Drug-Drug Interactions (DDIs)
Marc Imhotep Cray, M.D.
Learning Objectives By the end of this presentation the learner will be able to: 1. Explain the clinical relevance of adverse drug-drug interactions (DDIs) and provide some classic examples. 2. Explain the concept that the effects of one drug can be modified by the prior, or simultaneous, administration of a second drug. 3. Provide five examples of clinically useful drug-drug interactions. 4. Provide a classification of adverse drug-drug interactions based on mechanism and give examples in each class. 5. Explain the role that enzyme induction and inhibition of metabolic enzymes play in drug metabolism and adverse drug-drug interactions. 6. List some drug that are enzyme inducers and enzymes inhibiters along with their substrate(s) and the possible clinical consequences of their coadministration. Marc Imhotep Cray, M.D.
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Topics Outline
Introduction Useful drug interactions Trivial drug interactions Harmful drug interactions Adverse drug interactions grouped by mechanism • • • • •
Interaction of Absorption Interaction of Protein Binding Interaction of Metabolism Interaction of Receptor Binding Interaction of Excretion
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List of drugs / drug classes referenced in this presentation. 6-mercaptopurine ACE-Inhibitors Alcohol Allopurinol Amoxicillin Aspirin Azathioprine Benzodiazepines Beta blockers Carbidopa Cholestyramine Cilastin Cisplatin Clavulanic acid Cyclosporine Digoxin Furosemide Marc Imhotep Cray, M.D.
Gentamicin Heparin Imipenem Indomethacin Isoniazid Levodopa Lidocaine Lithium Losartan Methotrexate Metoclopramide Metolazone Naloxone NSAIDs Paclitaxel Penicillin Phenelzine
Phenylbutazone Phenytoin Potassium-sparing Diuretics Probenecid Propantheline Quinidine Ritonavir Salbutamol Saquinavir Spironolactone Sulfamethoxazole Sulfonamides Tetracycline Theophylline Trimethoprim Verapamil Warfarin 4
“Clinical Importance of DDIs in a Capsule” A clinically relevant Drug-Drug Interaction (DDI) occurs when the effectiveness or toxicity of one medication is altered by administration of another medicine or a substance that is administered for medical purposes… Adverse consequences of DDIs may result from either diminished therapeutic effect or toxicity. Among the various types of medical errors, the occurrence of adverse DDIs is one that is usually preventable. It is therefore essential that health professionals be able to evaluate the potential for DDIs and, when detected, to determine appropriate prevention or management strategies. The potential for clinically important DDIs can often be predicted based on the drug properties, method of drug administration, and patient specific parameters. Consequently, adverse outcomes resulting from DDIs can be prevented by making patient- and situation-specific assessments and, if appropriate, avoiding concomitant administration by implementing alternative therapeutic strategies, or taking precautionary measures such as dosage adjustments and increased monitoring. From: CredibleMeds : Common Drug-Drug Interactions [Emphasis mines.] Available at https://www.crediblemeds.org/healthcare-providers/drug-drug-interaction/ Accessed 2 April, 2017 Marc Imhotep Cray, M.D.
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Introduction Definition of DDI A Drug-Drug Interaction (DDI) is modification of action of one drug by another There are three kinds of mechanism for DDIs: 1. pharmaceutical 2. pharmacodynamic 3. Pharmacokinetic Drug interactions can be useful, of no consequence, or harmful Marc Imhotep Cray, M.D.
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Introduction (2) Pharmaceutical interactions occur by chemical reaction or physical interaction when drugs are mixed Pharmacodynamic interactions occur when different drugs each influence same physiological function (e.g. drugs that influence state of alertness or blood pressure)
Result of adding a second such drug during treatment w another may be to increase effect of first (e.g. alcohol increases sleepiness caused by benzodiazepines) Conversely for drugs w opposing actions result may be to reduce effect of first (e.g. indomethacin increases blood pressure in HTN pts. treated w an anti-HTN drug such as losartan)
Pharmacokinetic interactions occur when one drug affects PKs of another (e.g. by reducing its elimination from body or by inhibiting its metabolism) These mechanisms are discussed more fully in section on adverse interactions grouped by mechanism A drug interaction can result from one or a combination of these mechanisms Marc Imhotep Cray, M.D.
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Introduction (3) Drug interactions are important b/c, whereas careful use of more than one drug at a time can greatly benefit patients, adverse interactions are not uncommon, and may be catastrophic, yet are often avoidable Multiple drug use (polypharmacy) is very common, so potential for drug interactions is vast
For example One study showed that on average 14 drugs were prescribed to medical in-patients per admission
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Introduction (4) ď ąProblem of polypharmacy will remain, for several reasons: 1. Many drugs are not curative, but rather ameliorate chronic conditions (e.g. arthritis)  Populations are ageing, and elderly individuals not uncommonly have several co-morbid conditions requiring multiple medications
2. It is easy to enter an iatrogenic spiral where a drug results in an adverse effect that is countered by introduction of another drug... and so on NB: An out-patient visit or hospital admission provides the best opportunity for a healthcare provider to review all medications that any patient is receiving, as to ensure the overall regimen is rational. Marc Imhotep Cray, M.D.
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Introduction (5) Out-patients also often receive several prescribed drugs, plus OTC medicines, “alternative” remedies and “lifestyle” drugs Greater number of drugs taken, more likely things can go wrong (See next slide)
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Introduction (6)
Relationship of number of drugs administered to (a) adverse drug reactions, (b) mortality rate and (c) average duration of hospital stay.
Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
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Useful Drug Interactions Increased Effect Drugs can be used in combination to enhance their effectiveness Disease is often caused by complex processes drugs that influence different components of disease mechanism may have additive effects (e.g. an antiplatelet drug w a fibrinolytic in treating myocardial infarction) Another example is use of a β2 agonist w a glucocorticoid in treatment of asthma (to cause bronchodilation and suppress inflammation, respectively) Marc Imhotep Cray, M.D.
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Useful Drug Interactions (2) Increased Effect cont. Combinations of antimicrobial drugs are used to prevent selection of drug-resistant organisms TB is best example of a disease whose successful Tx requires this approach
Drug resistance via synthesis of a microbial enzyme that degrades antibiotic (e.g. penicillinase producing staphylococci) can be countered by using a combination of antibiotic w an inhibitor of enzyme: co-amoxiclav = a combination of clavulanic acid, an inhibitor of penicillinase, with amoxicillin Marc Imhotep Cray, M.D.
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Useful Drug Interactions (3) Increased Effect cont. Increased efficacy can result from pharmacokinetic interaction Imipenem is partly inactivated by a dipeptidase in kidney o This is overcome by administering imipenem in combination w cilastin ( a specific renal dipeptidase inhibitor) Another example is use of combination of ritonavir and
saquinavir in antiretroviral therapy Saquinavir increases systemic bioavailability of ritonavir by inhibiting its degradation by GI CYP3A and inhibits its fecal elimination by blocking P-glycoprotein that pumps it back into intestinal lumen
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Useful Drug Interactions (4) Increased Effect cont. Some combinations of drugs have a more than additive effect = synergy
Several antibacterial combinations are synergistic, including sulfamethoxazole w trimethoprim (co-trimoxazole), used in Tx of Pneumocystis carinii Several drugs used in cancer chemotherapy are also synergistic, e.g. cisplatin plus paclitaxel
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Useful Drug Interactions (5) Increased Effect cont. Therapeutic effects of drugs are often limited by activation of a physiological control loop particularly in case of CV drugs use of a low dose of a second drug that interrupts this negative feedback may enhance effectiveness substantially o Examples include combination of an angiotensin converting enzyme inhibitor (to block renin-angiotensin system) w a diuretic (effect of which is limited by activation of renin-angiotensin system) in treating hypertension
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Useful Drug Interactions (6) Minimize Side Effects There are many situations (e.g. hypertension) where low doses of two drugs may be better tolerated, as well as more effective, than larger doses of a single agent Sometimes drugs w similar therapeutic effects have opposing undesirable metabolic effects can-to some extent- cancel out when drugs are used together For example combination of a loop diuretic (e.g. furosemide=K+ depleting) w a K+ sparing diuretic (e.g. spironolactone)
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Useful Drug Interactions (7) Minimize Side Effects cont. Predictable adverse effects (AEs) can sometimes be averted by use of drug combinations Examples Isoniazid neuropathy is caused by pyridoxine deficiency prevented by prophylactic use of this vitamin (B6) Combination of a peripheral dopa decarboxylase inhibitor (e.g. carbidopa) w levodopa permits an equivalent therapeutic effect to be achieved w a lower dose of levodopa than is needed when it is used as a single agent while also reducing dose-related peripheral side effects of nausea and vomiting Marc Imhotep Cray, M.D.
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Useful Drug Interactions (8) Block Acutely an Unwanted (Toxic) Effect Drugs can be used to block an undesired or toxic effect For example When an anesthetist uses a cholinesterase inhibitor to reverse neuromuscular blockade When antidotes such as naloxone are used to treat opioid overdose Uses of vitamin K or of fresh plasma to reverse effect of warfarin
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Trivial Interactions Many interactions are based on in vitro experiments results of which cannot be extrapolated uncritically to clinical situation Many such potential interactions are of no practical consequence especially true of o Drugs w shallow dose–response curves and o Interactions that depend on competition for tissue binding to sites that are not directly involved in drug action but which influence drug distribution (e.g. to albumin in blood)
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Trivial Interactions (2) Shallow Dose–Response Curves Interactions are only clinically important when there is a steep dose–response curve and a narrow therapeutic window betw. minimum effective dose and minimum toxic dose of one or both interacting drugs This is often not the case For example, penicillin is so non-toxic that usual dose is more than adequate for therapeutic efficacy, yet far below that which would cause dose-related toxicity=Wide therapeutic index (TI) o Consequently, a second drug that interacts w penicillin is unlikely to cause either toxicity or loss of efficacy
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Drug dose–response curves illustrating likelihood of adverse effect if an interaction increases its blood level.
Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008. 22
Trivial Interactions (4) Plasma and Tissue Binding Site Interactions One large group of potential drug interactions that are seldom clinically important consists of drugs that displace one another from binding sites on plasma albumin or α-1 acid glycoprotein (AAG) or within tissues This is a common occurrence and can readily be demonstrated in plasma or solutions of albumin/AAG in vitro However, Expectation displacing drug will ↑ effects of displaced drug by ↑ its free (unbound) concentration is seldom evident in clinical practice o This is b/c drug clearance (renal or metabolic) also depends directly on concentration of free drug… Marc Imhotep Cray, M.D.
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Trivial Interactions (5) Plasma and Tissue Binding Site Interactions cont. Consider a pt. receiving a maintenance dose (MD) of a drug When a second displacing drug is started free conc. of first drug rises only transiently before ↑ renal or hepatic elimination reduces total (bound plus free) drug and restores free conc. to that which prevailed before second drug was started o Consequently, any ↑ effect of displaced drug is transient, and is seldom important in practice •
Marc Imhotep Cray, M.D.
It must, however, be taken into account if therapy is being guided by measurements of plasma drug concs. as most such determinations are of total (bound plus free) rather than just free conc. of drug
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Trivial Interactions (6) Plasma and Tissue Binding Site Interactions cont. An exception, where a transient ↑ in free conc. of a circulating substance (albeit not a drug) can have devastating consequences= bilirubin in premature babies whose ability to metabolize bile pigments is limited Unconjugated bilirubin is bound by plasma albumin injudicious Tx w drugs, such as sulfonamides, that displace bilirubin from albumin permits diffusion of free bilirubin across immature blood–brain barrier (BBB) consequent staining of and damage to basal ganglia (kernicterus) Acute bilirubin encephalopathy (ABE) in baby
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Trivial Interactions (7) Instances where clinically important consequences do occur on introducing a drug that displaces another from tissue binding sites are in fact often due to additional actions of second drug on elimination of first For example, quinidine displaces digoxin from tissue binding sites can cause digoxin toxicity but only b/c quinidine simultaneously reduces renal clearance of digoxin by a separate mechanism
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Trivial Interactions (8) Phenylbutazone (NSAID reserved for ankylosing spondylitis unresponsive to other drugs) displaces warfarin from binding sites on albumin causes excessive anticoagulation However, only b/c it also inhibits metabolism of active isomer of warfarin (S-warfarin) causing S-warfarin to accumulate at expense of inactive isomer
Indomethacin (another NSAID) also displaces warfarin from binding sites on albumin but does not inhibit its metabolism and does not further prolong prothrombin time (PT) in pts. treated w warfarin although indomethacin can cause bleeding by causing peptic ulceration and interfering w platelet function Marc Imhotep Cray, M.D.
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Harmful Interactions ď ąIt is not possible to memorize reliably the many clinically important drug interactionsďƒ thus, physicians and other prescribers should use suitable references (e.g. Physicians' Desk Reference [PDR] or National Formulary) to check for potentially harmful interactions NB: Frequency and consequences of an adverse interaction when two drugs are used together are seldom known preciselyďƒ every individual has a peculiar set of characteristics that determine their response to therapy (inter-individual variation)
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Harmful Interactions (2) There are certain drugs w steep dose–response curves and serious doserelated toxicities for which drug interactions are especially liable to cause harm and where special caution is required w concurrent therapy These include: warfarin and other anticoagulants anticonvulsants cytotoxic drugs drugs for HIV/AIDS immunosuppressants digoxin and other anti-dysrhythmic drugs oral hypoglycaemics agents xanthine alkaloids (e.g. theophylline) monoamine oxidase inhibitors Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
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Harmful Interactions (3) Risk of Adverse Drug Interactions In the Boston Collaborative Drug Surveillance Program (BCDSP), 234 of 3600 (about 7%) adverse drug reactions (ADRs) in acute-care hospitals were identified as being due to drug interactions In a smaller study in a chronic-care setting, prevalence of adverse interactions was much higher (22%) probably b/c of more frequent use of multiple drugs in elderly pts w multiple chronic pathologies Marc Imhotep Cray, M.D.
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Harmful Interactions (4) Severity of Adverse Drug Interactions Adverse drug interactions are diverse, including
Unwanted pregnancy (from failure of contraceptive pill due to concomitant medication) Hypertensive stroke (from hypertensive crisis in pts on monoamine oxidase inhibitors) Gastrointestinal or cerebral hemorrhage (in patients receiving warfarin) Cardiac arrhythmias (e.g. secondary to interactions leading to electrolyte disturbance or prolongation of QTc) Blood dyscrasias (e.g. from interactions betw. allopurinol and azathioprine)
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Key points ďƒ˜Drug interactions may be clinically useful, trivial or adverse. ďƒ˜Useful interactions include those that enable efficacy to be maximized, such as addition of an angiotensin converting enzyme inhibitor to a thiazide diuretic in a patient with hypertension inadequately controlled on diuretic alone. They may also enable toxic effects to be minimized, as in use of pyridoxine to prevent neuropathy in malnourished patients treated with isoniazid for tuberculosis, and may prevent the emergence of resistant organisms (e.g. multi-drug regimens for treating tuberculosis). Marc Imhotep Cray, M.D.
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Key points ďƒ˜Many interactions that occur in vitro (e.g. competition for albumin) are unimportant in vivo b/c displacement of drug from binding sites leads to increased elimination by metabolism or excretion and hence to a new steady state where total conc. of displaced drug in plasma is reduced, but concentration of active, free (unbound) drug is same as before interacting drug was introduced. ďƒ˜Interactions involving drugs with a wide safety margin (e.g. penicillin) are also seldom clinically important.
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Key points ďƒ˜Adverse drug interactions are not uncommon, and can have profound consequences, including death from hyperkalemia and other causes of cardiac dysrhythmia, unwanted pregnancy, transplanted organ rejection, etc.
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Adverse Interactions Grouped By Mechanism
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Pharmaceutical Interactions
Occur by chemical reaction or physical interaction when drugs are mixed Inactivation when drugs are mixed (e.g. heparin w gentamicin) Drugs may also interact in lumen of gut (e.g. tetracycline w iron, and cholestyramine w digoxin)
DDIs outside the body Mixture Thiopental and suxamethonium Diazepam and infusion fluids Phenytoin and infusion fluids Heparin and hydrocortisone Gentamicin and hydrocortisone Penicillin and hydrocortisone
Result Precipitation Precipitation Precipitation Inactivation of heparin Inactivation of gentamicin Inactivation of penicillin
Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
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Pharmacodynamic Interactions PD interactions are common most have a simple mechanism consisting of summation or opposition of effects of drugs w similar or opposing actions (respectively) Since PD interaction depends on effect of a drug, rather than on its specific chemical structure, such interactions are non-specific o For example drowsiness caused by an H1-blocking antihistamine and by alcohol pts must be warned of dangers of consuming alcohol concurrently when such antihistamines are prescribed (especially if driving or operate machinery)
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Pharmacodynamic Interactions (2) Non-steroidal anti-inflammatory agents and antihypertensive drugs provide another clinically important example
Anti-HTN drugs rendered less effective by concurrent use of NSAIDs, irrespective of chemical group Anti-HTN belong mechanism = b/c of inhibition of biosynthesis of vasodilator prostaglandins in kidney
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Pharmacodynamic Interactions (3) Drugs w negative inotropic effects can precipitate heart failure especially when used in combination Thus, beta blockers and verapamil may precipitate HF if used sequentially IV in patients w supraventricular tachycardia (SVT)
Warfarin interferes w hemostasis by inhibiting coagulation cascade, whereas aspirin influences hemostasis by inhibiting platelet function Aspirin also predisposes to gastric bleeding by direct irritation and by inhibition of prostaglandin E2 biosynthesis in t gastric mucosa There is therefore potential for serious adverse interaction betw. warfarin and aspirin
Important DDIs can occur betw. drugs acting at a common receptor generally useful when used deliberately, for example use of naloxone to reverse opiate intoxication Marc Imhotep Cray, M.D.
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Pharmacodynamic Interactions (4) One potentially important type of PD drug interaction involves interruption of physiological control loops this was mentioned above as a desirable means of increasing efficacy However,
In some situations such control mechanisms are vital For example use of β-blocking drugs in pts. w insulin-requiring diabetes is such a case, as these pts. may depend on sensations initiated by activation of β-receptors to warn them of insulininduced hypoglycemia
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Pharmacodynamic Interactions (5) Alterations in fluid and electrolyte balance is an important source of PD drug interactions Combined use of diuretics w actions at different parts of nephron (e.g. metolazone and furosemide) is valuable in Tx of resistant edema but without close monitoring of plasma urea levels such combinations readily cause excessive intravascular fluid depletion and prerenal kidney failure
Thiazide and loop diuretics commonly cause mild hypokalemia usually of no consequence However,
Binding of digoxin to plasma membrane Na+/K+ adenosine triphosphatase (Na+/K+ ATPase)--and hence its toxicity-- is increased when extracellular potassium concentration is low dysrrhythmias
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Pharmacodynamic Interactions (6) β2-Agonists, such as salbutamol, reduce plasma potassium concentration esp. when used IV Conversely, potassium-sparing diuretics may cause hyperkalemia if combined w potassium supplements and/or ACE-I (which reduce circulating aldosterone), esp. in pts. w renal impairment NB: Hyperkalemia is one of most common causes of fatal adverse drug reactions (ADRs). Marc Imhotep Cray, M.D.
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Interactions secondary to drug-induced alterations of fluid and electrolyte balance. Primary drug
Interacting drug
Result of effect interaction
Digoxin
Diuretic-induced hypokalemia
Digoxin toxicity
Lidocaine
Diuretic-induced hypokalemia
Antagonism of antidysrhythmic effects
Diuretics
NSAID-induced salt and water retention
Antagonism of diuretic effects
Lithium
Diuretic-induced reduction in lithium clearance
Raised plasma lithium
Angiotensin converting enzyme inhibitor
Potassium chloride and/ or potassium retaining diuretic induced hyperkalemia
Hyperkalemia
Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
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Pharmacokinetic Interactions Absorption In addition to direct interaction within gut lumen (see above), drugs that influence gastric emptying (e.g. metoclopramide, propantheline [antimuscarinic]) can alter rate or completeness of absorption of a second drug particularly if second drug has low bioavailability Drugs can interfere w enterohepatic recirculation of other drugs
Failure of oral contraception can result from concurrent use of antibiotics, due to this mechanism many different antibiotics have been implicated
Phenytoin reduces effectiveness of cyclosporine partly by reducing its absorption Marc Imhotep Cray, M.D.
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Pharmacokinetic Interactions (2) Distribution ď ą As explained previously, interactions that involve only mutual competition for inert protein- or tissue-binding sites seldom give rise to clinically important effects 
Examples of complex interactions where competition for binding sites occurs in conjunction w reduced clearance are mentioned in slides below
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Pharmacokinetic Interactions (3) Metabolism Decreased efficacy can result from enzyme induction by a second agent Historically, barbiturates were clinically most important enzyme inducers but w decline in their use, other anticonvulsants, notably carbamazepine and antituberculous drug rifampin, are now most common cause of CYP450 enzyme induction o These agents necessitate special care in concurrent therapy w warfarin, phenytoin, oral contraceptives, glucocorticoids or immunosuppressants (e.g. cyclosporine, sirolimus) Marc Imhotep Cray, M.D.
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Interactions due to enzyme induction Primary drug
Inducing agent
Effect of interaction
Warfarin
Barbiturates, Rifampin, Ethanol
Decreased anticoagulation
Oral contraceptives
Rifampin
Pregnancy
Prednisolone/ cyclosporine
Anticonvulsants
Reduced immunosuppression (graft rejection)
Theophylline
Smoking
Decreased plasma theophylline
Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
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Pharmacokinetic Interactions (5) Metabolism cont. Withdrawal of an inducing agent during continued admin. of a second drug can result in a slow decline in enzyme activity, w emergence of delayed toxicity from second drug due to what is no longer an appropriate dose For example, a pt. receiving warfarin may be admitted to hospital for an intercurrent event and receive Tx w an enzyme inducer During hospital stay, dose of warfarin therefore has to be ↑ in order to maintain international normalized ratio (INR) within therapeutic range Intercurrent problem is resolved, inducing drug discontinued and pt. discharged while taking larger dose of warfarin If INR is not checked frequently, bleeding may result from an excessive effect of warfarin days or weeks after D/C from hospital, as effect of enzyme inducer gradually wears off Marc Imhotep Cray, M.D.
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Pharmacokinetic Interactions (6) Metabolism cont.
Inhibition of drug metabolism produces adverse effects time-course is often more rapid than for enzyme induction, since it depends merely on attainment of a sufficiently high conc. of inhibiting drug at metabolic site Xanthine oxidase is responsible for inactivation of 6-mercaptopurine 6-MP itself a metabolite of azathioprine o Allopurinol markedly potentiates these drugs (6-MP & azathioprine) by inhibiting xanthine oxidase o Xanthine alkaloids (e.g. theophylline) are not inactivated by xanthine oxidase, but rather inactivated by a form of CYP450
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Pharmacokinetic Interactions (7) Metabolism cont. Theophylline has serious (sometimes fatal) dose-related toxicities, and clinically important interactions occur w inhibitors of CYP450 system
notably several antibiotics, including ciprofloxacin and clarithromycin Severe exacerbations in asthmatic pts are often precipitated by chest infections so an awareness of these interactions before commencing antibiotic Tx is essential, if pt. is on theophylline
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Interactions due to CYP450 or other enzyme inhibition Primary drug Inhibiting drug
Effect of interaction
Phenytoin
Isoniazid, Cimetidine, Chloramphenicol
Phenytoin intoxication
Warfarin
Allopurinol, Metronidazole, Phenylbutazone, Co-trimoxazole
Hemorrhage
Azathioprine, 6-MP
Allopurinol
Bone-marrow suppression
Theophylline
Cimetidine, Erythromycin
Theophylline toxicity
Cisapride
Erythromycin, Ketoconazole
Ventricular tachycardia
Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
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Pharmacokinetic Interactions (9) Metabolism cont. Hepatic CYP450 inhibition also accounts for clinically important interactions w phenytoin (e.g. isoniazid) and w warfarin (e.g. sulfonamides) Non-selective MAO inhibitors (e.g. phenelzine) potentiate action of indirectly acting amines such as tyramine, which is present in a wide variety of fermented products (most classically soft cheeses: =“cheese reaction”) CNS stimulation and hypertensive crisis Marc Imhotep Cray, M.D.
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Pharmacokinetic Interactions (10) Metabolism cont. Clinically important impairment of drug metabolism may also result indirectly from hemodynamic effects rather than enzyme inhibition Lidocaine is metabolized in liver and hepatic extraction ratio is high consequently, any drug that reduces hepatic blood flow (e.g. a negative inotrope) will reduce hepatic clearance of lidocaine cause it to accumulate o
accounts for ↑ lidocaine conc. and toxicity caused by β-blocking drugs
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Pharmacokinetic Interactions (11) Excretion Many drugs share a common transport mechanism in PCT and reduce one another’s excretion by competition Probenecid reduces penicillin elimination in this way Aspirin and NSAIDs inhibit secretion of methotrexate into urine as well as displacing it from protein-binding sites can cause methotrexate toxicity Many diuretics reduce Na+ absorption in loop of Henle or DCT this leads indirectly to ↑ PCT reabsorption of monovalent cations o ↑ PCT reabsorption of lithium in pts TX w lithium salts can cause lithium accumulation and toxicity Marc Imhotep Cray, M.D.
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Pharmacokinetic Interactions (12) Excretion cont. Digoxin excretion is reduced by spironolactone, verapamil and amiodarone all of which can precipitate digoxin toxicity as a consequence several of these interactions have complex mechanism, involving displacement from tissue binding sites, in addition to reduced digoxin elimination
Changes in urinary pH alter excretion of drugs that are weak acids or bases, and administration of systemic alkalinizing or acidifying agents influences reabsorption of such drugs Marc Imhotep Cray, M.D.
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Competitive interactions for renal tubular transport Primary drug
Competing drug
Effect of interaction
Penicillin
Probenecid
Increased penicillin blood level
Methotrexate
Salicylates, Sulfonamides
Bone marrow suppression
Salicylate
Probenecid
Salicylate toxicity
Indomethacin
Probenecid
Indomethacin toxicity
Digoxin
Spironolactone, Amiodarone, Verapamil
Increased plasma digoxin
Redrawn after: Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th Ed. London: Hodder Arnold, 2008.
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Key Points Summary There are three main types of adverse interaction: • pharmaceutical • pharmacodynamic • pharmacokinetic
Pharmaceutical interactions are due to in vitro incompatibilities, and they occur outside the body (e.g. when drugs are mixed in a bag of intravenous solution, or in the port of an intravenous cannula). Pharmacodynamic interactions between drugs with a similar effect (e.g. drugs that cause drowsiness) are common. In principle, they should be easy to anticipate, but they can cause serious problems (e.g. if a driver fails to account for the interaction an antihistamine and ethanol). Marcbetween Imhotep Cray, M.D.
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Key Points Summary ďƒ˜Pharmacokinetic interactions are much more difficult to anticipate. They occur when one drug influences the way in which another is handled by the body: a) absorption (e.g. broad-spectrum antibiotics interfere with enterohepatic recirculation of estrogens and can cause failure of oral contraception) b) distribution – competition for binding sites seldom causes problems on its own but, if combined with an effect on elimination (e.g. amiodarone/digoxin or NSAID/methotrexate), serious toxicity may ensue Marc Imhotep Cray, M.D.
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Key Points Summary c) metabolism – many serious interactions stem from enzyme induction or inhibition. Important inducing agents include ethanol, rifampin, rifabutin, many of the older anticonvulsants, St John’s wort, nevirapine and pioglitazone. Common inhibitors include many antibacterial drugs (e.g. isoniazid, macrolides, cotrimoxazole and metronidazole), the azole antifungals, cimetidine, allopurinol, HIV protease inhibitors; d) excretion (e.g. diuretics lead to increased reabsorption of lithium, reducing its clearance and predisposing to lithium accumulation and toxicity) Marc Imhotep Cray, M.D.
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Case history A 64-year-old Indian male was admitted to hospital with miliary tuberculosis. In the past he had had a mitral valve replaced, and he had been on warfarin ever since. Treatment was commenced with isoniazid, rifampin and pyrazinamide, and the INR was closely monitored in anticipation of increased warfarin requirements. He was discharged after several weeks with the INR in the therapeutic range on a much increased dose of warfarin. Rifampin was subsequently discontinued. Two weeks later the patient was again admitted, this time drowsy and complaining of headache after mildly bumping his head on a locker. His pupils were unequal and the INR was 7.0. Fresh frozen plasma was administered and neurosurgical advice was obtained. Marc Imhotep Cray, M.D.
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Case history comment This patient’s warfarin requirement increased during treatment with rifampin because of enzyme induction, and the dose of warfarin was increased to maintain anticoagulation. When rifampin was stopped, enzyme induction gradually receded, but the dose of warfarin was not readjusted. Consequently, the patient became over-anticoagulated and developed a subdural hematoma in response to mild trauma. Replacement of clotting factors (present in fresh frozen plasma) is the quickest way to reverse the effect of warfarin overdose.
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THE END
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Companion study tools: MedPharm Syllabus| Digital Guidebook 2015: Unit 1: General Principles of Pharmacology string (Pgs. 10-29). Sources and further study: Karalliedde LD, Clarke SF, Ursula Gotel U, Karalliedde J, Eds. Adverse Drug Interactions: A Handbook for Prescribers, 2nd ed. Boca Raton, FL: CRC Press, Taylor & Francis Group, 2016. Ritter JM, Lewis LD, Mant TG, Ferro A. A Textbook of Clinical Pharmacology and Therapeutics 5th ed. London: Hodder Arnold, 2008. Wecker L, Crespo L , et al. Brody’s Human Pharmacology : Molecular to Clinical , 5th ed. Philadelphia, PA: Mosby-Elsevier, 2010. E-learning resource center: IVMS Medical Pharmacology Cloud Folder
Marc Imhotep Cray, M.D.
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