, 1070 Meclofenamate, 625 Meclofenamic acid, 620f, 621t. See also Nonsteroidal antiinflammatory drugs (NSAIDs) Median effective dose (ED50 ), 36, 36f Median lethal dose (LD50 ), 13, 36, 36f Median toxic dose (TD50 ), 36, 36f Medical pharmacology, 1 Medroxalol, 162–163. See also β-receptor antagonist drugs Medroxyprogesterone (acetate), 703–704, 704t. See also Progestins clinical uses of, 707 structure of, 705f Medullary depression, in general anesthesia, 428 Medullary-periventricular pathway, 495 Mefloquine, for malaria, 888f, 890t, 893–894 Megakaryocyte growth factors, 580–581, 581t

Megaloblastic anemia, from vitamin B12 deficiency, 567, 583 Megestrol acetate, 703–704, 704t. See also Progestins Meglitinide analogs, 734, 735, 736f, 736t, 743t Melanoma agents, 1050 BRAF inhibitors, 1050 iplimumab, 1050 pegylated interferon, 1050 Melarsoprol, for trypanosomiasis and leishmaniasis, 901t, 904 Melatonin, 279f, 281b, 1104–1106 Melatonin receptor agonists, 382t Melatonin receptor, in sleep-wake cycle, 372b Meloxicam, 621t, 623 Melphalan, 922–927, 923f. See also Alkylating agents Memantine, for Alzheimer’s disease, 1028–1029 Membrane-delimited pathways, CNS, 357f, 358 Membrane electrical activity, ions in, 225–227, 226f Memory, types of, 427b Meningitis cephalosporin and vancomycin for, 769, 787 etiology and treatment of, case study on, 873, 885 iatrogenic fungal, 831b Meningococcal vaccines meningococcal conjugate, 1135t meningococcal polysaccharide, 1135t Menopause, 696 Menotropins, 650 Menstrual cycle, 696, 697f Meperidine, 545, 549t. See also Opioid agonists Mephenytoin, for seizures, 402 Mephobarbital, 382t. See also Barbiturates Mepivacaine, 442t, 443t, 452. See also Anesthetics, local Gio protein–coupled receptor activation by, 556t, 558, 560f Meprednisone, 686–692, 686t. See also Corticosteroids, synthetic Meprobamate, 371f Mequinol, for pigmentation disorders, 1040–1041 6-Mercaptopurine (6-MP), 928t, 930–931, 931f for inflammatory bowel disease, 1074, 1080t TPMT on metabolism of, 81 Mercurial diuretics, 257 Mercury, 993–995 history and epidemiology of, 993 intoxication with, 994 pharmacokinetics of, 988t, 993–994 treatment of for acute exposure, 994–995 for chronic exposure, 995 Meropenem, 770f, 781, 785t Mesalamine, for inflammatory bowel disease, 1071–1073, 1072f, 1080t Mescaline, 556t

Gio protein–coupled receptor activation by, 556t, 559 Meslimbic-mesocortical pathway, 495 Mesna, for hemorrhage from cyclophosphamide, 957 Mesolimbic dopamine system, in addiction, 553, 554f, 555b Mestranol, 699, 699f. See also Estrogens Meta-analyses, 15b Metabolic acidosis hyperchloremic from carbonic anhydrase inhibitors, 255t, 256 from potassium-sparing diuretics, 261 hypokalemic from loop diuretics, 258 from thiazide diuretics, 260 Metabolic alkalosis, carbonic anhydrase inhibitors for, 255t, 256 Metabolism, drug clinical relevance of, 64–71 age and sex in, 69 commensal gut microbiota in, 69 diet and environmental factors in, 69 diseases on, 71, 71t drug-drug interactions in, 69–71, 70t drug-endogenous compound interactions in, 71 genetic factors in, 64–69, 74–86 phase I enzyme polymorphisms in, 63f, 64–68, 66t–67t, 68f, 74–86 phase II enzyme polymorphisms in, 68–69, 74–86 individual differences in, 64 drug interactions on, 1118, 1131 drugs enhancing, 69–70, 70t drugs inhibiting, 70, 70t to toxic products, 63, 65f ultrarapid, 65 Metabolism, intermediate adrenoceptors in, 143 sympathomimetics on, 143 Metabolizer extensive, 65, 75t poor, 65, 75t ultrarapid, 65, 75t Metabotropic glutamate receptor agonists, 494–495 Metabotropic (metabolic) receptors, CNS, 357f, 358 Metalloproteins, 329–330, 330f Metals, heavy, 871, 987–995. See also specific types arsenic, 988t, 991–993, 993f chelators for, 995–999, 999t (See also Chelators) lead, 987–991, 988t mercury, 988t, 993–995 poisoning management for, 1011 Metals, toxic beryllium, 985

cadmium, 985 nanomaterials, 985–986 poisoning management for, 1011 Metaproterenol for asthma, 340, 352t structure of, 339f Metformin, 736–737, 743t on life span, 1024 Methacholine, 107, 107f Methadone, 544–545, 549t, 558, 565t. See also Opioid agonists Methallenesril, 699, 699f. See also Estrogens Methamphetamine, 146. See also Methylenedioxymethamphetamine (MDMA) on blood pressure, 87, 104 case studies on ammonium chloride for intoxication with, 1, 19 on blood pressure, 87, 104 trapping of, 9, 10f Methanol, 392–393, 393f, 394t poisoning management for, 1007t, 1011 Methenamine hippurate, 867, 871t Methenamine mandelate, 867, 871t Methicillin, 775 Methicillin-resistant staphylococci, cephalosporins for, 776f, 777t, 779 Methimazole, 670–671, 671f, 677t for Graves’ disease, 674, 675 for thyroid storm, 675 for thyrotoxicosis in pregnancy, 676 for toxic multinodular goiter, 675 Methotrexate (MTX) for cancer, 927–928, 928t for immunosuppression, 958 for inflammatory bowel disease, 1074, 1080t for rheumatoid arthritis, 627 Methoxamine, 140f Methoxsalen, for pigmentation disorders, 1041 Methoxy polyethylene glycol-epoetin beta, 577–578, 577t, 582t Methsuximide, for seizures, 412 Methylbenzene (toluene), 977–978 Methylcellulose, 1063 Methyl chloroform, 977–978 Methyldopa, 145. See also Sympathomimetic drugs, direct-acting for hypertension, 175–176, 175t Methylenedioxymethamphetamine (MDMA), 556t, 564 acamprosate for dependence on, 565t Methylnaltrexone (bromide), 548, 549t laxative action of, 1064 Methylphenidate, 146 Methylprednisolone, 686–692, 686t. See also Corticosteroids, synthetic antiemetic properties of, 1069

for asthma, 344–345, 352t Methyltestosterone, 716–719, 717t. See also Androgens and anabolic steroids Methylxanthine drugs. See also specific drugs for asthma, 341–342, 341f, 352t preparations of, available, 353t Metoclopramide, 1070 prokinetic activity of, 1062–1063 Metolazone, for diuresis, 259–260, 259f, 267t Metoprolol, 160t, 161. See also β-receptor antagonist drugs for angina pectoris, 206t (See also β-receptor antagonist drugs) for heart failure, 218, 219, 221t for hypertension, 175t, 179 structure of, 159f Metrifonate, 909t, 912–913 Metronidazole, 865, 871t for acne, 1036 for amebiasis, 898–899, 899t, 900f Metyrapone, 692f, 693 Metyrosine, 92, 167t Mexiletine for arrhythmia, 235t, 236t, 238, 246t on ion channels, 538b Micafungin, 831, 833t Miconazole, 1037 Microbiota, commensal gut, 69 Micro-RNAs (miRNAs), discovery of therapeutic uses of, 2 Microsomal drug oxidation, 58–59, 60t–61t Microsomal ethanol-oxidizing system (MEOS), 385, 385f Microsomal mixed function oxidase system, 58–59, 58f Microsomal triglyceride transfer protein (MTP) inhibitor, 614 Microsomes, 58 Midazolam, 382t. See also Benzodiazepines for anesthesia, 431f, 431t Midodrine, 145, 150t. See also Sympathomimetic drugs Mifebradil, for angina pectoris, 201. See also Calcium channel blockers Mifepristone, 713–714 for abortion, 324 Mifepristone (RU-486), 693–694 Miglitol, 738–739, 738t, 743t Migraine headache prophylaxis, 285 treatment β-receptor antagonists, 164–165 ergot alkaloids, 288–289 propranolol, 285 serotonin agonists, 282–285, 284f, 285t Milk of magnesia, 1063 Milk thistle (Silybum marianum), 1100–1101 Milnacipran, 147, 528t. See also Serotonin-norepinephrine reuptake inhibitors (SNRIs)

Milrinone, for heart failure, 216, 222t Miltefosine, for trypanosomiasis and leishmaniasis, 905 Mineralocorticoid antagonists drospirenone, 694 eplerenone, 694 spironolactone, 694 Mineralocorticoid receptor (MR) forms and interactions of, 682–684, 684f genes for, 682 Mineralocorticoids aldosterone, 691 deoxycorticosterone, 691–692 fludrocortisone, 692 preparations of, available, 695t Mineral oil, 1063 Minimal bactericidal concentration (MBC), 875 Minimal inhibitory concentration (MIC), 875 Minimum alveolar concentration (MAC), 425t, 427, 427b Minimum inhibitory concentration (MIC), 771 Minimum lethal dose, 13 Minoxidil for hypertension, 175t, 181 topical, 1049 Mipomersen, 614 Mirabegron, 136, 150t. See also Sympathomimetic drugs Mirtazapine, 528t. See also Antidepressant agents; Tetracyclic agents Misoprostadil, 315 Misoprostol for abortion, 324 for gastric mucosa protection, 1060–1061 for NSAID-induced peptic ulcer prophylaxis, 327 structure of, 325f Mithramycin on bone homeostasis, 756 for hypercalcemia, 757–758 Mitiglinide, 743t Mitomycin (mitomycin C), 932t, 935 Mitotane, 692f, 694 Mitoxantrone, 935 Mixed agonist-antagonist opioids, 531 Mixed function oxidases (MFOs), 58, 58f MK-0557, 310t. See also Neuropeptide Y antagonists Modafinil, 146 Moexipril, for hypertension, 184–185 Molecular size, drug, 3 Molecular target of rapamycin, (mTOR), 955 Molecular weights (MW), drug, 3 Molindone chemical structure of, 493f, 494

for psychosis, 494 Mometasone (furoate), 686–692, 686t. See also Corticosteroids, synthetic for asthma, 345 Monitored anesthesia care (MAC), 422b Monoamine hypothesis, for depression, 511, 512–514, 513f Monoamine neurotransmitters, CNS 5-hydroxytryptamine, 362f, 364t, 367 dopamine, 362f, 364t, 366 histamine, 364t, 367 norepinephrine, 362f, 364t, 366–367 Monoamine oxidase (MAO) alpha carbon substitutions on, 140, 140f catecholamine metabolism by, 94–96, 95f Monoamine oxidase inhibitors (MAOIs) for depression, 528t chemistry of, 517 clinical pharmacology of adverse effects in, 525 drug interactions in, 527

pharmacodynamics of, 520t, 521 pharmacokinetics of, 518t, 519 preparations of, available, 529t drug interactions of, 1128t for parkinsonism, 474f, 477f, 479, 487t poisoning with, treating, 1008 Monoamine transporters, targeting of, 138, 139f Monobactams, 770f, 780, 785t Monobenzone, for pigmentation disorders, 1040–1041 Monoclonal antibodies (MABs), 960–962 abciximab, 963 antitumor, 960–961 delivering isotopics and toxins to tumors, 961–962 denosumab, 963 eculizumab, 963 immunosuppressants and anti-inflammatory agents, 962–963, 962f palivizumab, 963 pegatinib, 963 ranibizumab, 963 raxibacumab, 963 Monoiodotyrosine (MIT), 664, 664f Monooxygenases, 58 Montelukast, 324. See also Leukotriene receptor antagonists for asthma, 327, 345–346, 350, 352t structure of, 346f Mood-stabilizing drugs, 502–507, 507t Moricizine, for arrhythmia, 235t, 236t, 239, 246t “Morning after” contraception, 712, 712t Morning sickness, H1 -receptor antagonists for, 278 Morphinans, 545. See also Opioid agonists mixed receptor actions of, 547 Morphine, 544, 549t. See also Opioid agonists Gio protein–coupled receptor activation by, 556t, 558, 560f Motility agents. See Gastrointestinal motility stimulators Motion sickness H1 -receptor antagonists for, 278 muscarinic receptor blockers for, 126 Movement disorders athetosis and dystonia, 472, 485 ballismus, 485 benign hereditary chorea, 485 drug-induced dyskinesias, 485 functional circuitry of, 473f Huntington’s disease, 483–484, 484f, 487t Parkinsonism, 473–482 (See also Parkinsonism) restless legs syndrome, 485–486 tics, 472–473, 484–485, 487t tremor, 472, 483–484 types of, 472–473

Wilson’s disease, 486 Moxonidine, 145. See also Sympathomimetic drugs, direct-acting MRP1 transporter, 9t mTOR, molecular target of rapamycin, 955 Mucormycosis treatment, 825, 834. See also Antifungal agents Mucosal protective agents, gastric bismuth compounds, 1061 mechanisms of, 1060 prostaglandin analogs, 1060–1061 sucralfate, 1060 Müllerian duct inhibitory factor, in testis, 716 Multicompartment pharmacokinetics, 45f, 46 Multidrug resistance-associated protein (MRP) transporters, 8, 9t Multidrug resistance (MDR) genes, 37 Multidrug resistance type 1 (MDR1) transporter, 8, 9t Multiple myeloma, chemotherapy for, 941 Mu opioid receptors, 531, 532t Mupirocin, 866, 1035 Muscarine, 107, 108f Muscarinic (M3 ) acetylcholine receptors, parietal cell, 1052–1053, 1053f Muscarinic alkaloids, direct-acting, 119t Muscarinic receptor blockers (antagonists), 121–129 anticholinergic, 131t, 132t for asthma, 342–344, 343f (See also specific drugs) clinical uses of, 343–344, 349 discovery of, 342 mechanism of action of, 342–343, 343f preparations, available, 353t chemistry and pharmacokinetics of, 121–122, 122f, 123f clinical pharmacology of, 126–129 adverse effects of, 129 contraindications to, 129 therapeutic applications of, 126–129 cardiovascular, 127 cholinergic poisoning, 128–129 CNS, 126 gastrointestinal, 127, 128t ophthalmologic, 126–127, 127t respiratory, 123f, 127 urinary, 127–128, 128t for parkinsonism, 481, 481t, 487t pharmacodynamics of, 122–126 mechanism of action in, 122, 124t organ system effects in, 122–126 cardiovascular system, 91f, 109f, 125, 125f CNS, 122–124 eye, 103f, 124–125, 124f gastrointestinal tract, 124t, 125–126, 126f genitourinary tract, 126, 126f

respiratory system, 125 sweat glands, 126 Muscarinic (M) receptors, 96, 97t M3 parietal cell, 1052–1053, 1053f subtypes and characteristics of, 31f, 105–106, 106f, 106t Muscarinic signaling, 108, 109f Muscarinic stimulants, direct-acting, toxicity of, 117 Muscle relaxants sedative-hypnotics, 377, 379–380 skeletal, 455–471 (See also specific types) neuromuscular blocking drugs, 455–465 preparations, available, 470t spasmolytic drugs, 465–468, 469t Mushroom poisoning muscarinic receptor blockers for, 129 types of, 129 Myasthenia gravis pathophysiology of, 116 treatment of cholinesterase inhibitors, 116–117 edrophonium, 116–117 Mycobacteria, 815 Mycobacterial drugs, 815–824, 823t. See also Antimycobacterial drugs; specific agents Mycobacterium avium, 822t Mycobacterium avium complex (MAC), 822, 822t Mycobacterium intracellulare, 822, 822t Mycobacterium kansasii, 821–822, 822t Mycophenolate mofetil (MMF) for immunosuppression, 956 for rheumatoid arthritis, 628 Mydriasis, from atropine, 124–125, 124f Myeloid growth factors (G-CSF, GM-CSF), 577t, 578–580, 579f, 581t Myenteric plexus, 89, 89f Myocardial hypertrophy, 213 Myocardial infarction, acute from female hormonal contraceptives, 711 thrombolytics for, 594–595, 594b Myocardial oxygen demand, 192, 192t Myocardial oxygen supply, 192 Myoclonic jerking, 415. See also Seizures Myxedema coma, 673 Myxedema, coronary artery disease and, 673 N Nabilone, 1071 as cannabinoid agonist, 559 Nabumetone, 620f, 621t, 624. See also Nonsteroidal anti-inflammatory drugs (NSAIDs) N-acetyltransferases (NATs), 63, 63f, 64t genetic polymorphisms in, 67t Na channels, epithelial, 253, 253f

Na+ Cl- cotransporter (NCC), 252, 252f Nadolol, 160t, 162. See also β-receptor antagonist drugs for hypertension, 179 NADPH-cytochrome P450 oxidoreductase (POR), 58, 60t–61t Nafarelin, 652–654, 715 Nafcillin, 775 Naftifine antifungal, 832 dermatologic topical, 1037 Na+/H+ exchanger (NHE3), 250, 251f Na+/K+/2Cl- cotransporter (NKCC2 or NK2CL), 252, 252f Na+/K+-ATPase, 226 in cardiac contractility, 210 digitalis on, 214 Nalbuphine, mixed receptor actions of, 547, 549t Nalmefene, 548, 549t Naloxone, 548, 549t, 558, 565t Naltrexone, 548, 549t, 558, 565t for alcoholism, 392, 394t, 395t for dependence and addiction, 564 Nandrolone decanoate, 716–719, 717t. See also Androgens and anabolic steroids Nanomaterials, toxic, 985–986 Nanoparticles, as drug vehicles, 7 Naproxen, 620f, 621t, 624 Natalizumab, 962 for Crohn’s disease, 1076–1077 Nateglinide, 735–736, 736f, 743t National Research Council wound classification criteria, 883b Natriuretic peptides, 302–303 clinical role of, 303 for heart failure, 222t on kidney, 254–255 pharmacodynamics and pharmacokinetics of, 303 preparations of, available, 311t synthesis and structure of, 302–303, 302f on vasoactive peptides, 310t Natural killer (NK) cells, 946, 947 Natural killer-T (NKT) cells, 946, 947 Nature of drugs, 3–5 physical nature in, 3 rational drug design in, 4 reactivity and drug–receptor bonds in, 3–4 receptor nomenclature in, 4–5 shape in, 4 size in, 3 Nausea and vomiting pathophysiology of, 1068–1069, 1068f of pregnancy, H1 -receptor antagonists for, 278 NAV receptors, 538b

NDA, 17 Nebivolol, 160t, 162. See also β-receptor antagonist drugs for heart failure, 218, 219, 221t for hypertension, 175t, 179–180 structure of, 159f Nedocromil, 275 for allergic rhinoconjunctivitis, 345, 352t for asthma, 345, 350 Nefazodone, 528t. See also 5-HT receptor modulators, for depression Negative allosteric modulators, 24 Nelfinavir, 844t, 852 Neoadjuvant chemotherapy, 919–920 Neomycin, 804–805 topical dermatologic, 1036 Neonicotinoids, 117 Neostigmine, 119t for neuromuscular blockade reversal, 464–465 prokinetic activity of, 1062 structure of, 113, 113f Nephrogenic diabetes insipidus from ADH antagonists, 263 from lithium, 506 Nephrolithiasis, diuretics for, 266 Nephron, 251t Nephrotic syndrome, 763 Nernst equation, 226 Nesiritide (BNP), 303. See also Natriuretic peptides for heart failure, 217, 222t on kidney, 254 on vasoactive peptides, 310t Netilmicin, 800f, 804 Neural tube defects, folic acid supplements and, 573f, 575b Neurocysticercosis drugs. See also Antihelminthic drugs albendazole, 909t, 910 praziquantel, 915 Neuroglia, 356, 356f Neurohypophysis, 643, 644f Neurokinin A, 306 Neurokinin B, 306 Neurokinin receptor antagonists, antiemetic properties of, 1069–1070 Neuroleptic malignant syndrome (NMS), 282b, 282t from antipsychotics, 502 dyskinesia in, 485 Neuromedin N, 307 Neuromuscular blocking drugs, 455–465, 469t chemistry of, 456–457, 457f, 458f clinical pharmacology of, 461–465 cardiovascular effects, 463 disease and aging on neuromuscular response, 464

drug interactions, 464 hyperkalemia, 463 intragastric pressure increase, 464 intraocular pressure increase, 463–464 muscle pain, 464 neuromuscular transmission assessment, 460f, 461–463 skeletal muscle paralysis, 461 fundamentals of, 455 history of, 455 mechanism of action of, 459–461 depolarizing drugs, 459f–461f, 460–461, 460t nondepolarizing drugs, 456f, 459, 459f, 460f, 460t normal neuromuscular function and, 455–456, 456f pharmacokinetics of, 457–459 depolarizing relaxant drugs, 458–459, 459t nondepolarizing relaxant drugs, 457–458, 459t preparations of, available, 470t reversal of nondepolarizing blockade in, 464–465 uses of, 465 Neuromuscular function, normal, 455–456, 456f Neuronal systems, brain, nonspecific vs. diffuse, 361–362, 362f Neurons, 356, 356f local circuit, 361, 361f relay (projection), 361, 361f Neuropathy target esterase (NTE), 979 Neuropeptides, CNS, 367 Neuropeptide Y (NPY), 92t, 308 Neuropeptide Y antagonists, 310t Neurotensin, 306–307 Neurotensin agonists, 310t Neurotensin antagonists, 310t Neurotransmitter chemistry, 88f, 90–96 autonomic adrenergic transmission in, 92–96, 93f–95f cholinergic and noradrenergic fibers in, 88f, 90 cholinergic transmission in, 90–92, 91f, 92t cotransmitters in, 90 cotransmitters in cholinergic and adrenergic nerves in, 92t, 96 Neurotransmitter pathways, diffuse brain, 361–362, 362f Neurotransmitter receptors, in central nervous system, 357–358, 357f Neurotransmitters, CNS, 362–368 acetylcholine, 362f, 364t, 366 amino acid, 363–366 GABA and glycine, 363–366, 364t glutamate, 363, 364t, 365f endocannabinoids, 365t, 367–368 monoamine 5-hydroxytryptamine, 362f, 364t, 367 dopamine, 362f, 364t, 366

histamine, 364t, 367 norepinephrine, 362f, 364t, 366–367 neuropeptides, 367 nitric oxide, 368 opioid peptides, 365t orexins, 365t, 367 purine, 368 tachykinins, 365t Neurotransmitter uptake carriers, 95b Neurotrophic hypothesis, for depression, 511–512, 511f Neutral antagonists, 6 Neutropenia, 568 cancer chemotherapy-induced, G-CSF for, 579, 579f, 581t Nevirapine, 844t, 848t, 850 New Drug Application (NDA), 17 New drug development, 11, 12f Niacin with bile-acid binding resins, 615 for dyslipidemia, 616t with ezetimibe, 615 with reductase inhibitors, 615 Nicardipine for angina pectoris, 191, 199–203, 206t for hypertension, 183 Niclosamide, 909t, 913 Nicorandil, for angina pectoris, 199 Nicotine, 119t abuse of, 556t for analgesia, on ion channels, 538b ionotropic receptors in, 560–561 mechanism of action of, 560–561 in pesticides, 980 prevalence of addiction to, 560 structure of, 107, 108f treatment for, 561, 565t Nicotine toxicity acute, 118 chronic, 118 Nicotinic acetylcholine receptor (nAChR), 455–456, 456f mechanism of action of, 29, 29f Nicotinic (N) receptor, 96, 97t subtypes and characteristics of, 29f, 88f, 106, 106f, 106t Nicotinic (N) receptor agonists direct-acting, 119t partial, in nicotine abuse, 561, 565t Nicotinic signaling, 108–110, 109f Nicotinic stimulants, direct-acting, toxicity of, 117–118 Nifedipine. See also Calcium channel blockers for angina pectoris, 191, 199–203, 206t

for hypertension, 183 Nifurtimox, for trypanosomiasis and leishmaniasis, 903t, 904 Nigrostriatal pathway, 495 Nilotinib, 936 Nilutamide, 719f, 720 for prostate cancer, 942 Nimodipine, for angina pectoris, 191, 199–203, 206t. See also Calcium channel blockers Nirvanol, 402 Nisoldipine, for hypertension, 183 Nitazoxanide, for giardiasis and Cryptosporidium parvum, 903 Nitrates inhalants, ionotropic receptors in, 562 as nitric oxide donors, 332 organic, 332 Nitrates and nitrites, for angina pectoris, 191, 193–199, 199t, 206t chemistry of, 194 clinical use of, 198–199, 199t for heart failure, 219 mechanism of action of, 192, 194f mechanisms of clinical effect of, 198, 198t nitrates alone vs. with beta or calcium channel blockers in, 205, 205t pharmacodynamics of mechanism of action in smooth muscle in, 194f, 195 organ system effects in, 195–196, 196f pharmacokinetics of, 194–195 preparations of, available, 208t tolerance to, 197–198 toxicity of acute adverse effects in, 196–197 carcinogenicity of derivatives in, 198 Nitrazepam for seizures, 414 structure of, 370f Nitric oxide (NO), 329–335, 334t in CNS, 368 in disease central nervous system, 334 infection and inflammation, 333–334 peripheral nervous system, 334 respiratory disorders, 334 septic shock, 332–333, 333t vascular effects, 332, 333f drugs increasing, mechanism of action of, 192, 194f endogenous, discovery of, 329 functions of, 92t inactivation of, 331 isoforms of, 329, 330t pharmacologic manipulation of nitric oxide donors, 331–332

nitric oxide synthesis inhibitors, 331–332 preparations of, available, 335t signaling mechanisms of, 329–331, 330f metalloproteins in, 329–330, 330f thiols in, 330–331 tyrosine nitration in, 331, 331t synthesis of, 329, 330f Nitric oxide donors, 331–332 Nitric oxide inhibitors, for septic shock, 332–333, 333t Nitric oxide synthase (NOS), CNS, 368 Nitric oxide synthesis inhibitors, 331–332 Nitrites. See also Nitrates and nitrites, for angina pectoris as nitric oxide donors, 332 organic, 332 Nitrofurantoin, 866–867, 871t Nitrogen oxides, 331, 331t, 974t, 975–976 Nitroglycerin for angina pectoris, 191, 193–199, 199t, 206t for heart failure, 220 mechanism of action of, 192, 194f Nitroprusside, 332 for heart failure, 220, 222t for hypertension, 171f, 182, 188t Nitrosothiols, 192, 194f Nitrosoureas, 923f, 924 Nitrous oxide, 422–430. See also Anesthetics, inhaled properties of, 425t structure of, 424f Nitro-vasodilators, for angina pectoris, 199 Nizatidine, 278, 290t, 1054–1056. See also H2 -receptor antagonists NMDA antagonists analgesic, ion channels and, 538b as drugs of abuse, 556t, 557 NMDA, CNS, 363 NMDA receptor in central sensitization, 538b in CNS, 363 NMDA receptor antagonists for depression, 514 ketamine and phencyclidine, 562 N-methyl-D-aspartate. See NMDA No-effect dose, 13 Nonabsorbable sugars or salts, 1063 Nonadherence, in elderly, 1031 Nonadrenergic, noncholinergic (NANC) neurons, 89f, 92t, 96 Non-coding region polymorphism, 75t Noncompetitive antagonist, 23f, 24 Noncompliance, in elderly, 1031 Nonketotic hyperosmolar coma, 724

Nonnucleoside reverse transcriptase inhibitors (NNRTIs), 849–851 delavirdine, 843t, 849 efavirenz, 843t, 850 etravirine, 843t, 850 fundamentals of, 846f, 849 nevirapine, 844t, 848t, 850 in pregnancy, 848t rilpivirine, 844t, 851 Nonsteroidal anti-inflammatory drugs (NSAIDs), 619–625, 621t adverse effects of, 620–621 chemistry and pharmacokinetics of, 619, 620f, 621t choice of, 625 drug interactions of, 1128t on eicosanoid synthesis, 323–324 pharmacodynamics of, 619–620, 622f specific drugs in aspirin (salicylates), 621, 621t, 622f COX-2 inhibitors, nonselective, 623–625 COX-2 inhibitors, selective, 621–623, 621t celecoxib, 621t, 623 meloxicam, 621t, 623 nonacetylated salicylates, 621t preparations, available, 639t uses of dermatologic, 1048 dysmenorrhea, 326 gout, 636 inflammation, 619 Nontoxic goiter, 676 Nonulcer dyspepsia drugs H2 -receptor antagonists, 1056 metoclopramide and domperidone, 1062 proton-pump inhibitors, 1059 NOP receptor, 532 Noradrenergic fibers, 88f, 90 Noradrenergic junction, 92–93, 93f Norepinephrine (NE) biosynthesis of, 94f in CNS, 362f, 364t, 366–367 in depression, 512–513, 513f functions of, 92t, 145 metabolism of, 94–96, 95f on renin release, 295 structure of, 140f Norepinephrine transporter (NET), 9t, 92–93, 93f, 95b, 138, 139f antidepressant drugs on, 93 cocaine on, 93 Norethindrone (acetate), 703–704, 704t, 705f. See also Progestins Norethynodrel, 703–704, 704t. See also Progestins

L-Norgestrel, 703–704, 704t. See also Progestins Noscapine, antitussive actions of, 547 Notice of Claimed Investigational Exemption for a New Drug (IND), 12f, 15 NovoSeven, 599 NPH, 723–733, 743t. See also Insulin NS3/4A inhibitors, 859, 860f NT69L, 310t. See also Neurotensin agonists NT79, 310t. See also Neurotensin agonists Nucleoside and nucleotide reverse transcriptase inhibitors (NRTIs), 842–849, 843t–845t abacavir, 842, 843t, 845 didanosine, 843t, 845–847, 846f emtricitabine, 843t, 847 fundamentals of, 842 lamivudine, 844t, 847–848 in pregnancy, 848t stavudine, 845t, 848 tenofovir, 845t, 848 zidovudine, 845t, 849 Nutraceuticals, toxicity of, 3 Nutritional anemias, 570–571, 570f, 581t–582t. See also specific types Nutritional rickets, 762 Nutritional supplements, purified, 1103–1106 coenzyme Q10, 1103–1104 glucosamine, 1104 melatonin, 1104–1106 Nystatin, topical, 832 dermatologic, 1038 O o-benzyl-p-chlorophenol, 869 Obesity treatment, 283b, 284t Obidoxime, 128–129 Occupational toxicology, 971–972 Octopamine, biosynthesis of, 94f Octreotide, 648f, 649 for diarrhea, 1065–1066 for variceal hemorrhage, 1078, 1080t Ofatumumab, 961 for chronic lymphocytic leukemia, 940 Off-labeled uses of drugs, 1115 Ogilvie’s syndrome, 1062 Ohm’s law, 226 Olanzapine for Huntington’s disease, 484 for psychosis, 494, 507t structure of, 493f Olcegepant, 307, 310t. See also Calcitonin gene-related peptide Olmesartan for hypertension, 185 on vasoactive peptides, 309t

Olodaterol, for asthma, 340 Olsalazine, for inflammatory bowel disease, 1071–1073, 1072f Omalizumab, 963 for asthma, 346, 350, 352t Omapatrilat, 303, 310t. See also Vasopeptidase inhibitors Omecamtiv mecarbil (CK-1827452) on contractile proteins, 210 for heart failure, 216–217 Omega-3 essential fatty acids, 328 Omega-6 essential fatty acids, 328 Omeprazole, 1056–1060. See also proton-pump inhibitors (PPIs) Omission, errors of, 1111 Onchocerciasis, ivermectin for, 911–912 Oncogenes, cancer, 919 Ondansetron, 285–286, 290t. See also Serotonin (5-HT) receptor antagonists antiemetic properties of, 1069 chemical structure of, 1067f 1,1,1-trichloroethane, 977–978 1,25-dihydroxyvitamin D (1,25(OH)2D), on bone homeostasis, 748, 749f On-off phenomenon, 476 o-phenylphenol, 869 Ophthalmic drugs. See also specific types in elderly glaucoma, 1030 macular degeneration, age-related, 1030 Opioid agonists, 544–547, 549t for diarrhea, 1065 educating prescribers of, 546b Gio protein–coupled receptor activation by, 556t, 558, 560f mild to moderate phenanthrenes, 545–546, 549t phenylheptylamines, 546 phenylpiperidines, 546 mixed receptor actions benzomorphans, 547 morphinans, 547 phenanthrenes, 546–547, 549t preparations of, available, 550t strong morphinans, 545 phenanthrenes, 544, 549t phenylheptylamines, 544–545, 549t phenylpiperidines, 545, 549t tapentadol, 547, 549t tramadol, 547, 549t Opioid antagonists, 548, 549t, 558 laxative action of, 1064 preparations of, available, 550t Opioid antitussives, 547, 549t, 550t

Opioid-induced hyperalgesia, 537 Opioid peptides, endogenous, 532, 532t Opioid receptors, 531, 532t distribution of, on analgesia, 534–537, 536f, 537f mechanism of action of, 532t, 533t, 534 Opioids, 531–551, 549t. See also Drugs of abuse; specific types abuse of, 556t analgesics, intravenous, 438 classification and chemistry of, 531, 532t clinical use of, 540–542 analgesia, 533t, 540–541 anesthesia, 541 buccal transmucosal, 542 diarrhea, 541 intranasal, 542 patient-controlled analgesia, 541–542 pulmonary edema, acute, 541 rectal suppositories, 542 shivering, 541 transdermal fentanyl patch, 542 in CNS, 365t contraindications and cautions with, 544 drug interactions of, 544, 544t endogenous opioid peptides, 532, 532t mixed agonist-antagonist, 531 pain treatment and, 540 pharmacodynamics of, 534–540 mechanism of action in, 534–537 cellular actions, 534, 535f hyperalgesia, 537 receptor distribution and analgesia, 534–537, 536f, 537f receptor types and physiologic effects, 532t, 533t, 534 tolerance and dependence, 537, 538, 539t organ system effects, morphine and surrogates, 539 CNS, 537–539, 539t peripheral, 539–540 pharmacokinetics of, 532–534, 533t poisoning management for, 1007t, 1011 preparations of, available, 550t source of, 531 toxicity and undesired effects of, 542–544, 542t addiction, 543 dependence, 542, 543 overdosage, 544 tolerance, 539t, 542–543 for trauma with COPD, 531, 551 Opisthorchiasis, praziquantel for, 914 Oprelvekin, 580–581, 581t Optimization, compound, 12–13

Oral antidiabetic agents, 733–742, 743t–744t Oral contraceptives, 708–713 beneficial effects of, 712–713 physiologic effects of, 704t, 705, 705f, 706t–707t Orexin receptor antagonists, 378b Orexins, in CNS, 365t, 367 Organic anion transporter (OATP1B1), genetic variations in, 77t, 79t, 82–83 Organochlorine pesticides, 978–979, 978t, 981f Organophosphate cholinesterase inhibitors, 119t absorption, distribution, and metabolism of, 113–114 aging of, 115 pharmacodynamics of, 114–115 poisoning with, case study on, 105, 120 structure of, 113, 114f Organophosphorus pesticides, 979–980, 979t Organ transplantation, immunosuppressive therapy for, 963–964 Orlistat, for obesity, 283b, 284t Orphan Drug Amendment of 1983, 16t, 18 Orphan drugs, 18 Orphanin FQ, 532 Orphanin opioid-receptor-like subtype 1 (ORL1), 532 Orphan receptors, 21 Orphenadrine, for parkinsonism, 481, 481t, 487t Ortho-phthalaldehyde (OPA), 870 Oseltamivir, for influenza, 861–862 Osmotic agents. See also specific agents nature of, 3 preparations of, available, 268t Osmotic diuretics, 251t, 262, 267t, 268t Osmotic laxatives balanced polyethylene glycol, 1063–1064 nonabsorbable sugars or salts, 1063 Osteodystrophy, intestinal, 761 Osteomalacia, tumor-induced, 762 Osteoporosis, 761–762, 761f androgens and anabolic steroids for, 718 definition of, 761 epidemiology of, 761 etiology of, 747, 766 treatment of, 747, 761–762, 761f, 766 (See also Bone mineral homeostasis drugs) new therapies in, 754b Ouabain, 214 Ovarian cancer, chemotherapy for, 943 Ovarian disturbances, 697 Ovarian hormones, 696–716. See also specific types androgens, 707–708 contraception, hormonal, in women, 708–713 estrogens, 697–703 functions of, normal, 696–697

inhibin and activin, 708 preparations of, available, 721t progestins, 703–707 relaxin, 708 Ovarian hyperstimulation syndrome (OHSS), 650, 652 Ovarian inhibitors estrogen and progesterone inhibitors and antagonists, 713–715 anastrozole, 714–715 danazol, 714 exemestane, 715 fadrozole, 715 fulvestrant, 715 GnRH and analogs, 715 letrozole, 715 mifepristone, 713–714 ovulation-inducing agents, 699f, 715–716 tamoxifen and related partial agonist estrogens, 713, 714f ovulation-inducing agents, other drugs, 716 Ovarian stimulation, controlled GnRH for, 653 gonadotropins for, 650–651, 651f Ovary, 696–697 contraceptives on, female hormonal, 708 normal cycle of, 696–697, 697f Overactive bladder treatment, OTC, 1090t Overshoot phenomenon, 38 Over-the-counter agents, 1084–1093 acid reducers H2 -antagonists, 1087t proton-pump inhibitors, 1087t acne preparations, 1087t agents switched from prescription to OTC status, 1086, 1086t allergy and “cold” preparations, 1087t analgesics and antipyretics, 1088t antacids, 1088t anthelmintics (pinworm), 1088t antidiarrheal agents, 1088t antifungal preparations topical, 1089t vaginal, 1089t anti-inflammatory preparations, topical, 1089t antitussives, 1089t in children, 1091 contraindications for specific ingredients in, 1085–1086 decongestants systemic, 1090t topical, 1089t definition and classification of, 1084 drug information sources on, 1091

emergency contraceptives, 1090t expectorants, 1090t guidelines for, 1085 hair growth stimulants, 1090t hidden ingredients in, 1092t importance of physician familiarity with, 1085 ingredients of, FDA safety and efficacy review of, 1085 laxatives, 1090t overactive bladder treatment, 1090t overuse or misuse of, 1086, 1091 pediculicides (head lice), 1091t selection of, 1085 sleep aids, 1091t smoking cessation aids, 1091t use of, 1084 weight loss aids, 1091t Ovulation-inducing agents clomiphene, 699f, 715–716 gonadotropins, 650–651, 651f Ovulation-suppressing agents, 702 Ovum, 696–697 Oxaliplatin, 925–927, 926t Oxaluria, enteric, 764 Oxamniquine, 909t, 913–914 Oxandrolone, 716–719, 717t. See also Androgens and anabolic steroids Oxazepam, 382t. See also Benzodiazepines for ethanol withdrawal, 394t, 562, 565t structure of, 370f Oxazolidinones, 796, 797t, 798t for seizures, 400f, 413 Oxcarbazepine, for seizures, 403–404, 418t Oxiconazole, 1037 Oxidation, drug, microsomal, 58–59, 60t–61t Oxides, 974t, 976 Oxprenolol, 162. See also β-receptor antagonist drugs Oxybutynin. See also Muscarinic receptor blockers for urinary disorders, 127–128 Oxycodone, 546, 549t. See also Opioid agonists Gio protein–coupled receptor activation by, 556t, 558, 560f Oxygen demand, myocardial, 192, 192t Oxygen supply, myocardial, 192 Oxymetazoline, 145. See also Sympathomimetic drugs Oxymetholone, 716–719, 717t. See also Androgens and anabolic steroids Oxymorphone, 544, 549t. See also Opioid agonists Oxytocin, 656–657, 657f, 660t Oxytocin antagonist, 657, 660t Ozone, 974t, 976 P P450 enzymes, human liver, 59–62

enzyme induction in, 59, 62t enzyme inhibition in, 59–61, 62t specific enzymes in, 59, 62t, 63f Pacemaker cells, 225f, 227 Paclitaxel, 932t, 933 Paget’s disease of bone, 763–764 Pain components of, 540 kinins in, 301 measurement of, 538 treatment of, 540 (See also Opioids) Paliperidone, 494 Palivizumab, 863, 963 for respiratory syncytial virus, 1139t Palonosetron, antiemetic properties of, 1069 Palosuran, 309, 310t. See also Urotensin antagonists Pamidronate on bone homeostasis, 754–755, 755f for hypercalcemia, 757 for osteoporosis, bone metastases, and hypercalcemia, 764t Pancreas, endocrine, 723–724, 724t Pancreatic enzyme supplements, 1077, 1080t Pancreatic hormones, 723–733 fundamentals of, 723–724 insulin, 724–733 (See also Insulin) Pancreatic insufficiency, exocrine, 1077 Pancreatic peptide, 723, 724t Pancreatic polypeptide (PP), 308 Pancreatin, 1077, 1080t Pancrelipase, 1077, 1080t Pancuronium. See also Neuromuscular blocking drugs properties of, 459t structure of, 457f, 458f Panitumumab, 936–938, 937t, 961 Pantoprazole, 1056–1060. See also proton-pump inhibitors (PPIs) Parabens, 871 Paracrine factors, kidney adenosine, 254 peptides, 254–255 prostaglandins, 254 Paragonimiasis, praziquantel for, 914 Paramethasone, 686–692, 686t. See also Corticosteroids, synthetic Paraquat, 981f, 982 Parasympathetic nervous system, 88–89, 88f preganglionic fibers of, 89 Parathion, 119t. See also Organophosphate cholinesterase inhibitors Parathyroid hormone (PTH) on bone mineral homeostasis, 748–751, 748f, 749f on gut, bone, and kidney, 752t

Parathyroid hormone (PTH) deficiency, 759 Paravertebral chains, 88 Paricalcitol. See also Vitamin D for bone homeostasis, 751, 751t, 764t for chronic kidney disease, 760 Parkinsonism, 473–482 from antipsychotics, 500–501 drug-induced, 482 drugs for (See also specific drugs) acetylcholine-blocking drugs, 481, 481t, 487t amantadine, 480 apomorphine, 480–481, 487t catechol-O-methyltransferase inhibitors, 479–480, 487t dopamine receptor agonists, 477–479, 487t levodopa, 474–477, 487t monamine oxidase inhibitors, 474f, 477f, 479, 487t functional circuitry of, 473f general drug management of, 482 gene therapy for, 481 neuroprotective therapy for, 481 non-motor manifestation therapy in, 482 pathogenesis of, 473–474, 474f surgical procedures for, 481 Parkinson’s disease, muscarinic receptor blockers for, 124t, 126, 481 Paromomycin (sulfate), 804–805 for amebiasis, 899t, 900–901, 900f for trypanosomiasis and leishmaniasis, 902t, 905 Paroxetine, 528t. See also Selective serotonin reuptake inhibitors (SSRIs) poisoning with, treating, 1008 Partial agonists, 5–6, 6f, 24–25, 25f Partial pressure, 422–423 Partial seizures antiseizure drugs for, 400–411 clinical pharmacology of epilepsy management in, 415 complex, 414 simple, 414 Passive immunization, 1133, 1137, 1138t–1139t Pasteurization, 867t Patent, drug, 17 Patent ductus arteriosus, alprostadil for, 326–327 Patient-controlled analgesia (PCA), opioids in, 541–542 Pay to delay, 18 Pazopanib, 937t, 938 PCSK9 inhibition, 614 PCSK9 mutations, 607 PD149163, 310t. See also Neurotensin agonists PDE-5 inhibitors, for erectile dysfunction, 197b Pediatric pharmacology, 1016–1020 dosage and dosage calculations in, 1022, 1022t

dosage forms and compliance in, 1020 drug absorption in, 1016, 1018t drug distribution in, 1018 drug excretion in, 1019 drug metabolism in, 1018–1019 neonate pharmacodynamics in, 1019–1020 placental and fetal drug metabolism in, 1014 Pediculicides, OTC, 1091t Pegatinib, 963 Pegfilgrastim, 577t, 578–580, 579f, 581t Pegloticase, 638 Pegvisomant, 649 Pegylated interferon. See also Interferons for melanoma, 1050 preparations of, available, 863t with ribavirin, 79t, 84–85 Pemetrexed, 928–929, 928t Penbutolol, 160t, 162. See also β-receptor antagonist drugs for hypertension, 179 Penciclovir for HSV and VZV, 837f, 838t, 839 topical dermatologic, 1039 Penicillamine (D-dimethylcysteine) for chelation, 996f, 998 for Wilson’s disease, 486 Penicillin-binding protein (PBP), 771–772, 771f Penicillin G, 774 Penicillins, 769–776, 784t adverse reactions to, 775–776 chemistry and structure of, 769, 770f classification of, 769–771, 770f antistaphylococcal penicillins, 770f, 771 extended-spectrum penicillins, 770f, 771 penicillins, 770–771, 770f units and formulation of, 771, 786t clinical uses of benzathine penicillin, 774–775 extended-spectrum penicillins, 775 fundamentals of, 774 penicillin G, 774 penicillin V, 774 procaine penicillin G, 774–775 staphylococcal beta lactamase–resistant penicillins, 775 dosing and administration of, 773–774, 774t mechanism of action of, 771–772, 771f–773f pharmacokinetics of, 772–774 preparations of, available, 786t resistance to, 772 Penicillin V. See also Penicillins

clinical uses of, 774 Pen injectors, portable insulin, 730 Pentamidine, for trypanosomiasis and leishmaniasis, 901–903, 901t–902t Pentasa, for inflammatory bowel disease, 1071–1073, 1072f Pentazocine, mixed receptor actions of, 547 Pentobarbital, 371f, 382t. See also Barbiturates Pentostatin, for immunosuppression, 958 Pentoxifylline on blood viscosity, 342 for peripheral artery disease and intermittent claudication, 206 Peptic ulcer disease H2 -receptor antagonists for, 1055–1056 proton-pump inhibitors for, 1058–1059 Peptide YY (PYY), 308 Peptidyl dipeptidase, 296–297, 297f Peracetic acid, 870–871 Perampanel, for seizures, 398f, 408, 419t Perchloroethylene, 977–978 Percutaneous absorption, 1033, 1034f Perfluorinated compounds (PFCs), 983–984 Performance anxiety, beta-receptor antagonists for, 165 Pergolide. See also Dopamine receptor agonists for Parkinson’s disease, 478 Perinatal pharmacology, 1013–1018. See also Pregnancy pharmacology Perindopril, for hypertension, 184–185 Peripheral artery disease (PAD), 205–206, 208t Peripheral blood stem cells (PBSCs), 578–580, 579f Peripheral nervous system (PNS), 87 Peripheral synapses, 100, 100t Peripheral vascular disease, α-receptor antagonists for, 157 Peritoneal dialysis, for poisoning, 1005t, 1006 Permeation, 7–8, 8f, 9t Permethrin, ectoparasiticidal action of, 1039–1040 Permissible exposure limit values (PELs), 974t Pernicious anemia, 570t, 574. See also Vitamin B12 deficiency Peroxisome proliferator-activated receptor-gamma (PPAR-γ), 737 Peroxisome proliferator-activated receptor-gamma (PPAR-γ) ligands, 737–738, 737t Peroxygen compounds, 870–871 Perphenazine, for psychosis, 492f, 493–494, 494t Personalized medicine, 74 Pertuzumab, 961 Pesticides, 978–980 botanical, 980, 981f carbamate, 980, 980t organochlorine, 978–979, 978t, 981f organophosphorus, 979–980, 979t pFOX inhibitors, for angina pectoris, 204 PGE1 analogs, for erectile dysfunction, 197b PGI2 analog, 315–316

for pulmonary hypertension, 326 P-glycoprotein transporter, 8 Pharmaceutical industry, 11–12, 1116 Pharmacodynamics. See also Receptor; specific drugs dose–effect in, 41, 42f principles of, 5–7 agonists in, 5, 6f (See also Agonist) antagonists in, 5, 6f (See also Antagonist) drug dose and clinical response in, 35–39 drug-receptor interaction types in, 5 duration of drug action in, 6–7 receptors and inert binding sites in, 7 of selected drugs, 43t–44t of target concentration intervention, 52 Pharmacogenetic testing, in drug therapy, 69 Pharmacogenomics, 74–85 definition of, 2, 74 enzyme genetic variations in, 75–82 other enzymes in, G6PD, 81–82, 82t phase I enzymes in, 75–80 phase II enzymes in, 80–81 future directions in, 85 history of, recent, 74 immune system function genetic variations in, 83–85 drug-induced hypersensitivity reactions, 77t, 79t, 83–84, 83t, 84f IFNL3 (IL-28B), 77t, 79t, 84–85 polygenic effects in, CYP2C9 and VKORC1, 77t, 79t, 85 terms in, 75t transporter genetic variations in, 77t, 79t, 82–83 Pharmacokinetics, 41–48. See also specific drugs bioavailability in, 47–48, 47f, 47t clearance in, 42–46 (See also Clearance (CL)) dose–concentration in, 41, 42f drug accumulation in, 46–47, 46f extraction ratio in first-pass effect and, 43t–44t, 47f, 48 formula for, 47 half-life in, 45f, 46, 46f models of, 42, 45f multicompartment, 45f, 46 principles of, 7–10 Fick’s law of diffusion in, 8–9 Henderson-Hasselbalch equation in, 9–10, 10t permeation in, 7–8, 8f, 9t of selected drugs, 43t–44t target concentration in, 43t–44t, 49–54 target concentration intervention in, 51–52 volume of distribution in, 42 Pharmacologic potency, 35–36, 35f

Pharmacologic profile, 12 Pharmacology definition of, 1 history of, 2–3 major areas of study in, 1–2, 2f medical, 1 principles of, 3–10 (See also Principles, pharmacology) Phase 1 clinical trials, 16 Phase 2 clinical trials, 16 Phase 3 clinical trials, 17 Phase 4 clinical trials, 17 Phase I enzyme pharmacogenomics, 75–80, 76t–79t CYP2C19, 76t, 78t, 80 CYP2D6, 75–80, 76t, 78t dihydropyrimidine dehydrogenase, 76t, 78t, 80 principles of, 75 Phase I enzyme polymorphisms, in drug metabolism, 63f, 64–68, 66t–67t, 68f Phase I reactions, 57, 57f, 60t–61t microsomal mixed function oxidase system and, 58–59, 58f Phase II enzyme pharmacogenomics, 76t–79t, 80–81 thiopurine S-methyltransferase, 77t, 78t, 81 UGT1A1, 74, 76t, 78t, 81, 86 Phase II enzyme polymorphisms, in drug metabolism, 68–69 Phase II reactions, 57, 57f, 62–63, 63f, 64t Phenacemide, for seizures, 402 Phenanthrenes, 544, 549t. See also Opioid agonists mild to moderate agonists, 545–546, 549t mixed receptor analgesic actions, 546–547, 549t Phencyclidine (PCP), 556t, 557 ionotropic receptors in, 562 Phenelzine, for depression, 528t. See also Antidepressant agents; Monoamine oxidase inhibitors (MAOIs) Phenmetrazine, 146 Phenobarbital, 382t. See also Barbiturates for seizures, 404, 418t structure of, 371f Phenol, 869 Phenolics, 869 Phenothiazines antiemetic properties of, 1070 derivatives of chemical structure of, 492f, 493–494, 494t for psychosis, 492f, 493–494, 494t Phenoxybenzamine, 24, 155, 155t, 285. See also Adrenoceptor antagonist drugs Phensuximide, for seizures, 412 Phentermine + topiramate, for obesity, 283b, 284t Phentolamine, 155, 155t. See also Adrenoceptor antagonist drugs D-Phenylalanine derivatives, 735–736, 736f, 743t Phenylbutazone, 620f, 621t. See also Nonsteroidal anti-inflammatory drugs (NSAIDs) Phenylephrine, 137t, 142f, 143f, 145, 150t. See also Sympathomimetic drugs

cardiovascular responses to, 142t ganglion blockers on cardiovascular response to, 141, 144f structure of, 140f Phenylethylamine, 140f. See also Catecholamines; Sympathomimetic drugs Phenylheptylamines. See also Opioid agonists mild to moderate, 546 strong, 544–545, 549t o-Phenylphenol, 869 Phenylpiperidines. See also Opioid agonists mild to moderate, 546 strong, 545, 549t Phenylpropanolamine, 146 Phenytoin drug interactions of, 1129t for seizures, 400–402, 400f, 401f, 418t Pheochromocytoma, alpha-receptor antagonists for, 156–157, 157f pH manipulation, urinary, for poisoning, 1006 Phosphate for bone, 764t, 765t on bone homeostasis, 747, 748f for hypercalcemia, 758 for hypophosphatemia, 759 Phosphate binders, for bone, 765t Phosphate levels, abnormal serum hyperphosphatemia, 759 hypophosphatemia, 759 3’-Phosphoadenosine 5’-phosphosulfate (PAPS), 62–63, 64t Phosphodiesterase inhibitors, 353t. See also specific drugs Phosphoinositides, 30 as second messengers, 33–34, 33f Phosphoinositide signaling pathway, 33–34, 33f Phosphorylation, 34 of G protein–coupled receptors, 31, 32f Physical dependence. See Dependence, physical Physical nature, of drugs, 3 Physician’s order sheet (POS), 1109 Physiologic antagonism, 25–26 Physiology, experimental, history of, 2 Physostigmine, 119t chemistry and pharmacokinetics of, 113–114, 113f for reversal of antimuscarinic intoxication, 117 structure of, 113, 113f Phytonadione, for warfarin reversal, 592 Picrolimus, dermatologic use of, 1039 Pigmentation agents, 1040–1041 hydroquinone, monobenzone, and mequinol, 1040–1041 trioxsalen and methoxsalen, 1041 Pilocarpine, 119t for salivary secretion, 116

structure of, 107, 108f Pimozide chemical structure of, 493f, 494 drug interactions of, 1129t for psychosis, 494 for tics, 485, 487t Pindolol, 160t, 162. See also β-receptor antagonist drugs for hypertension, 179 intrinsic efficacy of, 6 structure of, 159f Pinworm drugs. See also Antihelminthic drugs albendazole, 908–909, 909t mebendazole, 912 OTC, 1088t pyrantel pamoate, 915–916 Pioglitazone, 737, 737t, 743t Pipecuronium, 458f. See also Neuromuscular blocking drugs Piperaquine, for malaria, 888f, 889t, 891, 891t Piperazine, for helminths, 909t, 914 Pirbuterol, for asthma, 340 Piroxicam, 620f, 621t, 624–625. See also Nonsteroidal anti-inflammatory drugs (NSAIDs) Pitavastatin, 608–610, 609f, 616t Pitolisant (BF2649), 273 Pituitary, 643, 644f Pituitary hormones, anterior, 644–656, 658t–660t classification of, 644–645, 644f dopamine agonists, 655–656, 660t, 661t fundamentals, 644 GnRH receptor antagonists, 654–655 gonadotropin-releasing hormone and analogs, 652–654 actions of, 652 chemistry and pharmacokinetics of, 652 clinical pharmacology of, 653–654 pharmacodynamics of, 652–653 uses of, 652 gonadotropins, 649–652 chemistry and pharmacokinetics of, 649–650 clinical pharmacology of, 650–651, 651f pharmacodynamics of, 650 preparations of, available, 661t toxicity and contraindications to, 652 growth hormone, 646–648, 647t, 658t growth hormone antagonists, 648–649 fundamentals of, 648 pegvisomant, 649 somatostatin analogs, 648–649, 648f mecasermin, 648, 658t preparations of, available, 661t prolactin, 655

Pituitary hormones, for male contraception, 721 Pituitary hormones, posterior, 656–658, 660t oxytocin, 656–657, 657f, 660t oxytocin antagonist, 657 preparations of, available, 661t structures of, 657f vasopressin receptor agonists, 657–658, 660t, 661t vasopressin receptor antagonists, 658, 660t, 661t Pit viper antivenom, 1139t Placental drug metabolism, 1014. See also Pregnancy pharmacology Placental transporters, 1014 Plant systemics, 979 Plasma fractions, 598–599, 598t, 600t for coagulation disorders, 598–599, 598t, 600t Plasma protein binding, 53, 53b Plasma thromboplastin antecedent (PTA), 596t Plasma thromboplastin component (PTC), 596t Plasminogen activator inhibitor (PAI), 587, 587f Plasmodium life cycle, 886, 887f Platelet-derived growth factor (PDGF), 27–28 Platinum analogs, 925–927, 926t Plerixafor, 577t, 579f, 580, 581t Plexus of Auerbach, 89, 89f Plexus of Meissner, 89 Plicamycin on bone homeostasis, 756 for hypercalcemia, 757–758 for Paget’s disease of bone, 763–764 Pneumococcal vaccines pneumococcal conjugate, 1135t pneumococcal polysaccharide, 1135t Pneumocystosis, pentamidine for, 901–903 Pneumonia, community-acquired, cephalosporin and vancomycin for, 769, 787 Podofilox, dermatologic use of, 1047–1048 Podophyllum resin, for condyloma acuminatum and verrucae, 1047–1048 Poisoned patient management, 1001–1012. See also Toxicology; specific poisons epidemiology of, 1001 initial, 1003–1006 antidotes, specific, 1006, 1007t decontamination, 1005–1006 ECG and imaging, 1005, 1005f elimination enhancement dialysis, 1005t, 1006 forced diuresis, 1006 urinary PH manipulation, 1006 history and physical examination, 1003–1004 laboratory, 1004, 1004t toxicology screening tests, 1005, 1005t mechanisms of death in, 1002

toxicodynamics of, 1002 toxicokinetics of clearance, 1001–1002 volume of distribution, 1001 toxic syndromes, 1006–1012 Poison ivy, 952 Poisons, 3. See also Toxicology Poliovirus vaccine, inactivated (IPV), 1135t Polybrominated biphenyl esters (PBDEs), 983 Polybrominated biphenyls (PBBs), 983 Polycarbophil, 1063 Polychlorinated biphenyls (PCBs), 982–983 biomagnification of, 974b Polychlorinated dibenzofurans (PCDFs), 983 Polychlorinated dibenzo-p-dioxins (PCDDs, dioxins), 983 Polycystic kidney disease, autosomal dominant, ADH antagonists for, 263 Polyene macrolides. See also specific types amphotericin B, 825–828, 833t Polyethylene glycol (PEG), balanced, 1063–1064 Polyethylene glycol-electrolyte solution, for toxin elimination, 1006 Polygenic effects, CYP2C9 and VKORC1, 77t, 79t, 85 Polymerase inhibitors, for hepatitis C, sofosbuvir, 859 Polymorphic ventricular tachycardia, in torsade de pointes with long QT syndrome, 229b, 231f, 233f Polymorphism, 75t Polymyxin B sulfate, 1035–1036 Polymyxins, 866 Polyvinyl pyrrolidone (PVP), 868–869 Pomalidomide for immunosuppression, 956 for multiple myeloma, 941 Poor metabolizer (PM), 65, 75t Pork tapeworm drugs niclosamide, 913 praziquantel, 915 Portable pen injectors, insulin, 730 Portal hypertension, 1078 Portal venous system hormones, 643, 644f, 645t. See also Pituitary hormones, anterior; Pituitary hormones, posterior Posaconazole, 829t, 831 Positive allosteric modulators, 24 Postantibiotic effect (PAE), 801, 879–880, 879t Postantibiotic leukocyte enhancement (PALE), 879 Postcoital contraceptives, 712, 712t Posterior pituitary hormones, 656–658, 660t, 661t Postmenopausal hormonal therapy, estrogens for, 701–702 Postoperative nausea and vomiting, serotonin 5-HT3 -receptor antagonists for, 1069, 1080t, 1081t Postpartum hemorrhage, ergot alkaloids for, 289 Postsynaptic regulation, autonomic, 100–101, 101f Postural baroreflex, 171, 171f Potassium channels, 225

Potassium, for arrhythmia, 243, 247t Potassium iodide, 671–672, 677t, 678t Potassium ion (K+) on conductance, 227b effects of, 227b on electrochemical gradient, 227b in membrane electrical activity, 225–226, 226f Potassium perchlorate, 671 Potassium-sparing diuretics, 260–262, 260f, 261t, 267t combinations with loop or thiazide diuretics, 264 with proximal tubule diuretics, 264 drug interactions of, 1129t preparations of, available, 268t Potassium wasting, renal, from carbonic anhydrase inhibitors, 255t, 256 Potency definition of, 35 pharmacologic, 35–36, 35f Povidone-iodine, 868–869 Practical efficacy, 36 Prader-Willi syndrome, growth hormone for, 647 Pralatrexate, 928t, 929 Pralidoxime (PAM), 128–129 Pramipexole. See also Dopamine receptor agonists for Parkinson’s disease, 478, 487t for restless legs syndrome, 486, 487t Pramlintide, for diabetes mellitus, 741, 744t Pramoxine, antipruritic uses of, 1049 Pranlukast, 324 Prasudogrel, 596 Pravastatin, 608–610, 609f, 616t Praziquantel, for helminths, 909t, 914–915 Prazosin, 155, 155t. See also Adrenoceptor antagonist drugs for hypertension, 175t, 180 Preclinical safety and toxicity testing, 13, 13t Precocious puberty, central, gonadotropin-releasing hormone agonists for, 654 Prednisolone, 686–692, 686t. See also Corticosteroids structure of, 683f topical, 1044–1046, 1045t, 1046t Prednisone, 686–692, 686t. See also Corticosteroids for asthma, 344–345, 352t delayed-release, 633 topical, 1044–1046, 1045t, 1046t Pregabalin for analgesia, on ion channels, 538b for seizures, 406, 419t Preganglionic parasympathetic fibers, 89 Pregnancy hypothyroidism and, 673–674

multiple pregnancies in, 652 thyrotoxicosis in, 676 Pregnancy pharmacology, 1013–1018 lactation pharmacology in, 1020–1022, 1021t pharmacodynamics of, 1014–1015 pharmacokinetics of, 1013–1014 teratogenic drug actions in, 1015–1016, 1015f teratogens in, 1016, 1017t, 1018t toxic drug actions in fetus in, 1015 Preload, 213, 213f Prescribing errors, 1110–1111 Prescribing, rational, 1108–1109 Prescriptions, 1108–1116, 1109f abbreviations in, 1111t compliance in, 1112–1113 conversions for, 1110 elements of, 1109–1110, 1109f e-prescribing in, 1112, 1113 errors in, 1110–1111 errors of omission in, 1111 inappropriate drug prescriptions in, 1112 legal factors in, 1113–1115 controlled substances, 1113–1114, 1114t drug safety surveillance, 1115 e-prescribing, 1113 FDA, 1113 labeled and off-labeled uses, 1115 right to prescribe, 1114, 1114b poor writing of, 1112 rational prescribing in, 1108–1109 security of, 1113 socioeconomic factors in cost, 1116b generic prescribing, 1115–1116 other cost factors, 1116 Preservatives, 871 Presynaptic regulation, autonomic, 99–100, 100t Prevertebral ganglia, 88–89 Prilocaine, 443t, 452, 453t. See also Anesthetics, local Primaquine, for malaria, 888f, 889t, 890t, 894–895 Primary generalized glucocorticoid resistance, corticosteroids for, 687 Primary induction chemotherapy, 919 Primidone for seizures, 404–405, 405f, 418t for tremor, 483 Principal cells, 253, 253f Principles, pharmacology, 3–10. See also specific topics drug–body interactions in, 5–10 drug groups in, 10

nature of drugs in, 3–5 Prinzmetal angina, 191 Probenecid, drug interactions of, 1129t Probenicid, 635f, 636 Procainamide, for arrhythmia, 233–235, 235t, 236t, 246t Procaine, 441b Procaine penicillin G, 774–775. See also Penicillins Procarbazine, 924–925, 926t Prochlorperazine, 1070 Procyclidine, for parkinsonism, 481, 481t, 487t Prodrug, 7 Profile, pharmacologic, 12 Progabide, 467 Progesterone, 697f, 703–707 adverse effects of, 707 clinical uses of, 705–707 contraindications and cautions with, 707 diagnostic uses of, 707 pharmacokinetics of, 704 physiologic effects of, 704–705 Progesterone receptor synthesis, estrogens in, 701 Progestin-only contraception, 712 Progestins, 703–707 adverse effects of, 707 clinical uses of, 705–707 contraindications and cautions with, 707 diagnostic uses of, 707 natural (progesterone), 697f, 703 pharmacokinetics of, 704 physiologic effects of, 704–705 in synthetic progestins, 704t, 705, 705f, 706t–707t synthetic, 703–704, 704t Proguanil, for malaria, 888f, 889t, 890t, 896–897 Proinsulin, 724, 724f Projection neurons, 361, 361f Prokinetic agents, 1061–1063, 1079t cholinomimetic agents, 1062 macrolides, 1063 mechanism of action of, 1061–1062, 1062f metoclopramide and domperidone, 1062–1063 preparations of, available, 1081t Prolactin (PRL), 644, 644f, 645t, 655 Prolactin antagonist. See Dopamine agonists Proliferation signal inhibitors, 955–956 Promethazine, 1070 Propafenone, for arrhythmia, 235t, 236t, 238–239, 246t Prophylaxis, antimicrobial nonsurgical, 883, 884t NRC wound classification criteria and, 883b

surgical, 882–883, 883t Propiverine. See also Muscarinic receptor blockers for urinary disorders, 128 Propofol, for anesthesia, 430–433, 431f, 431t Propoxyphene, 546. See also Opioid agonists Propranolol, 160t, 161. See also β-receptor antagonist drugs for angina pectoris, 206t for arrhythmia, 239, 246t case study on, 20, 40 for hypertension, 175t, 178–179 for hyperthyroidism, 672, 675, 676, 677t for migraine headache prophylaxis, 285 structure of, 159f for tremor, 482 Propylene glycol as dermatologic vehicle, 1047 keratolytic actions of, 1047 Propylthiouracil (PTU), 670–671, 671f, 677t for thyrotoxicosis in pregnancy, 676 Prorenin receptors, 297f, 299 Prostacyclin (PGI2 ), 315 Prostaglandin analogs for gastric mucosa protection, 1060–1061 structures of, 325f Prostaglandin endoperoxide synthase products, 314–316, 315f Prostaglandin F2α (PGF2α), 325f Prostaglandins effects of, 320–323 on kidney, 254 structures of, 325f Prostanoid biosynthesis, 314–316, 315f Prostanoid mediators, from arachidonic acid, 619, 622f Prostanoid receptors, 318–320, 318f, 319t Prostate cancer treatment androgen suppression, 719, 719f, 721t chemotherapy, 942 degarelix and abarelix, 655 gonadotropin-releasing hormone agonists, 653–654 Prostatectomy, urinary frequency and incontinence after, 121, 132 Protamine sulfate, for heparin reversal, 590 Protease inhibitors (PIs) for hepatitis C, 859–861, 860f boceprevir, 856t, 859–860 simeprevir, 860 sofosbuvir, 859 telaprevir, 856t, 860–861 for HIV, 851–854 atazanavir, 843t, 851–852 darunavir, 843t, 852

fosamprenavir, 844t, 852 fundamentals of, 851 indinavir, 844t, 852 lopinavir, 844t, 852 nelfinavir, 844t, 852 ritonavir, 844t, 852 saquinavir, 844t, 852–853 tipranavir, 845t, 853 in pregnancy, 848t Protein binding albumin concentration in, 53 capacity-limited, 53 factors in, 53 plasma, 53, 53b Protein C, 586 Protein S, 586 Prothrombin complex concentrates, 596t for warfarin reversal, 592 Prothrombin deficiency, 598t Prothrombin time (PT), 591 Proton-pump inhibitors (PPIs), 1056–1060 adverse effects of, 1059–1060 chemistry and pharmacokinetics of, 1056–1058, 1057f, 1057t clinical uses of, 1058–1059 drug interactions of, 1060 OTC, 1087t pharmacodynamics of, 1058 preparations of, available, 1081t Prototype drugs, 10 Proximal convoluted tubule (PCT), 249–251, 250f, 251f Prucalopride, laxative action of, 1065 Prussian blue, 998–999 Pseudocholinesterase. See Butyrylcholinesterase (BCHE) Pseudoephedrine, 146 Pseudovitamin D deficiency rickets, 762 Psilocybin, 556t Gio protein–coupled receptor activation by, 556t, 559 Psoralens, for pigmentation disorders, 1041 Psoriasis drugs acitretin, 1043 biologic agents alefacept, 1043–1044 fumaric acid esters, 1044 TNF inhibitors, 1044 ustekinumab, 1044 calcipotriene and calcitriol, 1043 corticosteroids + calcipotriene/calcitriol + coal tar shampoo, 1033, 1051 tazarotene, 1043 Psychosis

drugs for, 490–502, 507t, 508t nature of, 491 Psyllium, 1063 Pteroylglutamic acid, 582t. See also Folic acid p-tertiary amylphenol, 869 Pulmonary disease. See also specific types on drug metabolism, 71 Pulmonary edema, acute, opioids for, 541 Pulmonary embolism heparin for, 584, 601 thrombolytics for, 595 Pulmonary hypertension eicosanoids for, 326 nitric oxide for, 334 preparations, available, 311t treatment of, 306b Purine analogs, for inflammatory bowel disease, 1074, 1080t Purine antagonists 6-thiopurines, 928t, 930–931, 931f cladribine, 928t, 931 fludarabine, 928t, 931 Purines, in CNS, 368 Pyrantel pamoate, 909t, 915–916 Pyrazinamide, for tuberculosis, 816t, 818–819, 823t Pyrethrum, 980, 981f Pyridostigmine, 119t for myasthenia gravis, 117 for neuromuscular blockade reversal, 464–465 Pyrimethamine, for malaria, 888f, 889t, 896 Pyrimidine analog, flucytosine, 827f, 828, 833t Pyrimidine synthase inhibitors, for immunosuppression, 957–958 Q Qinghaosu, for malaria, 888f, 889t, 890t, 891–892 Quantal dose–effect curves, 36–37, 36f Quantity, of exposure, 973 Quaternary ammonium compounds, 869 Quazepam, 382t. See also Benzodiazepines Quetiapine, 493f, 494, 507t “Quicksilver,” 993 Quinagolide, 655–656 Quinapril, for hypertension, 184–185 Quinestrol, 699, 699f. See also Estrogens Quinidine for arrhythmia, 235–236, 235t, 236t, 246t drug interactions of, 1129t–1130t for malaria, 888f, 889t, 890t, 892–893 Quinine, for malaria, 888f, 889t, 890t, 892–893 Quinolone antibiotics, drug interactions of, 1130t Quinupristin-dalfopristin, 794–795, 797t, 798t

R Rabbit syndrome, 485 Rabeprazole, 1056–1060. See also proton-pump inhibitors (PPIs) Rabies, immune globulin intravenous for, 1138t Rabies vaccine, 1135t Radiation, nausea and vomiting after, serotonin 5-HT3 -receptor antagonists for, 1069, 1080t, 1081t Radical cure, 886 Radioactive iodine (131 I, RAI), 672, 677t Radiofrequency catheter ablation, for cardiac arrhythmias, 242b Raloxifene, 713, 714f for osteoporosis, 754b, 762, 764t Raltegravir, 844t, 855–856 Ramelteon, 281b, 371, 372t, 382t. See also Melatonin receptor agonists for insomnia, 372b Ramipril, for hypertension, 184–185 Randomization, 15b Randomized controlled trails (RCTs), 15b Ranibizumab, 963 Ranitidine, 278, 290t, 1054–1056. See also H2 -receptor antagonists RANK ligand (RANKL), 750 RANK ligand (RANKL) inhibitors, for hyperparathyroidism, 764t, 765t Ranolazine for angina pectoris, 203–204, 207t, 208t for arrhythmia, 243 Rapamycin, 955–956 on life span, 1024 Rare disease treatment, 18 Rasagiline, for parkinsonism, 479, 487t Rasburicase, G6PD deficiency on metabolism of, 79t, 82 Rate of administration, 51 Rate of elimination, 45 Rational drug design, 4 Rational prescribing, 1108–1109 Rattlesnake envenomation management, 1011 Rattlesnake hyperimmune globulin, 960 Raxibacumab, 963 Reactive oxygen species (ROS), 63 Reactivity, drug. See also specific drugs bonds and, 3–4 Reboxetine, 147 Receptor, 20–35. See also specific types in addiction, 553, 556f alterations in number or function of, 37–38 autonomic, 96, 97t drug (See also specific drugs and receptors) history of, 2 drug concentration reaching, alteration in, 37 on drug dose and clinical response, 35–39 (See also Dose, clinical response and) response distal to, changes in components of, 38

Receptor classes. See also specific types as agonist and antagonist mediators, 20–21 definition of, 3, 20 on drug concentration and response, 20, 21–26 (See also Dose, on pharmacologic effects) drug development and, 34–35 in drug selectivity, 20 “gene-active,” 26–27 inert binding sites in, 7 intracellular, for lipid-soluble agents, 26–27, 27f macromolecular nature of, 21 nomenclature for, 4–5 orphan, 21 receptor concept and, 20–21 signaling mechanisms and drug action in, 26–34 spare, and receptor-effector coupling, 21–23, 22f types of, 21 Receptor–drug interactions, 5 Receptor-effector coupling, spare receptors and, 21–23, 22f Receptor ligand, endogenous, variation in concentration of, 37 Receptor recycling, opioid, 537 Receptor regulation, 30–31, 32f Receptor reserve, 22, 22f Receptor tyrosine kinases, 27–28, 28f Receptor tyrosine kinase signaling pathway, 27 Receptor uncoupling, opioid, 537 Recombinant factor VIIa (rFVIIa), 598t, 599, 600t for warfarin reversal, 592 Red blood cells, binding to, 53 Reductase inhibitors. See HMG-CoA reductase inhibitors Refractory period, 228–229, 228f Regadenoson, 203b Regulation, drug, 10–18. See also Development and regulation, drug Regulation, flexible, 34 Regulatory proteins, as drug receptors, 21

Relaxin, ovarian, 708 Relay neurons, 361, 361f Relcovaptan, 302. See also Vasopressin receptor antagonists on vasoactive peptides, 310t Release inhibitors, histamine in, 275 Remifentanil, 545, 549t. See also Opioid agonists Remodeling, cardiac, 213 Renal baroreceptor, on renin release, 295 Renal failure from ADH antagonists, 263 diuretics for, 265 from potassium-sparing diuretics, 262 Renal potassium wasting, from carbonic anhydrase inhibitors, 255t, 256 Renal tubule transport mechanisms, 249–255 in collecting tubule system, 250f, 252–254, 253f in distal convoluted tubule, 250f, 252, 252f in loop of Henle, 250f, 252, 252f nephron segments and functions in, 251t in proximal tubule, 249–251, 250f, 251f renal autacoids in adenosine, 254 peptides, 254–255 prostaglandins, 254 Renin, 294 control of release of, 295–296, 296f Renin-angiotensin-aldosterone system contraceptives on, female hormonal, 709 sites of action of drugs interfering with, 183, 184f Renin-angiotensin system inhibitors, 298–299 angiotensin-converting enzyme inhibitors, 298 angiotensin receptor blockers, 298–299 prorenin receptors, 299 renin inhibitors, 295f, 297f, 299 Renin-angiotensin system suppression, for hypertension, 294, 312 Renin inhibitors for heart failure, 217 for hypertension, 188t preparations of, available, 311t on renin-angiotensin system, 295f, 297f, 299 on vasoactive peptides, 309t Renshaw cells, 366 Repaglinide, 735, 736t, 743t Repinotan, 280 Research. See also specific topics basic, 14b translational, 12 Reserpine for Huntington’s disease, 487t for hypertension, 175t, 178, 187t

Resistance, antibiotic, 767 Respiratory depressants, sedative-hypnotics, 377 Respiratory syncytial virus (RSV), palivizumab for, 1139t Response axis, 35f, 36 Response elements, 26 Response fluctuations, from levodopa, 476 Responsiveness, drug idiosyncratic, 36 quantitative variations in, 37 variation in, 37–38 Resting potential on action potentials, 228–229, 228f of sodium channels, 228, 228f Restless legs syndrome, 485–486 Rest tremor, 483 Resynchronization, cardiac, for chronic heart failure, 220 Retapamulin, 1035 Reteplase, 595 Retigabine, for seizures, 408, 419t Retinoic acid derivatives, 1041–1042 Retrograde transmission, 88 Retroviral agents, 842–856 drug–drug interactions of two-drug combinations of, 847t entry inhibitors, 854–855 fundamentals of, 842 integrase strand transfer inhibitors, 855–856 nonnucleoside reverse transcriptase inhibitors, 849–851 nucleoside and nucleotide reverse transcriptase inhibitors, 842–849, 843t–845t in pregnancy, 848t protease inhibitors, 851–854 Reversal potential, 226 Rh0 (D) immune globulin micro-dose, 959–960 Rheumatoid arthritis, 625 Rheumatoid arthritis treatment, 619–633. See also Analgesics; specific drugs case study, 618, 641 disease-modifying antirheumatic drugs, 625–633, 639t nonsteroidal antiinflammatory drugs, 619–625, 621t Rh negative, in labor, immunotherapy for, 946, 969 Rho kinases (ROCK), 204 Rhythm, normal cardiac, 224–229. See also Cardiac rhythm electrophysiology, normal Ribavirin for hepatitis C, 861 for influenza A and B, 862–863 for Lassa fever and viral hemorrhagic fevers, 863 pegylated interferon with, 79t, 84–85 for respiratory syncytial virus, 862 Rickets hereditary vitamin D–resistant, 762–763 nutritional, 762

pseudovitamin D deficiency, 762 Rifabutin, for tuberculosis, 816t, 821 Rifampin drug interactions of, 1130t for leprosy, 822–823, 823t for tuberculosis, 816t, 817–818, 823t Rifapentine, for tuberculosis, 816t, 821 Right to prescribe, 1114, 1114b Rilonacept, 632–633, 966 Rilpivirine, 844t, 851 Riluzole, spasmolytic actions of, 467 Rimantadine, for influenza, 862 Rimonabant, for cannabinoid dependence, 564, 565t Riociguat, for pulmonary hypertension, 306b Risedronate on bone homeostasis, 754–755, 755f for bone metastases, 764t for hypercalcemia, 764t for osteoporosis, 754b, 762, 764t for Paget’s disease of bone, 763 Risk, 973 Risperidone, 493f, 494, 507t Ritanserin, 286 Ritonavir, 844t, 852 Rituximab, 961 for chronic lymphocytic leukemia, 940 for rheumatoid arthritis, 628 Rivaroxaban, 592–593 Rivastigmine, for Alzheimer’s disease, 1028 Rocuronium. See also Neuromuscular blocking drugs properties of, 459t, 460t, 469t structure of, 458f Roflumilast, 341 Rolofyline, diuretic actions of, 257 Romidepsin, dermatologic, 1050–1051 Romiplostim, 577t, 580–581, 581t Ropinrole. See also Dopamine receptor agonists for Parkinson’s disease, 478, 487t for restless legs syndrome, 486, 487t Ropivacaine, 442t, 443t, 452, 453t. See also Anesthetics, local historical development of, 441b Rosiglitazone, 737t, 738, 743t Rosuvastatin, 608–610, 609f, 616t Rotavirus vaccine, 1136t Rotenone, 980, 981f Rotigotine. See also Dopamine receptor agonists for Parkinson’s disease, 478 Routes of administration, alternative, first-pass effect and, 47t, 48 Routes of exposure, 973

Rubella, immune globulin for, 1139t Rufinamide, for seizures, 409, 419t S Sabal serrulata, 1102–1103 S-adenosyl-L-methionine (SAMe), 63, 64t Safety testing, preclinical, 13, 13t Salbutamol. See Albuterol Salicylates, 621, 621t, 622f drug interactions of, 1130t in OTC agents, 1092t poisoning management for, 1008–1009 Salicylic acid, keratolytic actions of, 1046–1047 Salicylism, 1047 Saline diuresis, for hypercalcemia, 757 Salivary glands, adrenoreceptors in, 143 Salmeterol for asthma, 340, 352t structure of, 339f Salt restriction, dietary, for chronic heart failure, 219 Salts, nonabsorbable, 1063 Sampatrilat, 303, 310t. See also Vasopeptidase inhibitors Sanitization, 867t Saquinavir, 844t, 852–853 Sarcomere, cardiac muscle, 210, 211f Sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA) transporter, 210 Sarcoserine, 494 Sargramostim, 577t, 578–580, 579f, 581t Sarin, 119t. See also Organophosphate cholinesterase inhibitors Saw palmetto (Serenoa repens, Sabal serrulata), 1102–1103 Saxagliptin, 740, 744t SB1440115, 310t. See also Urotensin antagonists Scavenger receptors, 602 Schild equation, 24 Schistosoma haematobium, metrifonate for, 912–913 Schistosoma mansoni, oxamniquine for, 913–914 Schistosomiasis, praziquantel for, 914 Schizoaffective disorders antipsychotics for, 497–498 lithium for, 505 Schizonticides, 886, 887f Schizophrenia dopamine hypothesis of, 491 glutamate hypothesis of, 492 nature of, 491 serotonin hypothesis of, 491 Schizophrenia treatment. See also Antipsychotic agents antipsychotics, 497 lithium, 505 psychosocial and cognitive remediation, 502

Scopolamine, 121–122. See also Muscarinic receptor blockers action of, 124–125, 124f antiemetic properties of, 1070 Scorpion antivenom, 960 Screening, drug, 12–13 Secobarbital, 371f, 382t. See also Barbiturates Secondarily generalized attack, 414 Second messengers, 30, 30f cAMP, 31–33, 33f cGMP, 34, 333f diffusible, in central nervous system, 357f, 358 phosphoinositides and calcium, 33–34, 33f Sedation, 422b. See also Anesthetics, general conscious, 422b deep, 422b Sedative-hypnotic drugs, 369–383, 382t actions of, general, 369 buspirone, 282, 371, 372b, 379t, 382t chemical classification of barbiturates, 370, 371f benzodiazepines, 369–370, 370f newer hypnotics, 370–371, 371f clinical pharmacology of, 378–379, 378t anxiety states, 378 delirium tremens, 379 dosages, 379t muscle relaxants, 379–380 other therapeutic uses, 379–380 sleep problems, 379 withdrawal from physiologic dependence, 379 dose-reponse curves for, 369, 370f in elderly, 1027 hypnotic actions, 369 pharmacodynamics of, 374–377 benzodiazepine binding site ligands in, 375 chloride channel GABA receptor complex versatility in, 374, 374f, 376b GABAA receptor molecular pharmacology in, 374–375, 374f GABA receptor heterogeneity and pharmacologic selectivity in, 375b neuropharmacology in, 375 organ level effects in, 376–377 pharmacokinetics of, 371–374 absorption and distribution in, 371 biodisposition in, factors in, 374 biotransformation in barbiturates, 373 benzodiazepines, 372–373, 373f, 373t newer hypnotics, 373–374, 373t excretion in, 374 poisoning management for, 1007t, 1011

preparations of, available, 383t ramelteon, 371, 372b, 382t sedative actions of, 369 tasimelteon, 371 tolerance and dependence on, 377 toxicology of direct toxic actions, 380 drug interactions in, 381 drug response alterations in, 381 Sedative-hypnotics, 376 Sedatives, 369 Seizures. See also Epilepsy (seizures) from antipsychotics, 501 case study on, 396, 420 classification of, 396, 397t generalized seizures, 414–415 partial (focal) seizures, 414 drugs for, 396–420 Selective estrogen receptor modulators (SERMs), 700, 713, 714f for bone, 764t for osteoporosis, 754b, 762, 764t preparations of, available, 765t Selective serotonin reuptake inhibitors (SSRIs), 528t. See also Antidepressant agents clinical pharmacology of adverse effects in, 524–525 drug interactions in, 526, 526t, 1130t pharmacodynamics of, 519–520, 520t pharmacokinetics of, 517–518, 518t preparations, available, 529t Selectivity, drug in beneficial vs. toxic effects, 38–39 definition of, 38 in structurally identical receptors, 27f, 34 Selegiline for depression, 528t for parkinsonism, 477f, 479, 487t structure of, 474f Semustine, 923f, 924 Senna, 1064 Sensitivity, target organ, on target concentration, 52 Sensitization, opioid, 532 Sepsis, 332 Septic shock, nitric oxide inhibitors for, 332–333, 333t Sequential scheduling, in cancer chemotherapy, 922 Serenoa repens, 1102–1103 Serine protease inhibitors, 600 Serotonin (5-HT), 279–285 chemical structure of, 1067f chemistry and pharmacokinetics of, 279–280, 279f

clinical pharmacology of, serotonin agonists in, 282 in CNS, 362f, 364t, 367 in depression, 512–513, 513f discovery of, 279 functions of, 92t pharmacodynamics of, 280–282 in schizophrenia, 491 Serotonin 5-HT3 receptor antagonists antiemetic, 1069, 1080t, 1081t for irritable bowel syndrome, 1066–1067, 1067f Serotonin 5-HT4 receptor agonists, laxative actions of, 1064–1065 Serotonin-norepinephrine reuptake inhibitors (SNRIs), 528t chemistry of, 514 clinical pharmacology of adverse effects in, 525 drug interactions in, 526 pharmacodynamics of, 520, 520t pharmacokinetics of, 518, 518t preparations of, available, 529t Serotonin (5-HT) receptor, 280, 280t in CNS, 367 Serotonin (5-HT) receptor agonists, 283–285, 290t, 382t clinical pharmacology of, 282 migraine headaches and, 283–285, 284f, 285t preparations of, available, 291t Serotonin (5-HT) receptor antagonists, 285–286, 290t, 291t Serotonin (5-HT) receptor modulators, for depression, 528t. See also Antidepressant agents chemistry of, 516 clinical pharmacology of adverse effects in, 525 drug interactions in, 526–527 pharmacodynamics of, 520t, 521 pharmacokinetics of, 518t, 519 preparations of, available, 529t Serotonin syndrome, 282, 282b, 282t, 1008 Serotonin transporter (SERT, SLC6A4), 95b MDMA (ecstasy) on, 564 Sertaconazole, 1037 Sertindole, 494 Sertoli cells, 716 Sertraline, 528t. See also Selective serotonin reuptake inhibitors (SSRIs) SERT transporter, 9t Serum sickness drug reactions, 951, 952f, 967 Sevelamer, for hyperphosphatemia, 759 Sevoflurane, 422–430. See also Anesthetics, inhaled properties of, 425t structure of, 424f Sex (gender), in drug metabolism, 69 Shape, drug, 4

Shivering, opioids for, 541 Short-bowel syndrome, teduglutide for, 1077 Sibutramine, 147 Sickle cell disease, hydroxyurea and, 568b Side effect, 38. See also Adverse drug event (ADE) Signaling mechanisms, drug action and, 26–34 cytokine receptors in, 28, 29f G proteins and second messengers in, 30, 30f, 31f, 31t interplay among, 34 intracellular receptors for lipid-soluble agents in, 26–27, 27f ligand- and voltage-gated channels in, 28–29, 29f of ligand-regulated transmembrane enzymes, 27–28, 28f mechanisms of, transmembrane, 26, 26f phosphorylation in, 34 receptor regulation in, 30–31, 32f receptor tyrosine kinases in, 27–28, 28f second messengers in cAMP, 31–33, 33f cGMP, 34, 333f phosphoinositides and calcium, 33–34, 33f Sildenafil, for erectile dysfunction, 197b Silodosin, 156 Silver nitrate, 871 Silver sulfadiazine, 871 Silybum marianum, 1100–1101 Simeprevir, for hepatitis C, 860 Simple partial seizure, 414 Simvastatin, 608–610, 609f, 616t Sinecatechins, for genital and perianal warts, 1048 Single nucleotide polymorphism (SNP), 68, 75t Single-twitch stimulation, 461–462 Sinoatrial (SA) node, 224, 225f Sinus rhythm, normal, ECG of, 232f Sirolimus, 955–956 on life span, 1024 Sirtuins, on life span, 1024 Sitagliptin, 740, 744t Sitaxsentan, 304–305, 310t. See also Endothelin inhibitors 6-mercaptopurine (6-MP), 928t, 930–931, 931f for inflammatory bowel disease, 1074, 1080t 6-thioguanine (6-TG), 928t, 930–931 TPMT on metabolism of, 81 6-thiopurines, 928t, 930–931, 931f Size, of drugs, 3 Skeletal muscle relaxants, 455–471. See also specific types neuromuscular blocking drugs, 455–465 preparations, available, 470t spasmolytic drugs, 465–468, 469t Skin. See Dermatologic pharmacology

SLC6A2. See Norepinephrine transporter (NET) SLCO1B1 gene pharmacogenomics, 77t, 79t, 82–83 Sleep aids, OTC, 1091t Sleep-enabling drugs, 378b Sleeping sickness. See African trypanosomiasis Sleep-wake cycle, melatonin receptors in, 372b Slow acetylator, 68 Slow-reacting substance of anaphylaxis (SRS-A), 317 Small interfering RNAs (siRNAs), therapeutic, 2 Smoking. See Nicotine Smoking cessation aids, OTC, 1091t Smooth muscle contraction, calcium channel blocking drugs on, 192–193, 193f Snake bite treatment coral snake, 960, 1139t rattlesnake, 960, 1011, 1139t SNAP-25, 90 Snaptotagmin, 90–91 Sniffing, 562 Sodium (Na+) in membrane electrical activity, 225–226, 226f in OTC agents, 1092t Sodium bicarbonate, antacid actions of, 1054 Sodium–calcium exchanger, in cardiac contractility, 210 Sodium channel, 226 antiarrhythmic state- and use-dependent block of, 232, 234f in cardiac action potential, 227–228, 227f resting potential of, 228, 228f Sodium channel blockers, for angina pectoris, 203–204, 207t, 208t Sodium channel blockers, for arrhythmia, 233–239, 235t, 236t, 246t class 1A disopyramide, 235t, 236–237, 236t, 246t procainamide, 233–235, 235t, 236t, 246t quinidine, 235–236, 235t, 236t, 246t class 1B lidocaine, 235t, 236t, 237–238, 237f, 246t mexiletine, 235t, 236t, 238, 246t class 1C flecainide, 235t, 236t, 238, 246t moricizine, 235t, 236t, 239, 246t propafenone, 235t, 236t, 238–239, 246t preparations of, available, 247t Sodium etidronate, for Paget’s disease of bone, 763 Sodium ferric gluconate complex, for iron-deficiency anemia, 572, 581t Sodium-glucose cotransporter 2 (SGLT2), 250, 251f Sodium glucose cotransporter 2 (SGLT2) inhibitors, 256–257, 267t, 268t, 740, 744t Sodium hypochlorite, 869 Sodium nitroprusside. See Nitroprusside Sodium phosphate, 1063 Sodium pump, 211f, 214, 226

Sodium removal, for chronic heart failure, 219 Sodium stibogluconate, for trypanosomiasis and leishmaniasis, 900f, 902t, 903 Sodium sulfacetamide, for acne, 1036 Sodium valproate, for seizures, 401f, 412–413, 419t Sofosbuvir, for hepatitis C, 859 Solanezumab, for Alzheimer’s disease, 1029 Solid organ transplantation, immunosuppressive therapy for, 963–964 Solifenacin, 131t. See also Muscarinic receptor blockers for urinary disorders, 128 Solvents, 976–978 aromatic hydrocarbons, 977–978 halogenated aliphatic hydrocarbons, 976–977 Somatic division, of autonomic nervous system, 87 Somatic motor nerves, 88f Somatostatin, 645, 648–649, 648f, 723, 724t, 1065 for variceal hemorrhage, 1078 Somatostatin analogs, 648–649, 648f Somatotropin. See Growth hormone (GH) Sorafenib, 937t, 938 Sorbitol, 1063 Sotalol, for arrhythmia, 235t, 236t, 239, 240–241, 246t Sources of information, 18–19 Spareness, degree of, 22f, 23 Spare receptors, 22, 22f Spasmolytic drugs, 465–468, 469t baclofen, 466–467, 466f, 469t botulinum toxin, 468 dantrolene, 429, 466f, 467–468, 469t diazepam, 466, 466f, 469t gabapentin, 467 glycine, 467 idrocilamide, 467 for local muscle spasm, 468 mechanisms of action of, 465–466, 466f preparations of, available, 470t progabide, 467 riluzole, 467 spasticity and, 465, 466f tizanidine, 466f, 467 Spasms, infantile, 415 drugs for, 416 Spasticity, 465, 466f Special carrier molecules, 8, 8f Spectinomycin, 805, 805t Spinosad, ectoparasiticidal action of, 1040 Spiramycin, for malaria, 897 Spironolactone, 221t, 694. See also Aldosterone antagonists; Diuretics antiandrogen actions of, 719f, 720 for diuresis, 260–262, 260f, 261t, 267t

drug interactions of, 1129t for heart failure, 217 SRX251, 302. See also Vasopressin receptor antagonists on vasoactive peptides, 310t SSR240612, 301 Stage fright, β-receptor antagonists for, 165 St. Anthony’s fire, 286 Staphylococcal beta lactamase–resistant penicillins, 775. See also Penicillins Staphylococcus aureus, transpeptidation reaction in, 771, 772f State-dependent drug action, 232, 234f Statins, 608–610, 609f, 616t OATP1B1 on metabolism of, 79t, 82–83 STATs (signal transducers and activators of transcription), 28, 29f Status epilepticus drugs, 416–417 Stavudine, 845t, 848 Steam, 871 Stearyl-Nle17 -VIP, 310t Stem cell transplantation, autologous, G-CSF for, 579–580 Stereoisomerism, 4 Sterilants, 867t, 871 Sterilization, 867t Sterilox, 870 Steroids, anabolic, 716–719, 721t. See also Androgens and anabolic steroids Steroid synthesis inhibitors, 719–720, 719f, 721t Sterol absorption inhibitors, 616t intestinal, 613–614, 616t Stevens-Johnson syndrome (SJS), 77t, 79t, 83–84, 83t, 84f Stimulant laxatives, 1064 Stimulants. See Amphetamines; specific types Stiripentol, for seizures, 409 St. John’s wort (Hypericum perforatum), 1101–1102 Stones calcium oxalate, 764 kidney from carbonic anhydrase inhibitors, 255t, 256 from potassium-sparing diuretics, 262 Stool surfactant agents (softeners), 1063 Strabismus, cholinomimetics for, 116 Streptogramins, 794–795, 797t, 798t Streptokinase, 587, 587f, 594–595 Streptomycin, 800f, 802–803, 805t for tuberculosis, 816t, 819, 823t Streptozocin, 924 Stress-related gastritis, H2 -receptor antagonists for, 1056 Stress-related mucosal bleeding, proton-pump inhibitors for prevention of, 1059 Strongyloidiasis ivermectin for, 912 thiabendazole for, 916 Strontium, for bone, 764t

Strontium ranelate on bone homeostasis, 756 for osteoporosis, 762 Structural proteins, as drug receptors, 21 Structure-activity relationship, 34 Stuart-Prower defect, 598t Stuart-Prower factor, 596t Submucous plexus, 89, 89f Substance P, 92t, 306–307 Substance P antagonists, 310t, 311t Substituted benzamides, 1070 Substrate stabilization, 59 Succimer (dimercaptosuccinic acid, DMSA), 996–997, 996f for arsenic poisoning, 993 for lead poisoning, 990–991 for mercury poisoning acute, 994 chronic, 995 Succinylcholine, 469t chemistry and structure of, 456–457, 457f clinical pharmacology of neuromuscular transmission assessment in, 461–463 skeletal muscle paralysis in, 461 malignant hyperthermia from, 429, 464 mechanism of action of, 459f–461f, 460–461, 460t pharmacokinetics of, 458–459, 459t properties of, 459t, 460t, 469t Sucralfate, for gastric mucosa protection, 1060 Sufentanil, 545, 549t. See also Opioid agonists Sugars, nonabsorbable, 1063 Suicide inhibitors, 61 Sulbactam, 780–781, 780f Sulconazole, 1037 Sulfadoxine, for malaria, 888f, 896–897 Sulfadoxine-pyrimethamine, for malaria, 889t Sulfasalazine, 628 for inflammatory bowel disease, 1071–1073, 1072f, 1080t Sulfate solution, 1063 Sulfinpyrazone, 635f, 636 Sulfonamides, 807–809, 813t adverse reactions of, 809 chemistry of, 807, 808f clinical uses of, 809 mechanism of action and antimicrobial activity of, 807, 808f pharmacokinetics of, 808, 808t preparations of, available, 813t resistance to, 808 trimethoprim and trimethoprim-sulfamethoxazole mixtures of, 809–810, 813t Sulfones, for leprosy, 822

Sulfonylurea receptor binding agents D-phenylalanine derivatives, 734, 735t,736, 736t, 743t meglitinide analogs, 734, 736t, 743t sulfonylureas, 733–734, 733t, 734t, 743t Sulfonylureas, 733–735, 743t efficacy and safety of, 734 first-generation, 734–735, 734f, 743t mechanism of action of, 733, 733t second-generation, 734f, 735, 743t structures of, 734f Sulfotransferases (SULTs), 62, 63f, 64t Sulfur dioxide, 974t, 975 Sulfur, ectoparasiticidal action of, 1040 Sulindac, 621t, 625 Sulpiride, 494 Sumatriptan, 283–285, 284f, 285t, 290t Sunitinib, 937t, 938 Sun protection factor (SPF), 1041 Sunscreens, 1041 Superoxidized water, 870 Supplements, dietary, 1103–1106 coenzyme Q10, 1103–1104 definition of, 1094 efficacy of, 3 glucosamine, 1104 historical and regulatory facts on, 1095 melatonin, 1104–1106 regulation of, 1094–1095 toxicity of, 3 Suramin, for trypanosomiasis and leishmaniasis, 901t, 904 Surface area, in dosage calculations, 1022, 1022t Surgery, nausea and vomiting after, 5-HT3 -receptor antagonists for, 1069, 1080t, 1081t Surgical anesthesia, 428 Susceptibility, organism, to specific agent, 875 Susceptibility testing, antimicrobial agent, 875 Suspensions, 1020 Suvorexant, 378b Sweat glands, apocrine, adrenoreceptors in, 143 Sympathetic nervous system, 88–89, 88f estrogens on, 701 functions of, 133 on renin release, 295 Sympathomimetic drugs, 133–151, 150t for asthma, 338–340, 339f, 352t (See also specific drugs) beta2 -selective, 340 preparations, available, 353t structures of, 339f toxicities of, 340 chemistry of, medicinal, 138–151

structure in, 138–140, 139f substitution on alpha carbon in, 140, 140f substitution on amino group in, 139–140 substitution on benzene ring in, 138–139, 140f substitution on beta carbon in, 140 definition of, 133 direct-acting, 133–134, 137t, 140f, 142f, 143f, 145–146, 145f (See also specific types) for heart failure, preparations, available, 223t indirect-acting, 133–134, 146–147 amphetamine-like, 94f, 140f, 146–147, 147t catecholamine reuptake inhibitors, 139f, 147 noradrenergic transmitter release by, 94 mixed-acting, 140f, 146 molecular pharmacology of, 134–138 adrenoreceptors in, 134–138 alpha, 134f, 135, 135t beta, 135–136, 135t, 136f dopamine, 135t, 136–137 polymorphisms of, 138 potencies of, 134–135 regulation of, 137 selectivity and affinities of, 137, 137t structure of, 134, 134f norepinephrine transporter in, 138, 139f organ system effects of cardiovascular, 98t, 99f, 140–142, 141t, 142t α1 -receptor activation in, 141, 142t, 143f, 144f α2 -receptor activation in, 141 β-receptor activation in, 141–142, 142t, 143f dopamine-receptor activation in, 142 noncardiac, 141t, 142–144 in OTC agents, 1092t preparations of, available, 151t specific drugs in, 144–147, 150t direct-acting sympathomimetics, 133–134, 137t, 140f, 142f, 143f, 145–146, 145f endogenous catecholamines, 142t, 143f, 144–145 indirect-acting, 146–147 amphetamine-like, 94f, 140f, 146–147, 147t catecholamine reuptake inhibitors, 139f, 147 noradrenergic transmitter release by, 94 mixed-acting sympathomimetics, 140f, 146 mixed, noradrenergic transmitter release by, 94 therapeutic uses of, 147–150, 150t additional, 150 anaphylaxis, 148–149 cardiovascular cardiac, 148 hypotension, acute, 147 hypotension, chronic orthostatic, 147–148

shock, 147 vasoconstriction, local, 148 CNS, 149 diarrhea in diabetics, 150 genitourinary, 149 narcotics craving, 150 ophthalmic, 149 pulmonary, 148 Sympathoplegics, 172, 172f, 174–180 adrenergic neuron-blocking agents, 187t guanethidine, 175t, 177–178, 187t reserpine, 175t, 178, 187t adrenoceptor antagonists (See Adrenoceptor antagonist drugs) α-adrenoceptor blockers, other, 180 β-adrenoceptor blocking agents, 175t, 178–180 (See also β-receptor antagonist drugs) esmolol, 180 labetalol, carvedilol, and nebivolol, 175t, 179–180, 188t metoprolol and atenolol, 175t, 179 nadolol, carteolol, betaxolol, and bisoprolol, 175t, 179 pindolol, acebutolol, and penbutolol, 175t, 179 propranolol, 175t, 178–179 centrally acting, 175–177, 175t, 187t clonidine, 175t, 176–177 guanabenz and guanfacine, 176 methyldopa, 175t, 176 preparations of, 189t ganglion-blocking agents, 177 prazosin and other α1 blockers, 175t, 180 Synapses autonomic, 90 of central nervous system, 358–359, 359f peripheral, 100, 100t Synaptic potential, 358–359, 359f Synaptic transmitters. See also Neurotransmitters, CNS for ligand- and voltage-gated channels, 28–29, 29f Synaptobrevin, 90 Synaptosomal nerve-associated proteins (SNAPs), 90, 91f Syndrome of inappropriate ADH secretion (SIADH), ADH antagonists for, 263 Synergism, in antimicrobial drug, 881–882 Synergistic killing, 801 Synergy studies, antimicrobial, 875 Synonymous SNPs, 75t Syntaxin, 90 Synucleinopathy, 473 Systolic heart failure, 209. See also Heart failure vs. diastolic heart failure, 218t T T3 , 663, 666–669, 677t. See also Thyroid drugs biosynthesis of, 664, 664f

effects of, 667, 668f in hypothalamic-pituitary-thyroid axis, 665, 667f mechanism of action of, 666–667, 669f peripheral metabolism of, 664–665, 665f pharmacokinetics of, 665t, 666 T4 , 663, 665t, 666–669, 677t. See also Thyroid drugs biosynthesis of, 664, 664f contraceptives on, female hormonal, 709 effects of, 667, 668f in hypothalamic-pituitary-thyroid axis, 665, 667f mechanism of action of, 666–667, 669f peripheral metabolism of, 664–665, 665f pharmacokinetics of, 665t, 666 Tachykinins, 306. See also specific types in CNS, 365t Tachyphylaxis, 36, 38 Tacrine, for Alzheimer’s disease, 117, 1028 Tacrolimus (FK 506), 955, 1039 Tadalafil, for erectile dysfunction, 197b Taenia saginata niclosamide for, 913 praziquantel for, 915 Taenia solium niclosamide for, 913 praziquantel for, 915 Tamoxifen, 713, 714f for breast cancer, 941 Tamsulosin, 155–156, 155t. See also Adrenoceptor antagonist drugs Tangier disease, 607–608 Tapentadol, 547, 549t, 550t Tapeworm drugs niclosamide, 913 praziquantel, 915 Tar compounds, dermatologic, 1046 Tardive akathisia, 485 Tardive dyskinesia, 485 from antipsychotics, 501 Tardive dystonia, 485 Target concentration, 49 of specific drugs, 43t–44t Target concentration approach, to rational dosage regimen, 49–51 loading dose in, 45f, 50–51, 51f maintenance dose in, 50, 50b, 51f Target concentration intervention, 51–54 pharmacodynamic variables in, 52 pharmacokinetic variables in, 51–52 strategy in, 52b Target, drug, 10–11. See also specific drugs Tasimelteon, 371

Tau protein, 1027–1028 Taxanes and other anti-microtubule drugs, 932t, 933–934 cabazitaxel, 933 docetaxel, 932t, 933 eribulin, 933–934 ixabepilone, 933 paclitaxel, 932t, 933 Tazarotene for acne, 1042 for psoriasis, 1043 Tazobactam, 780–781, 780f TCDD, 981f, 983 Teaserod, 285 Tedizolid, 796 Teduglutide, for short-bowel syndrome, 1077 Tegafur, dihydropyrimidine dehydrogenase on metabolism of, 78t, 80 Tegaserod chemical structure of, 1067f laxative action of, 1065 Teicoplanin, 782, 785t Telaprevir, for hepatitis C, 856t, 860–861 Telavancin, 782, 785t Telbivudine, for hepatitis B, 858 Telcagepant, 307, 310t. See also Calcitonin gene-related peptide Telithromycin, 794, 797t Tellipressin, 302 Telmisartan for hypertension, 185 on vasoactive peptides, 309t Temazepam, 382t. See also Benzodiazepines Temozolomide, for brain cancer, 944 Tenecteplase, 595 Tenofovir, 845t, 848 for hepatitis B, 858 Tenoxicam, 625 Teratogens, 1017t. See also Pregnancy pharmacology definition of, 1016 FDA risk categories for, 1018t Terazosin, 155, 155t. See also Adrenoceptor antagonist drugs for hypertension, 180 Terbinafine, 832, 833t dermatologic oral, 1039 topical, 1037 Terbutaline for asthma, 340, 352t structure of, 145f, 339f Teriflunomide, 957–958 Teriparatide, for osteoporosis, 751, 754b, 762, 764t

Terlipressin. See also Vasopressin receptor agonists for variceal hemorrhage, 1078 on vasoactive peptides, 309t p-Tertiary amylphenol, 869 Testicular cancer, chemotherapy for, 944 Testicular hormones, 716–721, 721t. See also specific hormones androgens and anabolic steroids, 716–719, 717t, 721t androgen suppression, 719, 719f, 721t antiandrogens, 719–720, 721t contraception in men, chemical cyproterenone acetate, 721 fundamentals of, 720–721 gossypol, 721 preparations, available, 721t Testis, 716 Testosterone, 716–719 adverse effects of, 718–719 clinical uses of, 717–718, 717t contraindications and cautions with, 719 mechanism of action of, 717 metabolism of, 716 pharmacologic effects of, 717 physiologic effects of, 716–717 preparations of, 717, 717t, 721t synthesis of, 681f, 698f, 716 synthetic steroids with androgenic and anabolic action n, 717, 717t in women, 707–708 Testosterone cypionate, 716–719, 717t Testosterone enanthate, 716–719, 717t Tetanic stimulation, 460f, 462 Tetanus immune globulin, 1139t Tetanus vaccines tetanus-diphtheria (Td, DT), 1136t tetanus, diphtheria, pertussis (Tdap), 1136t Tetrabenazine, for Huntington’s disease, 484, 487t Tetracaine, 441b Tetrachlorodibenzodioxin (TCDD), 981f, 983 Tetrachloroethylene, 977–978 Tetracyclic agents, 528t chemistry of, 516–517, 517f clinical pharmacology of adverse effects in, 525 drug interactions in, 526t, 527 pharmacodynamics of, 520t, 521 pharmacokinetics of, 518t, 519 preparations of, available, 529t Tetracyclines, 788–791, 797t adverse reactions to, 791 clinical uses of, 790–791

dosing of, 791 mechanism of action and antimicrobial activity of, 789, 789f pharmacokinetics of, 790 preparations of, available, 798t resistance to, 790 structure and chemistry of, 788–789 Tetraethylammonium (TEA), 130–131, 130f. See also Ganglion blockers Δ9-Tetrahydrocannabinol (THC) for analgesia, on ion channels, 538b Gio protein–coupled receptor activation by, 556t, 558–559, 560f mechanism of action of, 367 rimonabant for dependence on, 564, 565t targets of, 556f Tetraiodothyronine (thyroxine, T4 ). See T4 Tetrathiomolybdate, for Wilson’s disease, 486 Tezosentan, for heart failure, 217 Thalidomide for erythema nodosum leprosum, 822 immunomodulatory derivatives of, 956–957 for immunosuppression, 956–957 for multiple myeloma, 941 T helper lymphocytes (TH1 , TH2 ), 949 Theobromine for asthma, 341–342 structure of, 341f Theophylline. See also Methylxanthine drugs for asthma, 341–342, 341f, 348–349, 352t diuretic actions of, 257 drug interactions of, 1130t poisoning management for, 1007t, 1011–1012 structure of, 341f Therapeutic index, 37 Therapeutic window, 37 Thiabendazole, 909t, 916 Thiamine for alcohol withdrawal syndrome, 391 for ethanol withdrawal, acute, 394t for Wernicke-Korsakoff syndrome prophylaxis, 390–391 Thiazide diuretics, 221t, 259–260, 259f, 267t. See also Diuretics on bone homeostasis, 756 for heart failure, chronic, 219 for hypercalciuria, idiopathic, 763 with loop diuretics, 263–264 with potassium-sparing diuretics, 264 preparations of, available, 268t Thiazolidinedones, 737–738, 737t, 743t Thick ascending limb, 252, 252f Thienopyridines, 595–596 Thiethylperazine, 1070

Thimerosal, 871 Thioamides, 670–671, 671f, 677t 6-Thioguanine (6-TG), 928t, 930–931 TPMT on metabolism of, 81 Thiols, 330–331 Thiopental, for anesthesia, 431f, 431t Thiophosphate insecticides, 114 6-Thiopurines, 928t, 930–931, 931f Thiopurine S-methyltransferase (TMPT) genetic polymorphisms in, 67t, 68–69 pharmacogenomics of, 77t, 78t, 81 Thioridazine, 490–502, 492f, 507t. See also Antipsychotic agents for psychosis, 492f, 493–494, 494t (See also Antipsychotic agents) Thiotepa, 922–927, 923f. See also Alkylating agents Thiothixene, 490–502, 507t. See also Antipsychotic agents chemical structure of, 492f, 494, 494t Thiotropium, 123f. See also Muscarinic receptor blockers for COPD, 127 Thioxanthenes, 490–502, 492f, 507t. See also Antipsychotic agents derivatives of, 492f, 494, 494t structure of, 492f Thombopoetin (TPO), 580 Thorn apple, 121. See also Atropine; Muscarinic receptor blockers Threshold limit values (TLVs), 972 Thrombin, 585, 586f Thrombin inhibitors direct, 593–594 indirect, 587–590, 588f (See also Heparin) Thrombocytopenia, 568 Thrombolytics, for acute myocardial infarction, 594–595, 594b Thrombophlebitis, ascending, thrombolytics for, 595 Thromboplastin, 596t Thrombopoietin (TPO), 965t Thrombosis arterial, 597 nitric oxide prophylaxis for, 332, 333f venous, 597 Thromboxane A2 (TXA2 ), 316, 595 on kidney, 254 Thromboxanes, 320–323 Thyroid drugs, 666–669, 677t. See also Antithyroid drugs; specific types basic pharmacology of, 666–669 clinical pharmacology of, 672–674 hypothyroidism, 670t, 672–674, 672t myxedema coma, 673 preparations of, available, 678t Thyroid gland abnormal stimulators of, 665–666 autoregulation of, 664f, 665

function of on drug metabolism, 71 evaluation of, 665–666, 666t iodide metabolism in, 663 Thyroid hormones, 666–669 biosynthesis of, 663–664, 664f chemistry of, 665f, 666 effects of, 667, 668t mechanism of action of, 666–667, 669f metabolism of, peripheral, 664–665, 665f pharmacokinetics of, 665, 665t, 666, 668t preparations of, 667–669 transport of, 664 Thyroid neoplasms, 676–677 Thyroid–pituitary relationships, 665, 667f Thyroid-simulating hormone (TSH, thyrotropin), 644–645, 644f, 654t diagnostic uses of, 646t Thyroid storm, 675 Thyrotoxicosis amiodarone-induced, 676 manifestations of, 667, 670t in pregnancy, 676 Thyrotropin-releasing hormone (TRH), 645, 645t Thyroxine. See T4 Tiagabine, for seizures, 409–410, 419t Ticagrelor, 596 Ticlopidine, 595–596 Tics, 472–473, 484–485, 487t Tiludronate on bone homeostasis, 754–755, 755f for Paget’s disease of bone, 763 Time course of drug accumulation, 46–47, 46f of drug effect, 48–49 cumulative, 49 delayed, 46f, 49 immediate, 48–49, 49f of drug elimination, 46f Time-dependent killing, 879 Timing of samples, for drug concentration measurement, 53–54 Timolol, 159f, 160t, 162. See also β-receptor antagonist drugs Tinidazole, 866, 871t for amebiasis, 898–899, 899t, 900f Tinzaparin, 587–590, 588f. See also Heparin Tiotropium, 131t. See also Muscarinic receptor blockers (antagonists) for COPD, 344, 349 Tipranavir, 845t, 853 Tiprolisant, 279 Tirofiban, 585f, 596

Tissue factor-VIIa complex, 585–587, 586f Tissue plasminogen activator (t-PA), 587, 587f, 595 Tissue schizonticides, 886, 887f Tissue thromboplastin, 596t Tizanidine, 145, 150, 150t. See also Sympathomimetic drugs, direct-acting spasmolytic actions of, 466f, 467, 469t T-lymphocyte-associated antigen 4 (CTLA-4), 948–949 T lymphocytes, 947, 948f, 949–950, 949f TNF-α-blocking agents, 629–631 adalimumab, 629, 630f adverse effects of, 631 certolizumab, 629–630, 630f etanercept, 630, 630f golimumab, 630f, 631 infliximab, 630f, 631 structures of, 630f Tobramycin, 800f, 804, 805t Tocilizumab, 629, 962 Tofacitinib, 631–632 Tolazamide, 733–735, 734f, 743t. See also Sulfonylureas Tolbutamide, 733–735, 734f, 743t. See also Sulfonylureas Tolcapone, for parkinsonism, 479–480, 487t Tolerance, 36, 553–554 alcohol (ethanol), 388 clinical pharmacology of, 564 inducer, 70 nitrates and nitrites, 197–198 opioid, 537, 538, 539t, 542–543 sedative-hypnotic drugs, 377 Tolmetin, 620f, 621t, 625. See also Nonsteroidal anti-inflammatory drugs (NSAIDs) Tolnaftate, 1037–1038 Tolterodine, 131t. See also Muscarinic receptor blockers for urinary disorders, 128 Toluene, 977–978 Tolvaptan, 302, 658, 660t for diuresis, 263, 268t for heart failure, 220 Tonic-clonic seizures, generalized, 414, 415. See also Seizures antiseizure drugs for, 401–411 (See also Antiseizure drugs) clinical pharmacology of, 415 Topiramate for migraine headache prophylaxis, 285 for seizures, 410, 419t for tremor, 483 Topiramate + phentermine, for obesity, 283b, 284t Topotecan, 932t, 934 Torcetrapib, 614 Toremifene, 713, 714f Torsade de pointes, in long QT syndrome, 229b, 231f, 233f

Torsemide, for diuresis, 257–259, 257t, 258t, 267t Tourette’s syndrome. See Gilles de la Tourette’s syndrome Toxaphenes, 978–979, 978t, 981f Toxic dose, median (TD50 ), 36 Toxic effects, selectivity and, 38–39 Toxic epidermal necrosis (TEN), 77t, 79t, 83–84, 83t, 84f Toxicity, 3. See also specific drugs preclinical testing for, 13, 13t Toxic multinodular goiter, 675 Toxicology, 971–986 air pollutants, 973–976 carbon monoxide, 974–975, 974t nitrogen oxides, 974t, 975–976 ozone and other oxides, 974t, 976 permissible exposure limit values of, 974t sources of, 973–974 sulfur dioxide, 974t, 975 bioaccumulation and biomagnification in, 974b definition of, 1 ecotoxicology, 972 environmental, 972 environmental considerations in, 973 environmental pollutants, 982–984 asbestos, 984 coplanar biphenyls, 983 endocrine disruptors, 984 perfluorinated compounds (PFCs), 983–984 polybrominated biphenyl esters (PBDEs), 983 polybrominated biphenyls (PBBs), 983 polychlorinated biphenyls (PCBs), 982–983 polychlorinated dibenzofurans (PCDFs), 983 polychlorinated dibenzo-p-dioxins (PCDDs, dioxins), 983 heavy metals, 871, 987–995 (See also Heavy metals) chelators for, 995–999, 999t (See also Chelators) herbicides, 980–982 bipyridyl (paraquat), 981f, 982 chlorophenoxy (2,4-D, 2,4,5-T), 980–981, 981f glyphosate, 981–982, 981f metals beryllium, 985 cadmium, 985 nanomaterials, 985–986 occupational, 971–972 pesticides, 978–980 botanical, 980, 981f carbamate, 980, 980t organochlorine, 978–979, 978t, 981f organophosphorus, 979–980, 979t poisoned patient management in, 1001–1012 (See also Poisoned patient management)

solvents, 976–978 aromatic hydrocarbons, 977–978 halogenated aliphatic hydrocarbons, 976–977 terminology of, 972–973 Toxicology screening tests, 1005, 1005t Toxic products, drug metabolism to, 63, 65f Toxic syndromes, management of, 1006–1012 acetaminophen, 65f, 1006–1007, 1007t amphetamines and other stimulants, 1007–1008 anticholinergic agents, 1007t, 1008 antidepressants, 1007t, 1008 antipsychotics, 1008 aspirin (salicylate), 1008–1009 beta blockers, 1007t, 1009 calcium channel blockers, 1007t, 1009 carbon monoxide and other toxic gases, 1007t, 1009, 1010t cholinesterase inhibitors, 1007t, 1009–1010 cyanide and hydrogen cyanide, 1007t, 1010, 1010t digoxin, 1007t, 1010–1011 ethanol and sedative-hypnotic drugs, 1007t, 1011 ethylene glycol and methanol, 1007t, 1011 iron and other metals, 1011 opioids, 1007t, 1011 rattlesnake envenomation, 1011 theophylline, 1007t, 1011–1012 Toxic uninodular goiter, 675 Toxins, 3 Trademark, 17 Train-of-four (TOF) stimulation, 460f, 461–462 Tramadol, 547, 549t, 550t, 634 Trametinib, for melanoma, 944, 1050 Trandolapril, for hypertension, 184–185 Tranexamic acid, 600 Transferases, 62–63, 63f, 64t. See also specific types Transforming growth factor-β (TGF-β), 27–28 Transient neurologic symptoms (TNS), from local anesthetics, 450 Translational research, 12 Transmembrane enzymes, ligand-regulated, 27–28, 28f Transporter genetic variations, 82–83 Transporters. See also specific types MDR1, 8, 9t MRP1, 9t multidrug resistance-associated protein, 8, 9t SERT, 9t types of, 9t VMAT, 9t Transport proteins, as drug receptors, 21 Tranylcypromine, for depression, 528t Trapping, drug, 9, 10f

Trastuzumab, 961 for breast cancer, 941 Trauma surgery, emergency, muscle relaxant for, 455, 471 Travelers immunization for, 1139–1140 malaria prevention for, 889t Travoprost, for glaucoma, 328 Trazodone, 156, 528t. See also 5-HT receptor modulators, for depression Trematodes. See also Anthelmintic drugs praziquantel for, 914 Tremor, 472, 483–484 β-receptor antagonists for, 165 definition of, 472 essential, 482 intention, 483 from lithium, 505 rest, 483 Treprostinil, 315–316 for pulmonary hypertension, 326 Treprostinil sodium, 325f Triamcinolone (acetonide), 686–692, 686t. See also Corticosteroids, synthetic for asthma, 345 structure of, 683f Triamterene for diuresis, 257–259, 257t, 258t, 260–262, 261t, 267t drug interactions of, 1129t Triazolam, 370f, 382t. See also Benzodiazepines Trichlorfon, 909t, 912–913 1,1,1-Trichloroethane, 977–978 Trichloroethylene, 977–978 2,4,5-Trichlorophenoxyacetic acid (2,4,5-T), 980–981, 981f Trichogenic and antitrichogenic agents bimatoprost, 1049 eflornithine, 1049 finasteride, 1049 minoxidil, 1049 Trichomoniasis. See Amebiasis drugs Trichostrongylus orientalis, pyrantel pamoate for, 915–916 Trichuriasis drugs. See also Anthelmintic drugs albendazole, 908–909, 909t mebendazole, 912 Tricyclic antidepressants (TCAs), 528t. See also Antidepressant agents chemistry of, 515, 516f clinical pharmacology of adverse effects in, 525 drug interactions in, 526, 1121t intoxication with, 117 pharmacodynamics of, 520, 520t pharmacokinetics of, 518t, 519

poisoning with, treating, 1007t, 1008 preparations of, available, 529t Trientine hydrochloride, for Wilson’s disease, 486 Triethylenemelamine, 923f Trifluridine, for HSV and VZV, 837f, 838t, 839 Trihexyphenidyl, for parkinsonism, 481, 481t, 487t Triiodothyronine (T3 ). See T3 Trilostane, 693 Trimetazidine, for angina pectoris, 204 Trimethadione, for seizures, 400f, 413 Trimethobenzamide, 1070 Trimethoprim, 809–810, 813t Trimethoprim-sulfamethoxazole mixtures, 809–810, 813t Triorthocresyl phosphate (TOCP), 979 toxicity of, 118 Trioxsalen, for pigmentation disorders, 1041 Triptans, 283–285, 284f, 285t, 290t preparations of, available, 291t Triptoreliin, 652–654 Troglitazone, 738 Trophotropic nervous system, 97 Tropicamide, 131t. See also Muscarinic receptor blockers Tropisetron, antiemetic properties of, 1069 Trospium, 131t. See also Muscarinic receptor blockers for urinary disorders, 128 TRPA1, 538b TRPV1, 538b Trypanosomiasis drugs, 901–905, 901t–903t. See also Antiprotozoal drugs t-SNAREs, 90 Tuberculin hypersensitivity, 952 Tuberculosis drugs, 815–821, 823t ethambutol, 816t, 818, 823t isoniazid, 816–817, 816t, 823t preparations of, available, 824t pyrazinamide, 816t, 818–819, 823t rifampin, 816t, 817–818, 823t second-line, 819–821 aminosalicylic acid, 816t, 820 bedaquiline, 816t, 821 capreomycin, 816t, 820 cycloserine, 816t, 820 ethionamide, 816t, 819–820 fluoroquinolones, 820–821 kanamycin and amikacin, 816t, 820 linezolid, 821 rifabutin, 816t, 821 rifapentine, 816t, 821 streptomycin, 816t, 819, 823t types and dosing of, 815–816, 816t

Tuberculosis, with HIV, antimycobacterial drugs for, 815, 824 Tuberoinfundibular system, 495 Tubocurarine, 456, 469t. See also Neuromuscular blocking drugs properties of, 459t structure of, 457f Tumor-induced osteomalacia, 762 Tumor necrosis factor-α (TNF-α), 965–966, 965t Tumor necrosis factor-β (TNF-β), 965t Tumor necrosis factor (TNF) inhibitors, for psoriasis, 1044 Tumor suppressor genes, in cancer, 919 Turner syndrome, growth hormone for, 647 12(R)-HETE, effects of, 323 12(S)-HETE, effects of, 323 20-HETE, 317, 323 2-chlorodeoxyadenosine (cladribine), 928t, 931 2,4-dichlorophenoxyacetic acid (2,4-D), 980–981, 981f 2,4,5-trichlorophenoxyacetic acid (2,4,5-T), 980–981, 981f Type I hypersensitivity, 950, 951f, 966–967 Type II hypersensitivity, 950–951 Type III hypersensitivity, 951, 952f, 967 Type IV hypersensitivity, 951–952, 953f Typhoid vaccines Ty21a, oral, 1136t VI capsular polysaccharide, 1136t Tyramine, 94f, 146–147, 146t biosynthesis of, 94f noradrenergic transmitter release by, 94 Tyrosine hydroxylase inhibitors, 167t Tyrosine kinase inhibitors (TKIs), 27, 936, 937t Tyrosine kinase receptor, 27–28, 28f Tyrosine, nitration of, 331, 331t U UGT1A1 pharmacogenomics, 74, 76t, 78t, 81, 86 Ularitide. See also Natriuretic peptides for heart failure, 217 on kidney, 254–255 on vasoactive peptides, 310t Ultrarapid metabolism, 65 Ultrarapid metabolizer (UM), 65, 75t Unfractionated heparin (UFH), 587–590, 588f. See also Heparin Unicyclic agents, for depression, 528t. See also Antidepressant agents chemistry of, 516–517, 517f clinical pharmacology of adverse effects in, 525 drug interactions in, 526t, 527 pharmacodynamics of, 520t, 521 pharmacokinetics of, 518t, 519 preparations of, available, 529t Unipolar depression, antipsychotics for, 498. See also Antipsychotic agents

Unithiol, 997–998 for arsenic poisoning acute, 992 chronic, 993 for mercury poisoning acute, 994 chronic, 995 Unoprostone, for glaucoma, 328 Unstable angina, 191–192 vasodilators for, 205 Urantide, 309 Urapidil, 156 Urate lithiasis, 635 treatment of (See Gout agents) Urea, as humectant and keratolytic, 1047 Ureidopenicillins, 775. See also Penicillins Uricosuric agents, 635f, 636 Uridine 5-diphosphate (UDP)-glucuronosyl transferases (UGTs), 62, 63f, 64t genetic polymorphisms in, 67t, 69 Uridine 5’-diphosphoglucuronosyl transferase 1 (UGT1A1) pharmacogenomics, 74, 76t, 78t, 81, 86 Urinary antiseptics, 871t methenamine hippurate, 867, 871t methenamine mandelate, 867, 871t nitrofurantoin, 866–867, 871t Urinary frequency, after prostatectomy, 121, 132 Urinary obstruction, alpha-receptor antagonists for, 157 Urinary pH manipulation, for poisoning, 1006 Urinary tract infection, antibiotic choice, case study, 807, 814 Urokinase, 587, 587f, 594–595 Urotensin, 308–309 Urotensin antagonists, 310t Ursodiol, for gallstones, 1077–1078, 1080t Urticaria, 272, 277 Use-dependent drug action, 232, 234f Ustekinumab, 963 for psoriasis, 1044 Uterine leiomyomata (fibroids), gonadotropin-releasing hormone agonists for, 653 V Vaccines, 1133–1140, 1134t–1137t. See also Immunization; specific types routine childhood, recommended schedule for, 1133, 1137t Vaccinia immune globulin, 1139t Vagus nerve on cardiovascular function, 99 on immune function, 87 Vagus nerve stimulation (VNS), for epilepsy, 397 Valacyclovir for HSV and VZV, 837–839, 838t topical dermatologic, 1039 Valganciclovir, for cytomegalovirus, 840t, 841

Valomaciclovir, for HSV and VZV, 839 Valproic acid (valproate), 508t for bipolar disorder, 506, 508t for migraine headache prophylaxis, 285 for seizures, 401f, 412–413, 419t Valsartan for hypertension, 185 on renin-angiotensin system, 298–299 on vasoactive peptides, 309t Vancomycin, 773f, 781–782, 785t Vardenafil, for erectile dysfunction, 197b Varenicline, 119t for nicotine abuse, 561, 565t for smoking cessation, 118 Variant, 75t Variant angina, 191 ergot alkaloids for diagnosis of, 289 Variceal hemorrhage drugs β-receptor blocking drugs, 1078 preparations, available, 1081t somatostatin and octreotide, 1078, 1080t vasopressin and terlipressin, 1078 Varicella vaccine, 1136t Varicella-zoster immune globulin, 1139t Varicella-zoster virus (VZV) agents, 836–839 acyclovir, 836–837, 837f, 838t docosanol, 838t, 839 famciclovir, 838t, 839 penciclovir, 837f, 838t, 839 trifluridine, 837f, 838t, 839 valacyclovir, 837–839, 838t valomaciclovir, 839 varicella vaccine, 1136t varicella-zoster immune globulin, 1139t Vascular endothelial growth factor (VEGF), 938 Vascular endothelial growth factor (VEGF) inhibitors, 938 Vascular tone, 192–193, 192t, 193f, 194f Vasculitis (type III) drug reactions, 951, 952f, 967 Vasoactive intestinal peptide (VIP), 92t, 305–306 Vasoactive intestinal peptide agonists, 310t Vasoactive peptides, 294–312, 309t–310t adrenomedullin, 307–308 angiotensin, 294–297 angiotensin II, 297–299 calcitonin gene-related peptide, 307 endothelins, 303–305 kinins, 299–302 natriuretic peptides, 302–303 neuropeptide Y, 308

neurotensin, 307 preparations, available, 311t substance P, 306–307 urotensin, 308–309 vasoactive intestinal peptide, 305–306 vasopressin, 302 Vasodilators, for angina pectoris, 191–208, 206t–207t. See also specific agents agents in, principle, 191 allopurinol, 204 β blockers, 203, 206t calcium channel blockers, 199–203 clinical pharmacology of angina of effort, 204–205, 205f, 205t nitrates alone vs. with beta or calcium channel blockers, 205, 205t principles of, 204 unstable angina and acute coronary syndromes, 205 vasospastic angina, 205 with coronary artery disease and hyperlipidemia, 191, 208 drug action in, 193 newer drugs, 204t fasudil, 204 ivabradine, 204 pFOX inhibitors, 204 ranolazine, 203–204 nitrates and nitrites, 193–199, 199t, 206t nitro-vasodilators, other, 199 preparations of, available, 208t principles of, 191–192 special, 203b Vasodilators, for heart failure, 217, 222t acute, 220 chronic, 219 Vasodilators, for hypertension, 174f, 175t, 180–183, 188t calcium channel blockers, 175t, 183, 189t diazoxide, 182–183, 188t direct, 172 fenoldopam, 183, 188t hydralazine, 175t, 181 mechanisms and sites of action of, 180, 181t minoxidil, 175t, 181 preparations of, available, 189t sodium nitroprusside, 171f, 182, 188t Vasodilators, nitric oxide as, 332 Vasopeptidase inhibitors, 303, 310t Vasopressin (antidiuretic hormone, ADH), 302, 657–658, 660t for diuresis, 262 structures of, 657f for variceal hemorrhage, 1078 on vasoactive peptides, 309t

Vasopressin receptor, 302 Vasopressin receptor agonists, 262, 302, 309t, 657–658, 660t preparations of, available, 661t on vasoactive peptides, 309t Vasopressin receptor antagonists, 263, 268t, 302, 658, 660t preparations of, available, 311t, 661t on vasoactive peptides, 310t Vasospastic angina, 191 vasodilators for, 205 Vecuronium. See also Neuromuscular blocking drugs properties of, 459t, 469t structure of, 458f Vedolizumab, 963 Vehicles dermatologic, 1033–1034 drug, 7 Vemurafenib, for melanoma, 944, 1050 Vendamustine, 925, 926t Venlafaxine, 528t. See also Serotonin-norepinephrine reuptake inhibitors (SNRIs) poisoning with, treating, 1008 Venous thrombosis, 597 antithrombotic management for, 597, 598t, 600t from female hormonal contraceptives, 711 risk factors for, 597 Ventilation, alveolar, 423–424, 424f Ventilation control, neuromuscular blockers for, 465 Ventral tegmental area (VTA), in addiction, 553, 554f, 555b Ventricular fibrillation, ECG of, 232f Ventricular tachycardia ECG of, 232f polymorphic, in torsades de pointes with long QT syndrome, 229b, 231f, 233f Verapamil. See also Calcium channel blockers for angina pectoris, 191, 199–203, 206t (See also Calcium channel blockers, for angina pectoris) for arrhythmia, 235t, 236t, 241–242, 247t case study on, 20, 40 for hypertension, 175t, 183 for migraine headache prophylaxis, 285 Very-low-density lipoproteins (VLDLs), 602, 603, 604f Vesamicol, 90 Vesicle-associated membrane proteins (VAMPs), 90, 91f Vesicle-associated transporter (VAT), 90, 91f Vesicular glutamate transporter (VGLUT), 363 Vesicular monoamine transporter (VMAT), 92 Vesicular proteoglycan (VPG), 90 Vestibular disturbances, H1 -receptor antagonists, 278 Vigabatrin, for seizures, 410–411, 419t Vilanterol for asthma, 340, 352t for COPD, 148

Vildagliptin, 740, 744t Vinblastine for cancer, 931–932, 932t for immunosuppression, 958 Vincristine for cancer, 932t, 933 for immunosuppression, 958 Vinorelbine, 932t, 933 Viruses, 835 cancer from, 918–919 replication of, 835–836, 836f Vismodegib, dermatologic, 1050–1051 Vitamin B1 . See Thiamine Vitamin B12 deficiency, 570t, 572, 574 megaloblastic anemia from, 567, 583 Vitamin B12 therapy, for vitamin B12 deficiency, 572–574, 573f chemistry of, 572 clinical pharmacology of, 570t, 574 cyanocobalamin, 572, 574, 581t in hematopoiesis, 568 hydroxycobalamin, 572, 574, 581t pharmacodynamics of, 572–574, 573f pharmacokinetics of, 572 preparations of, available, 583t Vitamin D for bone homeostasis, 750f, 751–752, 751t, 764t on bone homeostasis, 748, 748f for chronic kidney disease, 760–761 on gut, bone, and kidney, 752t for hyperparathyroidism, 759 for hypocalcemia, 758–759 for hypoparathyroidism, 759 for intestinal osteodystrophy, 760 Vitamin D2 , for vitamin D deficiency/insufficiency, 760 Vitamin D3 on bone homeostasis, 748, 750f for vitamin D deficiency/insufficiency, 760 Vitamin D deficiency/insufficiency, nutritional, 759–760 Vitamin D preparations, 764t for chronic kidney disease, 760–761 forms of, available, 765, 765t Vitamin K1 for bleeding disorders, 597–598, 598t structure of, 590f, 597 for warfarin reversal, 592 Vitamin K epoxide reductase complex subunit 1 (VKORC1), polygenic effects in, 77t, 79t, 85 Vitamin K, for bleeding disorders, 590f, 597–598, 598t VKORC1, polygenic effects in, 77t, 79t, 85 VMAT transporter, 9t

Voglibose, 738, 743t Voltage-gated channels, 29. See also specific types in central nervous system, 357, 357f Volume of distribution (V), 42 initial predictions of, 54 revising individual estimates of, 54 on target concentration, 52 Vomiting, 1068–1069, 1068f von Willebrand disease, 598t cryoprecipitate for, 598t, 599 Voriconazole, 829f, 829t, 830 Vorinostat, dermatologic, 1050–1051 Vortioxetine, 528t. See also 5-HT receptor modulators, for depression v -SNAREs, 90 W Warfarin, 590–592 administration and dosage of, 591 chemistry and pharmacokinetics of, 590, 590f CYP2C9 and VKORC1 polymorphisms on, 79t, 85 drug interactions of, 591–592, 592t mechanism of action of, 586f, 586t, 590–591, 591f reversal of action of, 592 toxicity of, 591 Water, superoxidized, 870 Wearing-off, 476 Weight loss aids, OTC, 1091t Wernicke-Korsakoff syndrome, 388 thiamine for prevention of, 390–391 Whole bowel irrigation, for iron toxicity, 572 Wilson’s disease, 486 Withdrawal, 554–555. See also specific substances from alcohol, 391, 391f, 394t, 395t from opioids, 537 sedative-hypnotics for, 379 Withdrawal syndrome, 537 antagonist-precipitated withdrawal, 543 definition of, 531 Wolff-Chaikoff block, 664f, 665 Wolff-Parkinson-White syndrome, 230–231 Worm infections, 908 drugs for, 908–916, 909t (See also Antihelminthic drugs) Wuchereria bancrofti, diethylcarbamazine citrate for, 910–911 X Xanthines, 341f. See also Methylxanthine drugs Xenobiotics, 56 biotransformation of (See Biotransformation, drug) definition of, 3 X-linked agammaglobulinemia, 953

X-linked hypophosphatemia, 762 Xylene, 978 Y Yellow fever vaccine, 1136t YKP3089, 417 Yohimbine, 156 Z Zafirlukast, 324. See also Leukotriene receptor antagonists for asthma, 327, 345–346, 352t structure of, 346f Zaleplon, 370, 371f, 382t. See also Hypnotics, newer Zanamivir, for influenza, 861–862 Ziconotide, 538b, 550t Zidovudine, 845t, 849 Ziegler’s enzyme, 68 Zileuton, 324. See also Leukotriene receptor antagonists for asthma, 327, 345–346, 352t structure of, 346f Zinc acetate, for Wilson’s disease, 486 Ziprasidone, 493f, 494, 507t Ziv-aflibercept, 937t, 938 Zoledronate. on bone homeostasis, 754–755, 755f for bone metastases, 764t for hypercalcemia, 757, 764t for osteoporosis, 762, 764t Zolpidem, 370, 371f, 382t. See also Hypnotics, newer Zonisamide, for seizures, 411, 419t Zoster vaccine, 1136t Zotepine, 494