Anti-Inflammatory Drugs — NSAIDs, Corticosteroids, and Gout

Correct Answer

B) Celecoxib

Rationale

Celecoxib is the only selective cyclooxygenase-2 inhibitor currently marketed in the United States. It inhibits cyclooxygenase-2 at concentrations substantially lower than those required to inhibit cyclooxygenase-1. Naproxen, indomethacin, and ketorolac are nonselective nonsteroidal anti-inflammatory drugs that inhibit both cyclooxygenase-1 and cyclooxygenase-2.

Correct Answer

D) Misoprostol

Rationale

Misoprostol is a synthetic prostaglandin E1 analogue. It replaces the cytoprotective prostaglandins depleted by nonsteroidal anti-inflammatory drugs and is used to reduce the risk of nonsteroidal anti-inflammatory drug-associated gastric ulcers. Celecoxib is a selective cyclooxygenase-2 inhibitor, naproxen is a nonselective cyclooxygenase inhibitor, and ketorolac is a parenteral nonselective cyclooxygenase inhibitor.

Correct Answer

C) Naproxen

Rationale

Naproxen is a nonselective nonsteroidal anti-inflammatory drug that inhibits both cyclooxygenase-1 and cyclooxygenase-2. Celecoxib and valdecoxib are selective cyclooxygenase-2 inhibitors. Misoprostol is a synthetic prostaglandin E1 analogue, not a cyclooxygenase inhibitor.

Correct Answer

A) Aspirin

Rationale

Aspirin is the only cyclooxygenase inhibitor in clinical use that acts irreversibly. It permanently acetylates a serine residue in the cyclooxygenase active site, inactivating the enzyme for its lifetime. Ibuprofen, naproxen, and celecoxib are all reversible cyclooxygenase inhibitors whose effects resolve as plasma drug concentrations fall.

Correct Answer

B) Ibuprofen

Rationale

Ibuprofen inhibits cyclooxygenase reversibly, meaning its effect on cyclooxygenase activity resolves as plasma drug concentrations decline. This distinguishes it from aspirin, which permanently acetylates and inactivates cyclooxygenase for the lifetime of the enzyme. Celecoxib is also a reversible cyclooxygenase inhibitor but is classified primarily by its selectivity for cyclooxygenase-2. Misoprostol is a prostaglandin E1 analogue and is not a cyclooxygenase inhibitor.

Correct Answer

C) Diclofenac

Rationale

Diclofenac is classified as cyclooxygenase-2 preferential — it inhibits cyclooxygenase-2 at lower concentrations than cyclooxygenase-1, but at therapeutic doses it does not achieve the full selectivity of celecoxib. Celecoxib is the only fully selective cyclooxygenase-2 inhibitor currently marketed. Aspirin and naproxen are nonselective cyclooxygenase inhibitors that inhibit both isoforms at similar concentrations.

Correct Answer

B) Aspirin permanently acetylates the cyclooxygenase-1 active site in platelets, which cannot synthesize new enzyme

Rationale

Aspirin transfers an acetyl group to a serine residue in the cyclooxygenase-1 active site, forming a permanent covalent bond that irreversibly inactivates the enzyme. Because platelets are anucleate — they cannot synthesize new protein — the acetylated cyclooxygenase-1 cannot be replaced. Thromboxane A2 synthesis in that platelet is permanently abolished for the platelet's entire lifespan of approximately 8 to 10 days. The other options describe mechanisms belonging to different drug classes: adenosine diphosphate receptor blockade is the mechanism of clopidogrel and related agents, and phosphodiesterase inhibition is the mechanism of dipyridamole.

Correct Answer

D) Gastric mucosal injury from nonsteroidal anti-inflammatory drugs results from systemic suppression of cytoprotective prostaglandins, not from local contact with the tablet

Rationale

Nonsteroidal anti-inflammatory drug-induced gastropathy is a systemic pharmacological effect driven by cyclooxygenase-1 suppression in the gastric mucosa once the drug is absorbed into the bloodstream. The cytoprotective prostaglandins that maintain mucosal defense — stimulating mucus and bicarbonate secretion, maintaining mucosal blood flow, and inhibiting acid secretion — are depleted regardless of whether the drug reached the stomach as a plain or enteric-coated tablet. Parenteral nonsteroidal anti-inflammatory drugs cause the same rate of gastric mucosal injury as oral formulations, confirming that local contact plays no role.

Correct Answer

A) Ibuprofen reversibly occupies the cyclooxygenase-1 active site in platelets, blocking aspirin's access to the serine residue it must acetylate

Rationale

Aspirin must reach the cyclooxygenase-1 active site in platelets to transfer its acetyl group to the critical serine residue, permanently inactivating the enzyme. Ibuprofen, a reversible cyclooxygenase inhibitor, competes for the same active site. When ibuprofen is present, it occupies the active site and physically blocks aspirin from binding and acetylating it. If aspirin is taken first and allowed at least 30 minutes to complete acetylation before ibuprofen is introduced, the interaction is avoided. This interaction does not involve hepatic metabolism, protein binding displacement, or receptor activation.

Correct Answer

C) Glucocorticoids inhibit phospholipase A2 via annexin A1, blocking both the cyclooxygenase and lipoxygenase pathways, while nonsteroidal anti-inflammatory drugs block only the cyclooxygenase pathway

Rationale

Nonsteroidal anti-inflammatory drugs inhibit the cyclooxygenase enzyme, blocking the synthesis of prostaglandins and thromboxane A2. However, they leave the lipoxygenase pathway entirely intact. Glucocorticoids act upstream of both pathways by inducing annexin A1, an endogenous inhibitor of phospholipase A2. By blocking phospholipase A2, glucocorticoids prevent the release of arachidonic acid from membrane phospholipids, cutting off the substrate for both the cyclooxygenase and lipoxygenase branches simultaneously. This upstream block on the shared substrate is why glucocorticoids are more potent and broader anti-inflammatory agents than nonsteroidal anti-inflammatory drugs.

Correct Answer

B) Selective cyclooxygenase-2 inhibitors suppress endothelial prostacyclin production while leaving platelet thromboxane A2 synthesis intact, creating a prothrombotic imbalance

Rationale

Vascular endothelium constitutively expresses cyclooxygenase-2 as its source of prostacyclin — a prostanoid that inhibits platelet aggregation and promotes vasodilation. Platelets generate thromboxane A2 exclusively via cyclooxygenase-1, which promotes aggregation and vasoconstriction. Selective cyclooxygenase-2 inhibition removes the endothelial prostacyclin that normally counterbalances platelet thromboxane A2, shifting the vascular environment toward a prothrombotic, vasoconstrictive state. This mechanism was predicted pharmacologically before clinical trials confirmed increased rates of myocardial infarction and stroke with these agents.

Correct Answer

D) Alkaline urine ionizes salicylate, a weak acid, trapping it in the tubular lumen where it cannot be reabsorbed

Rationale

Salicylate is a weak acid. In alkaline tubular urine, salicylate exists predominantly in its ionized (charged) form. Ionized molecules cannot diffuse across lipid membranes — they are trapped in the tubular lumen and excreted in the urine rather than being reabsorbed into the bloodstream. This principle of ion trapping explains why sodium bicarbonate administration is an effective strategy for enhancing elimination in salicylate toxicity: raising urinary pH shifts the equilibrium toward the ionized form, dramatically increasing the fraction of filtered salicylate that is excreted rather than reabsorbed.

Correct Answer

A) Nonsteroidal anti-inflammatory drugs reduce renal prostaglandin synthesis, impairing the prostaglandin-dependent mechanisms that normally promote renal lithium excretion

Rationale

Lithium is excreted renally through a process that parallels sodium handling — it is filtered, partially reabsorbed, and the balance excreted. Renal prostaglandins normally oppose tubular sodium and lithium reabsorption. When nonsteroidal anti-inflammatory drugs suppress prostaglandin synthesis in the kidney, this restraint on reabsorption is lost, and more lithium is retained. Because lithium has a narrow therapeutic index, even a modest rise in plasma concentration from this interaction can produce toxicity. Lithium concentrations should be checked within five to seven days of starting or stopping a nonsteroidal anti-inflammatory drug in a patient taking lithium. Lithium is not metabolized by cytochrome P450 enzymes and is not protein-bound.

Correct Answer

C) Cyclooxygenase inhibition diverts arachidonic acid into the lipoxygenase pathway, increasing production of cysteinyl leukotrienes that cause bronchoconstriction

Rationale

In aspirin-exacerbated respiratory disease, blocking the cyclooxygenase pathway removes the route through which arachidonic acid would normally be metabolized to prostaglandins. The excess arachidonic acid is shunted into the lipoxygenase pathway instead, where it is converted to cysteinyl leukotrienes — potent bronchoconstrictors that trigger the acute respiratory reaction. This leukotriene shunting mechanism explains why celecoxib, which does not inhibit cyclooxygenase-1 at therapeutic doses, does not trigger this reaction and is the preferred nonsteroidal anti-inflammatory drug in patients with aspirin-exacerbated respiratory disease. The reaction is not mediated by histamine, cholinergic pathways, or complement.

Correct Answer

B) Ibuprofen reversibly occupies the cyclooxygenase-1 active site in platelets, preventing aspirin from accessing the serine residue it must acetylate to produce a permanent antiplatelet effect

Rationale

Aspirin produces its antiplatelet effect by permanently acetylating a serine residue in the cyclooxygenase-1 active site of platelets. Ibuprofen, a reversible cyclooxygenase inhibitor, competes for the same active site. When ibuprofen is present at the time aspirin is taken, it occupies the active site and blocks aspirin from binding and acetylating it. To avoid this interaction, aspirin should be taken at least 30 minutes before ibuprofen, allowing aspirin to complete its irreversible acetylation before ibuprofen arrives. Naproxen does not interfere with aspirin's antiplatelet effect to the same degree and is a preferred alternative.

Correct Answer

A) Cyclooxygenase inhibition diverts arachidonic acid into the lipoxygenase pathway, producing a surge of cysteinyl leukotrienes that cause bronchoconstriction

Rationale

This patient has aspirin-exacerbated respiratory disease — defined by asthma, chronic rhinosinusitis with nasal polyps, and acute respiratory reactions triggered by any cyclooxygenase-1 inhibiting nonsteroidal anti-inflammatory drug. The mechanism is pharmacological, not immunological: when cyclooxygenase is inhibited, arachidonic acid that would normally enter the cyclooxygenase pathway is shunted instead into the lipoxygenase pathway. In these patients, who have constitutively elevated leukotriene production, this shunting produces a surge of cysteinyl leukotrienes that triggers bronchoconstriction, rhinorrhea, and urticaria. Celecoxib, which does not inhibit cyclooxygenase-1 at therapeutic doses, does not trigger this reaction and is the appropriate alternative when a nonsteroidal anti-inflammatory drug is required.

Correct Answer

D) In the setting of heart failure, the kidney depends on prostaglandin-mediated afferent arteriolar vasodilation to maintain perfusion; ibuprofen suppresses these prostaglandins, removing the compensatory vasodilation and precipitating acute kidney injury

Rationale

In healthy, euvolemic patients, renal prostaglandins play a minor role in maintaining glomerular filtration and nonsteroidal anti-inflammatory drugs cause little reduction in kidney function. In hemodynamically stressed states — including heart failure, cirrhosis, volume depletion, and chronic kidney disease — the kidney becomes dependent on prostaglandin-mediated vasodilation of the afferent arteriole to maintain adequate perfusion pressure against elevated angiotensin II and catecholamines. Nonsteroidal anti-inflammatory drug-mediated suppression of these prostaglandins removes this critical compensatory mechanism, allowing afferent arteriolar constriction and a rapid decline in glomerular filtration rate. Nonsteroidal anti-inflammatory drugs should be avoided in patients with decompensated heart failure and in those with an estimated glomerular filtration rate below 30 mL per minute per 1.73 m².

Correct Answer

C) Aspirin irreversibly acetylates cyclooxygenase-1 in platelets, which are anucleate and cannot synthesize new enzyme, so the effect persists for the entire platelet lifespan

Rationale

Aspirin permanently inactivates cyclooxygenase-1 by transferring an acetyl group to a serine residue in the enzyme's active site, forming a covalent bond. Unlike nucleated cells, platelets lack a nucleus and cannot synthesize new protein, including new cyclooxygenase-1. The inactivated enzyme cannot be replaced, so thromboxane A2 production in that platelet is permanently abolished. The platelet's antiplatelet effect therefore persists for its entire circulating lifespan of approximately 8 to 10 days. Aspirin itself has a plasma half-life of only 15 to 20 minutes before hydrolysis to salicylate — the brief systemic exposure is sufficient because platelet acetylation occurs during first-pass absorption in the portal circulation. The sustained duration of effect reflects permanent enzyme inactivation in anucleate cells, not prolonged drug presence.