Antihypertensive Drugs

Correct Answer

A — Angiotensin converting enzyme inhibitor

Rationale

Captopril is an angiotensin converting enzyme inhibitor. Losartan is an angiotensin receptor blocker. Aliskiren is a direct renin inhibitor. Spironolactone is a mineralocorticoid receptor antagonist.

Correct Answer

D — Angiotensin receptor blockers

Rationale

Losartan is an angiotensin receptor blocker, the prototype agent of this class. Lisinopril is an angiotensin converting enzyme inhibitor. Amlodipine is a calcium channel blocker. Metoprolol is a beta-adrenergic receptor antagonist.

Correct Answer

B — Angiotensin receptor blocker

Rationale

Irbesartan is an angiotensin receptor blocker. Enalapril is an angiotensin converting enzyme inhibitor. Diltiazem is a calcium channel blocker. Bumetanide is a loop diuretic.

Correct Answer

C — Angiotensin converting enzyme inhibitor

Rationale

Ramipril is an angiotensin converting enzyme inhibitor. Valsartan is an angiotensin receptor blocker. Aliskiren is a direct renin inhibitor. Eplerenone is a mineralocorticoid receptor antagonist.

Correct Answer

A — Angiotensin converting enzyme inhibitor

Rationale

Fosinopril is an angiotensin converting enzyme inhibitor. Candesartan is an angiotensin receptor blocker. Bisoprolol is a beta-adrenergic receptor antagonist. Hydralazine is a direct arteriolar vasodilator.

Correct Answer

D — Angiotensin receptor blockers

Rationale

Olmesartan is an angiotensin receptor blocker. Lisinopril is an angiotensin converting enzyme inhibitor. Hydrochlorothiazide is a thiazide diuretic. Verapamil is a calcium channel blocker.

Correct Answer

B — Angiotensin I and bradykinin — blocking angiotensin I conversion reduces angiotensin II, while preventing bradykinin degradation accumulates a vasodilatory peptide that also causes cough and angioedema

Rationale

Angiotensin converting enzyme is a zinc-containing enzyme that acts on two substrates simultaneously. First, it converts angiotensin I (a biologically inactive decapeptide) to angiotensin II (a potent vasoconstrictor). Blocking this conversion is the primary therapeutic mechanism: reduced angiotensin II means lower total peripheral resistance, less aldosterone secretion, less sodium retention, and reduced cardiac and renal remodeling. Second, angiotensin converting enzyme is the principal degrader of bradykinin, a vasodilatory peptide. Inhibiting this function allows bradykinin to accumulate in tissues. Bradykinin accumulation contributes additional vasodilation and natriuresis — but it also causes the two characteristic adverse effects of the class: dry cough (bradykinin stimulating sensory nerves in the respiratory tract) and angioedema (bradykinin-mediated increased vascular permeability in subcutaneous and submucosal tissues). Both adverse effects are absent with angiotensin receptor blockers, which bypass angiotensin converting enzyme entirely.

Correct Answer

C — The angiotensin II type 1 receptor is blocked by the drug, so elevated angiotensin II instead preferentially stimulates angiotensin II type 2 receptors, which produce vasodilatory and anti-fibrotic counterregulatory effects

Rationale

Angiotensin receptor blockers block angiotensin II type 1 receptors, which are responsible for vasoconstriction, aldosterone release, sodium retention, and remodeling. When type 1 receptors are blocked, the reactive rise in circulating angiotensin II cannot act through its usual harmful pathway. Instead, elevated angiotensin II preferentially occupies angiotensin II type 2 receptors, which are counterregulatory: they promote vasodilation, natriuresis, inhibition of cell growth, and anti-fibrotic signaling. This shift toward type 2 receptor stimulation may contribute to some of the organ-protective benefits of angiotensin receptor blockers beyond simple blood pressure reduction. This mechanism does not occur with angiotensin converting enzyme inhibitors, which reduce angiotensin II levels rather than redirecting them.

Correct Answer

A — Bradykinin accumulation in the respiratory tract stimulates sensory nerve fibers; the cough is a class effect of all angiotensin converting enzyme inhibitors and requires switching to an angiotensin receptor blocker

Rationale

Angiotensin converting enzyme normally degrades bradykinin. When the enzyme is inhibited, bradykinin accumulates in airway tissues where it stimulates sensory C-fibers, producing a dry, non-productive cough. This effect is shared by all angiotensin converting enzyme inhibitors regardless of whether they are prodrugs or active forms — reducing the dose or switching to a different angiotensin converting enzyme inhibitor does not resolve it. Incidence is 5 to 20 percent overall, rising to 30 to 40 percent in patients of Asian descent due to pharmacogenomic differences in bradykinin metabolism. Because the mechanism is bradykinin-based (not histamine-based), antihistamines are ineffective. The definitive management is switching to an angiotensin receptor blocker, which blocks the angiotensin II type 1 receptor without inhibiting angiotensin converting enzyme and therefore does not accumulate bradykinin — cough rates with angiotensin receptor blockers are comparable to placebo.

Correct Answer

D — The angioedema is mediated by bradykinin-induced vascular permeability, not by histamine, so antihistamines and epinephrine targeting histamine pathways have limited efficacy

Rationale

Angiotensin converting enzyme inhibitor-associated angioedema results from bradykinin accumulation in subcutaneous and submucosal tissues. Bradykinin increases vascular permeability by acting on bradykinin B2 receptors, causing fluid to leak into the interstitium. This mechanism is entirely distinct from histamine-mediated allergic angioedema, which responds to antihistamines and epinephrine. Because bradykinin is not histamine, and because its receptors are not adrenergic targets, neither antihistamines nor epinephrine effectively reverses bradykinin-mediated edema. The clinical presentation also reflects this distinction: bradykinin angioedema typically lacks urticaria and pruritus, which are hallmarks of histamine-mediated reactions. All angiotensin converting enzyme inhibitors must be permanently avoided after this event. Angioedema carries life-threatening risk when laryngeal involvement occurs.

Correct Answer

B — Reduced angiotensin II decreases aldosterone secretion, which reduces potassium excretion in the renal collecting duct

Rationale

Angiotensin II normally stimulates the adrenal cortex to secrete aldosterone. Aldosterone then acts on mineralocorticoid receptors in the collecting duct to promote sodium reabsorption coupled with potassium excretion. When an angiotensin converting enzyme inhibitor reduces angiotensin II production, aldosterone secretion falls, and less potassium is driven into the tubular lumen for excretion. The result is potassium retention and hyperkalemia. This effect is shared by angiotensin receptor blockers through the same downstream mechanism. Hyperkalemia is particularly pronounced in patients with chronic kidney disease (reduced baseline potassium excretion capacity), diabetes mellitus (hyporeninemic hypoaldosteronism), and those taking potassium-sparing diuretics or potassium supplements concurrently. Serum potassium should be checked one to two weeks after initiating either class.

Correct Answer

C — Continue the drug — a creatinine rise of up to 30 percent from baseline is expected, reflects the mechanism of renoprotection, and does not indicate nephrotoxicity

Rationale

When an angiotensin converting enzyme inhibitor is started, reduced angiotensin II causes the efferent arteriole (the vessel exiting the glomerular capillary tuft) to dilate. This lowers intraglomerular pressure, which reduces the mechanical stress on the glomerular filtration barrier — the mechanism by which these drugs slow progression of diabetic nephropathy and other proteinuric kidney diseases. The reduction in filtration pressure causes a modest fall in glomerular filtration rate and a corresponding rise in serum creatinine. A rise of up to 30 percent from baseline is expected, acceptable, and should not prompt discontinuation. It reflects the drug working as intended. A rise above 30 percent warrants dose reduction and investigation for volume depletion or bilateral renal artery stenosis. A rise above 50 percent warrants holding the drug. Stopping an effective renoprotective agent due to a modest, expected creatinine rise deprives the patient of long-term kidney protection.

Correct Answer

A — Clinical trials showed no additional cardiovascular benefit compared with either agent alone, but caused substantially more hypotension, acute kidney injury, and hyperkalemia — the combination must not be used

Rationale

The hypothesis that combining an angiotensin converting enzyme inhibitor and an angiotensin receptor blocker would provide additive organ protection was appealing but was definitively refuted by clinical evidence. The ONTARGET trial showed that ramipril plus telmisartan produced no additional reduction in cardiovascular events compared with either drug alone, but caused substantially more hypotension, syncope, acute kidney injury, and hyperkalemia. The VA NEPHRON-D trial in type 2 diabetic nephropathy was stopped early because the combination produced excess acute kidney injury and hyperkalemia without renal benefit. There is no indication — including heart failure, diabetic nephropathy, or resistant hypertension — for which combining an angiotensin converting enzyme inhibitor with an angiotensin receptor blocker is recommended. The combination increases harm across all populations studied.

Correct Answer

D — The fetal renin-angiotensin-aldosterone system is essential for normal renal development; blocking it causes fetal renal dysgenesis, oligohydramnios, and neonatal renal failure

Rationale

The fetal renin-angiotensin-aldosterone system plays a critical role in normal renal organogenesis and in maintaining the amniotic fluid volume through fetal urine production. When either an angiotensin converting enzyme inhibitor or an angiotensin receptor blocker crosses the placenta and suppresses fetal renin-angiotensin-aldosterone system activity, fetal renal development is disrupted. The consequences include renal tubular dysplasia or agenesis, oligohydramnios (reduced amniotic fluid from impaired fetal urine output), pulmonary hypoplasia (from oligohydramnios compressing fetal lungs), neonatal renal failure, and fetal or neonatal death. The black-box warning applies to all trimesters — first-trimester exposure has been associated with cardiovascular and other malformations as well. Both classes are absolutely contraindicated throughout pregnancy, and women of childbearing age should be counseled about this risk before initiating treatment.

Correct Answer

C — Switch to candesartan or valsartan, which block the angiotensin II type 1 receptor without inhibiting angiotensin converting enzyme and therefore do not accumulate bradykinin

Rationale

The dry cough is caused by bradykinin accumulation in the respiratory tract — a class effect of all angiotensin converting enzyme inhibitors, including both prodrug and active forms. Switching to a different angiotensin converting enzyme inhibitor or reducing the dose does not resolve this effect because the mechanism is intrinsic to the enzyme being inhibited, not to the specific drug. Angiotensin receptor blockers bypass angiotensin converting enzyme entirely: they block the angiotensin II type 1 receptor directly and do not affect bradykinin degradation. Cough rates with angiotensin receptor blockers are indistinguishable from placebo. Candesartan and valsartan have trial evidence specifically in heart failure with reduced ejection fraction in angiotensin converting enzyme inhibitor-intolerant patients, making them the appropriate substitutes in this clinical context.

Correct Answer

B — Losartan — it inhibits urate transporter 1 in the proximal renal tubule, increasing uric acid excretion and mildly lowering serum uric acid levels

Rationale

Losartan is the only angiotensin receptor blocker with a clinically meaningful uricosuric effect. In addition to blocking the angiotensin II type 1 receptor, losartan and its active metabolite inhibit urate transporter 1 (also called URAT1) in the proximal renal tubule. This transporter is responsible for reabsorbing filtered uric acid back into the bloodstream; inhibiting it increases urinary uric acid excretion and lowers serum uric acid levels. This makes losartan the preferred choice among angiotensin receptor blockers when hypertension coexists with gout or hyperuricemia. No other angiotensin receptor blocker shares this pharmacological property. Thiazide diuretics — a common antihypertensive class — can raise serum uric acid and should be used cautiously in patients with gout, making losartan an especially useful choice in this setting.

Correct Answer

A — Continue losartan — the creatinine rise reflects reduced intraglomerular pressure from efferent arteriolar dilation, which is the mechanism of renoprotection, and a rise of up to 30 percent is expected and acceptable

Rationale

Angiotensin receptor blockers and angiotensin converting enzyme inhibitors lower intraglomerular pressure by dilating the efferent arteriole (the vessel leaving the glomerular capillary tuft), which reduces mechanical stress on the glomerular filtration barrier and slows diabetic nephropathy progression. This intended hemodynamic effect reduces the glomerular filtration rate modestly, causing a predictable and expected rise in serum creatinine. A rise of up to 30 percent from baseline is acceptable and should not prompt discontinuation. In this patient, a 19 percent rise falls well within this threshold. Discontinuing the drug to avoid a modest expected creatinine rise would deprive the patient of proven long-term renoprotection. Potassium at 4.8 milliequivalents per liter is within acceptable range and requires only routine monitoring. The creatinine should be rechecked in one to two weeks to confirm stability.

Correct Answer

D — The angioedema is driven by bradykinin-mediated vascular permeability, not histamine; epinephrine and antihistamines target histamine pathways and are largely ineffective against bradykinin-induced edema

Rationale

Angiotensin converting enzyme inhibitor-associated angioedema results from bradykinin accumulation in subcutaneous and submucosal tissues. Bradykinin acts on bradykinin B2 receptors to increase vascular permeability, causing fluid to leak into the interstitium. This mechanism is entirely distinct from histamine-mediated allergic or anaphylactic angioedema. Epinephrine works in anaphylaxis by reversing histamine-mediated bronchospasm and vasodilatation; diphenhydramine blocks histamine receptors. Neither agent has significant activity against bradykinin receptors. The clinical clues that distinguish bradykinin angioedema include the absence of urticaria and pruritus (both histamine-mediated), the partial or absent response to epinephrine and antihistamines, and the association with angiotensin converting enzyme inhibitor use. Lisinopril and all angiotensin converting enzyme inhibitors must be permanently discontinued after this event. Laryngeal involvement requires airway management as the primary emergency priority.