7.1 Antihypertensives
Antihypertensive drugs lower blood pressure through multiple mechanisms. Treatment reduces risk of stroke, heart failure, MI, and chronic kidney disease. Most patients require combination therapy.
ACE Inhibitors (ACEIs)
Mechanism
Inhibit angiotensin-converting enzyme (ACE)
Angiotensin I → Angiotensin II ✗ (blocked)
↓ Ang II → ↓ vasoconstriction, ↓ aldosterone, ↓ Na⁺/H₂O retention
Also ↓ bradykinin degradation → ↑ bradykinin (vasodilation, cough)
Common ACE Inhibitors
Lisinopril: long-acting, once-daily, not prodrug
Enalapril/Enalaprilat: IV available (enalaprilat)
Ramipril, perindopril: evidence in CV risk reduction
Captopril: short-acting, 2-3x daily (older agent)
Naming: "-pril" suffix
Clinical Uses
First-line for hypertension (especially with diabetes, CKD)
Heart failure (↓ afterload, ↓ remodeling, mortality benefit)
Post-MI (↓ remodeling, ↓ mortality)
Diabetic nephropathy (renoprotective—↓ intraglomerular pressure)
Adverse Effects
Dry cough (10-20%): ↑ bradykinin → switch to ARB if intolerable
Hyperkalemia: ↓ aldosterone → ↓ K⁺ excretion (monitor K⁺)
Angioedema (rare but serious): ↑ bradykinin → airway swelling
Acute kidney injury: bilateral renal artery stenosis (efferent arteriole dilation)
Teratogenic: Contraindicated in pregnancy (fetal renal dysgenesis)
ARBs - Angiotensin Receptor Blockers
Mechanism
Selective AT₁ receptor antagonists
Block Ang II effects: vasoconstriction, aldosterone release, sympathetic activation
No effect on bradykinin (no cough)
Common ARBs
Losartan: prototype, uricosuric (↓ uric acid)
Valsartan: heart failure, post-MI
Telmisartan: longest half-life (~24h), PPAR-γ agonist activity
Irbesartan, candesartan: diabetic nephropathy
Naming: "-sartan" suffix
Clinical Profile
Similar efficacy and indications as ACE inhibitors
Better tolerated—no cough, less angioedema
Alternative for ACE inhibitor-intolerant patients
Same contraindications: pregnancy, bilateral RAS, hyperkalemia risk
Calcium Channel Blockers (CCBs)
Dihydropyridines (DHP)
Examples: Amlodipine, nifedipine, felodipine
Vascular-selective L-type Ca²⁺ channel blockers
↓ Vascular smooth muscle contraction → vasodilation (arterioles > veins)
Minimal cardiac effects (reflex tachycardia possible)
Side effects: Peripheral edema (ankle), flushing, headache, gingival hyperplasia
Non-Dihydropyridines
Verapamil: cardiac > vascular effects
↓ HR, ↓ contractility, ↓ AV conduction (treat SVT, rate control)
Diltiazem: intermediate cardiac/vascular effects
Side effects: Constipation (verapamil), bradycardia, AV block
Avoid with β-blockers (additive cardiac depression)
Clinical Uses
Hypertension (especially elderly, Black patients—salt-sensitive HTN)
Angina (↓ O₂ demand, ↑ coronary flow)
Arrhythmias (non-DHP: SVT, atrial fibrillation rate control)
Diuretics
Thiazides (HCTZ, Chlorthalidone)
Inhibit Na⁺-Cl⁻ cotransporter in distal convoluted tubule
First-line for hypertension—↓ volume, ↓ vascular resistance
Chlorthalidone: longer t½ than HCTZ, superior CV outcomes
Side effects: Hypokalemia, hyperuricemia (gout), hyperglycemia, hyperlipidemia, hyponatremia
Loop Diuretics (Furosemide, Bumetanide)
Inhibit Na⁺-K⁺-2Cl⁻ cotransporter in thick ascending limb
More potent than thiazides—used for volume overload (CHF, edema)
Not first-line for HTN (short duration, more electrolyte imbalance)
Side effects: Hypokalemia, ototoxicity (especially with aminoglycosides)
K⁺-Sparing Diuretics
Spironolactone, eplerenone: aldosterone antagonists (collecting duct)
Heart failure with reduced EF (mortality benefit)
Side effects: Hyperkalemia, gynecomastia (spironolactone—less with eplerenone)
Amiloride, triamterene: ENaC blockers (rarely used)
Beta-Blockers
Mechanism for HTN
↓ Cardiac output (↓ HR, ↓ contractility)
↓ Renin release (β₁ in JG cells)
Central effects (↓ sympathetic outflow)
Selective β₁-Blockers
Metoprolol, atenolol, bisoprolol
Cardiac-selective (still affect β₂ at high dose)
Safer in asthma/COPD, diabetes
Non-Selective β-Blockers
Propranolol, timolol, nadolol
β₁ + β₂ blockade
Avoid in asthma (bronchospasm), peripheral vascular disease
Combined α/β-Blockers
Carvedilol, labetalol
Additional vasodilation (α₁-blockade)
Carvedilol: heart failure (mortality benefit)
Labetalol: hypertensive emergencies, pregnancy
Clinical Uses & Limitations
No longer first-line for uncomplicated HTN (less effective at ↓ stroke than other agents)
Compelling indications: CAD, post-MI, heart failure, arrhythmias
Side effects: Fatigue, erectile dysfunction, bradycardia, bronchospasm, mask hypoglycemia
Other Antihypertensives
α₁-Blockers (Doxazosin, Prazosin)
Block α₁-adrenergic receptors → vasodilation
Also for BPH (relax prostate/bladder neck)
Side effects: Orthostatic hypotension (first-dose syncope), dizziness
Not first-line (inferior to other agents)
Hydralazine
Direct arteriolar vasodilator (mechanism unclear)
Reflex tachycardia, fluid retention—combine with β-blocker + diuretic
Heart failure (with nitrates), pregnancy (eclampsia)
Chronic use: Drug-induced lupus (especially slow acetylators)
Clonidine
Central α₂-agonist → ↓ sympathetic outflow
Oral or transdermal patch
Side effects: Sedation, dry mouth, rebound HTN with abrupt discontinuation
Minoxidil
Potent K⁺ channel opener → arteriolar vasodilation
Refractory hypertension (requires diuretic + β-blocker)
Side effects: Hirsutism (used topically for hair growth), pericardial effusion