Principles Of Pharmacology 2 Flashcards
(23 cards)
Answer E
Antagonists are agents that bind to but do not activate receptors. Antagonists can be either competitive or noncompetitive. Competitive antagonists bind to the exact same receptor binding sites as endogenous or exogenous agonists, thereby preventing agonist binding and activation of the receptor. Competitive antagonism can be reversible (ionic bond) or irreversible (covalent bond). The effect of a reversible competitive antagonist can be overcome by high concentrations of agonist, which cause displacement of the antagonist from the receptors by mass action.
Noncompetitive antagonists, on the other hand, bind to receptors at a site other than the primary agonist binding site, thereby causing a conformational (allosteric) change in the receptor protein that modifies the agonist binding site and prevents agonist binding. By binding to a different site than the agonist, noncompetitive antagonists are able to remain bound to the receptor even when high concentrations of agonist are present because the agonist is unable to displace noncompetitive antagonists from the receptor.
The question has asked how the curve for bethanechol (Curve A) would be affected by the introduction of a reversible competitive antagonist. A reversible competitive antagonist is expected to require higher doses of the full agonist (bethanechol) to be present to achieve the same effect at each point along the curve. If enough of the original substrate is added, the reaction can still reach the same maximum effect. Thus, the log dose-response curve for a full agonist combined with a reversible competitive antagonist will exhibit a parallel shift to the right in the log-dose response curve, with an increase in the ED50 and no change in the maximum effect (Emax).
(Choice A) Curve A is the dose-response curve for the original agonist drug in the absence of modifiers such as antagonists.
(Choices B and C) Both Curves B and C represent the effect of adding a noncompetitive antagonist to the agonist. Note that the ED50 is unchanged (i.e. the ED50 for Curves A, B and C occur at the exact same log drug concentration). This is a distinguishing characteristic of noncompetitive antagonism. The maximum effect (Emax) of Curves B and C are reduced because the noncompetitive antagonist has effectively reduced the number of receptors available for binding. The decrease in Emax will depend on the dose of noncompetitive antagonist present and is illustrated by the difference between Curves B and C, where a higher concentration of antagonist is present in Curve C than in Curve B.
(Choice D) Curve D illustrates a rightward shift in the dose-response relationship, but the shift is not a parallel shift because the shape of the curve differs from that of Curve A, with changes in both Emax and ED50. This curve is not characteristic of any single antagonist effect and may be the result of adding multiple types of antagonists.
Educational Objective:
The changes in the log dose-response curve expected for the effect of a reversible competitive antagonist added to a full agonist are: 1) a parallel shift to the right in the log-dose response curve, illustrating an increase in the ED50, and 2) no change in the maximum effect (Emax).
- Competitive=change ED50=shift right; noncompetitive=change Emax=shift down.
Answer C
This patient who took large quantities of a pain medication initially had nausea and vomiting and has now developed scleral icterus, right upper quadrant pain, and markedly elevated aminotransferases. These findings are consistent with an overdose of acetaminophen, a commonly used analgesic.
When taken at appropriate doses, acetaminophen produces small amounts of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI), which is conjugated with glutathione in the liver and excreted. At supratherapeutic doses, glutathione becomes saturated, allowing excessive amounts of NAPQI to form adducts with hepatic proteins that disrupt hepatocyte mitochondrial function and cause oxidative injury.
Because acetaminophen-induced liver injury primarily affects hepatocytes (ie, hepatocellular liver injury), laboratory findings show markedly elevated aminotransferases with levels sometimes >1,000 U/L. Mild elevations of bilirubin and alkaline phosphatase can be seen but may be normal. Liver biopsy shows centrilobular hepatic necrosis, a common finding in ischemic or toxic liver injury.
(Choice A) Certain drugs (eg, carbamazepine, phenytoin) can trigger a robust CD4+ and CD8+ T-cell response against hepatic proteins, leading to drug reaction with eosinophilia and systemic symptoms (DRESS). Although hepatocellular liver injury can occur, fever, lymphadenopathy, and skin manifestations (eg, facial edema, coalescing erythema) would be expected.
(Choice B) Drug-mediated (eg, ceftriaxone) cholestatic liver injury typically causes biliary duct damage or interrupts the flow of bile. These patients have markedly elevated levels of alkaline phosphatase (and sometimes bilirubin), and aminotransferase levels are typically normal.
(Choice D) Microvesicular steatohepatitis, or small droplets of intracytoplasmic lipids within hepatocytes, is caused by drugs that disrupt fatty acid beta-oxidation. Ibuprofen and aspirin are commonly used analgesics that can rarely lead to this condition; however, marked aminotransferase elevations are not seen in ibuprofen toxicity, and aspirin toxicity is usually seen in young children with a recent viral infection (ie, Reye syndrome).
(Choice E) Chronic alcohol consumption can generate reactive oxygen species (ROS), which activate stellate cells and cause cirrhosis. Although NAPQI does create ROS, stellate cell activation does not occur, and this patient’s acute liver injury after analgesic ingestion makes this diagnosis unlikely.
Educational objective:
Excessive acetaminophen use causes toxicity through its metabolite N-acetyl-p-benzoquinone imine, which disrupts hepatocyte mitochondrial function and induces oxidative injury throughout the liver. The resulting hepatocellular liver injury markedly elevates aminotransferase, with levels sometimes exceeding 1,000 U/L.
Answer B
Efficacy and potency are terms that are commonly used and often confused. In pharmacology, efficacy refers to the intrinsic ability of a drug to elicit an effect, such as receptor activation or dilation of a vessel as described in the question stem. It is a measure of the maximum ceiling of activity [Emax] of a drug with respect to a particular pharmacodynamic end point. For example, loop diuretics such as furosemide or bumetanide will cause greater diuresis or natriuresis than any thiazide diuretic, irrespective of dose.
Potency, on the other hand, refers to the dose of drug that is required to produce a given effect. The potency of a drug is primarily affected by the affinity of the drug for its receptor and the amount of drug that is able to reach the target tissues Therefore, drugs that bind their receptors with a higher affinity or are better able to gain access to their target tissues will have greater potency. The potency of different agents can be compared by determining the dose of drug that is required to produce one-half (50%) of the maximum biological response. This dose is known as the ED50. The lower the ED50 of a drug, the more potent it is. For example, among the thiazide diuretics, 25mg of hydrochlorothiazide and 5mg chlorthalidone produce similar drops in blood pressure (similar efficacy), but chlorthalidone requires a lower dose, or lower ED50, than HCTZ to cause a similar effect (higher potency).
With respect to the question, drug 2 and drug 3 have similar maximum effects (efficacy). A much lower dose of drug 2 is required to produce the same effect as that seen with drug 3; therefore, drug 2 is more potent than drug 3 and has a lower ED50. To achieve this higher potency, the binding of drug 2 to its receptors (affinity) must be higher than that of drug 3 (Choice B), or drug 2 must be better able to reach its target (penetration) than drug 3.
(Choice A) Drug 1 has higher potency than Drug 2 because at low biological activity, it can cause the same effect with much lower concentrations of drug. However, it does not reach the same maximum effect as Drug 2.
(Choice C) Drug 1 demonstrates the lowest efficacy (ceiling of biological effect) of the three drugs graphed. Lower efficacy may be a result of partial agonism and other factors.
(Choice D) Drugs 2 and 3 exhibit a parallel shift in their relative biological effects exhibiting similar efficacy but different potency (The shapes of their graphs are identical, but at different dose ranges). Drug 3 may contain the same basic pharmocologic agent as Drug 2 but with a competitive antagonist mixed in; thus, the Emax is the same but the ED50 is higher. A competitive antagonist would bind to the same location as the original substance.
(Choice E) Drug 2 has a lower ED50 (greater potency) than drug 3. Both have equal efficacy.
Educational Objective:
Efficacy is a measure of the maximum pharmacodynamic effect achievable with a drug. Potency refers to the dose of drug that is required to produce a given effect. Drugs that bind their receptors with a higher affinity or are better able to gain access to their target tissues will have greater potency (lower ED50).
Answer D
This patient has muscle tenderness and weakness. The dark urine suggests myoglobinuria due to myocyte necrosis. In the context of ongoing statin therapy for hyperlipidemia, this presentation likely represents statin myopathy. Statin myopathy is due, likely at least in part, to decreased myocyte production of coenzyme Q10 (ubiquinone). Serum muscle breakdown markers (eg, creatine kinase) are often elevated, and severe cases may lead to rhabdomyolysis with subsequent acute kidney injury (eg, elevated BUN and creatinine).
Statin myopathy is most common in the initial weeks or months of therapy. However, it can occasionally occur later, and can be acutely triggered by medications that increase circulating statin levels. This patient’s myopathy is most likely related to the initiation of clarithromycin as part of a multidrug regimen for Helicobacter pylori.
Statins, primarily simvastatin, lovastatin, and atorvastatin, are metabolized by CYP3A4. This enzyme can be inhibited by macrolide antibiotics (eg, erythromycin, clarithromycin), leading to increased statin drug levels and subsequent statin myopathy. (Azithromycin does not significantly inhibit CYP3A4.) Other significant CYP3A4 inhibitors that can induce statin myopathy include ketoconazole, non–dihydropyridine calcium channel blockers (eg, diltiazem), amiodarone, and protease inhibitors (eg, ritonavir). Because pravastatin is not primarily metabolized by CYP3A4, patients who must take a CYP3A4 inhibitor may benefit from switching to this drug.
(Choice A) Amoxicillin does not inhibit CYP3A4 or increase circulating simvastatin levels. Penicillin antibiotics generally have only minor effects on the cytochrome P-450 system.
(Choice B) Bismuth subsalicylate can cause black stools due to the formation of bismuth sulfate in the gastrointestinal tract. However, this medication does not cause myopathy or myoglobinuria. Excessive intake of bismuth can cause motor weakness, but this is due primarily to neural rather than muscle toxicity.
(Choice C) Polyvalent cations (eg, calcium, iron) can form insoluble chelate complexes with certain antibiotics (eg, tetracyclines, fluoroquinolones) and other drugs (eg, levothyroxine, levodopa), leading to decreased drug absorption. Simvastatin does not form chelate complexes, and decreased absorption would lower, not increase, the risk for myopathy.
(Choice E) Both metronidazole and simvastatin carry a small risk for peripheral neuropathy. In some patients, the effect can be additive and lead to numbness, pain, and paresthesia in the hands and feet. However, this neuropathy would not cause muscle tenderness or myoglobinuria.
Educational objective:
Statins, primarily simvastatin, lovastatin, and atorvastatin, are metabolized by CYP3A4. Drugs that inhibit this enzyme (eg, macrolide antibiotics, ketoconazole, non–dihydropyridine calcium channel blockers, amiodarone) can cause increased statin drug levels and lead to statin myopathy.
Answer C
This patient is likely taking a first-generation antihistamine (eg, diphenhydramine), which are commonly used for treating environmental allergies and mast cell-related disorders. First-generation antihistamines are nonspecific and act as antagonists to multiple receptors, including the muscarinic acetylcholine receptor. This leads to anticholinergic effects (eg, fever, urinary retention, decreased sweating, altered mental status). In this patient, the flushing is likely a compensatory response to dissipate excess body heat due to decreased sweating, and the pupillary dilation is due to inhibition of the iris sphincter.
Although commonly described as H1 receptor antagonists, antihistamines are actually inverse agonists that stabilize the receptor in the inactive state. H1 receptors are found in the vascular endothelium and bronchial smooth muscle, where they mediate vascular permeability and bronchoconstriction, as well as in the central nervous system where they are involved in alertness. Antihistaminic effects relieve nasal congestion, rhinorrhea, sneezing, and itching. First-generation antihistamines cross the blood-brain barrier and cause sedation. By contrast, second-generation antihistamines (eg, loratadine) are more specific to the histamine H1 receptor and have less permeability through the blood-brain barrier; they are generally less effective than first-generation antihistamines but have significantly fewer side effects.
(Choice A) Flushing and mydriasis are due to antagonism of the cholinergic receptor, not the H1 receptor.
(Choice B) H2 receptors are found on parietal cells in the gastric mucosa. H2 antagonists block gastric acid secretion by parietal cells.
(Choice D) Nicotinic cholinergic receptors are found in sympathetic and parasympathetic ganglia and on skeletal muscle cells at the neuromuscular junction. Nicotinic receptor antagonists (eg, rocuronium) are used to induce paralysis in preparation for surgery or endotracheal intubation. Adverse effects include hemodynamic instability (eg, hypotension) and respiratory insufficiency.
(Choice E) Alpha-1 adrenoreceptors are located on smooth muscle and neurons. Activation of these receptors increases smooth muscle tone of the iris dilator (causing mydriasis) and blood vessels (causing vasoconstriction); alpha-1 adrenergic agonists (eg, phenylephrine, oxymetazoline) can be used in patients with allergic rhinitis because their vasoconstrictive action reduces nasal congestion. However, vasoconstriction inhibits flushing.
Educational objective:
First-generation antihistamines are nonspecific and interact with multiple receptors, including the muscarinic receptor. This leads to anticholinergic effects (eg, fever, flushing, mydriasis, urinary retention, tachycardia, altered mental status).
Answer C
Perception of motion and orientation is determined by input from the vestibular, visual, and somatosensory systems. These 3 systems are usually congruent, but conflicting input can lead to motion sickness, characterized by nausea, dizziness, and autonomic symptoms (eg, diaphoresis). Integration of these sensory pathways occurs in the vestibular nuclei via muscarinic and histaminic neurotransmission. As such, antimuscarinic agents (eg, scopolamine) and first-generation antihistamines (eg, meclizine, dimenhydrinate) are most effective for management of motion sickness. Anticholinergic side effects are common with these medications and may include blurry vision, dry mouth, urinary retention, and constipation.
(Choices A, D, and E) Cough, frequent urination, and nasal congestion are characteristic of stimulation rather than blockade of muscarinic pathways.
(Choice B) Diarrhea may be seen with dopamine receptor antagonists (eg, metoclopramide), but these drugs are primarily used for visceral (eg, diabetic gastroparesis), rather than vestibular, nausea.
Educational objective:
Antimuscarinic agents and antihistamines with antimuscarinic action are most effective for motion sickness prevention.
Answer G
Opioid therapy is the first-line treatment for chronic cancer pain, with effective management commonly requiring higher doses over prolonged periods. An increase in dosage is often necessary to maintain adequate pain control following the development of tolerance to analgesic effects. Tolerance to most opioid side effects is also expected to occur. However, tolerance to constipation and miosis does not readily occur, and constipation is the most common and persistent opioid side effect.
Opioids stimulate mu receptors in the gastrointestinal tract, causing decreased secretions and gastric motility. Normal bowel function rarely resumes. Patients who require prolonged opioid therapy should receive a prophylactic bowel regimen (increased fluid intake, dietary fiber, and laxatives) to minimize constipation.
(Choice A) Opioids can produce significant euphoria, mood alterations, and rewarding pleasurable effects. The mechanism of euphoria and rewarding properties may involve dopaminergic pathways in the nucleus accumbens. Tolerance to euphoric effects develops rapidly, underlying the addictive potential of this medication class.
(Choice B) In most cases, opioid-induced pruritus is mild and tolerance develops.
(Choice C) Nausea with or without vomiting is a common side effect during initiation of opioid therapy, but tolerance develops within days and persistent nausea is uncommon. Opioids stimulate the chemoreceptor trigger zone, leading to emesis.
(Choice D) Respiratory depression is the most serious, yet rare, side effect of opioid therapy. Opioids depress respiration by reducing responsiveness of brainstem respiratory centers to increased levels of carbon dioxide. Patients who take opioids regularly are unlikely to develop respiratory depression as tolerance to this side effect develops rapidly.
(Choice E) Sedation typically occurs during initiation of therapy and usually disappears after several days. It is not unusual for patients to be drowsy and sleep more during the first days of therapy.
(Choice F) Opioids block urinary voiding reflexes and also increase sphincter tone and bladder volume. This results in an antidiuretic effect and urinary retention. Tolerance to these effects develops rapidly.
Educational objective:
Chronic opioid use leads to the development of tolerance to analgesic effects and most side effects, with the exception of constipation and miosis. To prevent bowel complications, it is recommended that patients be treated prophylactically with adequate fluid intake and daily laxatives.
Answer D
This patient who recently received systemic chemotherapy for breast cancer and now has progressive hematuria and suprapubic tenderness most likely has hemorrhagic cystitis caused by a nitrogen mustard-based chemotherapeutic agent, such as cyclophosphamide or one of its analogs (eg, ifosfamide). These agents are metabolized by the kidneys into acrolein, which is then excreted in the urine. Acrolein is toxic to uroepithelial cells and can cause cell death and necrosis if allowed to be in contact with these cells for a prolonged period.
Hemorrhagic cystitis associated with nitrogen mustard-based chemotherapy can be prevented by aggressive hydration and the coadministration of mesna (2-mercaptoethanesulfonate), a sulfhydryl compound that binds and inactivates the toxic metabolites of the chemotherapeutic agents in the urine.
(Choice A) Dexrazoxane is an iron-chelating agent that can help prevent anthracycline-induced (eg, doxorubicin) cardiotoxicity.
(Choice B) Filgrastim is a granulocyte colony-stimulating factor (G-CSF) analog used to stimulate the proliferation and differentiation of granulocytes in patients with neutropenia, as can occur after chemotherapy. This patient is afebrile, and her urinalysis is not suggestive of a urinary tract infection.
(Choice C) Leucovorin, or folinic acid, is a drug used in the treatment of methotrexate overdose. It also enhances the cytotoxic action of 5-fluorouracil (5-FU) and is used in combination with 5-FU in some cases of colorectal cancer.
(Choice E) Ondansetron inhibits serotonin 5-HT3 receptors and is used primarily to treat nausea and vomiting following chemotherapy.
Educational objective:
Hemorrhagic cystitis during therapy with cyclophosphamide or ifosfamide is caused by the urinary excretion of the toxic metabolite acrolein. It can be prevented by aggressive hydration, bladder irrigation, and administration of mesna, a sulfhydryl compound that binds acrolein in the urine.
Answer B
This patient, with hypertension, hypercholesterolemia, and sudden-onset neurologic deficits (eg, right arm weakness, difficulty speaking) that fully resolved within minutes, most likely had a transient ischemic attack (TIA). In addition to optimal blood pressure control and statin therapy, low-dose aspirin is commonly used to prevent ischemic stroke in patients with TIA. It works by irreversibly acetylating/inhibiting the cyclooxygenase (COX) enzymes. At low doses, aspirin predominantly inhibits COX-1, preventing platelet synthesis of thromboxane A2, which impairs platelet aggregation and reduces vasoconstriction.
At least 2 distinct COX-1-dependent mechanisms contribute to the increased risk of upper gastrointestinal (GI) bleeding associated with aspirin therapy: Inhibition of platelet aggregation and impairment of prostaglandin-dependent GI mucosal protection. The risk of upper GI bleeding increases with higher doses but is increased 2- to 3-fold even with low-dose aspirin. Proton pump inhibitors can help reduce the risk of upper GI bleeding in patients taking aspirin.
(Choice A) Central nervous system depression is commonly seen with benzodiazepine use as these agents potentiate the effect of GABA (a major inhibitory neurotransmitter) on GABA-A receptors.
(Choice C) Very high doses of aspirin can cause salicylism (eg, vertigo, tinnitus, hearing loss) and hyperpnea (stimulates respiratory drive). Hyperpnea may result in respiratory alkalosis, whereas systemic salicylate accumulation often leads to a concurrent metabolic acidosis.
(Choice D) Orthostatic hypotension may occur with use of antihypertensive medications due to vasodilation (eg, nitrates, calcium channel blockers) and volume depletion (eg, loop and thiazide diuretics).
(Choice E) Sexual dysfunction is a common side effect of antidepressants (eg, selective serotonin inhibitors, tricyclics) and some antihypertensives (eg, thiazide diuretics, spironolactone, clonidine).
(Choice F) Pioglitazone (a thiazolidinedione) increases insulin sensitivity in patients with type II diabetes mellitus by binding to peroxisome proliferator-activated receptors. Long-term use may be associated with urinary bladder cancer.
Educational objective:
Gastrointestinal (GI) mucosal injury and bleeding are the most common side effects of aspirin. These are due primarily to cyclooxygenase-1 inhibition, which results in impaired prostaglandin-dependent GI mucosal defense and decreased platelet aggregation.
Answer D
The rate and extent of drug metabolism normally varies from person to person. These slight interpersonal variations in the ability to metabolize drugs are typically reflected graphically by a unimodal distribution, usually in the shape of a bell curve, when plasma levels of drug are measured at a fixed time following a fixed dose of drug. This is the method that was used to generate the graph given in the question stem. With most drugs, the majority of people fall within one standard deviation and 95% of people fall within two standard deviations of the population mean of plasma concentration. A single peak in this type of graph indicates that the population being tested possesses a similar genetic drug metabolizing capacity.
A bimodal (discontinuous, polymorphic) curve, as shown in the question stem, results from the presence of two apparently distinct groups within the study population and suggests a pharmacogenetic polymorphism in drug metabolizing capacity. In other words, the two peaks indicate two sets of responders to the drug within the population: one that rapidly converts the drug into its metabolite (considered normals) and another that converts the drug slowly, leading to accumulation of the original drug in the plasma.
Isoniazid is metabolized by acetylation to N-acetyl-isoniazid in the hepatic microsomal system by the enzyme N-acetyl transferase and is subsequently excreted in the urine. The first and second peaks in the above graph represent fast and slow acetylators, respectively. Slow acetylators of isoniazid also metabolize (acetylate) dapsone, hydralazine, and procainamide slowly, causing accumulation of these drugs as well. Slow acetylators of these drugs are at increased risk of toxic effects, while fast acetylators may require much higher therapeutic doses to achieve a therapeutic effect.
(Choice A) Methylation is an important drug biotransformation method to consider when prescribing drugs such as azathioprine and 6-mercaptopurine, drugs used in the treatment of some inflammatory disorders of the bowel and skin.
(Choice B) Glucuronidation is a biotransformation pathway utilized for the metabolism of numerous drugs as well as endogenous substances such as bilirubin. No bimodality has been described with this pathway, but conditions such as Gilbert syndrome involve dysfunction of the glucuronyl transferase system that can lead to toxic accumulation of some drugs.
(Choice C) Hydrolysis occurs with enzymes such as esterases and amidases. Isoniazid is not metabolized by this pathway, and hydrolysis does not exhibit polymorphic metabolism.
(Choice E) Amine oxidation is usually undertaken by monoamine oxidases or by cytochrome oxidative deamination. Neither process metabolizes isoniazid nor exhibits bimodality.
Educational Objective:
Isoniazid is metabolized by acetylation. The speed with which a patient is able to acetylate drugs depends on whether they are genetically “fast” or “slow” acetylators. The presence of fast and slow acetylators within the same population results in a bimodal distribution of the speed of isoniazid metabolism. Slow acetylators are at increased risk of adverse side effects.
Answer G
This patient has suffered a thromboembolic stroke, likely the result of a dislodged left atrial thrombus that formed due to an adverse drug interaction leading to inadequate anticoagulation. Many substances cause induction or inhibition of cytochrome P450 (CYP450) hepatic microsomal enzymes, which are responsible for the majority of drug metabolism. CYP450 interactions should be considered when selecting and dosing medications, as changes in enzyme activity affect the rate of drug metabolism.
Alterations in plasma drug levels are especially important when considering medications that are vital to a patient’s health or have a high propensity for toxicity, such as warfarin. For example, warfarin can interact with St John’s wort, an over-the-counter medicinal herb known for both its anti-inflammatory and antidepressant properties. St John’s wort induces hepatic CYP450 enzymes, resulting in increased warfarin metabolism, decreased drug levels, and inadequate anticoagulation.
(Choices A, B, C, D, and E) These drugs are known to inhibit CYP450 enzymes and increase warfarin levels, leading to an increased risk of bleeding complications.
(Choice F) Oral penicillin V and warfarin do not have any significant interactions. Antibiotics in general reduce the intestinal bacterial load, which reduces vitamin K synthesis and could potentiate warfarin’s anticoagulant effects.
Educational objective:
St John’s wort induces cytochrome P450 hepatic microsomal enzymes. As a result, a wide variety of drugs that are metabolized by these enzymes, such as warfarin, will have lower plasma concentrations and decreased efficacy.
Answer C
Statins (eg, atorvastatin) are the first-line therapy for most patients with hypercholesterolemia and are useful in primary and secondary prevention of acute coronary events. Statins inhibit HMG-CoA reductase, the enzyme responsible for the rate-limiting step in synthesis of cholesterol. Statins lower total cholesterol, LDL, and triglyceride levels.
The primary side effects of statins include myopathy and hepatitis. Statin-associated myopathy is usually characterized by mild muscular pain and resolves with discontinuation of the medication. However, some patients will develop severe myopathy with striking elevations in creatine kinase levels and occasional rhabdomyolysis. The risk of severe myopathy is increased when statins are given concurrently with fibrates (particularly gemfibrozil), which impair the hepatic clearance of statins and lead to excessive blood levels. An increased risk of statin myopathy is also likely with concurrent use of niacin or ezetimibe, but to a lesser extent (Choice B).
(Choice A) Concurrent use of bile acid sequestrants (eg, cholestyramine) with statins does not increase the risk of myopathy. However, bile acid sequestrants can reduce the gastrointestinal absorption of statins.
(Choice D) Fibrates can increase drug levels of ezetimibe but this does not have a significant impact on its side effects, which are generally mild and not dose-related. Ezetimibe does not alter the pharmacokinetics of fibrates and does not substantially influence their adverse effects.
(Choices E and F) The primary adverse effects of niacin include flushing, hyperglycemia, and hepatotoxicity. There are no significant interactions with the concurrent use of niacin and ezetimibe or gemfibrozil.
Educational objective:
The primary side effects of statins include myopathy and hepatitis. Fibrates such as gemfibrozil can impair hepatic clearance of statins, increasing the risk of severe myopathy.
Answer B
Nitrates, beta blockers, and calcium channel blockers are the mainstay of therapy for patients with chronic stable angina. Sublingual nitroglycerin is the therapy of choice in acute episodes for immediate relief of angina and for prevention of angina prior to engaging in strenuous physical activity. Chronic nitrate therapy with long-acting oral formulations (isosorbide dinitrate or mononitrate) is used to prevent recurrent anginal episodes in patients with chronic stable angina.
Sublingual nitroglycerin is absorbed rapidly from oral mucosa directly into the venous circulation and has a rapid onset of action within 2-5 minutes. Long-acting isosorbide dinitrate is absorbed via the gastrointestinal tract and undergoes extensive first-pass metabolism in the liver prior to release in the systemic circulation. This leads to low bioavailability and the need for much higher doses of oral formulations as compared to sublingual nitroglycerin.
(Choice A) Chronic nitrate therapy on a regular basis leads to nitrate tolerance, with attenuation of blood pressure response and anti-anginal effects. Higher doses do not prevent nitrate tolerance. On the contrary, use of sublingual nitroglycerin on an intermittent, as-needed basis (nitrate-free intervals) prevents the development of nitrate tolerance.
(Choices C and D) The oral nitrate preparations do not have high serum protein binding or volume of distribution.
(Choice E) Isosorbide dinitrate has rapid and nearly complete intestinal absorption. Its low bioavailability is due to considerable first-pass hepatic metabolism.
Educational objective:
Isosorbide dinitrate has a low bioavailability due to extensive first-pass hepatic metabolism prior to release in systemic circulation. Sublingual nitroglycerin is absorbed directly from oral mucosa into the venous circulation and has a higher bioavailability.
Answer C
Serotonin syndrome is characterized by a triad of autonomic instability (eg, hyperthermia, hypertension, tachycardia), altered mental status (eg, agitation, confusion), and neuromuscular hyperactivity (eg, tremor, hyperreflexia, myoclonus), as well as gastrointestinal symptoms and diaphoresis. It is due to an increased serotonergic effect in the central nervous system (eg, increased 5-HT1A and 5-HT2A receptor stimulation).
Serotonin syndrome rarely occurs with a single serotonergic drug used at therapeutic doses. More commonly, it is due to the combined effects of several serotonergic medications, overdose, and/or a drug-drug interaction. Serotonin effect is increased when a monoamine oxidase inhibitor (MAOI) is combined with a serotonergic antidepressant (selective serotonin reuptake inhibitor [SSRI], serotonin-norepinephrine reuptake inhibitor, or tricyclic antidepressant).
Linezolid is used to treat infections caused by gram-positive bacteria, particularly vancomycin-resistant enterococcus and methicillin-resistant Staphylococcus aureus. Linezolid has MAOI activity and therefore can precipitate serotonin syndrome with concomitant use of an SSRI (eg, paroxetine) or with other serotonergic medications.
(Choices A, B, D, and E) Clindamycin, doxycycline, penicillin, and vancomycin do not have MAOI effects. They do not cause serotonin syndrome when combined with a serotonergic antidepressant.
Educational objective:
Serotonin syndrome is characterized by a triad of autonomic instability, altered mental status, and neuromuscular irritability. It may develop when a monoamine oxidase inhibitor (MAOI) antidepressant or a non-antidepressant with MAOI activity (eg, linezolid) is combined with a serotonergic medication such as a selective serotonin reuptake inhibitor, serotonin-norepinephrine reuptake inhibitor, or tricyclic antidepressant.
Answer E
Monoclonal antibodies (mAbs) are used to treat a growing variety of malignant (eg, leukemia/lymphoma, melanoma) and autoimmune diseases (eg, Crohn disease, rheumatoid arthritis). The therapeutic effect of mAbs is achieved by binding to their target antigen in the plasma or on the cell surface and blocking deleterious receptor interactions or triggering a cytotoxic immune response against abnormal cells.
Because of their large molecular size, mAbs cannot be administered orally and must be given via intravenous or subcutaneous/intramuscular routes. Unlike most other drugs, mAbs are not eliminated by hepatic or renal clearance, but are instead removed from the body in 2 primary ways:
Target-mediated drug clearance: mAbs directed against cell surface antigens undergo internalization (receptor-mediated endocytosis) upon binding to their targets, removing them from the circulation
Nonspecific clearance: Immunoglobulins are constitutively taken up by reticuloendothelial macrophages (via binding to Fc receptors) and vascular endothelial cells (via pinocytosis)
Once internalized, immunoglobulins are catabolized into amino acids within lysosomes.
(Choices A and C) Many drugs undergo modifications by the cytochrome P450 system and subsequent conjugation reactions within hepatocytes that help facilitate excretion of the drug into the urine or bile. In contrast, immunoglobulins are not metabolized by these systems, but rather broken down by proteolytic enzymes.
(Choices B and D) Immunoglobulins are too large to undergo substantial filtration at the glomerular basement membrane and are not secreted by the renal tubules. Therefore, renal dysfunction does not significantly affect monoclonal antibody clearance.
Educational objective:
Monoclonal antibodies (mAbs) are not eliminated by hepatic or renal clearance. Therefore, no dose adjustment is necessary with impaired hepatic/renal function or use of cytochrome P450 inducers or inhibitors.
Answer C
This patient has esophagitis, with burning pain in the chest and dysphagia. Medication-induced esophagitis is a common adverse effect of bisphosphonates (eg, alendronate, risedronate) thought to be caused by disruption of the protective phospholipid barrier in the lower esophagus. This allows refluxing gastric acid to cause mucosal erosion and ulceration. Bisphosphonates are contraindicated in conditions that impair esophageal motility (eg, stricture, achalasia). When bisphosphonates are used, the risk of esophagitis can be lessened by taking the medication with a full glass of water (to ensure the pill is delivered fully into the stomach) and remaining upright for 30 minutes following administration (to avoid reflux of gastric contents).
Bisphosphonates are also associated with osteonecrosis of the jaw (mandible or maxilla) and atypical bone fractures (eg, stress fractures of the subtrochanteric zone and femoral shaft). The precise pathophysiology is debated and may vary, but proposed mechanisms include suppression of bone remodeling, impaired healing of microfractures, and decreased angiogenesis.
(Choice A) Medication-induced nephropathy can be due to interstitial nephritis (eg, cyclosporine), crystal nephropathy (eg, acyclovir), renal vasoconstriction (eg, amphotericin B, nonsteroidal anti-inflammatory drugs), or tubular injury (eg, aminoglycosides). Bisphosphonates are eliminated by the kidney and should be used with caution in patients with chronic kidney disease, but do not have substantial nephrotoxicity.
(Choice B) Bisphosphonates decrease bone resorption, thus lowering serum calcium levels. They are sometimes used in the treatment of severe hypercalcemia (eg, hypercalcemia of malignancy).
(Choice D) Venous thromboembolism is a recognized complication of selective estrogen receptor modulators (eg, raloxifene), but these medications do not often cause esophagitis. Bisphosphonates do not appreciably increase the risk of thromboembolism.
(Choice E) Vitamin B12 deficiency can be seen in long-term proton pump inhibitor (eg, omeprazole) therapy, possibly due to decreased acid-dependent cleavage of vitamin B12 from dietary proteins. Although proton pump inhibitors may be taken by patients with bisphosphonate-induced esophagitis, bisphosphonates do not affect vitamin B12 metabolism.
Educational objective:
Medication-induced esophagitis is a common adverse effect of bisphosphonates. Bisphosphonates are also associated with increased risk of osteonecrosis of the jaw and atypical femoral fractures.
Answer E
Toxoplasma gondii is a ubiquitous protozoan that rarely causes illness in healthy individuals but can cause severe infection in immunocompromised patients or those with congenital infection. Symptomatic congenital disease is often marked by intracranial calcification, hydrocephalus, chorioretinitis, jaundice, and/or thrombocytopenia. Early treatment with sulfadiazine and pyrimethamine reduces neurologic and retinal sequelae.
Sulfadiazine and pyrimethamine work synergistically to inhibit protozoal DNA synthesis by blocking 2 steps necessary for the formation of tetrahydrofolate (THF), a cofactor needed for synthesis of purine nucleic acids. Sulfadiazine inhibits dihydropteroate synthase, a microbial enzyme that generates dihydropteroate, which is converted to dihydrofolic acid. Pyrimethamine inhibits dihydrofolate reductase, an enzyme that converts dihydrofolic acid to THF.
Sulfadiazine does not impair host DNA synthesis because dihydropteroate synthase is not found in human cells. In contrast, pyrimethamine partially impairs host DNA synthesis because dihydrofolate reductase generates THF in host cells. However, leucovorin (folinic acid), a derivative of THF that does not require conversion by dihydrofolate reductase, is usually administered with pyrimethamine to provide a bypass substrate for the generation of host purine nucleic acids.
(Choice A) Patients are often treated with 2 different classes of antimicrobial medications to broaden the coverage of potential pathogens. Sulfadiazine and pyrimethamine both block the same metabolic pathway, so the combination is less useful for empiric antimicrobial therapy.
(Choice B) Gentamicin is often administered with an agent that targets the bacterial cell wall (eg, ampicillin, vancomycin) to allow gentamicin to enter the intracellular space. Use of sulfadiazine with pyrimethamine does not alter intracellular penetration.
(Choice C) Bacterial resistance can occur due to the production of an inactivating enzyme (eg, beta-lactamase). Administration of an agent that inhibits the enzyme (eg, clavulanic acid) can often restore the effect of the antibiotic (eg, amoxicillin).
(Choice D) Probenecid blocks the renal tubular excretion of most beta-lactam antibiotics, which can increase their serum level. Sulfadiazine and pyrimethamine are not used together to alter renal excretion.
Educational objective:
Congenital toxoplasmosis is treated with sulfadiazine plus pyrimethamine. These medications work synergistically to inhibit formation of tetrahydrofolate, a necessary cofactor for purine nucleotide synthesis.
Answer A
This patient has Gaucher disease, an autosomal recessive condition caused by a deficiency of lysosomal beta-glucocerebrosidase. This deficiency leads to the accumulation of glucocerebroside, a glycolipid component of cell membranes, within the lysosomes of macrophages, giving them the classic appearance of wrinkled tissue paper. Characteristic symptoms (eg, hepatosplenomegaly, pancytopenia, bone pain) develop as lipid-laden macrophages accumulate in the body’s tissues (eg, spleen, liver, and bone).
Lysosomal storage diseases can be treated through the delivery of a replacement enzyme into the lysosomes of affected cells; in the case of Gaucher disease, recombinant glucocerebrosidases (eg, imiglucerase) are available to replace the deficient enzyme. Almost all human enzymes, including lysosomal enzymes, are large polypeptides (eg, proteins) (Choice B). Although the oral route is often preferred for drug administration, most peptide-based drugs (eg, insulin, immunoglobulins) cannot be efficiently absorbed by the gastrointestinal tract due to the intestinal epithelial barrier and extensive proteolysis that takes place in the stomach and duodenum. As a result, large polypeptides such as a glucocerebrosidase must be administered intravenously to achieve adequate circulating levels.
Once in the circulation, exogenous glucocerebrosidase can enter cells by binding to mannose 6-phosphate receptors. These receptors are found in the Golgi network, where they help route newly synthesized lysosomal proteins (tagged by mannose 6-phosphate residues). They are also expressed on the cell surface, where they bind free lysosomal enzymes that are accidentally secreted. Exogenous glucocerebrosidase can bind to these cell surface receptors, inducing endocytosis of the bound enzyme. It is then carried by endosomes to lysosomes, where it can degrade accumulated glucocerebrosides, reducing disease manifestations.
(Choices C and D) Enzymes are large, polar polypeptides that are unable to effectively cross the cell membrane by passive diffusion. In contrast, steroid-based drugs are typically hydrophobic and can easily cross cell membranes by passive diffusion. However, steroidal drugs function by binding to receptors; they do not directly catalyze reactions.
(Choices E, F, G, and H) Unlike in lysosomal storage diseases, enzyme replacement therapy for pancreatic exocrine insufficiency is administered orally because pancreatic digestive enzymes normally function within the gastrointestinal lumen.
Educational objective:
Certain lysosomal storage diseases, including Gaucher disease, can be treated with enzyme-replacement therapy (eg, recombinant glucocerebrosidase). Because enzymes are large proteins that cannot be orally absorbed, the replacement enzyme must be administered intravenously. Entry into the cell occurs by endocytosis after the replacement enzyme binds to mannose 6-phosphate receptors on the cell surface.
Answer E
Atropine is an anticholinergic medication that can be administered prior to bronchoscopy to decrease respiratory mucus secretions and promote bronchodilation. Anticholinergic drugs competitively inhibit the muscarinic acetylcholine receptor both centrally (leading to delirium, coma, and respiratory failure) and peripherally (see toxidrome in table). The elderly are at particularly high risk of developing anticholinergic toxicity, likely due to decreased renal and hepatic clearance.
Cholinesterase inhibitors overcome this toxicity by inhibiting the degradation of acetylcholine, thereby increasing the concentration of acetylcholine at the synaptic cleft. Central nervous system (CNS) penetration and reversal of central symptoms are dependent on chemical structure:
Tertiary amines (eg, physostigmine, galantamine, donepezil, rivastigmine) are lipophilic (nonpolar) and can easily cross the blood-brain barrier to reverse both central and peripheral symptoms.
Quaternary amines (eg, neostigmine, edrophonium, pyridostigmine) are hydrophilic (polarized) and do not readily cross the blood-brain barrier. These drugs reverse peripheral symptoms only (Choices B and D).
(Choices A and C) Both diazepam and haloperidol can be used for sedation or cases of severe agitation. Haloperidol is an antipsychotic that blocks dopamine receptors in the CNS, and diazepam is a long-acting benzodiazepine that positively modulates GABA-A activity. Neither medication reverses the peripheral anticholinergic manifestations (eg, mydriasis, tachycardia).
Educational objective:
Physostigmine is a cholinesterase inhibitor with a tertiary ammonium structure that can reverse both the central and peripheral nervous system symptoms of anticholinergic toxicity. Neostigmine, edrophonium, and pyridostigmine have a quaternary ammonium structure that limits central nervous system penetration.
A large, multinational drug corporation conducts a phase I clinical trial to evaluate the safety profile and pharmacokinetic properties of a new drug designed to treat refractory epilepsy. Initial studies in animals showed that the drug undergoes extensive metabolism by the liver into glucuronidation byproducts that are primarily excreted by the kidneys. The curve below demonstrates the glucuronidation rate of the drug over a wide range of doses.
Which of the following is the most accurate statement about this drug’s metabolism?
A. A constant proportion of the drug is metabolized past point 3
B. Bioavailability of the drug is highest at point 1
C. Biotransformation of the drug ceases near point 2
D. Metabolism begins to switch to zero-order kinetics near point 2
E. The rate of drug metabolism is not dependent on dose before point 1
Answer D
The drug under investigation is glucuronated by the liver into water-soluble byproducts that can then be excreted by the kidney. The graph above shows how the rate of drug glucuronidation changes with increasing drug doses. At lower doses, the quantity of drug-glucuronide formed is directly proportional to the dose administered (ie, as more of the drug is administered, more drug-glucuronide is produced). Because a fixed proportion of drug is converted to the metabolite, this early portion of the graph represents first-order kinetics.
As the active sites on glucuronosyltransferase become saturated, the drug-glucuronide rate does not continue to rise with increasing doses of the substrate drug. At this point (2 on the graph), the kinetics change from first- to zero-order kinetics and the graph levels out to a zero slope. With zero-order kinetics, a constant amount of drug is metabolized and eliminated per unit of time regardless of its concentration or dose.
Zero- and first-order kinetics can also be represented graphically by showing the decrease in drug concentration over time after a single dose. Zero-order metabolism is indicated by a straight line with negative slope (fixed amount eliminated per unit of time), whereas first-order kinetics manifest as an exponential decay curve (fixed proportion eliminated per unit of time).
(Choice A) After point 3, the curve remains flat, indicating that a constant amount of drug is metabolized per unit of time regardless of the dose. As higher doses are administered, the proportion that is converted to the metabolite becomes smaller (ie, the proportion metabolized is non-constant after point 3).
(Choice B) Bioavailability is the fraction of an administered drug that reaches the systemic circulation unchanged. It usually decreases with oral administration due to incomplete absorption and first-pass metabolism compared to parenteral administration. In this case, higher doses of the drug are likely to have greater bioavailability due to the saturation of hepatic metabolism.
(Choice C) At point 2, biotransformation (ie, metabolism) of the drug begins to switch from first-order to zero-order kinetics due to enzyme saturation. However, drug metabolism does not stop.
(Choice E) Before point 1, drug metabolism proceeds via first-order kinetics. Therefore, the drug metabolization rate increases as higher doses are administered.
Educational objective:
In first-order kinetics, a constant fraction (or proportion) of drug is metabolized per unit of time, so the amount metabolized changes based on the serum concentration. In zero-order kinetics, a constant amount of drug is metabolized per unit of time, independent of serum levels.
Answer E
Methotrexate (MTX) is a folic acid analog that inhibits dihydrofolate reductase (DHFR), the enzyme that converts dietary folic acid to tetrahydrofolate (THF), through direct competition. THF is a single-carbon group donor in the synthesis of purines and thymidylic acid (which contributes to pyrimidine formation). MTX functions as a chemotherapeutic agent through inhibition of DNA synthesis and as an anti-psoriasis agent through immunomodulatory effects on activated T cells. However, MTX causes death of all rapidly dividing cells, particularly those of the gastrointestinal tract (GI) mucosa (explaining this patient’s aphthous ulcers) and bone marrow (explaining this patient’s pancytopenia).
Folinic acid (leucovorin) can reverse MTX toxicity if given early. It serves as a reduced form of folic acid thought not to require DHFR to be converted to THF and is therefore unaffected by MTX. Leucovorin is administered following high-dose MTX as part of a chemotherapeutic plan in which it serves to rescue bone marrow, and GI and other mucosal cells from MTX toxicity. In addition, when used in combination with 5-fluorouracil (5-FU), leucovorin potentiates the cytotoxic action of 5-FU (by binding thymidylate synthetase) and is frequently included in colorectal cancer chemotherapy regimens.
(Choice A) Allopurinol and its metabolite, oxipurinol, are predominantly noncompetitive inhibitors of xanthine oxidase. Allopurinol is used in the treatment of gout and for prevention of tumor lysis syndrome.
(Choice B) Amifostine is a cytoprotective free-radical scavenger used to decrease nephrotoxicity associated with platinum-containing and alkylating chemotherapeutic agents and to decrease xerostomia (dry mouth).
(Choice C) Dexrazoxane is an iron-chelating agent that can prevent anthracycline-induced cardiotoxicity.
(Choice D) Filgrastim is a granulocyte colony-stimulating factor analog used to stimulate the proliferation and differentiation of granulocytes in patients with neutropenia.
(Choice F) Mesna prevents hemorrhagic cystitis due to cyclophosphamide or ifosfamide. Mesna binds acrolein, the toxic metabolite formed by these agents.
(Choice G) Ondansetron (a serotonin 5-HT3 receptor inhibitor) is used to treat nausea and vomiting following chemotherapy.
Educational objective:
Folinic acid (leucovorin) can reverse the toxicity of methotrexate in non-cancerous cells in the gastrointestinal mucosa and bone marrow if administered at the appropriate time. Leucovorin serves as a reduced form of folic acid that does not require the action of dihydrofolate reductase.
Answer D
Morphine stimulates mu opioid receptors to provide the desired effect of analgesia, but in doing so can also precipitate many undesired effects. This patient has multiple signs of opioid toxicity, including miosis (ie, pinpoint pupils), respiratory depression (evidenced by slow respiratory rate and respiratory acidosis), and CNS depression (eg, somnolence, coma). Morphine is primarily metabolized by the liver via glucuronidation to form 2 major metabolites. These metabolites, morphine-3-glucoronide and morphine-6-glucoronide, then undergo renal elimination via excretion in the urine. Because the metabolites are metabolically active, renal dysfunction can lead to metabolite accumulation and opioid toxicity. Morphine-6-glucoronide is particularly responsible for toxicity, acting as a more potent mu opioid receptor agonist than morphine itself.
Due to its metabolically active and renally cleared metabolites, morphine requires careful monitoring when used in patients with renal dysfunction. When opioid pain control is needed in such patients, fentanyl or hydromorphone is often preferred as these drugs are predominantly hepatically cleared.
(Choice A) Decreased first-pass metabolism occurs with drugs that are given by a route other than orally, allowing the drug to reach the systemic circulation without passing through the portal circulation and the liver. Examples include drugs that are administered sublingually, rectally, or intravenously.
(Choice B) Decreased hepatic metabolism is common in the elderly or in patients with advanced liver disease (eg, cirrhosis). Although this patient has metastatic disease to the liver, accumulation of morphine metabolites is a more likely cause of toxicity in the setting of known renal failure.
(Choice C) Enterohepatic circulation occurs when a drug undergoes biliary excretion into the small intestine, where it is then reabsorbed back into the bloodstream. Such drugs typically demonstrate a prolonged half-life. Although the phenomenon may account for a prolonged duration of therapeutic effect, it rarely accounts for toxicity.
(Choice E) Drugs with a high volume of distribution (eg, amiodarone) are well distributed in the tissues and have a long half-life. These drugs may demonstrate prolonged therapeutic and/or adverse effects after discontinuation.
Educational objective:
Morphine generates 2 major metabolites that are metabolically active and renally cleared. These metabolites can accumulate in the bloodstream of patients with renal dysfunction and lead to opioid toxicity, evidenced by miosis, respiratory depression, and CNS depression.
Answer E
Cytochrome P450 (CYP) enzymes are a group of heme-containing proteins that are responsible for the majority of drug metabolism, which occurs predominately in the liver. Various CYP subtypes exist, with CYP3A, CYP2D, and CYP2C as the most active subtypes involved in drug metabolism. These enzymes generally function to deactivate drugs and facilitate excretion from the body by improving water solubility. However, they also metabolize certain compounds to their active forms.
Polymorphisms may occur in the genes coding for these enzymes, altering their expression or activity. Three important phenotypes exist: poor, intermediate, and rapid metabolizer. Identifying these variations on an individual basis provides a framework for optimizing therapy, predicting treatment efficacy, and minimizing toxicity.
Tamoxifen, a selective estrogen receptor modulator used in the treatment of estrogen receptor-positive breast cancer, is a prodrug metabolized by CYP2D to its active metabolite, endoxifen. Patients with genetic polymorphisms resulting in poor CYP2D activity are exposed to decreased levels of the active metabolite and have a higher risk of disease relapse.
(Choice A) Activation of downstream signal transducer proteins, such as KRAS, leads to activation of transcription factors that promote cell growth. Mutations in the KRAS gene are associated with the development of colorectal and lung cancers.
(Choice B) Decreased activity of hepatic N-acetyltransferase results in a diminished ability to metabolize drugs such as isoniazid and sulfonamides, leading to an increased likelihood of toxicity.
(Choice C) Thiopurine methyltransferase is responsible for the metabolism of thiopurine compounds such as the immunosuppressive drug 6-mercaptopurine. Enzyme deficiency leads to increased drug toxicity.
(Choice D) P-glycoprotein is a cell membrane protein that drives efflux of a number of substances out of the cell. Overexpression of p-glycoprotein in tumor cells has been identified as a cause of multidrug resistance.
Educational objective:
Cytochrome P450 enzymes found in the liver are responsible for the majority of drug metabolism. Polymorphisms occurring in the genes coding for these enzymes result in various phenotypes that differ in their rates of metabolism; individual differences in phenotype alter treatment efficacy and drug toxicity.
