Hypertension drugs
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"hypertension" AND "antihypertensive agents"
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Antihypertensive Drugs: A Complete Overview
First-Line Drug Classes
Guidelines (ACC/AHA 2017, ESC/ESH 2018) recommend initiating therapy with two or more agents from three primary groups: calcium-channel blockers (CCBs), ACE inhibitors/ARBs, and thiazide/thiazide-like diuretics. Beta-blockers are first-line when specific co-morbidities are present (e.g., heart failure, CAD). Most patients need two or more drugs for adequate control.
1. Thiazide / Thiazide-like Diuretics
Mechanism: Inhibit Na+/Cl- reabsorption in the distal convoluted tubule, reducing plasma volume. With long-term use, peripheral vascular resistance also decreases.
| Drug | Typical Dose (mg/day) | Frequency |
|---|---|---|
| Chlorthalidone | 12.5-25 | Once daily |
| Hydrochlorothiazide (HCTZ) | 25-50 | Once daily |
| Indapamide | 1.25-2.5 | Once daily |
| Metolazone | 2.5-5 | Once daily |
Key side effects: Hypokalemia, hyperglycemia, hyperuricemia (gout), hyponatremia, erectile dysfunction, hypercalcemia.
Contraindications: Gout (compelling); metabolic syndrome, glucose intolerance (relative).
Note: Chlorthalidone is preferred over HCTZ - longer half-life, lower trough-to-peak variability, and better evidence for cardiovascular outcomes (ALLHAT trial).
2. ACE Inhibitors (ACEIs)
Mechanism: Block angiotensin-converting enzyme, preventing conversion of angiotensin I to angiotensin II. Also prevent bradykinin breakdown (causes cough). Reduce aldosterone secretion, lower SVR, and provide renoprotective effects.
| Drug | Typical Dose (mg/day) | Frequency |
|---|---|---|
| Lisinopril | 10-40 | Once daily |
| Ramipril | 2.5-20 | Once or twice daily |
| Enalapril | 5-40 | Once or twice daily |
| Captopril | 12.5-150 | 2-3x daily |
| Perindopril | 4-16 | Once daily |
| Benazepril, Fosinopril, Quinapril | 10-40 | Once or twice daily |
Key side effects: Dry cough (bradykinin accumulation, 10-20% of patients), angioedema (rare, 0.1-0.5%), hyperkalemia, acute kidney injury (bilateral RAS).
Compelling contraindications: Pregnancy, angioedema, hyperkalemia, bilateral renal artery stenosis.
Preferred in: Diabetes (especially with proteinuria), heart failure, post-MI, CKD with proteinuria, prior stroke.
3. Angiotensin Receptor Blockers (ARBs)
Mechanism: Block AT1 receptors directly; do NOT affect bradykinin, so essentially no cough. Provide the same benefits as ACEIs for most indications.
| Drug | Typical Dose (mg/day) | Frequency |
|---|---|---|
| Losartan | 25-100 | Once or twice daily |
| Valsartan | 80-320 | Once daily |
| Candesartan | 8-32 | Once daily |
| Olmesartan | 20-40 | Once daily |
| Irbesartan | 150-300 | Once daily |
| Telmisartan | 20-80 | Once daily |
| Azilsartan | 40-80 | Once daily |
Key side effects: Hyperkalemia, renal impairment (same as ACEI but no cough). Azilsartan has the highest BP-lowering potency among ARBs.
Contraindications: Same as ACEIs (pregnancy, hyperkalemia, bilateral RAS).
Do NOT combine ACEIs + ARBs - dual RAS blockade increases hyperkalemia and AKI risk without additional BP benefit.
4. Calcium Channel Blockers (CCBs)
Dihydropyridines (vascular-selective)
Mechanism: Block L-type voltage-gated calcium channels in vascular smooth muscle, causing arterial dilation. Little effect on cardiac conduction.
| Drug | Typical Dose (mg/day) | Frequency |
|---|---|---|
| Amlodipine | 2.5-10 | Once daily |
| Nifedipine (extended-release) | 30-90 | Once daily |
| Felodipine | 2.5-10 | Once daily |
| Nicardipine | 60-120 | 2-3x daily |
| Clevidipine (IV) | titrated | Infusion |
Key side effects: Peripheral edema (dose-dependent, from arteriolar dilation), flushing, reflex tachycardia (more with short-acting formulations), gingival hyperplasia.
Note: Amlodipine is comparable to chlorthalidone for reducing cardiovascular events (except heart failure). Its antihypertensive effects are NOT attenuated by high salt intake or NSAIDs - a major advantage.
Non-dihydropyridines (cardiac-selective)
Mechanism: Slow SA/AV nodal conduction; used for rate control.
| Drug | Typical Dose (mg/day) | Notes |
|---|---|---|
| Verapamil | 120-480 | Most negative inotrope; constipation |
| Diltiazem | 120-540 | Intermediate; good for angina + HTN |
Contraindications: AV block grade 2-3, severe LV dysfunction/heart failure, concurrent beta-blocker use (risk of complete block).
5. Beta-Blockers (BBs)
Mechanism: Block beta-1 adrenoceptors - reduce heart rate, cardiac output, and renin release. Some also have beta-2 blockade (non-selective) or additional alpha-1 blockade (carvedilol, labetalol).
| Drug | Selectivity | Dose (mg/day) | Notes |
|---|---|---|---|
| Metoprolol succinate | Beta-1 selective | 25-200 | Once daily (SR) - preferred in HF |
| Bisoprolol | Beta-1 selective | 2.5-10 | Once daily; stable PK |
| Atenolol | Beta-1 selective | 25-100 | Renal excretion |
| Carvedilol | Non-selective + alpha-1 | 6.25-50 | Used in HFrEF |
| Labetalol | Non-selective + alpha-1 | 200-800 | IV form for hypertensive emergencies, pregnancy |
| Nebivolol | Beta-1 + NO release | 5-40 | Vasodilatory; less metabolic effects |
| Propranolol | Non-selective | 40-160 | Also used for tremor, migraine |
Key side effects: Bradycardia, fatigue, erectile dysfunction, bronchospasm (non-selective), masking hypoglycemia, increased triglycerides, impaired glucose tolerance.
Compelling contraindications: Asthma (non-selective), AV block grade 2-3.
Preferred in: Post-MI, stable angina, HFrEF (metoprolol, bisoprolol, carvedilol), aortic aneurysm, atrial fibrillation (rate control).
6. Mineralocorticoid Receptor Antagonists (MRAs)
Mechanism: Block aldosterone receptors in the distal nephron, causing natriuresis while retaining potassium. Useful in resistant hypertension and primary hyperaldosteronism.
| Drug | Dose (mg/day) | Notes |
|---|---|---|
| Spironolactone | 12.5-100 | Can cause gynecomastia |
| Eplerenone | 25-50 | More selective - less gynecomastia |
Contraindications: Hyperkalemia, creatinine >2.5 mg/dL (men) or >2.0 mg/dL (women).
7. Renin Inhibitors
| Drug | Dose | Notes |
|---|---|---|
| Aliskiren | 150-300 mg/day | Direct renin inhibitor; avoid with ACEIs/ARBs in diabetics |
8. Alpha-1 Blockers
Mechanism: Block alpha-1 adrenoreceptors in vascular smooth muscle, causing vasodilation. Also relax prostate/bladder neck smooth muscle.
| Drug | Dose | Notes |
|---|---|---|
| Doxazosin | 2-16 mg/day | Once daily; also for BPH |
| Prazosin | 1-10 mg/day | 2-3x daily; first-dose hypotension |
| Terazosin | 1-20 mg/day | Once daily |
9. Central Alpha-2 Agonists
Mechanism: Stimulate central alpha-2 receptors in the brainstem (locus coeruleus), reducing sympathetic outflow.
| Drug | Dose | Notes |
|---|---|---|
| Clonidine | 0.1-0.8 mg/day | Rebound hypertension on abrupt withdrawal; also available as patch |
| Methyldopa | 250-500 mg 2x/day | Drug of choice in pregnancy |
| Guanfacine | 1-2 mg/day | Less withdrawal effect |
10. Vasodilators (Direct-Acting)
Used as add-on therapy for resistant hypertension or emergencies:
| Drug | Route | Notes |
|---|---|---|
| Hydralazine | Oral / IV | Arteriolar dilator; causes reflex tachycardia; used in pregnancy (IV) |
| Minoxidil | Oral | Most potent oral vasodilator; causes fluid retention + reflex tachycardia (requires concurrent BB + diuretic); causes hypertrichosis |
| Sodium nitroprusside | IV | Hypertensive emergencies; cyanide toxicity with prolonged use |
| Nitroglycerin | IV | Hypertensive emergency with acute coronary syndrome |
| Fenoldopam | IV | Dopamine D1 agonist; useful with renal insufficiency |
Drug Selection by Comorbidity
(From Goodman & Gilman's, Table 32-4)
| Condition | Preferred Drug(s) |
|---|---|
| Diabetes mellitus | ACEI, ARB, CCB, thiazides |
| Diabetes + proteinuria | ACEI, ARB |
| CKD / microalbuminuria | ACEI, ARB |
| Heart failure (HFrEF) | ACEI/ARB, BB (carvedilol/metoprolol/bisoprolol), diuretics, MRA |
| Post-MI | ACEI, ARB, BB |
| Coronary artery disease | ACEI, ARB, BB |
| Stable angina | BB, CCB |
| Atrial fibrillation (rate control) | BB, non-DHP CCB (verapamil/diltiazem) |
| Atrial fibrillation (prevention) | ACEI, ARB, BB |
| LV hypertrophy | ACEI, ARB, CCB |
| Previous stroke | ACEI, ARB, diuretics |
| Isolated systolic hypertension | ACEI, ARB, CCB, diuretics |
| Peripheral artery disease | ACEI, CCB |
| Hyperaldosteronism | MRA (spironolactone) |
| Aortic aneurysm | BB |
| Metabolic syndrome | ACEI, ARB, CCB |
| Pregnancy | Methyldopa, labetalol, nifedipine (oral) |
Combination Therapy Principles
(Goodman & Gilman's, p. 660)
- ~2/3 of patients need 2 or more drugs
- Preferred combinations: ACEI/ARB + CCB; ACEI/ARB + thiazide; CCB + thiazide
- Thiazides + RAS inhibitors are synergistic - thiazides activate renin, which makes RAS inhibitors more effective, while RAS inhibitors reduce thiazide-induced hypokalemia
- Avoid: ACEI + ARB (dual RAS blockade), BB + non-DHP CCB (complete AV block risk), BB + thiazide in patients with metabolic syndrome
- Fixed-dose single-pill combinations improve adherence significantly
Special Populations
| Population | Notes |
|---|---|
| Elderly | Thiazides reasonable first step; CCBs effective and well tolerated; BBs less preferred unless CHF present; watch for orthostatic hypotension |
| Pregnancy | Methyldopa (safest, most evidence), labetalol, nifedipine (oral); ACEIs/ARBs contraindicated in all trimesters |
| CKD with proteinuria | ACEI or ARB preferred; monitor potassium and creatinine |
| Black patients | CCBs and thiazides more effective as monotherapy (RAS inhibitors less effective without diuretic combination) |
Recent Evidence (2024-2026)
A 2025 Lancet meta-analysis of randomized trials confirmed that all major antihypertensive drug classes effectively lower BP and that combinations produce additive effects - supporting the current guideline emphasis on early combination therapy over monotherapy dose escalation. A network meta-analysis (2025) on antihypertensives in pregnancy found labetalol and nifedipine have the most favorable evidence profiles.
Sources: Goldman-Cecil Medicine (pp. 750-834), Goodman & Gilman's Pharmacological Basis of Therapeutics (pp. 655-660), Katzung's Basic and Clinical Pharmacology 16e, Textbook of Family Medicine 9e.
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