Antihypertensive Drugs

Correct Answer

C — Mineralocorticoid receptors

Rationale

Spironolactone is a mineralocorticoid receptor antagonist. It competitively blocks mineralocorticoid receptors in the renal collecting duct, preventing aldosterone from promoting sodium reabsorption and potassium excretion. This makes it the targeted pharmacological therapy for primary aldosteronism, where autonomous aldosterone secretion drives hypertension. Angiotensin II type 1 receptors are blocked by angiotensin receptor blockers such as losartan. Alpha-1 adrenergic receptors are blocked by drugs such as prazosin. Beta-1 adrenergic receptors are blocked by beta-adrenergic receptor antagonists such as metoprolol.

Correct Answer

A — Non-selective irreversible alpha-adrenergic receptor antagonist

Rationale

Phenoxybenzamine blocks both alpha-1 and alpha-2 adrenergic receptors irreversibly, forming a covalent bond that cannot be displaced by catecholamines regardless of their concentration. This property makes it particularly valuable in pheochromocytoma, where catecholamine surges are massive — a reversible blocker could be overcome. Selective alpha-1 antagonists such as doxazosin block only alpha-1 receptors and do so reversibly. Non-selective beta-adrenergic receptor antagonists such as propranolol block beta-1 and beta-2 receptors. Direct arteriolar vasodilators such as hydralazine act independently of adrenergic receptors.

Correct Answer

D — Selective mineralocorticoid receptor antagonist

Rationale

Eplerenone is a selective mineralocorticoid receptor antagonist. Losartan is an angiotensin receptor blocker. Furosemide is a loop diuretic. Metoprolol is a beta-adrenergic receptor antagonist.

Correct Answer

B — Dihydropyridine calcium channel blockers

Rationale

Amlodipine belongs to the dihydropyridine subclass of calcium channel blockers, which act predominantly on vascular smooth muscle to cause arteriolar vasodilation. Dihydropyridines have minimal effect on cardiac conduction and are the preferred calcium channel blockers in hypertension. Non-dihydropyridine calcium channel blockers — verapamil and diltiazem — have significant cardiac effects including slowed conduction through the atrioventricular node and reduced contractility, and are avoided in combination with calcineurin inhibitors because they inhibit cytochrome P450 3A4, raising calcineurin inhibitor blood levels.

Correct Answer

C — Non-selective alpha-adrenergic receptor antagonist

Rationale

Phentolamine blocks both alpha-1 and alpha-2 adrenergic receptors, making it a non-selective alpha-adrenergic receptor antagonist. It is used acutely to counteract catecholamine-mediated vasoconstriction in pheochromocytoma hypertensive crises and cocaine-associated hypertension. Unlike phenoxybenzamine, phentolamine binds reversibly. Selective alpha-1 antagonists such as doxazosin and prazosin block only alpha-1 receptors. Beta-adrenergic receptor antagonists are contraindicated in catecholamine excess crises because they remove beta-2 vasodilation while leaving alpha-1 vasoconstriction unopposed. Centrally acting alpha-2 agonists such as clonidine reduce sympathetic outflow from the brainstem.

Correct Answer

A — Thiazide diuretics

Rationale

Hydrochlorothiazide is the prototype thiazide diuretic. Furosemide is the prototype loop diuretic. Amiloride and triamterene are potassium-sparing diuretics. Spironolactone and eplerenone are aldosterone antagonists.

Correct Answer

D — Beta blockade removes beta-2-mediated vasodilation while alpha-1-mediated vasoconstriction from catecholamine excess remains unopposed

Rationale

In pheochromocytoma, circulating catecholamines activate both alpha-1 receptors (causing vasoconstriction) and beta-2 receptors (causing vasodilation) simultaneously. The net vascular tone reflects the balance of these two opposing effects. When a beta-adrenergic receptor antagonist is given without prior alpha blockade, it removes the beta-2-mediated vasodilatory component while the alpha-1-mediated vasoconstriction from ongoing catecholamine excess remains fully active and unopposed. This shifts the balance dramatically toward vasoconstriction, precipitating a severe or potentially fatal hypertensive crisis. The correct sequence is alpha blockade first — established for 10 to 14 days before surgery — followed by beta blockade only after adequate alpha blockade is confirmed.

Correct Answer

B — They inhibit renal prostaglandin synthesis, reducing afferent arteriolar vasodilation and impairing natriuresis

Rationale

Renal prostaglandins — particularly prostaglandin E2 and prostacyclin — normally vasodilate the afferent arteriole and promote sodium excretion. Nonsteroidal anti-inflammatory drugs inhibit cyclooxygenase enzymes, reducing prostaglandin synthesis throughout the body including in the kidney. The loss of prostaglandin-mediated afferent arteriolar vasodilation reduces renal blood flow and glomerular filtration, impairing natriuresis and causing sodium and water retention. This effect blunts the response to diuretics (which require adequate renal perfusion) and renin-angiotensin-aldosterone system inhibitors (which depend partly on prostaglandin pathways for their vasodilatory effects). The average blood pressure rise is 3 to 5 millimeters of mercury, with greater effects in elderly patients and those with chronic kidney disease. Cyclooxygenase-2 selective inhibitors carry the same renal risk as non-selective agents.

Correct Answer

A — Spironolactone blocks androgen and progesterone receptors in addition to mineralocorticoid receptors, producing hormonal effects unrelated to its antihypertensive action

Rationale

Spironolactone is a non-selective steroid receptor antagonist. In addition to blocking mineralocorticoid receptors (its therapeutic target), it also antagonizes androgen receptors and has some activity at progesterone receptors. Androgen receptor blockade in men reduces testosterone signaling, causing gynecomastia and breast tenderness, and can cause decreased libido and erectile dysfunction. In women, it can cause menstrual irregularities. These effects are entirely off-target — they arise from receptor cross-reactivity, not from the drug's mineralocorticoid action. Eplerenone, which is structurally modified to bind selectively to mineralocorticoid receptors, avoids these hormonal adverse effects and is the preferred alternative in men who experience them.

Correct Answer

C — Dihydropyridine calcium channel blockers

Rationale

In bilateral renal artery stenosis, the renin-angiotensin-aldosterone system is activated to maintain glomerular filtration pressure through angiotensin II-mediated efferent arteriolar constriction. Angiotensin converting enzyme inhibitors and angiotensin receptor blockers remove this compensatory mechanism and precipitate acute kidney injury. Direct renin inhibitors act upstream in the same pathway and carry the same risk. Dihydropyridine calcium channel blockers such as amlodipine lower blood pressure by dilating peripheral arterioles without interfering with efferent arteriolar tone, making them safe alternatives. Centrally acting agents such as clonidine or methyldopa are also acceptable. Non-selective beta-adrenergic receptor antagonists reduce renin release, which further depends on the same angiotensin II pathway and may worsen perfusion; calcium channel blockers are the preferred class.

Correct Answer

D — Estrogen stimulates hepatic production of angiotensinogen, increasing substrate availability for the renin-angiotensin-aldosterone system

Rationale

Angiotensinogen is the precursor protein produced by the liver that is cleaved by renin to form angiotensin I. Estrogen upregulates hepatic angiotensinogen synthesis, increasing the substrate available for the renin-angiotensin-aldosterone system cascade. More angiotensinogen means more angiotensin I, more angiotensin II, more aldosterone, and ultimately more sodium retention and vasoconstriction — elevating blood pressure. This effect is reversible on discontinuation of estrogen-containing contraceptives. Progesterone-only contraceptives carry substantially less hypertensive risk because they do not share this hepatic mechanism. The same pathway explains why pregnancy — which involves large estrogen surges — can precipitate or worsen hypertension in susceptible individuals.

Correct Answer

B — They inhibit cytochrome P450 3A4, the enzyme responsible for cyclosporine metabolism, causing toxic cyclosporine accumulation

Rationale

Diltiazem and verapamil — both non-dihydropyridine calcium channel blockers — are potent inhibitors of cytochrome P450 3A4, the hepatic enzyme that metabolizes calcineurin inhibitors including cyclosporine and tacrolimus. Inhibiting this enzyme reduces calcineurin inhibitor clearance, causing drug accumulation and raising the risk of nephrotoxicity, neurotoxicity, and other concentration-dependent adverse effects. The preferred antihypertensive in transplant recipients is amlodipine, a dihydropyridine calcium channel blocker that does not inhibit cytochrome P450 3A4 and may even partially mitigate calcineurin inhibitor nephrotoxicity by its vasodilatory effect on the afferent arteriole.

Correct Answer

A — Masked hypertension — office readings underestimate true blood pressure burden, leaving cardiovascular risk undetected and untreated

Rationale

Masked hypertension is defined as normal blood pressure in the office but elevated readings on ambulatory blood pressure monitoring or home monitoring. Because office readings appear reassuring, the condition goes unrecognized and untreated — yet patients carry a cardiovascular risk similar to those with sustained hypertension. Ambulatory blood pressure monitoring is more accurate than office measurement for predicting cardiovascular outcomes precisely because it captures true blood pressure burden across the full 24-hour cycle, including during sleep. White coat hypertension is the opposite pattern: elevated office readings with normal out-of-office readings — this carries lower cardiovascular risk than sustained hypertension. Sustained hypertension features elevations in both settings.

Correct Answer

C — Ambulatory monitoring captures the full 24-hour blood pressure burden including nocturnal values, identifying patterns such as masked hypertension that office readings cannot detect

Rationale

The predictive superiority of ambulatory blood pressure monitoring comes from its breadth of coverage. A single office reading or even averaged office readings reflect blood pressure only during the brief clinic encounter and can be distorted by the white coat effect, anxiety, or recent activity. Ambulatory monitoring provides readings across the entire 24-hour cycle — including sleep, when blood pressure should normally dip by 10 to 20 percent (the dipping pattern). Absent nocturnal dipping is associated with greater cardiovascular risk independent of daytime readings. Ambulatory monitoring also identifies masked hypertension, white coat hypertension, and morning surge patterns, none of which are visible with office measurement alone. These additional dimensions of blood pressure behavior explain its stronger correlation with target organ damage and cardiovascular events.

Correct Answer

B — Establish alpha-adrenergic receptor blockade first; add beta blockade for heart rate control only after adequate alpha blockade is confirmed

Rationale

In pheochromocytoma, circulating catecholamines activate both alpha-1 receptors (vasoconstriction) and beta-2 receptors (vasodilation) simultaneously. If a beta-adrenergic receptor antagonist is started without prior alpha blockade, it removes beta-2-mediated vasodilation while alpha-1-mediated vasoconstriction remains fully active and unopposed — precipitating a severe or fatal hypertensive crisis. The correct sequence is alpha blockade first: phenoxybenzamine (non-selective, irreversible) or doxazosin (selective alpha-1) is started 10 to 14 days before surgery. Once adequate alpha blockade is established and blood pressure is controlled, a beta-adrenergic receptor antagonist may be added for heart rate management. Angiotensin converting enzyme inhibitors and aldosterone antagonists do not address the primary catecholamine-mediated mechanism.

Correct Answer

D — Switch to eplerenone, a selective mineralocorticoid receptor antagonist that does not block androgen or progesterone receptors

Rationale

The gynecomastia (breast enlargement) and breast tenderness are caused by spironolactone's off-target blockade of androgen receptors, reducing androgenic signaling and creating a relative estrogen excess in breast tissue. This effect is dose-related and class-specific to spironolactone. Eplerenone is structurally modified to bind selectively to mineralocorticoid receptors without significant androgen or progesterone receptor activity. Switching to eplerenone preserves the therapeutic benefit of aldosterone blockade — controlling blood pressure and protecting serum potassium — while eliminating the hormonal adverse effects. Loop diuretics do not block aldosterone receptors and are not appropriate substitutes for targeted mineralocorticoid receptor antagonism in primary aldosteronism.

Correct Answer

A — Ibuprofen inhibits renal prostaglandin synthesis, reducing natriuresis and counteracting the mechanisms of both his diuretic and his angiotensin converting enzyme inhibitor

Rationale

Renal prostaglandins maintain afferent arteriolar tone, support glomerular filtration, and promote sodium excretion. Ibuprofen inhibits cyclooxygenase enzymes, reducing prostaglandin synthesis in the kidney. The resulting sodium and water retention blunts the natriuresis on which hydrochlorothiazide depends, and also antagonizes the vasodilatory prostaglandin pathways that contribute to the blood pressure-lowering effect of lisinopril. The net result is a clinically significant rise in blood pressure despite unchanged antihypertensive doses. This interaction is a common and underrecognized cause of apparent antihypertensive treatment failure. The appropriate clinical action is to discontinue the nonsteroidal anti-inflammatory drug and use acetaminophen or a topical agent for osteoarthritis pain instead.

Correct Answer

C — Thiazide diuretics promote potassium excretion at the distal convoluted tubule, which would worsen the existing hypokalemia driven by autonomous aldosterone excess

Rationale

Primary aldosteronism already produces hypokalemia through aldosterone-driven potassium excretion in the collecting duct. Thiazide diuretics independently promote potassium loss by increasing sodium delivery to the collecting duct, where the elevated aldosterone then drives even greater potassium secretion in exchange. Adding a thiazide in this setting compounds the potassium wasting from two separate mechanisms simultaneously — the result can be severe or life-threatening hypokalemia. The appropriate targeted therapy is a mineralocorticoid receptor antagonist (spironolactone or eplerenone), which directly blocks the driving mechanism and is potassium-sparing rather than potassium-wasting. If surgical cure is not feasible, this drug class is both more effective and safer than thiazide diuretics in primary aldosteronism.