2.1 Antihypertensives & RAAS Agents

RAAS Inhibitors: ACE Inhibitors and ARBs

The renin-angiotensin-aldosterone system (RAAS) raises blood pressure through angiotensin II-mediated vasoconstriction and aldosterone-mediated sodium retention. Angiotensin-converting enzyme (ACE) inhibitors - lisinopril, ramipril, enalapril, perindopril - block the conversion of angiotensin I to angiotensin II. Because ACE is also the enzyme that degrades bradykinin, inhibiting it raises bradykinin levels, which explains the class-defining adverse effects:

• Dry, persistent, tickling cough (roughly 5-20% of patients, more common in women): caused by bradykinin and substance P accumulation in the airways. It does not resolve with dose reduction; the correct response is to stop the ACE inhibitor and switch to an ARB, which does not raise bradykinin.
• Angioedema (about 0.1-0.7%, higher risk in Black patients): bradykinin-mediated swelling of lips, tongue, or airway. It can occur after years of tolerated therapy and is a permanent contraindication to all ACE inhibitors. Note that the neprilysin inhibitor combination sacubitril/valsartan is also avoided after ACE-inhibitor angioedema (see section 2.2).
• Hyperkalemia: reduced aldosterone means reduced renal potassium excretion.
• First-dose hypotension, especially in volume-depleted or sodium-restricted patients.
• Acute kidney injury in bilateral renal artery stenosis (or stenosis of a solitary kidney): angiotensin II constricts the efferent arteriole to maintain glomerular filtration pressure; removing that drive collapses filtration. Expect a modest creatinine rise (up to ~30% is acceptable) after starting any RAAS blocker; a larger rise should prompt evaluation for renal artery stenosis.

Contraindications and monitoring: ACE inhibitors are contraindicated in pregnancy (fetal renal toxicity, oligohydramnios, skull hypoplasia - particularly in the second and third trimesters), in prior ACE-inhibitor angioedema, and in bilateral renal artery stenosis. The combination with the direct renin inhibitor aliskiren is avoided in diabetes or renal impairment. Monitor blood pressure, serum creatinine, and serum potassium at baseline and about 1-2 weeks after initiation and each dose increase.

ARBs - losartan, valsartan, candesartan, irbesartan, telmisartan - block the angiotensin II type 1 (AT1) receptor directly. They produce the same hemodynamic and renal effects as ACE inhibitors, including hyperkalemia and the same pregnancy and bilateral renal artery stenosis contraindications, but because bradykinin is unaffected, cough is rare and angioedema much less common. Losartan is partly a prodrug with a long-acting active metabolite (EXP3174) and is uniquely uricosuric, a helpful property in patients with gout.

Classic exam trap: never combine an ACE inhibitor with an ARB. Dual RAAS blockade (as tested in the ONTARGET trial) gives no cardiovascular outcome benefit but more hyperkalemia, hypotension, and renal impairment. The same logic applies to any duplicated RAAS blockade.

Calcium Channel Blockers

Calcium channel blockers (CCBs) block vascular and cardiac L-type calcium channels. The two subclasses behave very differently:

DHP-induced ankle edema is due to precapillary arteriolar dilation raising capillary hydrostatic pressure - it is not fluid retention, so diuretics do not help; adding an ACE inhibitor or ARB (postcapillary dilation) does. Amlodipine is a first-line agent for isolated systolic hypertension in older adults and in Black patients without heart failure or CKD. Non-DHPs are also CYP3A4 inhibitors and substrates: verapamil and diltiazem raise levels of simvastatin, digoxin, and many other CYP3A4 substrates, and grapefruit juice increases felodipine/nifedipine exposure.

Classic exam trap: combining verapamil (or diltiazem) with a beta-blocker produces additive AV-nodal depression and can cause severe bradycardia, high-grade heart block, or asystole. Avoid the combination.

Diuretics

Thiazide and thiazide-like diuretics - hydrochlorothiazide (HCTZ), chlorthalidone, indapamide - inhibit the Na-Cl cotransporter in the distal convoluted tubule. They are first-line antihypertensives with strong outcome data. Signature electrolyte and metabolic effects:

• Hypokalemia and hypomagnesemia (arrhythmia risk, especially with digoxin)
• Hyponatremia (more common in elderly women; chlorthalidone is the worst offender)
• Hypercalcemia (thiazides increase distal calcium reabsorption - useful in osteoporosis, dangerous in hyperparathyroidism)
• Hyperglycemia, dyslipidemia, and hyperuricemia - they can precipitate gout
• Photosensitivity with HCTZ

Chlorthalidone is 1.5-2 times as potent as HCTZ with a much longer duration (24-72 hours) and the best outcome evidence, at the cost of more hypokalemia and hyponatremia. Indapamide is largely metabolically neutral. All thiazides lose diuretic efficacy when eGFR falls below roughly 30 mL/min - switch to a loop diuretic in advanced CKD.

Loop diuretics - furosemide, bumetanide, torsemide - inhibit the Na-K-2Cl cotransporter (NKCC2) in the thick ascending limb. They are agents for fluid overload and edema, not routine hypertension. Adverse effects: hypokalemia, hypomagnesemia, hyperuricemia, and ototoxicity (high-dose IV therapy or combination with aminoglycosides).

Potassium-sparing diuretics come in two mechanistic families: the aldosterone (mineralocorticoid) receptor antagonists spironolactone and eplerenone, and the epithelial sodium channel (ENaC) blockers amiloride and triamterene. Their shared danger is hyperkalemia, which becomes life-threatening when combined with ACE inhibitors, ARBs, potassium supplements, salt substitutes, or renal impairment. Spironolactone additionally causes gynecomastia, breast tenderness, and menstrual irregularities through anti-androgen effects; eplerenone is more receptor-selective. Spironolactone is the preferred fourth-line agent for resistant hypertension (PATHWAY-2 trial).

Beta-Blockers as Antihypertensives

Beta-blockers are not first-line for uncomplicated hypertension - they are inferior to CCBs and RAAS blockers for stroke prevention in older patients (e.g., the LIFE trial, atenolol vs losartan). They are first-line when a compelling indication exists: prior myocardial infarction, HFrEF, stable angina, or tachyarrhythmia rate control. Beta-1-selective agents (metoprolol, bisoprolol) are preferred; labetalol and carvedilol add alpha-1 blockade. Adverse effects include bradycardia, fatigue, cold extremities, bronchospasm (non-selective agents), masking of hypoglycemia warning symptoms in diabetes, and sexual dysfunction. Never stop a beta-blocker abruptly - upregulated receptors produce rebound tachycardia, hypertension, and ischemia.

First-Line Selection by Compelling Indication

Trap summary for the exam: ACE inhibitor + ARB = no; potassium-sparing diuretic + ACE inhibitor/ARB + CKD or K supplements = hyperkalemia alert; verapamil/diltiazem + beta-blocker = heart block risk; thiazide + digoxin = hypokalemia-driven digoxin toxicity.