PHARMACOLOGY MEDICAL SCHOOL C RASH COURSE ™
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Table of Contents Introduction .................................................................................................................. 1 Section 1....................................................................................................................... 1 Chapter 1: Pharmacokinetics ...................................................................................................... 1
Conclusion ........................................................................................................................ 4 Key Points ......................................................................................................................... 4 Questions........................................................................................................................... 5 Chapter 2: Pharmacodynamics................................................................................................... 9
Conclusion ...................................................................................................................... 10 Key Points ....................................................................................................................... 10 Questions......................................................................................................................... 11 Chapter 3: Different Receptors ................................................................................................. 13
Conclusion ...................................................................................................................... 15 Key Points ....................................................................................................................... 15 Questions......................................................................................................................... 16 Chapter 4: Metabolism of drugs ............................................................................................... 19
Conclusion ...................................................................................................................... 21 Key Points ....................................................................................................................... 21 Questions......................................................................................................................... 21 Chapter 5: Toxicity Leading to Poisoning................................................................................ 25
Conclusion: ..................................................................................................................... 26 Key Points ....................................................................................................................... 26 Questions......................................................................................................................... 26 Chapter 6: The effects of genetics on individual drugs .......................................................... 29
Conclusion ...................................................................................................................... 31 Key points ....................................................................................................................... 31 Questions......................................................................................................................... 31 Section 2..................................................................................................................... 35
Chapter 7: Diuretics ................................................................................................................... 35
Conclusion: ..................................................................................................................... 39 Key Points ....................................................................................................................... 39 Questions......................................................................................................................... 39 Chapter 8: Three Hormones ...................................................................................................... 43
Renin-Angiotensin and Aldosterone ............................................................................... 43 Conclusion ...................................................................................................................... 44 Key Points ....................................................................................................................... 45 Questions......................................................................................................................... 45 Chapter 9: Medications for Hypertension ................................................................................ 47
Conclusion ...................................................................................................................... 50 Key Points ....................................................................................................................... 50 Questions......................................................................................................................... 51 Chapter 10: Treatment Drugs for Chronic Heart Failure ......................................................... 53
Conclusion ...................................................................................................................... 54 Key Points ....................................................................................................................... 55 Questions......................................................................................................................... 55 Chapter 11: Heart Rhythm Regulating Drugs .......................................................................... 57
Conclusion ...................................................................................................................... 60 Key Points ....................................................................................................................... 60 Question .......................................................................................................................... 60 Chapter 12: Drugs for Cholesterol and Lipid Therapy ............................................................ 63
Conclusion ...................................................................................................................... 65 Key Points ....................................................................................................................... 65 Questions......................................................................................................................... 65 Chapter 13: Antiplatelet and Anticoagulation drugs............................................................... 67
Conclusion ...................................................................................................................... 70 Key Points ....................................................................................................................... 70 Questions......................................................................................................................... 71 Section 3..................................................................................................................... 73 Chapter 14: Treatments for Depression and Anxiety.............................................................. 73
Conclusion ...................................................................................................................... 75 Key points ....................................................................................................................... 75 Questions......................................................................................................................... 75 Chapter 15: Drug Treatments for Psychosis and Mania ......................................................... 77
Conclusion ...................................................................................................................... 79 Key Points ....................................................................................................................... 79 Questions......................................................................................................................... 80 Chapter 16: Drug Treatments for Epilepsy .............................................................................. 83
Conclusion ...................................................................................................................... 85 Key Points ....................................................................................................................... 85 Questions......................................................................................................................... 86 Chapter 17: Local Anesthetics and Anesthetic Drugs ............................................................ 89
Conclusion ...................................................................................................................... 92 Key Points ....................................................................................................................... 92 Questions......................................................................................................................... 93 Chapter 18: Drugs to Treat CNS Disorders .............................................................................. 95
Conclusion ...................................................................................................................... 97 Key Points ....................................................................................................................... 97 Questions......................................................................................................................... 98 Chapter 19: Drugs Affecting Muscarinic Receptors ............................................................. 101
Conclusion .................................................................................................................... 103 Key points ..................................................................................................................... 104 Questions....................................................................................................................... 104 Section 4................................................................................................................... 107 Chapter 20: Hypo/Hyper Thyroid Drugs ................................................................................. 107
Conclusion .................................................................................................................... 109 Key Points ..................................................................................................................... 109 Questions....................................................................................................................... 110 Chapter 21: Estrogens, Progestin Therapy, and Contraceptives ........................................ 113
Conclusion .................................................................................................................... 116 Key Points ..................................................................................................................... 116
Questions....................................................................................................................... 116 Chapter 22: ACTH and Adrenal Steroids............................................................................... 119
Conclusion .................................................................................................................... 121 Key Points ..................................................................................................................... 121 Questions....................................................................................................................... 121 Chapter 23: Insulin Therapy and Glucose Lowering Drugs ................................................. 123
Conclusion .................................................................................................................... 125 Key Points ..................................................................................................................... 126 Questions....................................................................................................................... 126 Section 5................................................................................................................... 129 Chapter 24: NSAIDS/Acetaminophen and Gout .................................................................... 129
Conclusion .................................................................................................................... 132 Key Points ..................................................................................................................... 132 Questions....................................................................................................................... 133 Section 6................................................................................................................... 135 Chapter 25: Drugs for Asthma ................................................................................................ 135
Conclusion .................................................................................................................... 137 Key Points ..................................................................................................................... 137 Questions....................................................................................................................... 137 Section 7................................................................................................................... 139 Chapter 26: Penicillin’s and Cephalosporin’s ....................................................................... 139
Conclusion .................................................................................................................... 141 Key Points ..................................................................................................................... 141 Questions....................................................................................................................... 142 Chapter 27: Aminoglycosides ................................................................................................. 145
Conclusion .................................................................................................................... 146 Key Points ..................................................................................................................... 146 Questions....................................................................................................................... 146 Chapter 28: Antifungals and Tuberculosis Drugs ................................................................. 149
Conclusion .................................................................................................................... 151 Key Points ..................................................................................................................... 151
Questions....................................................................................................................... 152 Chapter 29: Sulfonamides ....................................................................................................... 155
Conclusion .................................................................................................................... 156 Key Points ..................................................................................................................... 156 Questions....................................................................................................................... 157 Chapter 30: Antivirals .............................................................................................................. 159
Conclusion .................................................................................................................... 161 Key Points ..................................................................................................................... 161 Questions....................................................................................................................... 162 Section 8................................................................................................................... 163 Chapter 31: Chemotherapy drugs .......................................................................................... 163
Conclusion .................................................................................................................... 164 Key Points ..................................................................................................................... 165 Questions....................................................................................................................... 165 Questions for “Pharmacology for the Student of Medicine” ................................ 167
Introduction Knowledge of Pharmacology may be the most important building block of medical knowledge for any physician. Ninety percent of all patient interactions involve some form of drug therapy manipulating a patient’s physiology. This involves what needs to be a lifetime of study, with continual updates. The booklet that follows is a review and focuses on the medications you could use on any given day. It is meant to be a basic text work and in depth knowledge of each section can be found in major Pharmacology texts.
Section 1 Chapter 1: Pharmacokinetics Welcome to Section 1 Chapter 1. This Chapter deals with the principles of Pharmacokinetics. When you think of Pharmacokinetics you think of the flow of a drug through the body. This includes the absorption of the drug, the distribution of the drug, the metabolism of the drug and the elimination of the drug from the body. When you prescribe a drug, you will be directly or indirectly thinking of these principles of Pharmacokinetics. For a drug to be absorbed, it may need to pass several cell membrane layers on its way to a therapeutic effect. This process involves consideration for the molecular size of the drug, the ionization of the drug, whether the drug is lipid soluble and if the drug binds to blood proteins. Let’s discuss these cell membranes for a minute. There are four common ways for drugs to cross a membrane. First, on a basic level, cell membranes are permeable to water. If a drug is not bound to a protein in the blood, then the drug can potentially use the movement of water through the cell membrane to help it cross over into the cell. This is the process of water diffusion. The drug is, in effect, carried across a membrane as water moves across. Some cells, as in the central nervous system, have tighter membranes and a drug being carried by water diffusion is not as likely. Secondly, the process of moving a drug across a membrane can be aided by a concentration differential. If a drug on the outside of a membrane has a higher concentration, then it can move across the membrane to equalize the concentration. Factors involved in this movement are the concentration gradient, the drug’s solubility in the lipid layer of the membrane and the amount of the drug spread out over the surface area of the membrane. This is the process of using a concentration gradient. A third way a drug can be transported across a membrane in an active fashion. This activity involves the use of energy from the cell to accomplish the transfer of a drug. Active transport is needed if a drug is to be moved against a concentration gradient. This is the process of active transport. The fourth and least likely mechanism of transfer across a cell membrane involves something called facilitated diffusion. This facilitation does not involve the use of energy. This facilitated diffusion involves what can be called an assist by another substance that attaches to the drug and helps it cross the membrane. This is the process of facilitated transport. 1
The ionized or unionized form of a drug can change the absorption profile in any of the four common ways to cross a membrane. It is the unionized form that most easily crosses a membrane. Every drug will be absorbed to some extent, but it is the bioavailability that is in question. In other words, how much of the original drug is available to provide the clinical effect that is desired. The factors involved in achieving a high bioavailability percentage are numerous. These factors include the route of administration, the extent of metabolism and consideration of extended release preparations. At this point, let’s look at the multiple ways a drug can be given to a patient. There are over ten methods to deliver a drug. The list of drug delivery methods includes oral, sublingual, transdermal, rectal, intravenous, interosseous, subcutaneous, intrathecal, pulmonary, topical and intra-arterial. The choice of delivery method depends on the clinical situation and the patient’s condition. The clinical reasons for a specific mode of delivery include a need to target a specific area, the need to avoid first pass metabolism in the liver or possibly because there is a lack of access to other delivery methods. Examples of these would be to give a drug via the sublingual route to avoid the metabolism of the liver on the first pass, using an inhaler to focus on the lungs for COPD or giving an intrathecal dose to avoid the blood/brain barrier. Let’s take a quick look at each method of drug delivery. Oral delivery is the most common method of drug delivery. It usually provides easy access and is probably the safest. It has a disadvantage in the nauseated patient and provides low bioavailability. Sublingual delivery of a drug gives quick access to the blood and has its advantage in an emergency situation. Rectal delivery of a drug may be used due to persistent nausea or for site relief. Intravenous delivery can be used if there is already access to a vein or the need for speed of delivery. Subcutaneous delivery is easy and safe, but can only be used for drugs that are not irritating. Absorption of a drug can be distinctly variable in sick patients. Intramuscular injections for drug delivery are not used too often due to patient discomfort and variable absorption rates. The drug must also be in an aqueous solution. Single dose antibiotics can be given this way. Inter-arterial delivery is for very specific situations. This could be for some form of neuropathic pain syndrome. Intrathecal delivery can be for pain relief or to delivery medications that otherwise could not get past the blood brain barrier. Pulmonary delivery for COPD or asthma focuses the medication where it is needed. Pulmonary delivery has also been used for specific antibiotics
Interosseous delivery is mostly for patients in which intravenous access is difficult and access to the central circulation is needed. We will discuss the distribution of drugs next. In this context, we are talking about the time period after the drug has been absorbed into the blood stream. There are many factors that can affect the rate of distribution, up or down. Basic physiological principles apply to the ability of a drug to get maximal distribution. Cardiac output has a clear effect on distribution. If cardiac output is up, drug distribution will be up. If cardiac output is down, drug distribution will be down. Increased blood flow to certain areas can increase drug distribution, with the reverse also being true. The percentage of cardiac output received by an organ will determine its drug distribution. So, vital organs will have a high distribution of drug, muscles less and skin even less drug distribution. The concept of volume of distribution is somewhat complicated. First, for each drug a volume of distribution can be calculated. After this, we see that the calculated volume of distribution does not tell you where it is specifically distributed. In equation form, volume of distribution is the amount of drug given divided by the concentration. The concentration is a plasma value. If the volume of distribution is large, this indicates a significant distribution throughout the body. A small volume of distribution indicates a small compartmental focus. An example of this could be a highly protein bound drug mostly carried in the blood. Two drugs with the same numerical volume of distribution value may not be distributed to the same areas of the body. This is not an exact volumetric calculation because the body is a dynamic organism, metabolism and elimination are occurring during the calculation and the plasma level may not be a perfect representative value. Delivery of a drug to a tissue area makes it potentially available, but this is then limited by the amount of drug that is bound by blood proteins. The main protein involved in the carrying of drugs is albumin. These drugs are usually acidic. If a drug is of the basic variety, alpha-one glycoprotein is the carrier. This bond by these proteins is reversible. The unbound form of a drug is the form which can cross a membrane. In states of protein deficiency, the main drug percentage can be the unbound form. This situation can cause overdosed and excessive drug effects. Determining the levels at which a drug is bound or unbound has many factors. Most drugs have a somewhat unvarying bound and unbound percentage. Secondary factors that can affect the distribution of a drug are the binding of a drug in certain tissues, buildup of a drug in a non-vital reservoir like fatty tissue and even redistribution with a drug coming back into circulation. Distribution of drugs to all tissues is not always a good thing. This can be the case in a pregnant patient. The placenta is basically a membrane and is slightly more acidic than the mother’s blood. This can lead to basic drugs crossing over and becoming trapped in the placenta. The metabolism and excretion of drugs is as important as the absorption and distribution. Drugs can be eliminated through metabolism or released unchanged. Highly lipid soluble drugs usually need to have their form changed through metabolism to enable elimination. Almost all organs have
some capability to metabolize, but the kidney, liver and lungs are the main eliminating/metabolic organs. The kidney and gastrointestinal tract are mainly involved in elimination. The kidney has several methods it uses for removal and elimination of a drug. These are the basic functioning properties of the kidney which include filtration, tubular secretion and passive reabsorption. Of the drug that presents to the kidney only the unbound form is filtered. Changing the pH of the blood being filtered by the kidney can aid in the elimination of the drug present in an overdose situation. If the overdose drug is an acid, then making the urine more basic could be appropriate. The liver is active in metabolism and elimination of drugs. The liver has a major role in changing drugs so they present to the kidney as soluble. Many of the drugs that present to the liver are excreted into the gastrointestinal tract. The gastrointestinal tract can also be used to stop absorption of certain compounds like cholesterol. The metabolism of a drug follows two basic pathways. These are classified as phase one or phase two. Both phase one and phase two pathways can leave the drug in a modified but still active form. Phase one is similar to a hydrolysis reaction and phase two uses conjugation. Some drugs use these systems to become active after they are metabolized in the body. They are called prodrugs.
Conclusion Each drug that is considered for a patient needs the determination of the pharmacokinetics of that drug. When this occurs then the drug will be safely prescribed. This needs to be an automatic thought process. Thoughts of the absorption, volume of distribution, half-life and elimination of a drug all part of the complete package of ordering a drug, along with the disease process it is ordered for.
Key Points •
Pharmacokinetics—how the drug flows through the body—absorption, distribution, metabolism and elimination
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Drugs move across membranes—this is by water diffusion, concentration gradients, transportation and facilitated diffusion
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Drugs in the unionized form pass membranes
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There are over ten ways to give a drug to a patient.
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Rate of distribution is effected by many physiological parameters
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Delivery of a drug to tissues is affected by the amount of protein binding
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All tissues are involved to some extent in metabolism
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A drug needs to be changed from a lipid form to be eliminated.
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Metabolism of a drug follows either phase 1 or phase 2
Questions 1. The study of absorption, distribution and elimination is called a. Pharmacodynamics b. Drug tolerance c. Pharmacokinetics d. Drug efficacy The answer is c, pharmacokinetics 2. Pharmacokinetics refers to the relationship of a drug a. Dose to dose concentration in blood plasma b. Dose to drug at the receptor site c. Concentrations to drug effect d. Dose to drug effect The answer is a, dose to dose concentration in blood plasma 3. We measure drug levels in the plasma because it is the same as the body tissues. a. True b. False The answer is a, true 4. Which of the following is true about cell membranes? a. Cell membranes are basically impervious to water b. A drug can be transported across a membrane in an active fashion c. Central nervous system membranes are more impervious to allow cerebral spinal fluid in d. The ionized form of a drug is most likely to cross The answer is b, a drug can be transported across a cell membrane in an active fashion
5. Which of the following drug delivery methods gives the quickest access to the blood stream a. Oral b. Subcutaneous c. Sublingual d. Intramuscular The answer is c, sublingual 6. Intrathecal drug deliver suited for drugs that need to reach the a. Liver b. Pancreas c. Lungs d. Brain The answer is d, brain 7. The interosseous drug delivery method is used for difficult IV sticks a. True b. False The answer is a, true 8. Drug distribution is affected by a. Cardiac output b. Decreased blood flow to an organ c. The percentage of cardiac output received d. All of the above The answer is d, all of the above 9. What does the formula “amount of drug given divided by the concentration” represent? a. Creatinine clearance b. Cardiac index c. Drug receptor efficacy d. Volume of Distribution The answer is d, volume of distribution
coupled receptors. Two important second messengers from G coupled receptors are cyclic AMP and calcium. Transmembrane receptors include in their domain insulin receptors, receptors responsible for innate immunity, growth factors and those for tumor necrosis factor. Growth factor receptors, when activated, increase cell survival and in some cells lead to proliferation. The activation of growth factors leads to a protein kinase process called the mitogen activated protein kinase pathway. This is a major factor in the stimulation of a cell nucleus. Drugs involved with these receptors include insulin and several anti-leukemic drugs. Figure 2 describes transmembrane receptors of different types:
Figure 2 The aspect of immunity related to transmembrane receptors has them classified as toll-like receptors. These toll like receptors have a high density in hematopoietic cells. Pathogens activate these receptors, leading to an inflammatory reaction against them. Tumor necrosis factor works in a fashion like a toll receptor. Included in the transmembrane receptor class are the natriuretic peptide receptors. There are three of these, atrial natriuretic peptide, brain natriuretic peptide and C type natriuretic peptide. The actions of these peptides are to decrease blood pressure, reduce cardiac enlargement and stimulate growth of the long bones. Atrial peptide is stored in granular form and released due to increased intravascular volume. C type peptide and brain peptide are formed on the spot and respond to growth factors and stressed vascular cells. The cell responds to the peptide stimulation by increasing intercellular cyclic GMP. Cyclic GMP in turn stimulates phosphodiesterase’s and protein kinase.
Figure 4 shows the different parts of the renin angiotensin system:
Figure 4 When the regulation of the RAAS pathway become pathologic the body pays a high price. Renin may be involved in over half of the cases of essential hypertension. Low renin hypertension is found more often in older patients, African-Americans and type 2 diabetics. The role of RAAS in congestive heart failure is significant. The reduced vascular volume in congestive heart failure leads to increased levels of renin and subsequently increases aldosterone. This will increase the afterload on the heart, decreasing the heart’s function further. Abnormal levels of angiotensin converting enzyme or abnormal angiotensin receptors may also cause hypertensive conditions. After the initial clarification of the role of RAAS in the body, drugs were targeted at the system through renin blockers. This was short lived due to the inability of the drugs to be formulated as an oral drug. The search for blockers continued on to ACE inhibitors and angiotensin receptor blockers.
Conclusion Many drugs affect the renin/angiotensin aldosterone system (RAAS). A clear knowledge of how these hormones are connected is needed to use drugs that target them. At the head of a nephron is the glomerulus. Alongside the glomerulus are juxtaglomerular cells. This cell release renin.
Questions for “Pharmacology for the Student of Medicine”
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