Pharm 5001 Pharmacodynamics Quiz 2 {2020} - St. George's University | Pharm5001 Pharmacodynamics Quiz 2 {2020} - A Grade

Pharmacodynamics 1. The set of properties that characterize the effects of a drug on the body is called (A) Distribution (B) Permeation (C) Pharmacodynamics (D) Pharmacokinetics (E) Protonation Answer: C. Pharmacodynamics is the term given to drug actions on the body. Drug-Receptor Interaction 2. What does the term tachyphylaxis mean? (A) An increase in the rate of the response, for example, an increase of the rate of muscle concentration (B) Immediate hypersensitivity reactions (ie, anaphylaxis) (C) Prompt conformational changes of the receptor such that agonists, but not antagonists, are able to bind and cause a response (D) Quick and progressive rises in the intensity of drug response, with repeated administration, even when the doses are unchanged (E) Rapid development of tolerance to the drug’s effects Answer: E. Tachyphylaxis is loosely defined as rapidly developing tolerance to the effects of a drug that is administered repeatedly, even if the dosages given after the first one are not changed or even progressively increased to overcome the phenomenon. It is sometimes also called desensitization or down-regulation of the receptor(s), but those phenomena do not explain all the mechanisms by which tachyphylaxis (or tolerance in general) occurs. The mechanism behind the development of tachyphylaxis or slower-developing drug tolerance in general-varies depending on which drug is being used, the biochemical processes by which the drug exerts its effects, and what the effector and the response(s) are. For example, consider the rapidly diminished response of a variety of cells/tissues to repeated administration of amphetamine, which acts by releasing neuronal norepinephrine. Challenge the system repeatedly and the amount of intraneuronal NE available to be released-which is essential for causing the ultimate response-goes down. Another example, with more clinical relevance, is the somewhat slower development of “tolerance” of airway smooth muscles, and their ability to relax (i.e., cause bronchodilation) in response to repeated administration of β-adrenergic agonists, such as albuterol, arguably the most widely used adrenergic bronchodilator for asthma. (Note: There is no magical number that distinguishes between tachyphylaxis and “regular” tolerance. The brevity with which the tolerance develops is the key point in the working definition of tachyphylaxis.)3. A patient is taking L-dopa as a treatment for their Parkinson’s Disease. Over a 3 month period of taking the drug they notice that the effect of the same dose of L-dopa is diminished. Assuming that the disease has not progressed in this 3 month period, and without knowledge of the physiological mechanism, it can be stated that the decrease in effectiveness of the L-dopa is due to: (A)Receptor inactivation (B) Tolerance (C) Receptor desensitization (D)Receptor down-regulation (E) An increase in the refractory period Answer: B. Tolerance may be defined as when repeated administration of a drug leads to an increased dose being required to produce the same effect. This is the same as saying the same dose gives a diminished response after time. This is a general term that does explain the decrease in L-dopa effectiveness. Receptor inactivation is when repeated drug-receptor binding leads to the receptor being turned off. This could be described as complete desensitization. Receptor desensitization is a process which is defined by a decreased ability of receptors to respond to stimulation by a drug. That is the drug binds to the receptor but does not produce its usual response within the cell. Down-regulation is a process which is defined by repeated drug-receptor interaction resulting in the removal of the receptor from the site of drug-receptor interaction. Although these may explain to some extent the decrease in effect of L-dopa without know the mechanism you cannot specify this as the reason there has been a decrease in the L-dopa effectiveness (there are other mechanisms that may also explain this change). An increase in refractory period would affect a response that involves the activation of voltage-dependent channels. This would decrease the frequency of response to stimulation and so decrease the response. Levodopa acts by increasing dopamine levels in the brain increasing action at the receptor. Most dopamine receptors are involved with G protein activation though binding to some receptors will decrease voltage-dependent Ca2+ channel activity. This will hyperpolarize the membrane and so an increase in refractory period would if anything increases the patient response to L-dopa (lots of assumptions made here). There is no evidence given that Ldopa produces this effect and so you can not specify this as the reason there has been a decrease in the L-dopa effectiveness. 4. A patient has been taking a dopamine agonist for several months in order to treat their Parkinson’s Disease. The drug has been starting to lose it’s effectiveness due to receptor sequestration decreasing the number of receptors on the target cell membrane. This process of receptor sequestration is known as: (A)Tachyphylaxis (B) Desensitization (C) Down-regulation (D)Tolerance (E) Inactivation Answer: C. Down-regulation is a process which is defined by repeated drug-receptor interaction resulting in the removal of the receptor from the site of drug-receptor interaction. This would include receptor sequestration. Therefore the process described that leads to thedecreased response of a patient to a drug over time is down-regulation. Tachyphylaxis is defined as a diminished response to a drug over time. Tachyphylaxis definitely describes an acute diminished response to a drug BUT some will argue that a diminished response observed over several months is better described by the term tolerance. Whichever side you are on tachyphylaxis is a general term whereas the question is specifically asking what describes the actual process of receptor sequestration. Desensitization is a process which is defined by a decreased ability of receptors to respond to stimulation by a drug. That is the drug binds to the receptor but does not produce its usual response within the cell. Although this could explain a decreased response of a patient to a drug over time it does not involve receptor sequestration. Tolerance may be defined as when repeated administration of a drug leads to an increased dose being required to produce the same effect. There is some argument over the use of tachyphylaxis and tolerance, however the example of a decreased response to a dopamine agonist over time definitely is tolerance. The question however is specifically asking what describes the actual process of receptor sequestration. Inactivation is when repeated drug-receptor binding leads to the receptor being turned off. This could be described as complete desensitization. This does not describe a mechanism that involves receptor sequestration. 5. Carbamazepine, a drug used in the treatment of epilepsy is metabolized by the one of the cytochrome P450 enzymes. However, it also induces this enzyme such that over time, the therapeutic effectiveness of carbamazepine is reduced. Which of the following best describes this phenomenon? (A)Pharmacodynamic tolerance (B) Tachyphylaxis (C) Up regulation (D)Pharmacokinetic tolerance (E) Sensitization Answer: D. This is an example of a pharmacokinetic tolerance where one drug affects the metabolism of another drug. Pharmacodynamic tolerance would be a drug that interacts with another drug at the receptor level. Tachyphylaxis and up-regulation and sensitization are changes that occur at the receptor themselves. 6. The effects of atropine at the muscarinic receptor can be overcome by increasing the level of acetylcholine. What type of bond is atropine LEAST likely to make with the muscarinic receptor? (A)Ionic bond (B) Van der Waal’s bond (C) Hydrogen bond (D)Covalent bond Answer: D. Atropine is a competitive antagonist at the muscarinic receptor. It is unlikely therefore that it will make a covalent bond with the receptor since this type of bonding is very strong.7. Dopamine, epinephrine (or norepinephrine), and histamine are important neurotransmitter agonists. When these ligands interact with their cellular receptors, how do they mainly elicit their responses? (A) Activate adenylyl cyclase, leading to increased intracellular cAMP levels (B) Activate phospholipase C (C) Induce or inhibit synthesis of ligand-specific intracellular proteins (D) Open or close ligand-gated ion channels (E) Regulate intracellular second messengers through G protein-coupled receptors Answer: E. The general issue of ligand-receptor-response coupling involves signal transduction. The specific agonists noted in the question transduce their signals and eventually cause a response by processes involving G proteins, a family of guanine nucleotide-binding proteins. These ligands bind to the extracellular face of the transmembrane protein. The various G proteins (e.g., Gi, Gq, Gs) bind to intracellular portions of the receptor. They then couple the initial ligand interaction to the eventual response through a series of effector enzymes or enzyme systems that are G proteinregulated. For example, adenylyl cyclase can be activated, catalyzing the formation of cAMP that then activates a particular kinase that phosphorylates specific intracellular proteins. But the actual steps that occur after ligand binding depend on what the ligand is, what specific G protein is involved, which kinases are activated, and what proteins they phosphorylate. And what happens (i.e., what the response is) depends on all of the above and, of course, which cell type is being affected. Activation of adenylyl cyclase and increased cAMP levels may occur in one system, but the opposite may occur in another. Some signal transduction pathways involve phospholipase C, others do not. A calcium channel may be affected in one system and a potassium channel (or no ion channel at all) in others. By way of review, recall that there are three other main mechanisms or pathways for signal transduction about which we have reasonable knowledge. One uses a receptor protein that spans the cell membrane, but G proteins are not involved. On the inner membrane face the protein possesses enzymatic activity that is regulated by the presence or absence of ligand bound to the extracellular face. The tyrosine kinase pathway is an example, and the overall pathway is responsible for the activity of various growth factors and insulin (which is also a growth-regulating hormone). Another mechanism is used by very lipid-soluble ligands that cross cell membranes easily and act on some intracellular receptor. For example, glucocorticosteroids ultimately act in the nucleus and, through interaction with heat-shock protein (hsp90), eventually alter transcription of specific genes. The third involves transmembrane ion channels, the “open” or “closed” states of which arecontrolled by ligand binding to the channel. This process applies to some of the important neurotransmitters, especially those in the brain (GABA, the main inhibitory neurotransmitter) and such amino acids as glycine, which exert “excitatory” actions. The nicotinic receptor for ACh fits in this category too. 8. Pitocin is a drug that binds to oxytocin receptors on the uterus in order to help initiate childbirth. This activates Gαq proteins in the smooth muscle membrane that in turn leads to the: (A)Activation of adenylyl cyclase (B) Activation of phospholipase C (C) Activation of tyrosine kinase (D)Inactivation of adenylyl cyclase (E) Inactivation of tyrosine kinase Answer: B. A ligand (such as pitocin) that binds to an oxytocin receptor will - - - - - - - - - - - - - - - - - - - 00:5. 18. Two cholesterol-lowering drugs, X and Y, were studied in a large group of patients, and the percentages of the group showing a specific therapeutic effect (20% reduction in LDL cholesterol) were determined. The results are shown in the following table. Which of the following statements about these results is correct? Drugs Dose (mg) % Responding to Drug X % Responding to Drug Y 5 1 10 10 5 20 20 10 50 50 50 70 100 70 90 (A) Drug X is safer than drug Y (B) Drug Y is more effective than drug X (C) The 2 drugs act on the same receptors (D) Drug X is less potent than drug Y (E) The therapeutic index of drug Y is 10Answer: D. No information is presented regarding the safety of these drugs. Similarly, no information on efficacy is presented; this requires graded dose-response curves. Although both drugs are said to be producing a therapeutic effect, no information on their receptor mechanisms is given. Since no data on toxicity are available, the therapeutic index cannot be determined. Because the ED50 of drug Y (20 mg/d) is less than that of drug X (50 mg/d), drug Y is more potent. 19. The data presented in the figure below show that… (A) Drugs A and C have equal efficacy (B) Drug A is more potent than drug B (C) Drug B is a partial agonist (D) Drugs A and B have the same affinity and efficacy (E) Drugs A and B are partial agonists Answer: B. The typical log dose-response figure with the parallel nature of the curves suggests that the three drugs are interacting with the same receptor system. Drugs A and B are full agonists because they achieve the maximal response. They have similar efficacy, but drug A is more potent than drug B. Drug C is a partial agonist with less efficacy than either of the other two drugs.20. The curves in this figure represent isolated tissue responses to two drugs. Which of the following statements is accurate? (A) Drug A has greater efficacy than drug B (B) Drug A is more potent than drug B (C) Drug B is more potent than drug A (D) Drug B has greater efficacy than drug A (E) Both drugs have the same affinity Answer: D. The curves in the figure suggest that drugs A and B have similar receptor binding: Drug A is a partial agonist, and drug B is a full agonist, having greater efficacy. Drug A appears more potent than drug B below the 50% response but has no effectiveness at all above the 50% response. 21. The diagram below shows the change in effect of a drug as a function of its concentration. Which one of the following must be less for Drug B when compared to Drug A? (A)Kd (B) Affinity (C) Efficacy (D)Potency (E) EC50 log [L] E/E max Drug A Drug BAnswer: D. The potency of a drug is inversely proportional to the concentration of drug that is required to produce 50% of the maximum response (EC50). The lower the EC50 is, the greater the potency is. As you can see from the above graph the EC50 for Drug B is greater than Drug A. Therefore the potency of Drug B is less than that of Drug A. The affinity of a drug for a particular receptor is determined by the Kd value. The lower the Kd value the greater the affinity. Kd is simply the log [L] at which you see the half of the receptors bound by the Drug. As this is a dose-response curve and there is no information in the question regarding spare receptors, and thus the Kd cannot be determined from these graphs. Therefore you cannot determine if Drug B has less affinity or Kd than Drug A. Efficacy is the maximum response that can be produced by the drug (Emax). As you can see from the graph above both Drug A and B can produce a response up to the Emax. Therefore they have the same efficacy. 22. Which statement describes the finding of this experimental study involving drugs X, Y, and Z? (A) Drug X is most efficacious because its ED50 is lowest (B) Drug Y is the least potent drug among the three drugs shown (C) Drug Z is the most potent cardiac inotrope (D) Drug Y is more potent than drug Z, and more efficacious than drug X (E) Drug X is more potent than drug Y, and more efficacious than drug Z Answer: D. The most basic definition of efficacy is simply the ability to cause an effect. More important is the question “how big an effect?" Aspirin, for example, will alleviate headache pain for many patients, but it simply cannot, at safe doses, alleviate severe pain from, for example, an abdominal incision. So, in the setting of severe pain, aspirin is less efficacious than, say, morphine. If relief of simple headache pain is the goal, then such drugs as aspirin, acetaminophen, and ibuprofen, are equally efficacious. What differs is how many milligrams of each are necessary to do that. Ibuprofen is more potent thanacetaminophen, which is slightly more potent than aspirin: 400 mg of ibuprofen, 600 mg of acetaminophen, and 650 mg of aspirin are reasonable dosages. In the question provided here, drugs X, Y, and Z all have efficacy: they all increase contractile force development by the isolated cardiac muscle preparation. But it should be obvious that drug Y and drug Z are more efficacious than drug X. The ED50 of drug X is lower than that of the other drugs (choice A), but that doesn’t mean that it is more efficacious: indeed, its maximal effect on the test muscle’s force of contraction is about less than half of that for drug Y and drug Z. Drug Y is more potent than drug Z, its ED50 is lower than that of drug Z, but Y and Z are equally efficacious since their peak effects are identical (choice B). The ED50 for drug Z is higher than that of drug Y, and so Z is less potent (choice C). Although the ED50 of drug X is lower than the ED50s of Y and Z, the maximum intensity of drug X’s response is much lower than those of Y and Z (choice E). 23. The results shown in the graph below were obtained in a comparison of drugs that increase the force of cardiac contraction. Which of the following statements is correct? (A) Drug A is most effective (B) Drug B is least potent (C) Drug C is most potent (D) Drug B is more potent than drug C and more effective than drug A (E) Drug A is more potent than drug B and more effective than drug C Answer: D. Drug A produces 50% of its maximum effect at the lowest dose and thus is the most potent; drug C is the least. Drug A is less efficacious than drugs B and C.Use the diagram below to answer the next 4 questions. Log [DRUG] E/EMAX Drug A Drug B Drug C Drug D Drug E Match the statement below that matches the Drug in the graph above. 24. The drug with the highest potency Answer: E. It has the lowest EC50. 25. The drug with the highest efficacy Answer: D. It has the highest Emax. 26. The drug with the highest affinity Answer: Cannot determine. This is not a drug-receptor binding curve. 27. The competitive agonist to Drug E Answer: Cannot determine. No information about their interactions to each other.Use below diagram to answer question 28 and 29 28. Use the diagram above to answer the following question. This diagram shows the doseresponse curve for Drug A alone as well as in the presence of a Drug X at both a low and high concentration. Which point indicates the EC50 for Drug A? Answer: Point 1. Point 1 indicates the concentration of Drug A that produces a response that is 50% of the maximum response when there is no other drug present. This is the EC50. Point 2 indicates the concentration of Drug A that produces a response that is 70% of the maximum response when a high concentration of Drug X is present. Point 3 indicates the concentration of Drug A that produces a response that is 90% of the maximum response when there is no other drug present. Point 4 indicates the concentration of Drug A that produces a response that is 30% of the maximum response when a low concentration of Drug X is present. Point 5 indicates the concentration of Drug A that produces a response that is 55% of the maximum response when a low concentration of Drug X is present. Point 2 to 5, they are not the EC50 for Drug A. 29. Above diagram shows the dose-response curve for Drug A alone as well as in the presence of a Drug X at both a low and high concentration. Assuming there are no spare receptors which ONE of the following statements is most likely to be TRUE? (A)Drug A is a competitive antagonist (B) Drug X is a competitive antagonist (C) Drug X is a non-competitive antagonist (D)The number of receptors bound by Drug A at Point 2 is the same as at Point 5 (E) The number of receptors bound by Drug A at point 4 is more than point 2Answer: B. If Drug X is a competitive antagonist then addition of Drug X alone would not produce a response. We do not have this data so we cannot make a decision from this. We can see however that addition of Drug X at set concentrations shift the dose-response curve of Drug A to the right, with a greater concentration of Drug X moving the curve even further across. The maximum response to Drug A can still be produced even in the presence of the high concentration of Drug X and there are no spare receptors. All this evidence means Drug X is a competitive antagonist. If Drug A was a competitive antagonist then addition of Drug A alone would produce no response. By definition a competitive antagonist binds to the active site of the receptor and does not produce a response (does not activate the receptor). As you can see from the graph addition of Drug A does indeed produce a response (it acts as an agonist) so it is not a competitive antagonist. If Drug X is a non-competitive antagonist (and we know there are no spare receptors) then it will cause the dose-response curve to Drug A to shift downwards with a decrease in the maximum response that Drug A can elicit. This does not happen as addition of Drug X shifts the doseresponse curve of Drug A to the right. If Drug X was a non-competitive antagonist it could only produce this response if there were spare receptors. The graph is a dose-response curve not a drug-receptor binding curve therefore it is difficult to ascertain how many receptors are bound. As you can see from the graph Point 2 produces a larger response than Point 5, therefore if anything you would expect Point 2 to be bound to a greater number of receptors, not the same, as Point 5. Point 4 is on the dose-response curve to Drug A with a low concentration of Drug X present. Point 2 is on the dose-response curve for Drug A with a high concentration of Drug X. Therefore the concentration of Drug X at Point 2 is higher, and it has shifted the dose response curve to the right. As there are no spare receptors you can ascertain the Drug X is a competitive antagonist as it shifts this curve to the right. This means Drug A is able to compete with Drug X for receptor binding. As Point 2 produces a greater response you would say Drug A is most likely to be bound to more receptors at this point than at Point 4 where the response is much smaller. The more receptors bound the greater response you would expect, no matter what the concentration of antagonist present. Spare Receptors 30. Which of the following statements most accurately describes a system having spare receptors? (A) The number of spare receptors determines the maximum effect (B) Spare receptors are sequestered in the cytosol (C) A single drug-receptor interaction results in many cellular response elements being activated (D) Spare receptors are active even in the absence of agonist (E) Agonist affinity for spare receptors is less than their affinity for non-spare receptors Answer: C. One explanation for the existence of spare receptors is that any one agonistreceptor binding event can lead to the activation of many more cellular response elements.Thus, only a small fraction of the total receptors need to be bound to elicit a maximum cellular response. 31. Several studies have indicated that about 90% of β adrenoceptors in the heart are spare receptors. Which of the following statements about spare receptors is most correct? (A) Spare receptors, in the absence of drug, are sequestered in the cytoplasm (B) Spare receptors may be detected by finding that the drug-receptor interaction lasts longer than the intracellular effect (C) Spare receptors influence the maximal efficacy of the drug-receptor system (D) Spare receptors activate the effector machinery of the cell without the need for a drug (E) Spare receptors may be detected by the finding that the EC50 is smaller than the Kd for the agonist Answer: E. Although some types of receptors appear to be sequestered in the cytoplasm under certain conditions, there is no difference between “spare” and other receptors. Spare receptors may be defined as those that are not needed for binding drug to achieve the maximum effect. Spare receptors influence the sensitivity of the system to an agonist because the statistical probability of a drug-receptor interaction increases with the total number of receptors. They do not alter the maximal efficacy. If they do not bind an agonist molecule, spare receptors do not activate an effector molecule. EC50 (the dose produces 50% of the maximal effect) less than Kd (the dose 50% of receptors are occupied) is an indication of the presence of spare receptors. Quantal-Dose Response Curves 32. Graded and quantal dose-response curves are used for drug evaluation in the animal laboratory and in the clinic. Which of the following statements best describes quantal doseresponse covers? (A) More precisely quantitated than ordinary-graded dose-response curves (B) Obtainable from the study of intact subject but not from isolated tissue preparations (C) Used to determine the maximal efficacy of a drug (D) Used to determine the statistical variation (standard deviation) of the maximal response to the drug (E) Used to determine the therapeutic index of a drug Answer: E. Graded (not quantal) dose-response curves must be used to determine maximum efficacy (maximum response). Quantal dose-response curves show only the frequency of occurrence of a specified response, which may be therapeutically effective (ED) or toxic (TD). Dividing the TD50 by the ED50 (both obtained from quantal doseresponse curves) gives the therapeutic index.33. Variation in the sensitivity of a population of individuals to increasing doses of a drug is best determined by which of the following? (A) Efficacy (B) Potency (C) Therapeutic index (D) Graded dose-response curve (E) Quantal dose-response curve Answer: E. Only a quantal dose-response curve gives information about differences in the sensitivity of individuals to increasing doses of a drug. 34. Which of the following provides information about the variation in sensitivity to a drug within the population studied? (A) Drug potency (B) Graded dose-response curve (C) Maximal efficacy (D) Quantal dose-response curve (E) Therapeutic index Answer: D. Quantal dose-response curves provide information about the statistical distribution of sensitivity to a drug. Therapeutic Index/Window 35. Which of the following is the correct definition for the range of doses that have a high probability of therapeutic success? (A)Therapeutic index (B) Efficacy (C) Potency (D)Therapeutic window (E) Intrinsic activity Answer: D. Therapeutic index is the ratio, TD50/ED50, thus it is not the range of dose. 36. Which of the following parameters is used to indicate the ability of a drug to produce the desired therapeutic effect relative to a toxic effect? (A) Potency (B) Intrinsic activity (C) Therapeutic index (D) Efficacy (E) Bioavailability Answer: C. Lithium is an example of drug with a very low therapeutic index, which requires frequent monitoring of the plasma level to achieve the balance between the desired effect and untoward toxicity. Potency of the drug is the amount of drug needed to produce a given response. Intrinsic activity of the drug is the ability to elicit a response. Efficacy of the drug is the maximal drug effect that can be achieved in a patient under a given set of conditions. Bioavailability of the drug is the fraction of the drug that reaches the bloodstream unaltered.Agonist/Antagonist 37. Which of the following terms best describes a drug that blocks the action of epinephrine at its vascular α receptors by occupying the epinephrine receptor-binding sites without activating them? (A) Allosteric antagonist (B) Chemical antagonist (C) Inverse agonist (D) Pharmacologic antagonist (E) Physiologic antagonist Answer: D. A pharmacologic antagonist occupies the agonist receptor sites without activating them. 38. Which of the following names best describes an antagonist that interacts directly with the agonist and not at all, or only incidentally, with the receptor? (A) Chemical antagonist (B) Noncompetitive antagonist (C) Partial agonist (D) Pharmacologic antagonist (E) Physiologic antagonist Answer: A. A chemical antagonist interacts directly (chemically) with the agonist drug and not with a receptor. 39. Leukotrienes cause bronchoconstriction (mediated at leukotriene receptors) in a patient with asthma. When albuterol (acting at β adrenoceptors) is given to the patient during an asthma attack, bronchodilation usually results. Which of the following expressions best describes the action of albuterol in this situation? (A) Chemical antagonist (B) Noncompetitive antagonist (C) Partial agonist (D) Pharmacologic antagonist (E) Physiologic antagonist Answer: E. Because albuterol interacts with adrenoceptors and leukotriene with leukotriene receptors, albuterol cannot be a pharmacologic antagonist of leukotriene. Because the results of adrenoceptors activation oppose the effects of leukotriene receptor activation, albuterol must be a physiologic antagonist. 40. Which of the following is an action of a noncompetitive antagonist? (A) Alters the mechanism of action of an agonist (B) Alters the potency of an agonist (C) Shifts the dose-response curve of an agonist to the right (D) Decreases the maximum response to an agonist (E) Binds to the same site on the receptor as the agonistAnswer: D. A noncompetitive antagonist decreases the magnitude of the response to an agonist but does not alter the agonist’s potency (i.e., the ED50 remains unchanged). A competitive antagonist interacts at the agonist binding site. 41. Which of the following statements is correct? (A) If 10 mg of Drug A produces the same response as 100 mg of Drug B, Drug A is more efficacious than Drug B (B) The greater the efficacy, the greater the potency of a drug (C) In selecting a drug, potency is usually more important than efficacy (D) A competitive antagonist increases the ED50 (E) Variation in response to a drug among different individuals is most likely to occur with a drug showing a large therapeutic index Answer: D. In the presence of a competitive antagonist, a higher concentration of drug is required to elicit a given response. Efficacy and potency can vary independently, and the maximal response obtained is often more important than the amount of drug needed to achieve it. For example, in Choice A, no information is provided about the efficacy of Drug A, so all one can say is that Drug A is more potent than Drug B. Variability between patients in the pharmacokinetics of a drug is most important clinically when the effective and toxic doses are not very different, as is the case with a drug that shows a small therapeutic index. 42. A drug X has an intrinsic activity of 40%. X is most likely a… (A)Partial agonist (B) Competitive antagonist (C) Full agonist (D)Functional antagonist (E) Non-competitive antagonist Answer: A. Intrinsic activity denotes the ability of a drug to “activate” (cause a conformational change) the receptor. A drug with a reduced ability to activate the receptor is classified as a partial agonist. A full agonist has 100% intrinsic activity and an antagonist has no intrinsic activity. 43. In the absence of other drugs, pindolol causes an increase in heart rate by activating β adrenoceptors. In the presence of highly effective β stimulants, however, pindolol causes a dose-dependent, reversible decrease in heart rate. Which of the following expressions best describes pindolol? (A) A chemical antagonist (B) An irreversible antagonist (C) A partial agonist (D) A physiologic antagonist (E) A spare receptor agonistAnswer: C. Choices involving chemical or physiologic antagonism are incorrect because pindolol is said to act at β receptors and to block β stimulants. The drug effect is reversible, so choice B is incorrect. “Spare receptor agonist” is a nonsense distracter. 44. Two new drugs X and Y are tested for their ability to contract the guinea pig ileum and a dose-response curve is plotted for both drugs. A sigmoid plot of the results shows that the slope of each is the same and that both have the same maximal efficacy. Which of the following best categorizes these two drugs? (A)X is a full agonist, Y is a partial agonist (B) X is a full agonist, Y is a competitive antagonist (C) X is a full agonist, Y is a full agonist (D)X is a partial agonist, Y is a full agonist (E) X is a partial agonist, Y is a competitive antagonist Answer: C. Both drugs produced an effect, thus they are agonist. Since both have the same maximal efficacy, if drug X is said to be a full agonist, drug Y is so too. Since they had the same slope, their potencies and EC50s are the same also. 45. A drug X was tested, in varying doses, on the guinea pig ileum and the - - - - - - - - - - - - - - - - - - - - - - - - - - - - not its class (E) Peaks at around age 18 to 20 years, with half-lives being much longer at younger or older ages Answer: D. How (or even whether) age or extremes of age affects the overall elimination half-life of a drug (and thus the right dose and dosing interval) depends on what the drug is. While renal function or a measure of it such as creatinine clearance (choice B) change over certain age ranges, it is not universally applicable to the elimination or elimination rates of all drugs. Remember that many drugs are completely metabolized to inactive substances, and so changes of renal function are largely unimportant in the elimination (and plasma half-lives) of such drugs.104.A new drug was administrated intravenously, and its plasma levels were measured for several hours. A graph was prepared as shown below, with the plasma levels plotted on a logarithmic ordinate and time on a linear abscissa. It was concluded that the drug has firstorder kinetics. From this graph, what is the best estimate of the half-life? (A) 0.5 h (B) 1 h (C) 3 h (D) 4 h (E) 7 h Answer: C. Drugs with first-order kinetics have constant half-lives, and when the log of the concentration in a body compartment is plotted versus time, a straight line results. The half-life is defined as the time required for the concentration to decrease by 50%. As shown in the graph, the concentration decreased from 16 units at 1 h to 8 units at 4 h and 4 units at 7 h; therefore the half-life is 4 h minus 1 h or 3 h. 105.Administration of an IV loading dose to a patient of drug X yields an initial plasma concentration of 100 mcg/L. The table below illustrates the plasma concentration of X as a function of time after the initial loading dose. What is the half-life (in hours) of drug X? Time (hours) Plasma Conc. (mcg/L) 0 100 1 50 5 25 9 12.5 (A) 1 (B) 2 (C) 4 (D) 5 (E) 9Answer: C. Inspection of the plasma concentration values indicates that the half-life of drug does not become constant until 1-9 hours after administration. The drug concentration decreases by 1/2 (from 50 to 25 mcg/L) between 1 and 5 hours (a 4-hour interval) and again decreases by 1/2 (from 25 to 12.5 mcg/L) between 5 and 9 hours (again, a 4-hour interval). This indicates the half-life of the drug is 4 hours. The rapid decrease in plasma concentration between 0 and 1 hour, followed by a slower decrease thereafter (and the constant half-life thereafter) indicates that this drug obeys a two-compartment model with an initial distribution phase followed by an elimination phase. The half-life is always determined from the elimination phase data. 106.A patient was given a 160-mg dose of a drug IV, and 80 mg was eliminated during the first 120 minutes. If the drug follows first-order elimination kinetics, how much of the drug will remain 6 hours after its administration? (A) None (B) 10 mg (C) 20mg (D) 40 mg (E) 60 mg Answer: C. One half of the drug dose is eliminated in 120 min, so its elimination half-life = 2 hours. With the passage of each half-life, the amount in the body (or in the blood) will decrease to 50% of a former level. Thus, at 6 hours after drug administration, the amount of drug remaining is 160 divided by (2×2×2) or 160/8 = 20 mg. 107.A drug achieves a plasma level of 16 mg/L shortly after the administration of the first oral dose. If the half-life and the dosing interval are both 6 hours, what is the approximate plasma level shortly before the administration of the 5th dose? (A) 15 mg/L (B) 24 mg/L (C) 28 mg/L (D) 30 mg/L (E) 31 mg/L Answer: A. The key word in this question is before the 5th dose. Immediately “after” the 5th dose, the plasma level should be approximately 30 mg/L, but just before it would be close to half of that level. 108.Despite your careful adherence to basic pharmacokinetic principles, your patient on digoxin therapy has developed mild digitalis toxicity. The plasma digoxin level is now 4 ng/mL. Renal function is normal, and the plasma t1/2 for digoxin in this patient is 1.5 days. How long should you withhold digoxin to reach a safer yet probably therapeutic level of 1 ng/mL? (A) 1.5 days (B) 2.5 days (C) 3 days (D) 5 days (E) 6 days Answer: C. Since the blood level for a drug with first-order kinetics drops by 50% during each half-life, the level will be 2 ng/mL after 1.5 days and 1 ng/mL after 3 days. After 3days, you might restart dioxin administration at a lower dosage. 109.A patient who is supposed to be taking a drug once a day gets confused and for a couple of days takes excessive daily doses, leading to toxicity. The drug has a mean plasma half-life of 40 hours. Right now, the patient’s plasma concentration of the drug is 6 mcg/mL. although what to do next will depend on actual blood tests for drug levels the usual plan in this case is to have the patient skip one or several daily doses of the drug unit blood levels first enter the therapeutic and nontoxic range, which in this case is 0.8 mcg/mL. Assume the drug is eliminated by first-order kinetics. How much daily doses should be withheld? (A) 1 (B) 2 (C) 3 (D) 4 (E) 5 Answer: E. After a 40-hour (about 1.67 days) drug-free interval passes the concentration of the drug will fall, as predicted by the half-life, to 3 mcg/mL; to 1.5 mcg/mL 40 hours after that; and to 0.75 mcg (now in the nontoxic range) after yet another 40 hours pass. Thus we have to wait 120 hours, or 5 daily doses skipped, to achieve our goal. Half-Lives of Drugs (Calculation) 110.In a patient weighing 70 kg, acetaminophen has a Vd = 70 L and Cl = 350 mL/min. The elimination half-life of the drug is approximately (A) 35 min (B) 70 min (C) 140 min (D) 210 min (E) 280 min Answer: C. Use the relationship: T1/2 = (Make sure that all units are the same.) = = = 140 min 111.A normal volunteer will receive a new drug in a phase I clinical trial. The clearance and Vd of the drug in this subject are 1.386 L/h and 80 L, respectively. What is the predicted halflife of the drug in this subject? (A) 83 h (B) 77 h (C) 58 h (D) 40 h (E) 0.02 h Answer: D. Half-life can be estimated from… t1/2 = Vd × = 80 L × = 80 L × = 40h112.A drug has a volume of distribution of 50 L and undergoes zero-order elimination at a rate of 2 mg/hour at plasma concentrations greater than 2 mg/L. If a patient is brought to the ER with a plasma concentration of 4 mg/L of the drug, how long will it take (in hours) for the plasma concentration to decrease 50%? (A) 1 (B) 2 (C) 10 (D) 25 (E) 50 Answer: E. For the plasma concentration of drug to decrease by 50%, half the drug present in the body initially must be eliminated. The amount of drug in the body initially is the volume of distribution × the plasma concentration (50 liters × 4 mg/liter = 200 mg). When the plasma concentration falls to 2 mg/liter, the body will contain 100 mg of drug (50 L × 2 mg/L = 100 mg). Since the body eliminates the drug at a rate of 2 mg/hour, it will require 50 hours for 100 mg of the drug to be eliminated. Steady-State 113.If the oral dosing rate of a drug is held constant, what will be the effect of increasing the bioavailability of the preparation? (A) Increase the half-life for first-order elimination (B) Decrease the first-order elimination rate constant (C) Increase the steady-state plasma concentration (D) Decrease the total body clearance (E) Increase the volume of distribution Answer: C. If the oral dosing rate is constant but bioavailability increases, the fraction of the administered dose that reaches the general circulation unaltered increases. This, in turn, will increase the steady-state plasma concentration. 114.You administer to a patient an oral maintenance dose of drug calculated to achieve a steadystate plasma concentration of 5 mcg/L. After dosing the patient for a time sufficient to reach steady state, the average plasma concentration of drug is 10 mcg/L. A decrease in which of the following parameters explains this higher than anticipated plasma drug concentration? (A) Bioavailability (B) Volume of distribution (C) Clearance (D) Half-life Answer: C. Steady-state plasma concentration of drug = (dose rate)/(clearance). Thus, a decrease in clearance will increase the plasma drug concentration, whereas an increase in any of the other three parameters will decrease the steady state plasma concentration.115.What is the main determinant of how long it will take for blood levels of IV drug to reach steady-stare (plateau; no change of mean blood levels over time)? (A) Bioavailability of the drug (B) Concentration of drug in the solution that will be infused (C) Half-life of the drug (D) Presence or absence of cardiovascular or renal disease (E) Plasma creatinine concentration (or creatinine clearance) (F) Total dose per 24 hours (G) Volume of drug administered per minute Answer: C. With intravenous infusions of a drug, only the drug’s half-life determines how long it will take for blood levels to reach a steady state (on average, neither rising nor falling thereafter) so long as the infusion rate is not changed. By definition, when steady state is reached, the amount of drug entering the blood per unit time is equal to the rate at which drug is being eliminated, whether by excretion, metabolism, or a combination of both (depending on the drug). The apparent volume of distribution has no impact on time to Css. Bioavailability does not either, because with IV drug administration the bioavailability is 1.0 (100%). Clearance, a parameter that relates elimination rate of a drug to the drug’s concentration (Cl = rate of elimination [mg/h]/drug concentration [mg/mL]). Because clearance considers a rate of drug elimination, it affects the Css but it is not a determinant of it. The infusion rate clearly affects the blood concentration reached at steady state, but it does not affect the time needed to reach it. 116.You administer a 100 mg tablet of drug X to a patient every 24 hours and achieve an average steady-state plasma concentration of the drug of 10 mg/L. If you change the dose regimen to one 50 mg tablet every 12 hours, what will be the resulting average plasma concentration (in mg/L) of the drug after five half-lives? (A) 2.5 (B) 5 (C) 10 (D) 20 (E) 40 Answer: C. A 100 mg tablet every 24 hours is a dose rate of 4.17 mg/hour (100/24 = 4.17), which is the same dose rate as one 50 mg tablet every 12 hours (50/12 = 4.17). Thus, the average plasma concentration will remain the same, but decreasing both the dose and the dose interval will decrease the peak to trough variation of plasma concentration.Time to Reach Steady-State Plasma Concentration (Css, Cpss) 117.We are repeatedly administering a drug orally. Every dose is 50 mg; the interval between doses is 8 hours, which is identical to the drug’s plasma (overall elimination) half-life. The bioavailability is 0.5. For as long as the drug is administered no interacting drugs are added or stopped, and there are no applicable factors affecting such things as absorption or elimination that might change the drug’s pharmacokinetics. Which formula gives the best estimate of how long it will take for the drug to reach steady-state plasma concentrations (Css)? Abbreviations: Cl = clearance (mL/min) D = dose (mg) F = bioavailability ke= elimination rate constant t1/2 = half-life (h) Vd = volume of distribution (A) (0.693 × Vd)/Cl = (t1/2) (B) 1/ke (C) 4.5 × t1/2 (D) (t1/2) × (ke) (E) D/(F × t1/2) Answer: C. If you give doses of a drug repeatedly at intervals that are equal to or less than the drug’s overall elimination half-life, and keep every other pertinent variable constant (dose, route, elimination status, etc.), you simply multiply the half-life by 4 or 5 (hence, my use of 4.5 to take a middle ground) to arrive at the approximate time until Css, the time at which “drug in = drug out” is reached. The figure below shows what happens with repeated administration of a drug at intervals equal to the drug’s half-life. Note that the average plasma concentration (Cav) does not appear to “flatten out,” or reach a plateau, until at least 4 doses (= 4 half-lives) have been given. After that, and assuming nothing else changes (dose, dose interval, route of administration, elimination kinetics, starting or stopping other drugs), although there will st - - - - - - - - - - - - - - - - - - - - - - - - - -rug? (A) Doubling the rate of infusion (B) Maintaining the rate of infusion but doubling the loading dose (C) Doubling the rate of infusion and doubling the concentration of the infused drug (D) Tripling the rate of infusion (E) Quadrupling the rate of infusion Answer: A. The steady-state concentration of a drug is directly proportional to the infusion rate. Increasing the loading dose provides a transient increase in drug level, but the steadystate level remains unchanged. Doubling both the rate of infusion and the concentration of infused drug leads to a four-fold increase in the steady-state drug concentration. Tripling or quadrupling the rate of infusion leads to either a three- or four-fold increase in the steadystate drug concentration.128.A pharmacologically inert but easily measured substance, X, is eliminated in a manner that follows linear kinetics (first-order; plot of log drug concentration vs time during elimination is a straight line), The plasma half-life is 30 minutes. Bolus IV doses well in excess of 100 mg must be given in order to saturate the enzymes responsible for metabolizing the drug, which will then lead to zero-order elimination kinetics. We infuse a solution of X intravenously. The concentration of the solution is 2 mg/mL; the infusion rate is 1 mL/min and is kept constant at that. We continue the infusion for 24 hours. After allowing ample time for the drug to be eliminated completely we repeat the administration. This time the concentration of the solution of X is 4 mg/mL, and we infuse it at a rate of 2 mL/min. Which other variable will also be changed as a result of the stated changes to the infusion protocol? (A) Elimination rate constant (B) Half-life (C) Plasma concentration when Css is reached (D) Time to reach steady-state concentration (Css) (E) Total body clearance (F) Volume of distribution Answer: C. Only the drug concentration at steady state will change: it will be greater with this altered protocol. Do not be misled by the numbers. The time to reach Css with a constant drug infusion is a function of half-life (or the elimination rate constant, which is related to it: kel = 0.693/t1/2), and that will not change under the conditions stated. Likewise, with the vast majority of drugs eliminated by first-order kinetics, there will be no change of total body clearance or of volume of distribution. 129.A patient with a bacterial infection requires intravenous antibiotic therapy. The chosen drug has a clearance of 70 mL/min. the apparent volume of distribution is 50 L. The plan is to administer the drug intravenously every 6 hours and achieve a 4 mg/L steady-state blood level of the drug. No loading dose strategy is to be used. What maintenance dose is needed achieve this? (A) 14 mg (B) 24 mg (C) 100mg (D) 300 mg (E) 1,200 mg Answer: C. Steady-state blood levels occur when the rate of “drug in” equals the rate of “drug out.” The volume of distribution, given in the question, is irrelevant for the calculations. The rate of drug out is given as a Cl = 70 mL/min Recall that the dose (D) = Cl × CssTherefore, with a little rearranging, the dose can be computed as: Desired plasma level = Cl × Css = 70 mL/min × 4 mg/L = 0.28 mg/min = 0.28 mg/min × 60 min/h × 6 h = 100.8 mg 130.Mr. Jones is receiving tobramycin, and its clearance and Vd are 80 mL/min and 40 L What maintenance dose should be administered intravenously every 6 h to eventually obtain average steady-state plasma concentrations of 4 mg/L? (A) 0.32 mg (B) 19.2 mg (C) 115 mg (D) 160 mg (E) 230 mg Answer: C. Maintenance dosage is a function of the target steady-state plasma level, bioavailability, and clearance only: Rate in = Rate out at steady state Dosage = = = 0.32 mg/min The arithmetic is correct to this point, but the drug is to be given at 6-h intervals, thus, Dosage = 0.32 mg/min × 60 min/h × 6 h = 115.2 mg/dose every 6 hours. 131.A postoperative patient will require prolonged analgesia. We choose a drug that has the following pharmacokinetic properties: Half-life: 12 hours Clearance: 0.08 L/min Volume of distribution: 60 L The patient has an indwelling venous catheter with a slow drip of 0.9% NaCl, and we will use this to administer intermittent injections of the drug every 4 hours. The target blood level of the drug, following each injection, is 8 mcg/mL. With this plan in mind, and using no loading dose of the drug, which one of the following comes closest to the dose that should be administered every 4 hours? (A) 0.960 mg (or 1 mg) (B) 6.4 mg (or 6 mg) (C) 25.6 mg (or 25 mg) (D) 150 mg (E) 550 mg Answer: D. The dose (D) to give equals the product of the target blood concentration and the drug’s clearance: D = Cdesired × Cl. To simplify things, let’s make the units of volume the same for both clearance and concentration. The clearance of 0.08 L/min = 80 mL/min. Therefore, D = 8 mcg/mL × 80 mL/min = 640 mcg/min = 640 mcg/min × 60 min/h × 4 h= 153,500 mcg = ~150 mg.132.A 60-year-old man with rheumatoid arthritis will be started on a nonsteroidal antiinflammatory drug (NSAID) to suppress the joint inflammation. Published pharmacokinetic data for this drug include: Bioavailability (F): 1.0 (100%) Plasma half-life (t1/2) = 0.5 hour Apparent volume of distribution (Vd): 45 L For this drug it is important to maintain an average plasma steady-state concentration of 2.0 mcg/mL in order to ensure adequate and continued anti-inflammatory activity. The drug will be taken every 4 hours. What dose will be needed to obtain this 2 mcg/mL average steady-state drug concentration? (A) 5 mg (B) 100 mg (C) 325 mg (D) 500 mg (E) 625 mg Answer: D. Calculate the drug’s elimination rate constant: ke = 0.693/t1/2 = 0.693/0.5 h = 1.386/h Then calculate the clearance: Cl = ke × Vd = 1.386/h × 45 L = 62.37 L/h Recall that: Cave = (Bioavailability (F)/Cl) × (Dose (D)/dosing interval (t)) Rearrange to solve for the dose: D = (Cave × Cl × t)/F = [(2 mcg/mL) × (62370 mL/h) × 4h]/1.0 = 499,000 mcg, or 499 mg (close enough to 500 mg). 133.An IV infusion of a drug is started at 400 mg/h. If Cl = 50 L/h, what is the anticipated plasma level at steady state? (A) 2 mg/L (B) 4 mg/L (C) 8 mg/L (D) 16 mg/L (E) 32 mg/L Answer: C. An infusion rate (k0), which is a “maintenance dose”, is given by: k0 = Cl × Css → rearrange Css = k0/Cl = = 8 mg/L 134.A 74-year-old retired mechanic is admitted with a myocardial infarction and a severe acute cardiac arrhythmia. You decide to give lidocaine to correct the arrhythmia. A continuous intravenous infusion of lidocaine, 1.92 mg/min, is started at 8 AM. The average pharmacokinetic parameters of lidocaine are: Vd = 77 L; clearance = 640 mL/min; half-life = 1.4 h. What is the expected steady-state plasma concentration? (A) 40 mg/L (B) 3.0 mg/L (C) 0.025 mg/L (D) 7.2 mg/L (E) 3.46 mg/L Answer: B. The drug is being administered continuously and the steady-state concentration (Cpss) for a continuously administered drug is given by the equation; Dosage = Plasmalevelss × Clearance → 1.92 mg/min = Cpss × 640 mL/min → CPss = = 0.003 mg/mL or 3 mg/L Metabolisms 135.Which of the following pairs of properties are drug metabolites most likely to possess? (A)Decreased water solubility, increased pharmacological activity (B) Increased toxic potential, no pharmacological activity (C) Decreased water solubility, increased pharmacological activity (D)Increased water solubility, no pharmacological activity (E) Increased water solubility, increased toxic potential Answer: D. Often, metabolism increases the metabolite’s water solubility (so that it is easier to excreted renally) and inactivate it (so that it won’t damage while waiting to be eliminated). It is not the case all the time though. For next two questions. You are planning to treat asthma in a 19-year-old patient with recurrent, episodic attacks of bronchospasm with wheezing. You are concerned about drug interactions caused by changes in drug metabolism in this patient. 136.Drug metabolism in humans usually results in a product that is… (A) Less lipid soluble than the original drug (B) More likely to distribute intracellularly (C) More likely to be reabsorbed by kidney tubules (D) More lipid soluble than the original drug (E) Less water soluble than the original drug Answer: A. Biotransformation usually results in a product that is less lipid-soluble. This is needed to eliminate drugs that would otherwise be reabsorbed from the renal tubule. 137.If therapy with multiple drugs causes induction of drug metabolism in your asthma patient, it will… (A) Be associated with increased smooth endoplasmic reticulum (B) Be associated with increased rough endoplasmic reticulum (C) Be associated with decreased enzymes in the soluble cytoplasmic fraction (D) Require 3-4 months to reach completion (E) Be irreversible Answer: A. The smooth endoplasmic reticulum, which contains the mixed function oxidasedrug-metabolizing enzymes, is selectively increased by inducers. Biotransformation (Phase I) 138.Which of the following is a phase I drug metabolism reaction? (A) Acetylation (B) Glucuronidation (C) Methylation (D) Reduction (E) Sulfation Answer: D. The reductive biotransformation of certain drug molecules containing aldehyde, ketone, or nitro groups can be catalyzed by cytochrome P450, and such reactions represent phase I drug metabolism. Phase II drug metabolism involves the transfer of chemical groupings (e.g., acetyl, glucuronide, glutathione) to drugs or their metabolites via conjugation reactions. 139.A new drug, drug A, undergoes a series of Phase I reactions before its metabolites ultimately are eliminated. Which statement best describes the characteristics of drug A, or the role of Phase I reactions in its metabolism or actions? (A) Complete metabolism of drug A by Phase I reactions will yield products that are less likely to undergo renal tubular reabsorption (B) Drug A is a very polar substance (C) Drug A will be biologically inactive until it is metabolized (D) Phase I metabolism of drug A involves conjugation, as with glucuronic acid or sulfate (E) Phase I metabolism of drug A will increase its intracellular access and actions Answer: A. Phase I metabolic reactions generally convert (via addition or unmasking of such polar functional groups as -NH2 or –OH through, say, oxidations, reductions, or deamination) very nonpolar (i.e., very lipid-soluble) drugs into more polar (more watersoluble) metabolites. Among other things, polar metabolites of drugs, in general, are less likely to undergo tubular reabsorption. We can generalize by saying that Phase I reactions play a role in forming metabolites that are “more easily excreted.” lf drug A, the parent drug, was already very polar (choice B), there would be little need for Phase I metabolism There is no reason to assume that drug A will lack intrinsic biological activity (choice C); and because it is quite lipid-soluble to begin with, once in the circulation it should have good ability to diffuse across membranes and reach intracellular sites (choice E). Finally note that those reactions described as Phase II that further increase polarity (watersolubility) of some drugs via forming conjugates with glucuronic acid or sulfate.140.Verapamil and phenytoin are both eliminated from the body by metabolism in the liver. Verapamil has a clearance of 1.5 L/min, approximately equal to liver blood flow, whereas phenytoin has a clearance of 0.1 L/min. When these compounds are administered along with rifampin, a drug that markedly increases hepatic drug-metabolizing enzymes, which of the following is most likely? (Hint: verapamil’s elimination is perfusion limited.) (A) The half-lives of both verapamil and phenytoin will be markedly increased (B) The clearance of both verapamil and phenytoin will be markedly decreased (C) The clearance of verapamil will be unchanged, whereas the clearance of phenytoin will be increased (D) The half-life of phenytoin will be unchanged, whereas the half-life of verapamil will be increased (E) The clearance of both drugs will be unchanged Answer: C. Verapamil is metabolized so readily that only the rate of delivery to the liver regulates its disappearance; that is, its elimination is blood flow-limited, not metabolismlimited. Therefore, further increases in liver enzymes could not increase its elimination. However, the rate of elimination of phenytoin is limited by its rate of metabolism since clearance is much less than hepatic blood flow. Therefore, the clearance of phenytoin can rise if some other agent causes an increase in liver enzymes. P-450 Inducers & Inhibitors 141.Which subfamily of cytochrome P-450s is responsible for the highest fraction of clinically important drug interactions resulting from metabolism? (A) CYP1A (B) CYP2A (C) CYP3A (D) CYP4A (E) CYP5A Answer: C. the CYP3A subfamily is responsible for roughly 50% of the total cytochrome P450 activity present in the liver and is estimated to be responsible for approximately 12 of all clinically important untoward drug interactions resulting from metabolism. 142.A drug is administered in the form of an inactive pro-drug. The pro-drug increases the expression of a cytochrome P-450 that converts the pro-drug to its active form. With chronic, long-term administration of the pro-drug, which of the following will be observed? (A) The potency will decrease (B) The potency will increase (C) The efficacy will decrease (D) The efficacy will increase Answer: B. the induction of the cytochrome P-450 following chronic administration will increase the conversion of the inactive pro-drug to the active form. This will shift the doseresponse curve of the pro-drug to the left (i.e., increase its potency) without changing its efficacy.143.With chronic administration, which one of the following drugs is LEAST likely to induce the formation of hepatic microsomal drug-metabolizing enzymes? (A) Carbamazepine (B) Ethanol (C) Ketoconazole (D) Phenobarbital (E) Rifampin Answer: C. Azole antifungals (e.g., ketoconazole) are inhibitors of cytochrome P450, especially CYP3A4, the most abundant isozyme form in human liver, which metabolizes a wide range of drugs. All of the other drugs listed are known to be inducers of cytochrome P450 with chronic use. 144.Reports of cardiac arrhythmias caused by unusually high blood levels of 2 antihistamines, terfenadine and astemizole, led to their removal from the market. Which of the following best explains these effects? (A) Concomitant treatment with phenobarbital (B) Use of these drugs by smokers (C) A genetic predisposition to metabolize succinylcholine slowly (D) Treatment of these patients with ketoconazole, an azole antifungal agent Answer: D. Treatment with phenobarbital and smoking are associated with increased drug metabolism and lower, not higher, blood levels. Ketoconazole, itraconazole, erythromycin, and some substances in grapefruit juice slow the metabolism of certain older non-sedating antihistamines. 145.Which of the following factors is likely to increase the duration of action of a drug that is metabolized by CYP3A4 in the liver? (A) Chronic administration of phenobarbital before and during therapy with the drug in question (B) Chronic therapy with cimetidine (C) Displacement from tissue-binding sites by another drug (D) Increased cardiac output (E) Chronic administration of rifampin Answer: B. Phenobarbital and rifampin can induce drug-metabolizing enzymes and thereby may reduce the duration of drug action. Displacement of drug from tissue may transiently increase the intensity of the effect but decreases the volume of distribution. Cimetidine is recognized as an inhibitor of P450 and may also decrease hepatic blood flow under some circumstances.146.Which of the following drugs may inhibit the hepatic microsomal P450 responsible for warfarin metabolism? (A) Amiodarone (B) Ethanol (C) Phenobarbital (D) Procainamide (E) Rifampin Answer: A. Amiodarone is an important antiarrhythmic drug and has a well-documented ability to inhibit the hepatic metabolism of many drugs. 147.Which of the following agents, when used in combination with other anti-HIV drugs, permits dose reductions? (A) Cimetidine (B) Efavirenz (C) Ketoconazole (D) Procainamide (E) Quinidine (F) Ritonavir (G) Succinylcholine (H) Verapamil Answer: F. Ritonavir inhibits hepatic drug metabolism, and its use at low doses in combination regimens has permitted dose reductions of other HIV protease inhibitors (e.g., indinavir). Biotransformation (Phase II) 148.Which of the following is a phase II drug-metabolizing reaction? (A) Acetylation (B) Deamination (C) Hydrolysis (D) Oxidation (E) Reduction Answer: A. Acetylation is a phase II conjugation reaction. 149.The elimination of a drug and its numerous metabolites is described as being heavily dependent on Phase II metabolic reactions. Which of the following is a Phase II reaction? (A) Glucuronidation (B) Decarboxylation (C) Ester hydrolysis (D) Nitro reduction (E) Sulfoxide formation Answer: A. Biotransformation reactions involving the oxidation, reduction, or hydrolysis of a drug are classified as Phase I (or nonsynthetic) reactions, examples of which are noted in choice B, C, D, and E. In general, these reactions may result in either the activation (as in the case of a prodrug) or, much more commonly, the inactivation of a pharmacologic agent. Phase II reactions involve conjugation of the drug (or its metabolites) with an amino acid, carbohydrate, acetate, sulfate-or glucuronic acid as noted in the question. The conjugated form(s) of the drug or its derivatives are more easily excreted than the parent compound.150.The addition of glucuronic acid to a drug: (A) Decreases its water solubility (B) Usually leads to inactivation of the drug (C) Is an example of a Phase I reaction (D) Occurs at the same rate in adults and newborns (E) Involves cytochrome P450 Answer: B. The addition of glucuronic acid prevents recognition of the drug by its receptor. Glucuronic acid is charged, and the drug conjugate has increased water solubility. Conjugation is a Phase II reaction. Neonates are deficient in the conjugating enzymes. Cytochrome P450 is involved in Phase I reactions. 151.Glucuronidation reactions… (A) Are considered phase I reactions (B) Require an active center as the site of conjugation (C) Include the enzymatic activity of alcohol dehydrogenase (D) Located in mitochondria are inducible by drugs (E) Require nicotinamide adenine dinucleotide phosphate (NAPDH) for the enzymatic reaction Answer: B. Glucuronidation reactions, which are considered phase II reactions, require an active center (a functional group) as the site of conjugation. Phase I reactions are biotransformation reactions, not conjugation reactions. Alcohol dehydrogenase is an example of a phas