Antihypertensive Drugs

Definition and Goals of Treatment

Classification of Antihypertensive Drugs

1. DIURETICS

a. Thiazide and Thiazide-like Diuretics

• Examples: Hydrochlorothiazide (HCTZ), Chlorthalidone, Indapamide
• Mechanism: Inhibit NaCl cotransporter in distal tubule → natriuresis and volume depletion acutely; chronically reduce peripheral vascular resistance
• Notes: Chlorthalidone is more potent than HCTZ. In the ALLHAT trial, chlorthalidone was superior to amlodipine in preventing heart failure and superior to lisinopril in preventing stroke
• Adverse effects: Hypokalemia, hyperglycemia, hyperuricemia (gout), hyponatremia, dyslipidemia, erectile dysfunction
• Contraindications: Gout (compelling); metabolic syndrome, glucose intolerance, pregnancy (precautions)

b. Loop Diuretics

• Examples: Furosemide, Torsemide, Bumetanide
• Mechanism: Block Na-K-2Cl cotransporter in thick ascending limb of Henle
• Use in HTN: Preferred in patients with renal insufficiency (GFR <30) or edema/heart failure

c. Potassium-sparing Diuretics / Mineralocorticoid Receptor Antagonists (MRA)

• Examples: Spironolactone, Eplerenone (MRAs); Amiloride, Triamterene
• Use: Resistant hypertension, heart failure, primary hyperaldosteronism
• Contraindications: Hyperkalemia, serum creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women)

2. RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) INHIBITORS

a. ACE Inhibitors (ACEIs)

• Examples: Lisinopril, Enalapril, Ramipril, Captopril, Perindopril
• Mechanism: Block conversion of angiotensin I → angiotensin II; reduce aldosterone secretion; increase bradykinin (vasodilatory, but causes cough)
• Key benefits: Renoprotective (reduce proteinuria), cardioprotective post-MI, beneficial in heart failure and diabetes
• Adverse effects: Dry cough (bradykinin-mediated, in ~10-15%), angioedema (rare but serious), hyperkalemia, acute kidney injury in bilateral renal artery stenosis, teratogenic
• Contraindications: Pregnancy, angioedema history, hyperkalemia, bilateral renal artery stenosis

b. Angiotensin Receptor Blockers (ARBs)

• Examples: Losartan, Valsartan, Telmisartan, Irbesartan, Candesartan
• Mechanism: Block AT1 receptors directly; no effect on bradykinin (no cough)
• Advantage over ACEIs: No cough; preferred when ACEI cough is intolerable
• Contraindications: Same as ACEIs except no angioedema risk; pregnancy contraindicated

c. Direct Renin Inhibitors

• Example: Aliskiren
• Mechanism: Blocks renin, preventing cleavage of angiotensinogen to angiotensin I
• Use: Limited; not combined with ACEIs or ARBs due to risk of hyperkalemia and renal failure

Note: ACEI + ARB combination is generally avoided due to increased adverse effects without added cardiovascular benefit.

3. CALCIUM CHANNEL BLOCKERS (CCBs)

a. Dihydropyridines (DHPs)

• Examples: Amlodipine, Nifedipine, Felodipine, Nicardipine, Clevidipine (IV)
• Mechanism: Block L-type Ca²⁺ channels in vascular smooth muscle → vasodilation; minimal cardiac effect at therapeutic doses
• Advantages: Effective in elderly, African Americans; useful in angina + HTN; no metabolic adverse effects
• Adverse effects: Peripheral edema (dose-dependent), reflex tachycardia (especially short-acting nifedipine), flushing, headache
• Precautions: Tachyarrhythmia, heart failure (use with caution)

b. Non-Dihydropyridines

• Examples: Verapamil, Diltiazem
• Mechanism: Block L-type Ca²⁺ channels in both myocardium and vasculature → negative chronotropy and inotropy + vasodilation
• Uses: HTN + atrial fibrillation (rate control), HTN + angina
• Adverse effects: Bradycardia, AV block, constipation (verapamil), heart failure exacerbation
• Contraindications: AV block grade 2-3, severe LV dysfunction, heart failure; caution with CYP3A4/P-glycoprotein drugs (statins, digoxin)

4. BETA-ADRENERGIC BLOCKERS (β-Blockers)

• Examples: Metoprolol, Atenolol (β1-selective); Carvedilol, Labetalol (α+β); Propranolol (non-selective); Nebivolol
• Mechanism: Block β1 receptors → reduce heart rate and cardiac output; reduce renin release; central sympatholytic effect
• Key indications for HTN:
  • Post-MI, coronary artery disease
  • Heart failure with reduced EF (carvedilol, bisoprolol, metoprolol)
  • Aortic aneurysm
  • Angina
  • Atrial fibrillation (rate control)
• Note: Beta blockers are NOT recommended as first-line for uncomplicated hypertension (less effective in reducing CV events than other classes)
• Adverse effects: Bradycardia, AV block, bronchospasm, fatigue, erectile dysfunction, masking hypoglycemia, dyslipidemia
• Contraindications: Asthma, AV block grade 2-3; caution in COPD, metabolic syndrome, depression

5. VASODILATORS

a. Direct Vasodilators

• Hydralazine: Arteriolar vasodilator; causes reflex tachycardia and fluid retention (must combine with β-blocker + diuretic); used in pregnancy-induced HTN (IV) and heart failure (with nitrates in African Americans)
• Minoxidil: Potent arteriolar vasodilator (K⁺ channel opener); reserved for severe/resistant HTN; causes reflex tachycardia, fluid retention, hypertrichosis; must be given with a β-blocker and diuretic

b. Nitroprusside (IV)

• Releases NO → balanced arteriolar + venous dilation; used in hypertensive emergencies; risk of cyanide toxicity with prolonged use

6. ALPHA-ADRENERGIC BLOCKERS

• Alpha-1 blockers: Prazosin, Doxazosin, Terazosin
• Mechanism: Block postsynaptic α1 receptors → vasodilation
• Special use: Useful in men with benign prostatic hyperplasia (BPH) + HTN
• Adverse effects: First-dose orthostatic hypotension, dizziness
• Contraindication: Heart failure (ALLHAT showed increased heart failure risk with doxazosin)

7. CENTRAL SYMPATHOLYTICS

• Examples: Clonidine, Methyldopa, Moxonidine
• Mechanism: Stimulate central α2 receptors (or imidazoline receptors) → reduce sympathetic outflow → lower heart rate and BP
• Uses: Resistant HTN (clonidine); Methyldopa is preferred in pregnancy-induced HTN
• Adverse effects: Sedation, dry mouth, erectile dysfunction, rebound hypertension on abrupt withdrawal (clonidine)
• Contraindications: Depression, AV block grade 2-3

First-Line Drug Classes (Current Guidelines)

Drug Selection Based on Comorbidities

Combination Therapy

• Preferred: Thiazide + ACEI/ARB (K⁺-sparing benefit; synergistic BP lowering)
• Effective triple: Diuretic + ACEI/ARB + CCB
• 4th drug if needed: Add clonidine or β-blocker
• Avoid: ACEI + ARB (dual RAAS blockade); CCB dihydropyridine + non-DHP (risk of severe bradycardia/heart block)

Special Populations

Elderly

• Thiazides and CCBs are preferred first-line choices
• β-blockers less useful unless heart failure or CAD present
• ACEIs less useful unless heart failure or diabetes present
• Avoid powerful agents (minoxidil) unless necessary
• Monitor for orthostatic hypotension (risk of falls and cerebral ischemia)

Renal Insufficiency

• Loop diuretics preferred over thiazides when GFR <30
• ACEIs/ARBs slow progression of diabetic nephropathy but monitor K⁺ and creatinine

Hypertensive Emergency

• IV agents: Nitroprusside, Nicardipine, Labetalol, Hydralazine, Clevidipine
• Goal: Reduce MAP by ~20-25% in first hour, then gradually to target over 24-48 hours

Key Adverse Effects Summary

Recent Evidence (2024-2025)