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Autacoids and Anti-inflammatory Drug Pharmacology

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Question 1

About 10% to 20% of asthma patients aged 20 years to 30 years develop wheezing or more severe respiratory s igns and symptoms in response to a certain class of The offending drugs indirectly shunt (redirect) arachidonic acid metabolism to the formation of leukotrienes, which have bronchoconstrictor and proinflammatory properties. To which one of the following drugs or drug groups does this explanation most l ikely apply?

A	Acetylcholinesterase inhibitors (eg, neostigmine)
B	β-Adrenergic blockers (propranolol, many others)
C	Histamine
D	Nonsteroidal anti-inflammatory drugs (traditional agents such as aspirin)
E	Opioids such as morphine

Question 1 Explanation:

Arachidonic acid is a by-product of phospholipid metabolism (via phospholipases) in most cells. Recall that there are two main pathways for further arachidonic acid metabolism: (1) via the cyclooxygenase pathway; and (2) via the lipoxygenase pathway. Traditional NSAIDs, including aspirin, inhibit both cyclooxygenase-1 and -2. In those patients with what is generically called “aspirin-sensitive” asthma (also called traid or Sampter asthma), the working hypothesis is that when arachidonate metabolism via COX is inhibited, arachidonic acid must still be metabolized. That occurs via increased metabolism through the lipoxygenase pathway. This results in greater formation of leukotrienes that cause bronchoconstriction and additional airway inflammation. Acetylcholinesterase inhibitors (a) clearly can provoke severe bronchospasm in asthmatic patients. That is a direct effect, apparently involving increased airway smooth muscle reactivity to a host of bronchoconstrictor substances, one of which is acetylcholine. The response is independent of leukotriene metabolism. The same applies to β-adrenergic blockers (b). In their case, airway problems arise from inhibition of important β-2- mediated bronchodilator effects of epinephrine. Histamine’s effects (c) are direct and do not involve arachidonic acid metabolism, but there is no doubt that histamine is a particularly powerful bronchoconstrictor in patients with asthma. Opioids (e) may cause excessive bronchoconstriction in some asthma patients. That is almost certainly due to morphine’s ability to release histamine from mast cells and basophils. It has nothing to do with specific inhibition of COX or lipoxygenase pathways of arachidonic acid metabolism.

Question 2

Febuxostat i s the fi rst new drug in i ts class in four It i s indicated for managing hyperuricemia, including that which i s drug-induced, but i s not indicated for symptom-suppression during an acute gout attack. Its basic mechanism of action i s inhibition of purine degradation at the formation of hypoxanthine (HX), preventing further metabolism of HX to xanthine and uric acid. It should not be administered to patients receiving purine antimetabolites (eg, mercaptopurine, thioguanine, for certain cancers) because the metabolic inactivation of those anticancer drugs will be inhibited and toxicity may occur. Based on the description given, what drug i s most s imilar to febuxostat?

A	Allopurinol
B	Aspirin
C	Colchicine
D	Indomethacin
E	Probenecid

Question 2 Explanation:

The description of febuxostat in the question—actions, uses, drug interactions and more—applies directly to allopurinol, which is classified as a xanthine oxidase inhibitor and has been available for decades. As you should recall, allopurinol (and now febuxostat) is indicated for managing hyperuricemia, whether idiopathic, associated with certain diseases (including many malignancies), or drug-induced (eg, by thiazide or loop diuretics, and cancer chemotherapeutic agents). Aspirin (b) has no effects on purine metabolism in general or specifically on xanthine oxidase. At all but very high dosages, it can raise plasma uric acid (and xanthine) levels by inhibiting tubular secretion of uric acid, and is generally contraindicated for patients with hyperuricemia or gout. Colchicine (b) is an antiinflammatory drug used for acute gout, or for prophylaxis, but it has no effect on endogenous purine metabolism or the metabolism of purine antimetabolites such as mercaptopurine. Indomethacin (d) is a traditional NSAID (tNSAID) that has many indications, including treating inflammation secondary to gout, but once again it shares none of the other properties noted in the question. Probenecid (e) can be considered the prototype uricosuric drug: indicated for prophylaxis, but not for treatment, of gout. Therapeutic blood levels of probenecid lower plasma uric acid levels by blocking tubular reabsorption of urate.

Question 3

A patient receives a drug that inhibits the l ipoxygenase pathway of arachidonic acid What naturally occurring metabolite(s) will be produced in lesser amounts in response to this drug?

A	Leukotrienes
B	Prostacyclin (PGI2)
C	Prostaglandins
D	Thromboxanes
E	Uric acid

Question 3 Explanation:

The arachidonic acid (AA) “cascade” begins with AA synthesis from membrane phospholipids by phospholipase A2. Once arachidonic acid is formed, the metabolic pathways diverge into the lipoxygenase pathway (that forms cysteinyl leukotrienes [LTs]) and the cyclooxygenase pathways that synthesize prostaglandins, including prostacyclin and thromboxane A2. One important intermediate early on in the LP pathway is LTA4. From that we get LTB4, which mainly regulates chemotaxis (cytokine activity) and activates phagocytosis in white blood cells. Also derived from LTB4 are, sequentially, LTC4, LTD4, and LTE4 (cysteinyl leukotrienes, historically and collectively called SRS-A, for slow-reacting substance of anaphylaxis), which cause mainly bronchoconstriction. Leukotriene synthesis can be inhibited by zileuton (no longer used clinically), a 5′-lipoxygenase inhibitor. The leukotriene receptors can be blocked by montelukast and zafirlukast, which are used prophylactically (“control meds”) to suppress airway inflammation and bronchoconstriction in asthma. They should not be used in lieu of corticosteroids (oral or inhaled) when control of airway inflammation is necessary. Prostaglandins (c), including prostacyclin (b), and thromboxane A2 (d) are synthesized via the cyclooxygenase pathways. Uric acid (e) is synthesized by what is generally referred to as the ATP (purine) degradation pathway, in which the final two steps in the pathway (conversion of hypoxanthine to xanthine, and conversion of xanthine to uric acid) are catalyzed by xanthine oxidase.

Question 4

A patient has mild cutaneous and systemic manifestations of a seasonal allergic Before you prescribe a short course of diphenhydramine for symptom relief, you should realize that this drug has one mechanism of action resembling, causes many s ide effects s imilar to, and shares many contraindications, that apply to an “autonomic” drug which you should be very familiar. What i s that drug?

A	Atropine
B	Bethanechol
C	Norepinephrine
D	Phentolamine
E	Physostigmine
F	Propranolol

Question 4 Explanation:

Diphenhydramine, an older or “first-generation” antihistamine, is a competitive antagonist of histamine’s effects on H1 receptors, and also strongly blocks muscarinic cholinergic receptors. Other older H1 blockers (but none of the second-generation H1 blockers, such as fexofenadine) possess this atropine-like effect, often to a lesser degree than diphenhydramine. (If you wished to argue that because diphenhydramine was more like scopolamine, because it causes not only anticholinergic effects but also a considerable degree of sedation, you would be correct.) Thus, common side effects related to antimuscarinic activity include sedation, dry mouth, photophobia, and cycloplegia (paralysis of accommodation). Key contraindications include prostatic hypertrophy, bowel or bladder obstruction or hypomotility, tachycardia, and narrowangle (angle-closure) glaucoma. To refresh your memory about the other drugs listed, bethanechol (b) is a muscarinic agonist, norepinephrine (c) is an effective agonist for β1- and α-adrenergic receptors, phentolamine (d) is a nonselective α blocker, physostigmine (e) is an acetylcholinesterase inhibitor, and propranolol (f) is, of course, the prototypic nonselective β-adrenergic blocker.

Question 5

A patient presents with a history of frequent and severe migraine When we give one of the more commonly used drugs for abortive therapy, sumatriptan, upon which of the following “local control substances” i s i t mainly acting?

A	Histamine
B	PGF2α
C	Prostacyclin
D	Serotonin
E	Thromboxane A2

Question 5 Explanation:

Acute migraine therapy often involves giving a drug that mimics the effects of endogenous serotonin (5-hydroxytryptamine), thereby reversing the cerebral vasodilation that contributes significantly to migraine signs and symptoms. A good example is sumatriptan (member of a small group of drugs called triptans). These are 5-HT1B/2D receptor agonists. Histamine (a), and to a lesser extent prostacyclin (PGI2, answer c), are vasodilators, too, but they don’t seem to have appreciable roles in migraine, nor are they targets of antimigraine drug activity. Activation of β2-adrenergic receptors in the cerebral vasculature also leads to vasodilation and migraine symptoms. The β-adrenergic blockers (particularly propranolol) are useful for some migraineurs, but only for prophylaxis, not for abortive therapy

Question 6

A male patient with severe arthritis will be placed on long-term therapy with You recognize the ri sk of NSAID-induced gastrointestinal ulceration, and so want to prescribe another drug for ulcer prophylaxis. Which drug would you most l ikely choose, as an add-on to indomethacin, assuming that there are no specific contraindications to i ts use?

A	Celecoxib
B	Cimetidine
C	Diclofenac
D	Diphenhydramine
E	Misoprostol

Question 6 Explanation:

Misoprostol is a long-acting synthetic analog of PGE1, and its only use (outside of reproductive medicine) is prophylaxis of NSAID-induced gastric ulcers. Its main effects are suppression of gastric acid secretion (modest); and, more importantly, enhanced gastric mucus production (a so-called mucotropic or cytoprotective effect). The need for the drug arises, of course, because such drugs as indomethacin (and most other COX-nonselective inhibitors) inhibit PGE1 synthesis (as well as that of other prostaglandins, prostacyclin, and thromboxane A2). Although cimetidine (b) might help reduce gastric acid secretion (via H2 blockade) and diphenhydramine (c) may too (via antimuscarinic effects), their antisecretory effects (with respect to gastric acid) are weak, and they don’t increase formation of the stomach’s protective mucus. Celecoxib (a), a COX-2 selective NSAID, is associated with a lower risk or incidence of GI ulcers than more traditional COX-1/-2 NSAIDs, includingindomethacin (or diclofenac, ibuprofen, many others). However, adding a COX-2 inhibitor would be irrational in terms of reducing ulcer risk. Diclofenac (c) is a traditional NSAID that, when used long-term (eg, as an alternative to indomethacin or any of the other reasonable options), may cause ulcers just as indomethacin may. In fact, a fixed-dose combination product containing diclofenac and misoprostol is available, the latter drug being used to reduce the risk of ulcers caused by the former.

Question 7

Aspirin causes s ignificant bronchoconstriction and bronchospasm in a patient who was subsequently identified as being “aspirin-sensitive.” Which mechanism summarizes best why or how aspirin provoked the respiratory problems in this patient?

A	Induced drug-mediated hypersensitivity of H1 receptors on airway smooth muscles
B	Induced drug-mediated hypersensitivity of muscarinic receptors on airway smooth muscles
C	Enhanced formation of antibodies directed against the salicylate on airway mast cells
D	Inhibited synthesis of endogenous prostaglandins that have bronchodilator activity
E	Reduced (blocked) epinephrine binding to β2-adrenergic receptors on airway smooth muscle cells

Question 7 Explanation:

Inhibited synthesis of prostaglandins that are bronchodilators (mainly PGE2) are thought to be responsible for severe or fatal responses to aspirin in some asthmatics. Note that aspirin and other traditional NSAIDs inhibit the synthesis of PGF2α and of TXA2, both of which are bronchoconstrictors. As a result, one would predict reduced bronchoconstriction with aspirin. However, in those patients with aspirin-sensitive asthma (about 20% of adult asthmatics overall), the adverse effects arising from inhibited PGE2 synthesis tend to predominate, and so aspirin and other efficacious NSAIDs are generally contraindicated. Aspirin does not cause increased responsiveness of airway smooth muscle cells to the bronchoconstrictor effects of histamine (a) or muscarinic agonists (b). It does not elicit antibody formation (c) or have any effect on the interaction between β2 agonists and their cellular receptors (e).

Question 8

A child takes what comes close to being a lethal dose of What i s the most l ikely pathology that ultimately can lead to death involved in this drug overdose?

A	Acute nephropathy
B	A-V conduction disturbances, heart block
C	Liver failure
D	Status asthmaticus
E	Status epilepticus

Question 8 Explanation:

The primary cause of death from acetaminophen overdoses is hepatic necrosis. The drug’s main toxic metabolite is N-acetyl-benzoqinoneimine. It reacts with sulfhydryl groups that are constituents of key macromolecules and metabolic cofactors (eg, glutathione) in the liver. If acetaminophen doses are low, glutathione conjugates the metabolite. With toxic doses, however, glutathione is depleted and other—SH groups on hepatocyte proteins are attacked and irreversibly altered. Concomitant with overall hepatic damage we find, eventually, profound hypoglycemia (as the liver’s stores of glycogen are depleted) and coagulopathies (as hepatic clotting factor synthesis stops and the patient begins bleeding spontaneously). Nephropathy (a) is not a primary or important consequence of acetaminophen toxicity. If AV conduction disturbances, heart block, or other cardiac electrophysiologic anomalies (b) occur, they are secondary to hepatic dysfunction. Status asthmaticus (d) and acute seizures (e) are not likely or direct consequences of acetaminophen poisoning. Note: Let’s summarize the main events or “stages” (they’re arbitrary) of what otherwise would be a lethal dose of acetaminophen: for an otherwise-healthy child, it is around 12 g taken all at once; for otherwise healthy adults it is around 25 g. Various illnesses, and consuming other drugs (including aspirin) can dramatically lower the dose sufficient to cause serious or lethal toxicity. A “standard strength” acetaminophen tablet contains 300 mg. Be aware that acetaminophen toxicity is the most common drug cause of liver failure in the United States. And, most of those cases are not caused by suicide attempts in which the drug is taken all at once. More often, the toxicity develops gradually, with excessive acetaminophen use over time. A major contributor to that problem is that acetaminophen is found in so many products, most available OTC, and the consumer simply isn’t aware that he or she is ultimately taking many doses of a product that contains this hepatotoxin.

Question 9

A patient with asymptomatic hyperuricemia i s started on In a couple of days, he develops acute gout. What i s the mechanism by which probenecid, early in the course of treatment with i t, triggered this acute gouty arthritic episode?

A	Accelerated synthesis of uric acid
B	Co-precipitated with uric acid in the joints
C	Induced an idiosyncratic response that triggered urate precipitation
D	Induced systemic acidosis, favoring uric acid crystallization
E	Reduced renal excretion of uric acid

Question 9 Explanation:

It has been said that the initial phase of uricosuric therapy is the most worrisome period for a hyperuricemic patient. Probenecid is a uricosuric drug (one that increases renal elimination of uric acid), but that effect is highly dose-dependent. Desired uricosuric actions depend on having therapeutic probenecid blood levels that are sufficient to inhibit active tubular reabsorption of urate. At subtherapeutic blood levels, the main effect is inhibition of tubular secretion of urate, which reduces net urate excretion and raises plasma urate levels (sometimes to the point of causing clinical gout). It is only once probenecid levels are therapeutic that the desired effects to inhibit tubular urate reabsorption (ie, increase excretion) predominate. Thus, and intuitively, once a patient starts probenecid therapy drug levels must rise and pass through that stage in which urate excretion will actually go down, plasma urate levels up. Some texts suggest using a short course of colchicine or another (non-aspirin) NSAID that is indicated for gout when probenecid therapy is started. That is for prophylaxis of acute gout that might occur. Although this may be acceptable, other rules are perhaps more important: (1) do not administer a uricosuric during a gout attack; (2) if the patient has had a gout attack recently, suppress the inflammation for 2 to 3 months with a suitable anti-inflammatory; and (3) do not use uricosurics for patients with “severe hyperuricemia” and/or poor renal function. Doing otherwise is associated with a great risk of potentially severe renal tubular damage as the uricosuric shifts large amounts of uric acid from the blood (with its large volume, that keeps urate relatively “dilute”) into a small volume of acidic urine, which concentrates urate and lowers its solubility via pHdependent mechanisms. (The patient who skips doses of probenecid also becomes very vulnerable to the “paradoxical” extra risk, because doing this may allow drug levels to fall into that subtherapeutic range in which more urate is retained than eliminated.)

Question 10

Epidemiologic data published in the early 1980s found a probable relationship between aspirin and a serious adverse response when the drug was administered to children with influenza, chickenpox, and other vi ral i l Although no causal relationship between aspirin, vi ral i l lness, and this adverse effect was proven, you sti l l caution the parents or caregivers of children to avoid giving any aspirin or aspirin-containing product when there i s even a remote possibility that a child’s i l lness might involve a vi rus. Avoidance of aspirin i s necessary to avoid which specific adverse response?

A	Asthma
B	Cardiomyopathy
C	Renal failure
D	Reye syndrome
E	Thrombocytopenia and related bleeding disorders

Question 10 Explanation:

Before the warning was issued, over 500 children with any viral illness and who received aspirin (even in usual recommended doses at the time) developed Reye syndrome. It is characterized by encephalopathy and fatty liver degeneration. The mortality rate ranged from about 20% to 30%, and many more patients developed permanent and serious CNS and/or liver dysfunction. Nowadays there are fewer than five cases of Reye syndrome per year as a result of the aspirin/viral illness “interaction.” (Note: the age range for which aspirin should not be administered in the presence of viral illness is debatable; some suggest the risk of Reye syndrome lessens dramatically by the age of 12 years, but many experts suggest that the risk may persist up to 18-20 years of age.) Asthma (a) is the most common cause of hospitalizations in children, and many patients have their asthma provoked or worsened by aspirin or other NSAIDs. However, the potential asthma—NSAID problems are unrelated to the presence or absence of viral illnesses. There is no evidence of a linkage between aspirin and cardiomyopathies (b). Long-term high dose administration of NSAIDs (other than aspirin) may cause renal dysfunction or failure (c). Here, too, there is no linkage between viral illness, and the kidney problems are not at all focused on the pediatric population. Aspirin obviously has antiplatelet-aggregatory effects, but whether the patient is a child or older, thrombocytopenia (e) is not a concern.

Question 11

Such drugs as methotrexate, hydroxychloroquine, or penicillamine are often turned to for managing rheumatoid arthritis that i s not controlled adequately with “traditional” NSAIDs (eg, aspirin, ibuprofen, diclofenac, or indomethacin). Which statement most correctly summarizes how those drugs differ from a typical NSAID?

A	Activate the immune system to neutralize inflammatory mediators
B	Are primary therapies for gouty arthritis
C	Are remarkably free from serious toxicities
D	Provide much quicker relief of arthritis s igns, symptoms
E	Slow, stop, possibly reverse joint pathology in rheumatoid arthritis

Question 11 Explanation:

Methotrexate, gold salts, and penicillamine are members of a diverse group of drugs called DMARDs (disease-modifying antirheumatic drugs) or SAARDs (slow-acting antirheumatic drugs). The former term derives from the ability of these drugs to slow, stop, or in some cases reverse joint damage associated with rheumatoid arthritis (RA). They do more than merely mask or relieve RA symptoms, which is mainly what the traditional NSAIDs do. The second acronym derives from the fact that it may take a month (or a couple more) for meaningful symptom relief to develop; they are not at all quick-acting drugs. Their actions probably are due to suppression of immune responses that often contribute to the etiology of RA. Their toxicities can be serious, which is one reason why, until not long ago, these agents were considered third-line or even last resort treatments for refractory rheumatoid disease. (Methotrexate is now being used much earlier, and safely, for RA, now that we know better how to use it and monitor for serious toxicities.) Most of these drugs can cause serious blood dyscrasias; in addition, penicillamine can cause renal and pulmonary toxicity; hydroxychloroquine is associated with vision impairments/retinopathy.

Question 12

For quite a while the “coxibs” (selective COX-2 inhibitors) were prescribed in preference to nonselective cyclooxygenase inhibitors for managing such conditions as rheumatoid Now we have basically one drug in this class, celecoxib. Which statement best describes an action or property of this COX-2 inhibitor?

A	Associated with a lower ri sk of gastric or duodenal ulceration
B	Cures arthritis, rather than just give symptom relief
C	Effectively inhibits uric acid synthesis
D	Has a lower ri sk of adverse or fatal cardiac events
E	Has s ignificantly faster onset of action

Question 12 Explanation:

Celecoxib, by virtue of selective COX-2 inhibition, does not interfere as much with synthesis of PGE2, which normally suppresses a component of gastric acid secretion and stimulates gastric mucus production. Overall, then, the risks of gastric and duodenal ulcers are reduced. The selectivity also means that COX-2 inhibitors do not interfere with the production of other eicosanoids, such as TXA2. That is both good and bad, clinically. On the good side, this means that COX-2 inhibitors don’t cause antiplatelet effects and increase the risk of excessive or spontaneous bleeding. On the other hand, this lack of effect renders them unsuitable for causing desired antiplatelet-aggregatory effects, as might be wanted when we administer aspirin. This may explain the finding that some COX-2 inhibitors have been associated with (cause?) a higher risk of sudden cardiac death (d) in vulnerable patients, and why some have been pulled off the market (and are subjects of considerable litigation). Selective COX-2 inhibitors, such as the nonselective alternatives, aren’t cures for arthritis (b); they alleviate signs and symptoms but seem to have no demonstrable impact on the underlying pathophysiology. They have no effect on uric acid metabolism (c) or excretion. Their onsets of action are, overall, no faster (e) than those of a typical NSAID.

Question 13

Glucocorticoids are widely used for a host of inflammatory reactions and the diseases they In terms of inflammatory responses and underlying metabolic reactions, which enzyme or process i s the main target of these drugs when they are given at pharmacologic (supraphysiologic) doses?

A	Cyclooxygenases (COX-1 and -2)
B	Histidine decarboxylase
C	5′-l ipoxygenase
D	Phospholipase A2 (PLA2)
E	Xanthine oxidase

Question 13 Explanation:

Anti-inflammatory doses of glucocorticosteroids inhibit phospholipase A 2 activity. In doing so, they inhibit arachidonic acid synthesis and, therefore, synthesis of all subsequent products of the cyclooxygenase and lipoxygenase pathways, both of which originate with arachidonic acid. This action of glucocorticoids is indirect because their initial or direct effect is induced synthesis of annexins (previously called lipocortins), which are the moieties that directly inhibit PLA2 activity. Glucocorticoids have no intrinsic or direct inhibitory effects on later steps in AA metabolism, that is, no direct effects on cyclooxygenase or lipoxygenase activity. Cyclooxygenases (a) are inhibited by traditional NSAIDs such as aspirin (nonselective COX-1 and -2 inhibitors), or the “coxibs” (celecoxib), which relatively selectively inhibit COX-2. We have no clinically useful inhibitors of histamine synthesis (which involves histidine decarboxylase activity; b). As noted elsewhere, zileuton inhibits 5′-lipoxygenase (c) and the subsequent formation of leukotrienes. Allopurinol inhibits the synthesis of xanthine and uric acid by inhibiting xanthine oxidase (e). The same applies to the new allopurinol alternative, febuxostat.

Question 14

Bradykinin plays important roles in local responses to ti ssue damage and a variety of inflammatory It also has vasodilator activity. Which statement i s correct about this endogenous peptide?

A	Captopril inhibits i ts metabolic inactivation
B	Drugs that are metabolized to, or generate, nitric oxide, counteract bradykinin’s vascular effects
C	Increased blood pressure i s the predominant cardiovascular response
D	Newer histamine H1 blockers (eg, fexofenadine; “second-generation” antihistamine) also competitively block bradykinin receptors
E	The main renal responses to endogenous bradykinin are arteriolar constriction and reduced GFR

Question 14 Explanation:

Bradykinin is metabolized to biologically inactive peptides by an enzyme that has at least three names: angiotensin-converting enzyme (ACE; recall that the prototype ACE inhibitor is captopril), bradykininase, and kininase II. The name that is used depends on the substrate. When the substrate is angiotensin I, the enzyme is called ACE. When the substrate is bradykinin we call it either bradykininase or kininase II. Bradykinin, whether injected experimentally or derived from endogenous sources (kininogens cleaved by specific proteases called kallikreins), exerts significant vasodilator effects that can lower systolic and diastolic blood pressures. Although this may not be an important pressureregulating mechanism in normotensive individuals, it probably is in many (most?) patients with essential hypertension. Clearly, bradykinin does not increase blood pressure (c) or constrict the renal vasculature (e). Recall that ACE inhibitors lower blood pressure in many hypertensive patients. One mechanism involves “preserving” bradykinin by inhibitingits enzymatic inactivation. Bradykinin also causes prerenal arteriolar vasodilation and increases GFR, leading to diuretic effects. The peptide’s vascular effects are mediated by endothelial cell-derived nitric oxide, and they are enhanced (not counteracted, b) by other drugs that cause vasodilation by a nitric oxide-related mechanism. Bradykinin receptor blockers prevent the peptide’s vasodilator effects. However, no currently approved drugs, including the so-called secondgeneration antihistamines such as fexofenadine (d) exert that effect.

Question 15

A newborn has oxygenation and hemodynamic problems because of a patent (open) ductus Which drug usually would be administered in an attempt to close the lesion?

A	Cimetidine
B	Diphenhydramine
C	Indomethacin
D	Misoprostol
E	Prostaglandin E1 (PGE1; alprostadil)

Question 15 Explanation:

The ductus arteriosus in neonates may remain patent largely because of the vasodilator effects of endogenous PGE1, formed via the cyclooxygenase pathway. When the goal is to close a patent ductus after birth we generally use a prostaglandin synthesis (COX-1/-2) inhibitor (indomethacin, historically; or ibuprofen more often nowadays). (Conversely, there are times when surgical procedures are required on a congenitally anomalous heart in newborns, and we want to keep the ductus open until surgery. In that case, alprostadil [PGE1, answer e] may be administered.) Misoprostol (d) is a prostaglandin analog. Giving it to a newborn with a patent ductus is likely to keep the lesion open, not close it. None of the H 2 blockers (eg, cimetidine, a) nor H1 blockers (diphenhydramine, b, and many others) have any important effects on prostaglandin synthesis, nor are they used either to close a patent ductus arteriosus or to keep it open for subsequent surgery.

Question 16

A 29-year-old woman develops frequent, debilitating migraine Sumatriptan i s prescribed for abortive therapy. Not long after taking the drug she i s rushed to the hospital. Her vi tal s igns are unstable, and she has muscle rigidity, myoclonus, generalized CNS i rri tability and altered consciousness, and shivering. You learn that for several months she had been taking another drug with which the triptan interacted. Which add-on drug most l ikely caused these acute and serious problems?

A	Acetaminophen
B	Codeine
C	Diazepam
D	Fluoxetine
E	Phenytoin

Question 16 Explanation:

This patient has what is almost certainly the serotonin syndrome. The triptan “adds” serotonin to serotoninergic synapse, and serotonin’s neuronal reuptake will be blocked by fluoxetine (or sertraline, others), which is classified as a selective serotonin reuptake inhibitor (SSRI) antidepressant. When sumatriptan (or other triptans used for migraine) is added, rapid accumulation of serotonin and/or the triptan in the brain synapses can occur. The other drugs listed (acetaminophen, a; codeine, b; diazepam, c; and phenytoin, e) are not likely to interact with serotoninergic drugs.

Question 17

A patient (assume he or she i s taking no other drugs) has been taking doses of aspirin that are too high for several Low-grade aspirin toxicity (salicylism) develops. What s ign or symptom would be consistent with salicylism and the high salicylate levels that caused i t?

A	Constipation
B	Cough
C	Hypertension
D	Myopia
E	Tinnitus

Question 17 Explanation:

Tinnitus, along with a feeling of dizziness or lightheadedness, GI upset (including nausea and some pain or other discomfort, and diarrhea more so than constipation), and such visual changes as blurred or diplopia (but not myopia, d), all are part of a low-grade aspirin “toxicity” syndrome called salicylism. It is not necessarily worrisome (provided the physician intentionally prescribed the drug at dosages likely to produce the syndrome), dangerous, or indicative of imminent and severe toxicity. Indeed, some patients experience one or more signs or symptoms of salicylism in response to high (antiarthritic) doses of aspirin. Constipation (a) or hypertension (c) are not causally associated with salicylate administration, regardless of the dose used. Cough (b) may occur, but that is only likely to occur in patients who have “aspirin-sensitive” asthma, and for those patients bronchoconstriction is more likely than cough to be the response.

Question 18

Aspirin generally should be avoided as an anti-inflammatory, analgesic, or antipyretic drug by patients with hyperuricemia or That i s because i t counteracts the effects of one important drug the hyperuricemic patient may be taking. Which drug has i ts desired uric acid-related effects reduced or eliminated by this prototypic NSAID?

A	Acetaminophen
B	Allopurinol
C	Colchicine
D	Indomethacin
E	Probenecid

Question 18 Explanation:

Probenecid (and the related drug, sulfinpyrazone) are classified as uricosurics: at sufficiently high (therapeutic) doses, they enhance the renal elimination of uric acid by inhibiting tubular reabsorption of filtered urate. Aspirin significantly impairs the uricosurics’ actions. Important note: Aspirin (given alone) has blood level-dependent effects on urate elimination by the kidneys. At “low doses” perhaps up to about 1 g/day, it selectively inhibits tubular secretion of urate and so can raise plasma urate levels. At doses much higher than that (including doses sometimes prescribed for arthritis other than gout), the predominant effect (and the net, or overall, effect) is uricosuria due to blockade of tubular reabsorption of urate (this effect is greater than the drug’s inhibitory effect on tubular secretion of urate). Nonetheless, aspirin is not used as a uricosuric drug because the doses/blood levels needed to increase urate elimination are sufficiently high that they cause significant side effects (eg, salicylism; see Question 326) that don’t arise with the traditional uricosurics such as probenecid. Acetaminophen (a) has no appreciable or clinically useful effects on uric acid elimination or synthesis. Allopurinol (b, and the new related drug febuxostat) inhibits uric acid synthesis, but its xanthine oxidase-inhibitory effects are not altered by aspirin. However, since allopurinol is used to lower plasma urate levels it is largely irrational to use aspirin at the same time. The same applies to colchicine (c) and indomethacin (d), both of which are used for in acute gout and neither of which has its main biochemical effects (suppression of inflammation) impaired by aspirin.

Question 19

Misoprostol, an analog of PGE₁, i s sometimes used adjunctively to stimulate gastric mucus production and help reduce the incidence of gastric ulcers associated with long-term or high-dose NSAID therapy for What i s the other main use for this l ipid-derived autacoid?

A	Closure of a patent ductus arteriosus in newborns
B	Contraception in women who should not receive estrogens or progestins
C	Induction of abortion in conjunction with mifepristone (“RU486”)
D	Prophylaxis of asthma in l ieu of a corticosteroid
E	Suppression of uterine contractility in women with premature labor

Question 19 Explanation:

In addition to misoprostol’s use as a cytoprotective/mucotropic drug for some patients taking NSAIDs, misoprostol is also used as an adjunct to mifepristone to induce therapeutic abortion. This capitalizes on the prostaglandin analog’s strong uterine-stimulating effects (thus, answer e is incorrect). The drug is sometimes used to maintain patency of an open ductus arteriosus, not to close it (a). It is not a contraceptive in the typical sense, such as we would associate with estrogen-progestin oral contraceptives. Given the drug’s abortifacient effects, it is contraindicated for women who are pregnant, or wish to become pregnant (b). Misoprostol has bronchodilator activity, but it is relatively weak and the drug is not suitable as a substitute for corticosteroids (d) or other typical asthma medications.

Question 20

A patient who was transported by ambulance to the Emergency Department took a potentially lethal overdose of What drug would be a helpful, i f not l i fesaving, adjunct to manage this severe aspirin poisoning?

A	Acetaminophen
B	Amphetamines (eg, dextroamphetamine)
C	N-acetylcysteine
D	Phenobarbital
E	Sodium bicarbonate

Question 20 Explanation:

Adjunctive use of sodium bicarbonate (IV) can be an important adjunct to managing severe salicylate poisoning for two main reasons: (1) it helps raise blood pH, which as stated earlier is profoundly reduced from metabolic plus respiratory acidosis; (2) it alkalinizes the urine, which (via a pH-dependent mechanism, a la Henderson-Hasselbach) converts more aspirin molecules into the ionized form in the tubules, thereby reducing tubular reabsorption of a substance we want to eliminate from the body as quickly as possible. Acetaminophen (a), even though it is usually an effective antipyretic, is not good for managing fever of severe aspirin poisoning. It would add yet another drug that might complicate the clinical picture, and ordinary (and ordinarily safe) doses aren’t likely to do much to lower temperature quickly or sufficiently. (Thus, we use physical means to lower body temperature.) N-acetylcysteine (c), the antidote for acetaminophen poisoning, does nothing for salicylate poisoning. Amphetamines (b) might seem rational for managing ventilatory depression that characterizes late stages of severe aspirin poisoning. The more likely outcome of giving an amphetamine is simply to hasten the onset of seizures. Phenobarbital (d), or other CNS depressants, would aggravate an already bad state of CNS/ventilatory depression. (However, if seizures develop they must be managed —eg, with IV lorazepam and phenytoin, even though they cause CNS depression. Without them, the patient may quickly die from status epilepticus.) Just as I provided a table (answer to Question 317) to summarize the general sequence of events in acetaminophen toxicity, I’ll provide one here for aspirin overdoses. Again, the “stages” I present are arbitrary, but they should be helpful—knowing what is likely to come next as toxicity progresses helps you prepare for what you’ll probably need to do next. Note that the average lethal dose for an otherwise healthy child is between around 5 g and 8 g, taken all at once. For adults, it is between around 10 g and 30 g. “Usual strength” aspirin tablets—those used for aches, pains, mild inflammation, and fever—contain 325 mg of the drug. (“Heart dose” aspirin tablets contain 81 mg.) Higher doses may be prescribed for arthritis—several grams a day—and although these usually are not sufficient to cause death they are likely to cause side effects that often are disturbing enough that the physician will prescribe anotherantiarthritic drug instead of plain, cheap, aspirin.

Question 21

We look at data that summarize the actions of two prototypic histamine receptor blockers: diphenhydramine as the exemplar of the older antihistamines (competitive histamine receptor antagonists); and fexofena-dine as a representative agent of the “second-generation” antihistamines. Which statement correctly describes, compares, or contrasts these drugs or the pharmacologic groups to which they belong?

A	Diphenhydramine and other drugs in i ts class (ethanolamines) tend to cause drowsiness more often than fexofenadine and related second- generation antihistamines
B	Diphenhydramine i s a preferred antihistaminic for patients with prostate hypertrophy or angle-closure glaucoma, whereas fexofenadine and related drugs are contraindicated
C	Diphenhydramine overdoses tend to cause bradycardia, whereas fexofenadine overdoses tend to cause s ignificant increases of heart rate
D	Fexofenadine and related second-generation histamine antagonists have intrinsic bronchodilator activity, which makes them suitable as primary/sole therapy for people with asthma
E	Fexofenadine, and drugs in i ts class, have better efficacy in terms of suppressing histamine-mediated gastric acid secretion

Question 21 Explanation:

One of the main advantages of the first-generation antihistamines (fexofenadine, loratadine, others) over the older (second-generation) H-1 antagonists such as diphenhydramine is a relative lack of CNS depressant (sedating) effects when administered at usual recommended doses. The implication of this difference is that the newer agents are much less likely to cause daytime drowsiness or other problems that might interfere with daytime activities requiring alertness. Sedation is a particular problem with diphenhydramine, doxylamine, and other members of the ethanolamine class of first-generation antihistamines, yet it also provides a clinically useful effect based on this action: they are useful as OTC (diphenhydramine, doxylamine) and prescription (diphenhydramine) sleep-aids. Diphenhydramine, and to a large degree all the other first-generation antihistamines, tend to cause appreciable muscarinic receptor-blocking (atropinelike) effects, and so they are unsuitable or potentially dangerous for patients with such atropine-related comorbidities as prostatic hypertrophy, hypomotility disorders of the urinary or GI tracts, tachycardia, or angle-closure glaucoma (so answer b is not correct). Owing to antimuscarinic effects, diphenhydramine overdoses are more likely to cause tachycardia (by blocking parasympathetic-ACh-muscarinic receptor influences on the SA node) than bradycardia (c). The second-generation antihistamines do block histamine-related bronchoconstriction, but in the absence of histamine they have no intrinsic bronchodilator activity. More important is the fact that these drugs play no role as primary therapy for asthma. They may be preferred to older antihistamines (largely because they lack the antimuscarinic-related mucus-thickening effects of such drugs as diphenhydramine), but they should be used only as adjuncts to more appropriate asthma drugs such as inhaled corticosteroids (to suppress airway inflammation) and inhaled β-adrenergic drugs for control or rescue therapy. None of the H 1 blockers—first-generation or second-generation agents—has H2 blocking activity that is necessary to suppress histaminemediated acid secretion by gastric parietal cells.

Question 22

A patient has been taking one of the drugs l i sted below for about 4 months, and i s experiencing the desired therapeutic effects from i t. The physician now prescribes indomethacin to treat a particularly severe flare-up of rheumatoid Within a matter of days the therapeutic effects of the fi rst drug wane dramatically, i ts actions antagonized by the indo-methacin. Which drug was affected by the indomethacin?

A	Allopurinol, given for prophylaxis of hyperuricemia
B	Captopril, given for essential hypertension
C	Fexofenadine, given for managing seasonal allergy responses
D	Sumatriptan, given for abortive therapy of migraine headaches
E	Warfarin, given for prophylaxis of venous thrombosis

Question 22 Explanation:

A major component of the antihypertensive actions of captopril and other ACE inhibitors is prostaglandin-dependent. That element of drug action is antagonized by indomethacin due to its great efficacy to inhibit prostaglandin synthesis. Other drugs with actions that may be inhibited by prostaglandin synthesis inhibitors such as indomethacin include the thiazide and loop diuretics and (allegedly) many if not most of the β-blockers. The actions of none of the other drugs listed are antagonized by indomethacin. You should note, however, that giving indomethacin to a patient taking warfarin or any of the antiplatelet drugs (used for prophylaxis of arterial thrombosis) is risky. One of the major toxicities of the NSAIDs is gastric mucosal damage and the risk of GI bleeds. In the presence of anticoagulants or antiplatelet drugs the risk of a serious GI bleed, perhaps progressing to hemorrhage, goes up markedly. However, this is not due to a typical pharmacodynamic or pharmacokinetic interaction between the drugs, and the anticoagulants’ effects certainly are not inhibited by the NSAID.

Question 23

A patient takes an acute, massive overdose of aspirin that, without proper intervention, will probably be What would you expect to occur in the advanced (late) stages of aspirin (salicylate) poisoning?

A	Hypothermia
B	Metabolic alkalosis
C	Respiratory alkalosis
D	Respiratory plus metabolic acidosis
E	Ventilatory stimulation

Question 23 Explanation:

Late, severe aspirin poisoning is characterized by a combination of respiratory and metabolic acidosis. In early stages of aspirin poisoning (or even with high “therapeutic” doses of the drug), ventilatory stimulation occurs. That induces a respiratory alkalosis (c; net CO2 loss, relative HCO3 retention). The kidneys compensate for this by increasing HCO3 excretion to help normalize blood pH and causing what has been called “compensated respiratory alkalosis.” As plasma levels of aspirin rise, however, blood pH falls precipitously. Part of that is due to the accumulation of acidic salicylic acid in the blood, and part is due to inhibited oxidative phosphorylation that shifts metabolism from oxidative to glycolytic (with lactic acid being the key end product). No longer synthesizing ATP effectively, the mitochondria generate metabolic heat, which contributes to fever (not hypothermia; a). Ventilatory failure (not stimulation; e) ensues, leading to respiratory acidosis (from CO2 retention) along with the metabolic acidosis. Cardiovascular collapse and seizures eventually cause death. Note that hepatotoxicity is not a component of this: that is the main cause of morbidity and mortality with acetaminophen poisoning.

Question 24

A patient presents in the emergency department with an overdose of a The physician knows what the drug i s , and so orders appropriate “symptomatic and supportive care,” plus multiple doses of N-acetylcysteine. Upon which drug did the patient overdose?

A	Acetaminophen
B	Aspirin
C	Colchicine
D	Diphenhydramine
E	Loratadine
F	Methotrexate

Question 24 Explanation:

Acetaminophen’s main toxic metabolite is Nacetylbenzoqinoneimine. It reacts with sulfhydryl groups (particularly with glutathione) in hepatocytes, ultimately leading to hepatic necrosis when acetaminophen levels are sufficiently high. N-acetylcysteine is rich in—SH groups. It therefore reacts with the imine, hopefully sparing endogenous sulfhydryl compounds from further attack and, hopefully, allowing time for the hepatocytes to recover from the biochemical stress. This foul-smelling antidote must be given early after acetaminophen poisoning occurs or is likely (it is usually given orally), and it must be given repeatedly (see specialty texts for more information). It is a preventative against hepatotoxicity, not a reversing agent. As an aside, various nomograms are available to give some reasonable of whether a particular acetaminophen dose (more precisely, blood level) is likely to be hepatotoxic or not. They plot plasma acetaminophen levels as a function of time after drug ingestion (yielding, basically, an elimination rate and an elimination half-life). If the patient’s acetaminophen level at a specified time following intake is above the line, hepatotoxicity is probable. Such a finding, however, does not mean that N-acetylcysteine administration will be without benefit and so should not be done. (See the explanation for Question 317 for more information, and a look at this issue from a somewhat different perspective.) All of the other drugs listed can exert toxic effects (often serious) with overdoses, but N-acetylcysteine is not an appropriate or effective antidote for any of them

Question 25

A patient has acute The physician initially thinks about prescribing just one or two oral doses of colchicine, 12 hours apart, but then decides otherwise. What i s the main and most common reason for avoiding colchicine, even with a very short oral course, and prescribing another drug for the acute gout instead?

A	Bone marrow suppression
B	Bronchospasm
C	GI distress that i s almost as bad as the acute gout discomfort
D	Hepatotoxicity
E	One or two oral doses seldom relieve gout pain
F	Refractoriness/tolerance with just a dose or two

Question 25 Explanation:

The main reason why many physicians are shunning oral colchicine for acute gout is that many patients develop horrible GI discomfort, vomiting, diarrhea, and the like. For some, the “cure” is almost as bad as the disorder for which the drug is given. This GI distress can be alleviated somewhat by giving colchicine IV, but more serious systemic responses can develop if the IV dose is too great or too many IV doses are given in a short period of time. (These are among the reasons why IV formulations of colchicine are no longer available.) Indomethacin seems to have become one of the preferred alternatives for anti-inflammatory therapy of acute gout or prophylaxis of recurrences. (And clearly indomethacin is not without side effects or toxicities; the risks and discomforts are simply more acceptable, for some patients, with it.) But when colchicine does work in acute gout, relief may be dramatic and occur literally “overnight” with just a dose or two. The likely mechanism of action involves impaired microtubular assembly or function in leukocytes, which limits their migration to the area of crystal deposition and so limits their ability to amplify the inflammatory reaction. Bone marrow suppression can occur, but that is mainly with long-term, high-dose oral or parenteral colchicine administration (the latter of which must be avoided). The same applies to frank gastric damage (with the possibility of gastric bleeding or hemorrhage) and to blood dyscrasias (bone marrow toxicity).

Question 26

A patient with hyperuricemia i s placed on an “antigout” Before starting the drug you measure the total uric acid (amount, not concentration) in a 24-hour urine sample and then do the same several weeks after continued drug therapy at therapeutic doses. The post- treatment sample shows a s ignificant reduction in urate content. There were no new pathologies developing during therapy, and the patient’s daily purine intake did not change at all. What drug most l ikely accounted for these findings?

A	Acetaminophen
B	Allopurinol
C	Colchicine
D	Indomethacin
E	Probenecid

Question 26 Explanation:

You may think that reductions in urate content in a 24-hour urine sample would be bad for the hyperuricemic patient, but that is because you probably automatically (and incorrectly) equate less urine urate with increased plasma urate. Not necessarily so. Allopurinol inhibits uric acid synthesis by inhibiting xanthine oxidase: less uric acid made, less to be excreted in theurine, and less to be detected there. This is one manifestation of allopurinol “at work.” Acetaminophen (a) has no effects on uric acid synthesis, excretion, or solubility. Colchicine (c) is sometimes used for prophylaxis or treatment of gout, but its actions derive from its anti-inflammatory action and, probably, suppression of neutrophil chemotaxis by interfering with microtubular function. It has no effects on urate synthesis or elimination. The same applies to indomethacin (d): anti-inflammatory actions, but no effects per se on uric acid. Probenecid (e) is a uricosuric drug that acts by inhibiting tubular reabsorption of urate when plasma levels of the drug are therapeutic. As a result, the more likely outcome of this drug is an increase of urate concentrations in a urine sample. Probenecid does not affect uric acid synthesis.

Question 27

We administer sodium bicarbonate to a patient who has severe hyperuricemia and i s at great ri sk of developing urate stones in his urinary What i s the basis for using the bicarbonate?

A	Causes antidiuretic effect, reducing urate content of the urine
B	Causes metabolic alkalosis that inhibits catalytic activity of xanthine oxidase
C	Counteracts metabolic acidosis that i s characteristic of severe hyperuricemia
D	Lowers urate elimination by lowering glomerular fi l tration rate
E	Reduces solubility of urate in the urine

Question 27 Explanation:

The use of sodium bicarbonate (unless otherwise contraindicated) for prophylaxis of urate stone formation in the renal tubules is based on the fact that uric acid (sodium urate) is poorly soluble in body fluids and solubility is greatly influenced by local pH. When local pH falls, more urate crystallizes (ie, the KSP falls). Considering that urine pH is lower than blood (or synovial fluid) pH, and since relatively large amounts of urate is excreted in the urine (even in the absence of a uricosuric drug, eg, probenecid), there is a greater tendency for urate to crystallize in the urinary tract. Conversely, as urine pH rises (as occurs with sodium bicarbonate administration), urate is more soluble (for a given concentration) and less likely to precipitate. This pH-related phenomenon also contributes to the “vicious cycle” that starts when an acute gout attack in a joint occurs. An additional body load of sodium bicarbonate will induce, through normal renal compensatory processes, a diuretic (not antidiuretic, answer a) effect; this should also increase the amount of urate that is lost into the urine. Although sodium bicarbonate raises blood pH, that has no clinically relevant effect on formation of xanthine and uric acid by xanthine oxidase (b). There is no metabolic acidosis that is characteristic of severe hyperuricemia (c). Sodium bicarbonate does not lower GFR and/or urate elimination (d).

Question 28

A patient with annoying hay fever (seasonal allergy) symptoms (mainly rhinorrhea) goes to the store, intent on purchasing an oral medication to make them more comfortable. They see the prices for loratadine and related second-generation antihistamines and are shocked about how high they are. Nearby on the shelf they see store-brand allergy relief pills that are much less expensive, the cheapest ones having diphenhydramine as the sole active ingredient. If they were to take full therapeutic doses of the diphenhydramine, based on label directions, which effects or s ide effects are they most l ikely to experience as an additional price to be paid for their allergy relief?

A	Bradycardia
B	Diarrhea
C	Drowsiness, somnolence
D	“Heartburn” from increased gastric acid secretion
E	Urinary frequency

Question 28 Explanation:

Diphenhydramine, a member of the ethanolamine class of H1 antagonists and arguably the prototype of all the older (“first-generation” antihistamines), possesses two main properties in addition to effective competitive blockade of H 1 receptors: sedation (c), in part due to the drug’s lipophilicity; and muscarinic (cholinergic) receptor blockade that is also competitive. Both effects occur commonly, and can be quite intense. The CNS depressant effects of diphenhydramine are such that this drug is the main (if not only) active ingredient in OTC sleep aids, helping one drift off to sleep even in the absence of allergy signs and symptoms and probably in a way that is unrelated to the drug’s peripheral H-1 blocking activity. The antimuscarinic (atropine-like effects) would be manifest by such side effects as tachycardia (not bradycardia; a); constipation (not diarrhea; b); a suppression of ACh-induced gastric acid secretion (not the opposite; d); and a tendency for urinary retention (not frequency; e). The strong anti-muscarinic effects of diphenhydramine earn it the same precautions and contraindications we normally apply to atropine itself, including prostatic hypertrophy and angle-closure glaucoma. Other side effects include xerostomia, blurred vision, paralysis of accommodation, and inhibition of sweating. Diphenhydramine toxicity manifests in ways that are markedly similar to what occurs with atropine poisoning, and is managed in the same way, including the use of physostigmine (ACh esterase inhibitor with actions in both the peripheral and central nervous systems) for severe or life-threatening toxicity. As an important aside, loratadine, desloratadine, fexofenadine, and related newer (second generation) H-1 blockers (piperidine class) are associated with much less CNS depression. (they are advertised as “nonsedating”—usually with a disclaimer, in fine print, “when taken as directed.”) Unlike diphenhydramine and most of the older H-1 blockers, the newer agents cause no antimuscarinic effects and have no atropinerelated precautions or contraindications.

Question 29

Your patient has rheumatoid arthritis that has been largely refractory to diclofenac, ibuprofen, indomethacin, and In addition, she has experienced s ignificant GI distress, and several GI bleeds, following attempts to get better anti-inflammatory effects by raising the doses. We start her on therapy with etanercept. What i s the most l ikely mechanism by which etanercept suppresses the s igns, symptoms, or underlying patho-physiology of rheumatoid arthritis?

A	Inhibits eicosanoid synthesis by inhibiting phospholipase A2
B	Inhibits leukocyte migration by blocking microtubular formation
C	Neutralizes ci rculating tumor necrosis factor (TNF-α)
D	Selectively and effectively inhibits COX-2
E	Stimulates collagen and mucopolysaccharide synthesis in the joints

Question 29 Explanation:

Etanercept (and the related drug infliximab) binds to and neutralizes TNF-α, which is one of the primary pathophysiologic mediators in rheumatoid arthritis and Crohn disease. It functions, then, as an antibody. Etanercept has no effect on eicosanoid synthesis (a, d) or leukocyte migration (b). It does not stimulate collagen, mucopolysaccharide, or synovial fluid synthesis (e)

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II. Preview all questions below

1.About 10% to 20% of asthma patients aged 20 years to 30 years develop wheezing or more severe respiratory s igns and symptoms in response to a certain class of The offending drugs indirectly shunt (redirect) arachidonic acid metabolism to the formation of leukotrienes, which have bronchoconstrictor and proinflammatory properties. To which one of the following drugs or drug groups does this explanation most l ikely apply?

Acetylcholinesterase inhibitors (eg, neostigmine)
β-Adrenergic blockers (propranolol, many others)
Histamine
Nonsteroidal anti-inflammatory drugs (traditional agents such as aspirin)
Opioids such as morphine

2. Febuxostat i s the fi rst new drug in i ts class in four It i s indicated for managing hyperuricemia, including that which i s drug-induced, but i s not indicated for symptom-suppression during an acute gout attack. Its basic mechanism of action i s inhibition of purine degradation at the formation of hypoxanthine (HX), preventing further metabolism of HX to xanthine and uric acid. It should not be administered to patients receiving purine antimetabolites (eg, mercaptopurine, thioguanine, for certain cancers) because the metabolic inactivation of those anticancer drugs will be inhibited and toxicity may occur. Based on the description given, what drug i s most s imilar to febuxostat?

Allopurinol
Aspirin
Colchicine
Indomethacin
Probenecid

3. A patient receives a drug that inhibits the l ipoxygenase pathway of arachidonic acid What naturally occurring metabolite(s) will be produced in lesser amounts in response to this drug?

Leukotrienes
Prostacyclin (PGI₂)
Prostaglandins
Thromboxanes
Uric acid

4. A patient has mild cutaneous and systemic manifestations of a seasonal allergic Before you prescribe a short course of diphenhydramine for symptom relief, you should realize that this drug has one mechanism of action resembling, causes many s ide effects s imilar to, and shares many contraindications, that apply to an “autonomic” drug which you should be very familiar. What i s that drug?

Atropine
Bethanechol
Norepinephrine
Phentolamine Physostigmine
Propranolol

5. A patient presents with a history of frequent and severe migraine When we give one of the more commonly used drugs for abortive therapy, sumatriptan, upon which of the following “local control substances” i s i t mainly acting?

Histamine
PGF2α
Prostacyclin
Serotonin
Thromboxane A₂

6. A male patient with severe arthritis will be placed on long-term therapy with You recognize the ri sk of NSAID-induced gastrointestinal ulceration, and so want to prescribe another drug for ulcer prophylaxis. Which drug would you most l ikely choose, as an add-on to indomethacin, assuming that there are no specific contraindications to i ts use?

Celecoxib
Cimetidine
Diclofenac
Diphenhydramine
Misoprostol

7. Aspirin causes s ignificant bronchoconstriction and bronchospasm in a patient who was subsequently identified as being “aspirin-sensitive.” Which mechanism summarizes best why or how aspirin provoked the respiratory problems in this patient?

Induced drug-mediated hypersensitivity of H₁ receptors on airway smooth muscles
Induced drug-mediated hypersensitivity of muscarinic receptors on airway smooth muscles
Enhanced formation of antibodies directed against the salicylate on airway mast cells
Inhibited synthesis of endogenous prostaglandins that have bronchodilator activity
Reduced (blocked) epinephrine binding to β₂-adrenergic receptors on airway smooth muscle cells

8. A child takes what comes close to being a lethal dose of What i s the most l ikely pathology that ultimately can lead to death involved in this drug overdose?

Acute nephropathy
A-V conduction disturbances, heart block
Liver failure
Status asthmaticus
Status epilepticus

9. A patient with asymptomatic hyperuricemia i s started on In a couple of days, he develops acute gout. What i s the mechanism by which probenecid, early in the course of treatment with i t, triggered this acute gouty arthritic episode?

Accelerated synthesis of uric acid
Co-precipitated with uric acid in the joints
Induced an idiosyncratic response that triggered urate precipitation
Induced systemic acidosis, favoring uric acid crystallization
Reduced renal excretion of uric acid

10. Epidemiologic data published in the early 1980s found a probable relationship between aspirin and a serious adverse response when the drug was administered to children with influenza, chickenpox, and other vi ral i l Although no causal relationship between aspirin, vi ral i l lness, and this adverse effect was proven, you sti l l caution the parents or caregivers of children to avoid giving any aspirin or aspirin-containing product when there i s even a remote possibility that a child’s i l lness might involve a vi rus. Avoidance of aspirin i s necessary to avoid which specific adverse response?

Asthma
Cardiomyopathy
Renal failure
Reye syndrome
Thrombocytopenia and related bleeding disorders

11. Such drugs as methotrexate, hydroxychloroquine, or penicillamine are often turned to for managing rheumatoid arthritis that i s not controlled adequately with “traditional” NSAIDs (eg, aspirin, ibuprofen, diclofenac, or indomethacin). Which statement most correctly summarizes how those drugs differ from a typical NSAID?

Activate the immune system to neutralize inflammatory mediators
Are primary therapies for gouty arthritis
Are remarkably free from serious toxicities
Provide much quicker relief of arthritis s igns, symptoms
Slow, stop, possibly reverse joint pathology in rheumatoid arthritis

12. For quite a while the “coxibs” (selective COX-2 inhibitors) were prescribed in preference to nonselective cyclooxygenase inhibitors for managing such conditions as rheumatoid Now we have basically one drug in this class, celecoxib. Which statement best describes an action or property of this COX-2 inhibitor?

Associated with a lower ri sk of gastric or duodenal ulceration
Cures arthritis, rather than just give symptom relief
Effectively inhibits uric acid synthesis
Has a lower ri sk of adverse or fatal cardiac events
Has s ignificantly faster onset of action

13. Glucocorticoids are widely used for a host of inflammatory reactions and the diseases they In terms of inflammatory responses and underlying metabolic reactions, which enzyme or process i s the main target of these drugs when they are given at pharmacologic (supraphysiologic) doses?

Cyclooxygenases (COX-1 and -2)
Histidine decarboxylase
5′-l ipoxygenase
Phospholipase A2 (PLA2)
Xanthine oxidase

14. Bradykinin plays important roles in local responses to ti ssue damage and a variety of inflammatory It also has vasodilator activity. Which statement i s correct about this endogenous peptide?

Captopril inhibits i ts metabolic inactivation
Drugs that are metabolized to, or generate, nitric oxide, counteract bradykinin’s vascular effects
Increased blood pressure i s the predominant cardiovascular response
Newer histamine H₁ blockers (eg, fexofenadine; “second-generation” antihistamine) also competitively block bradykinin receptors
The main renal responses to endogenous bradykinin are arteriolar constriction and reduced GFR

15. A newborn has oxygenation and hemodynamic problems because of a patent (open) ductus Which drug usually would be administered in an attempt to close the lesion?

Cimetidine
Diphenhydramine
Indomethacin
Misoprostol
Prostaglandin E1 (PGE1; alprostadil)

16. A 29-year-old woman develops frequent, debilitating migraine Sumatriptan i s prescribed for abortive therapy. Not long after taking the drug she i s rushed to the hospital. Her vi tal s igns are unstable, and she has muscle rigidity, myoclonus, generalized CNS i rri tability and altered consciousness, and shivering. You learn that for several months she had been taking another drug with which the triptan interacted. Which add-on drug most l ikely caused these acute and serious problems?

Acetaminophen
Codeine
Diazepam
Fluoxetine
Phenytoin

17. A patient (assume he or she i s taking no other drugs) has been taking doses of aspirin that are too high for several Low-grade aspirin toxicity (salicylism) develops. What s ign or symptom would be consistent with salicylism and the high salicylate levels that caused i t?

Constipation
Cough
Hypertension
Myopia
Tinnitus

18. Aspirin generally should be avoided as an anti-inflammatory, analgesic, or antipyretic drug by patients with hyperuricemia or That i s because i t counteracts the effects of one important drug the hyperuricemic patient may be taking. Which drug has i ts desired uric acid-related effects reduced or eliminated by this prototypic NSAID?

Acetaminophen
Allopurinol
Colchicine
Indomethacin
Probenecid

19. Misoprostol, an analog of PGE₁, i s sometimes used adjunctively to stimulate gastric mucus production and help reduce the incidence of gastric ulcers associated with long-term or high-dose NSAID therapy for What i s the other main use for this l ipid-derived autacoid?

Closure of a patent ductus arteriosus in newborns
Contraception in women who should not receive estrogens or progestins
Induction of abortion in conjunction with mifepristone (“RU486”)
Prophylaxis of asthma in l ieu of a corticosteroid
Suppression of uterine contractility in women with premature labor

20. A patient who was transported by ambulance to the Emergency Department took a potentially lethal overdose of What drug would be a helpful, i f not l i fesaving, adjunct to manage this severe aspirin poisoning?

Acetaminophen
Amphetamines (eg, dextroamphetamine)
N-acetylcysteine
Phenobarbital
Sodium bicarbonate

21. We look at data that summarize the actions of two prototypic histamine receptor blockers: diphenhydramine as the exemplar of the older antihistamines (competitive histamine receptor antagonists); and fexofena-dine as a representative agent of the “second-generation” antihistamines. Which statement correctly describes, compares, or contrasts these drugs or the pharmacologic groups to which they belong?

Diphenhydramine and other drugs in i ts class (ethanolamines) tend to cause drowsiness more often than fexofenadine and related second- generation antihistamines
Diphenhydramine i s a preferred antihistaminic for patients with prostate hypertrophy or angle-closure glaucoma, whereas fexofenadine and related drugs are contraindicated
Diphenhydramine overdoses tend to cause bradycardia, whereas fexofenadine overdoses tend to cause s ignificant increases of heart rate
Fexofenadine and related second-generation histamine antagonists have intrinsic bronchodilator activity, which makes them suitable as primary/sole therapy for people with asthma
Fexofenadine, and drugs in i ts class, have better efficacy in terms of suppressing histamine-mediated gastric acid secretion

22. A patient has been taking one of the drugs l i sted below for about 4 months, and i s experiencing the desired therapeutic effects from i t. The physician now prescribes indomethacin to treat a particularly severe flare-up of rheumatoid Within a matter of days the therapeutic effects of the fi rst drug wane dramatically, i ts actions antagonized by the indo-methacin. Which drug was affected by the indomethacin?

Allopurinol, given for prophylaxis of hyperuricemia
Captopril, given for essential hypertension
Fexofenadine, given for managing seasonal allergy responses
Sumatriptan, given for abortive therapy of migraine headaches
Warfarin, given for prophylaxis of venous thrombosis

23. A patient takes an acute, massive overdose of aspirin that, without proper intervention, will probably be What would you expect to occur in the advanced (late) stages of aspirin (salicylate) poisoning?

Hypothermia
Metabolic alkalosis
Respiratory alkalosis
Respiratory plus metabolic acidosis
Ventilatory stimulation

24. A patient presents in the emergency department with an overdose of a The physician knows what the drug i s , and so orders appropriate “symptomatic and supportive care,” plus multiple doses of N-acetylcysteine. Upon which drug did the patient overdose?

Acetaminophen
Aspirin
Colchicine
Diphenhydramine Loratadine
Methotrexate

25. A patient has acute The physician initially thinks about prescribing just one or two oral doses of colchicine, 12 hours apart, but then decides otherwise. What i s the main and most common reason for avoiding colchicine, even with a very short oral course, and prescribing another drug for the acute gout instead?

Bone marrow suppression
Bronchospasm
GI distress that i s almost as bad as the acute gout discomfort
Hepatotoxicity
One or two oral doses seldom relieve gout pain
Refractoriness/tolerance with just a dose or two

26. A patient with hyperuricemia i s placed on an “antigout” Before starting the drug you measure the total uric acid (amount, not concentration) in a 24-hour urine sample and then do the same several weeks after continued drug therapy at therapeutic doses. The post- treatment sample shows a s ignificant reduction in urate content. There were no new pathologies developing during therapy, and the patient’s daily purine intake did not change at all. What drug most l ikely accounted for these findings?

Acetaminophen
Allopurinol
Colchicine
Indomethacin
Probenecid

27. We administer sodium bicarbonate to a patient who has severe hyperuricemia and i s at great ri sk of developing urate stones in his urinary What i s the basis for using the bicarbonate?

Causes antidiuretic effect, reducing urate content of the urine
Causes metabolic alkalosis that inhibits catalytic activity of xanthine oxidase
Counteracts metabolic acidosis that i s characteristic of severe hyperuricemia
Lowers urate elimination by lowering glomerular fi l tration rate
Reduces solubility of urate in the urine

28. A patient with annoying hay fever (seasonal allergy) symptoms (mainly rhinorrhea) goes to the store, intent on purchasing an oral medication to make them more comfortable. They see the prices for loratadine and related second-generation antihistamines and are shocked about how high they are. Nearby on the shelf they see store-brand allergy relief pills that are much less expensive, the cheapest ones having diphenhydramine as the sole active ingredient. If they were to take full therapeutic doses of the diphenhydramine, based on label directions, which effects or s ide effects are they most l ikely to experience as an additional price to be paid for their allergy relief?

Bradycardia
Diarrhea
Drowsiness, somnolence
“Heartburn” from increased gastric acid secretion
Urinary frequency

29. Your patient has rheumatoid arthritis that has been largely refractory to diclofenac, ibuprofen, indomethacin, and In addition, she has experienced s ignificant GI distress, and several GI bleeds, following attempts to get better anti-inflammatory effects by raising the doses. We start her on therapy with etanercept. What i s the most l ikely mechanism by which etanercept suppresses the s igns, symptoms, or underlying patho-physiology of rheumatoid arthritis?

Inhibits eicosanoid synthesis by inhibiting phospholipase A₂
Inhibits leukocyte migration by blocking microtubular formation
Neutralizes ci rculating tumor necrosis factor (TNF-α)
Selectively and effectively inhibits COX-2
Stimulates collagen and mucopolysaccharide synthesis in the joints

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