Antihypertensives compared — mechanism and drug choice
Verified · Oct 2026Every antihypertensive lowers volume, vascular resistance or cardiac output — and the site it acts on predicts its potassium effect, its signature adverse effect and the patients it suits best. The second table collects the drug-choice logic the class pages teach.
How each class lowers blood pressure
In the renin–angiotensin–aldosterone system, ACE inhibitors block the converting enzyme, which is also kininase II, so bradykinin accumulates; ARBs block angiotensin II at the AT1 receptor without affecting bradykinin; aliskiren inhibits renin itself. Less angiotensin II means less arteriolar and venous constriction and less aldosterone.
Diuretics act along the nephron. Loop diuretics compete with chloride at NKCC2 in the thick ascending limb; thiazides bind NCC in the distal convoluted tubule; in the collecting duct, spironolactone and eplerenone block the mineralocorticoid receptor while amiloride and triamterene block ENaC. Thiazides lower pressure acutely by reducing blood volume and cardiac output; with chronic use plasma volume returns toward normal but peripheral vascular resistance falls.
Dihydropyridine calcium-channel blockers block vascular L-type channels with about 100-fold vascular selectivity, while verapamil and diltiazem also slow the SA and AV nodes. The antihypertensive mechanism of β-blockers is not settled — lower cardiac output, central sympathetic outflow and renin are proposed. α1-blockers block norepinephrine at vascular α1 receptors, clonidine and methyldopa reduce central sympathetic outflow, and hydralazine and minoxidil dilate arterioles directly.
Comparison
The classes compared
| Class | Target | Potassium | Signature adverse effect | Pregnancy | Key interaction |
|---|---|---|---|---|---|
| ACE inhibitors | ACE (kininase II) → less angiotensin II, more bradykinin | Hyperkalemia (less aldosterone) | Dry cough (5–20%); bradykinin-mediated angioedema | Boxed fetal toxicity | Neprilysin inhibitor (sacubitril) — contraindicated together or within 36 hours; potassium-sparing diuretics raise potassium |
| ARBs | AT1 receptor blockade; bradykinin unaffected | Hyperkalemia | Cough 1–4%, comparable to placebo; angioedema reported, including after ACE-inhibitor angioedema | Boxed fetal toxicity | Aliskiren in diabetes contraindicated; dual RAAS blockade avoided |
| Aliskiren | Direct renin inhibitor → lower plasma renin activity | Hyperkalemia | Acute renal failure in RAAS-dependent kidneys | Boxed fetal toxicity | Not with an ACE inhibitor or ARB in diabetes |
| Thiazides | NCC in the distal convoluted tubule | Hypokalemia | Hyponatremia; hyperglycemia and hyperuricemia; calcium retention | — | Lithium toxicity (less renal clearance); hypokalemia leaves digoxin unopposed |
| Loop diuretics | NKCC2 in the thick ascending limb | Hypokalemia (more common than with thiazides) | Ototoxicity; hyperuricemia; calciuresis; volume depletion | — | Aminoglycosides (additive ototoxicity); lithium |
| Potassium-sparing diuretics | Mineralocorticoid receptor (spironolactone, eplerenone) or ENaC (amiloride, triamterene) | Hyperkalemia (boxed for amiloride and triamterene) | Gynecomastia with spironolactone (eplerenone comparable to placebo); hyperchloremic metabolic acidosis | — | ACE inhibitors, ARBs and potassium supplements raise hyperkalemia risk |
| Dihydropyridine CCBs | Vascular L-type Ca²⁺ channels (about 100-fold vascular selectivity) | — | Ankle edema from precapillary arteriolar dilation; flushing, headache, reflex tachycardia; gingival overgrowth | Long-acting nifedipine is a preferred agent | The edema responds to adding an ACE inhibitor or ARB, not a diuretic |
| Verapamil, diltiazem | Nodal and myocardial L-type Ca²⁺ channels → slower SA and AV nodes | — | Bradycardia, AV block; constipation | — | Additive AV block with β-blockers; verapamil raises digoxin levels |
| β-blockers | β1 receptors → lower cardiac output and renin (mechanism not settled) | — | Bradycardia, AV block; bronchospasm from β2 blockade; masked hypoglycemia; rebound on abrupt withdrawal | IV labetalol for severe hypertension in pregnancy | Additive AV block with verapamil or diltiazem |
| α1-blockers | Vascular α1 receptors | — | First-dose orthostatic hypotension and syncope | — | — |
| Clonidine, methyldopa | Central α2 agonism → less sympathetic outflow | — | Clonidine: rebound hypertension on abrupt stop, dry mouth, sedation; methyldopa: positive Coombs test, rarely hemolytic anemia | Methyldopa is a preferred agent | Withdraw a β-blocker several days before stopping clonidine |
| Hydralazine, minoxidil | Direct arteriolar vasodilation (minoxidil opens K-ATP channels) | — | Reflex tachycardia and fluid retention; hydralazine lupus; minoxidil hypertrichosis and pericardial effusion | Hydralazine first-line in eclampsia | Given with a β-blocker (minoxidil also with a loop diuretic) |
— = no statement for that cell on the class page
Choosing by situation
| Situation | Choice | Why |
|---|---|---|
| Uncomplicated hypertension | A thiazide-like diuretic (chlorthalidone, indapamide) or a dihydropyridine CCB | Thiazide-like diuretics reduced cardiovascular events more than thiazide-type in a meta-analysis; CCBs reduce cardiovascular events comparably to thiazides except heart failure, and dihydropyridines are the preferred subclass |
| CKD with albuminuria, or diabetic nephropathy | An ACE inhibitor or ARB | Relaxing the efferent arteriole lowers intraglomerular pressure and proteinuria and slows kidney-disease progression; StatPearls relays KDIGO 2024: in CKD with severely increased albuminuria, an ACE inhibitor should be started |
| Dry cough on an ACE inhibitor | Switch to an ARB | ARBs do not inhibit kininase II, so bradykinin does not rise |
| Previous ACE-inhibitor angioedema | Never rechallenge; an ARB only with great caution | Rechallenge is absolutely contraindicated, and angioedema has been reported on ARBs in patients with prior ACE-inhibitor angioedema |
| HFrEF | ACE inhibitor (or candesartan/valsartan), carvedilol, bisoprolol or metoprolol succinate, plus a mineralocorticoid-receptor antagonist | Each lowers mortality or hospitalization; aldosterone escapes suppression on chronic ACE-inhibitor or ARB therapy, which the antagonist counters |
| Hypertension with symptomatic BPH | Doxazosin or terazosin | Labeled for both: α1 blockade relaxes prostatic and bladder-neck smooth muscle |
| Chronic hypertension in pregnancy | Methyldopa, labetalol or long-acting nifedipine — never a RAAS blocker | ACE inhibitors, ARBs and aliskiren carry boxed fetal-toxicity warnings |
| Hypertensive emergency | IV nicardipine or clevidipine, IV labetalol, or nitroprusside for minute-to-minute titration | Nicardipine and clevidipine are first-line IV agents; nitroprusside acts within minutes but needs continuous BP monitoring |
| Asthma or COPD needing a β-blocker | A β1-selective agent | Bronchospasm comes from β2 blockade; selectivity fades at higher doses |
| Primary hyperaldosteronism or resistant hypertension | Spironolactone or eplerenone | Mineralocorticoid-receptor antagonists are first-line medical therapy for autonomous aldosterone |
| Ankle edema on a dihydropyridine | Add an ACE inhibitor or ARB rather than a diuretic | The edema comes from precapillary arteriolar dilation, not fluid retention |
| Hypertension with gout | Losartan; avoid loop and thiazide diuretics in diagnosed gout | Losartan lowers uric acid by inhibiting URAT1; loops and thiazides raise urate reabsorption |
| Diabetes, already on an ACE inhibitor or ARB | Do not add aliskiren | Contraindicated — dual RAAS blockade raises the risk of renal impairment, hyperkalemia and hypotension |
| Recurrent calcium stones with hypercalciuria | A thiazide, often with potassium citrate | Thiazides cut urinary calcium by up to 50%; they also lower potassium and urinary citrate |
High-yield
Practice questions
Q1A 66-year-old man with hypertension has nocturia, hesitancy and a weak urinary stream from benign prostatic hyperplasia. He asks for one drug that could help both problems.
Which drug fits best?
- A.Doxazosin
- B.Hydrochlorothiazide
- C.Lisinopril
- D.Amlodipine
- E.Metoprolol
Show answer
A. Doxazosin — Alpha-1 receptors in the prostate and bladder neck set the smooth-muscle tone of the dynamic component of BPH, and blocking them lowers urethral resistance; doxazosin and terazosin are labeled for both BPH and hypertension. Selective alpha-1 blockers are second-line for hypertension because of orthostatic hypotension, and they are taken at night — doxazosin is started at bedtime to minimize first-dose syncope.
Q2A 64-year-old man with heart failure with reduced ejection fraction needs better blood pressure control, and his physician reviews the antihypertensives he could add.
Which drug should be avoided because of its negative inotropic effect?
- A.Amlodipine
- B.Lisinopril
- C.Furosemide
- D.Spironolactone
- E.Verapamil
Show answer
E. Verapamil — Nondihydropyridines such as verapamil and diltiazem depress ventricular contractility, which can precipitate or worsen heart failure in patients with reduced systolic function; they are relatively contraindicated in HFrEF. Dihydropyridines are potent vasodilators with limited effects on cardiac pacemaker activity and contractility. The other options are used in heart failure: ACE inhibitors such as lisinopril lower vascular resistance and raise cardiac output, loop diuretics such as furosemide are the cornerstone of diuretic therapy, and spironolactone reduces hospitalizations and mortality in heart failure.
Q3A 31-year-old woman with chronic hypertension, controlled on lisinopril, is found to be 10 weeks pregnant.
What is the most appropriate change to her treatment?
- A.Losartan
- B.Continue lisinopril at a lower dose
- C.Aliskiren
- D.Methyldopa
Show answer
D. Methyldopa — ACE inhibitors, ARBs and aliskiren all carry boxed warnings for fetal toxicity: drugs acting on the renin–angiotensin system in the second and third trimesters reduce fetal renal function and cause oligohydramnios, lung and skull hypoplasia and death, so they are stopped as soon as pregnancy is detected. Labetalol, methyldopa and long-acting nifedipine are preferred alternatives in pregnancy.
Q4A 55-year-old man has taken hydrochlorothiazide for a year. He presents with an acutely painful, swollen first metatarsophalangeal joint; his serum potassium is 3.1 mEq/L.
Which mechanism best explains his hyperuricemia?
- A.Thiazides increase hepatic purine synthesis
- B.Thiazides block uric acid secretion by ENaC
- C.Thiazides are secreted by organic anion transporters in exchange for urate, increasing urate reabsorption
- D.Hypokalemia directly inhibits xanthine oxidase
- E.Thiazides cause tumor lysis
Show answer
C. Thiazides are secreted by organic anion transporters in exchange for urate, increasing urate reabsorption — Loop and thiazide diuretics are anions secreted in exchange for urate through organic anion transporters, so urate is reabsorbed and gout attacks become more likely; they are contraindicated in diagnosed gout. His hypokalemia has a separate cause: more sodium reaches the aldosterone-sensitive collecting duct, which excretes potassium in exchange. Thiazides bind the chloride site of NCC, their lone target in the distal convoluted tubule — ENaC, on collecting-duct principal cells, is blocked by the potassium-sparing ENaC blockers — and hydrochlorothiazide decreases uric acid excretion rather than raising its production.
Sources
- Therapeutic Uses of Diuretic Agents — StatPearls (NCBI)
- Antihypertensive Medications — StatPearls (NCBI)
- Angiotensin II Receptor Blockers (ARB) — StatPearls (NCBI)
- Nursing Pharmacology 2e, Ch. 6 — ARBs (losartan) — Open RN (NCBI Bookshelf)
- TEKTURNA (aliskiren) — FDA label — FDA / DailyMed
- Calcium Channel Blockers — StatPearls (NCBI)
- Beta Blockers — StatPearls (NCBI)
- Minoxidil tablets — FDA label — FDA / DailyMed
- Physiology, Renin Angiotensin System — StatPearls (NCBI)
- ZESTRIL (lisinopril) tablets — FDA label — FDA / DailyMed
- TOPROL-XL (metoprolol succinate) — FDA label — FDA / DailyMed
- CARDURA (doxazosin) — FDA label — FDA / DailyMed
- Clonidine — StatPearls (NCBI)
- Angiotensin-Converting Enzyme (ACE) Inhibitors — StatPearls (NCBI)
- DIOVAN (valsartan) — FDA label — FDA / DailyMed
- LASIX (furosemide) tablets — FDA label — FDA / DailyMed
- ALDACTONE (spironolactone) — FDA label — FDA / DailyMed
- Methyldopa tablets — FDA label — FDA / DailyMed
- Hydralazine HCl tablets — FDA label — FDA / DailyMed
- VASOTEC (enalapril maleate) tablets — FDA label — FDA / DailyMed
- ATACAND (candesartan) — FDA label — FDA / DailyMed
- Hydrochlorothiazide capsules — FDA label — FDA / DailyMed
- Hypercalciuria — StatPearls (NCBI)
- Thiazide Diuretics — StatPearls (NCBI)
- Eplerenone — StatPearls (NCBI)
- Hypertensive Crisis — StatPearls (NCBI)
- Amlodipine — StatPearls (NCBI)
- Nifedipine — StatPearls (NCBI)
- Verapamil HCl ER tablets — FDA label — FDA / DailyMed
- Selective Beta-1 Blockers — StatPearls (NCBI)
- Labetalol hydrochloride tablets, Zydus Pharmaceuticals USA — FDA label — FDA / DailyMed
- Labetalol hydrochloride injection, Hospira — FDA label — FDA / DailyMed
- Sodium Nitroprusside — StatPearls (NCBI)
- Diagnosis and Treatment of Eclampsia. J Cardiovasc Dev Dis 2024 — MDPI (PMC)
- Candesartan — StatPearls (NCBI)
- CATAPRES-TTS (clonidine transdermal) — FDA label — FDA / DailyMed
- Alpha-Blockers — StatPearls (NCBI)
- Calcium Channel Blocker Toxicity — StatPearls (NCBI)
- Captopril tablets — FDA label — FDA / DailyMed
- Cozaar (losartan) — FDA label — FDA / DailyMed
- Loop Diuretics — StatPearls (NCBI)
- Thalitone (chlorthalidone) — FDA label — FDA / DailyMed
- Verapamil — mechanism, extracellular dihydropyridine site, pharmacokinetics — StatPearls (NCBI)
- Inderal LA (propranolol) — membrane action, metabolism, overdosage (FDA label) — FDA / DailyMed
- Doxazosin — StatPearls (NCBI)
- Hydralazine — calcium handling, baroreceptor reflex, acetylation — StatPearls (NCBI)
- Ramipril capsules (Aurobindo) — ramiprilat, tissue ACE, pharmacokinetics (FDA label) — FDA / DailyMed
- Methyldopa — conversion to methylnorepinephrine — StatPearls (NCBI)
- Minoxidil — K-ATP channel opening, hair-follicle effects — StatPearls (NCBI)
- The use of stems in the selection of INN (stems -entan, -afil, -ciguat, prost) — World Health Organization
- Spironolactone — StatPearls (NCBI)
- Amiloride — StatPearls (NCBI)
- Angioedema — bradykinin- vs histamine-mediated, treatment resistance, DPP-4 — StatPearls (NCBI)
- Hyperkalemia — StatPearls (NCBI)
- Hydrochlorothiazide — StatPearls (NCBI)
- Chlorthalidone — duration and efficacy versus hydrochlorothiazide, elimination — StatPearls (NCBI)
- Ethacrynic Acid — StatPearls (NCBI)
- Edecrin (ethacrynic acid) — FDA label — FDA / DailyMed
- Dyrenium (triamterene) — FDA label — FDA / DailyMed
- Procardia XL (nifedipine) — half-life, CYP3A4, grapefruit (FDA label) — FDA / DailyMed
- Drug-Induced Gingival Overgrowth — fibroblast calcium and folate uptake, collagenase activation — StatPearls (NCBI)
- Cardizem (diltiazem) — bioavailability, half-life, desacetyl metabolite (FDA label) — FDA / DailyMed
- Beta 1 Receptors — StatPearls (NCBI)
- Propranolol — β2 blockade, cocaine toxicity — StatPearls (NCBI)
- Labetalol — StatPearls (NCBI)
- Terazosin capsules (Jubilant Cadista) — FDA label — FDA / DailyMed
- Prazosin HCl capsules (ANI) — FDA label — FDA / DailyMed
- Metolazone tablets — FDA label — FDA / DailyMed
- Heart Failure — carvedilol, bisoprolol and metoprolol succinate in HFrEF — StatPearls (NCBI)
- Prazosin — StatPearls (NCBI)
- Sodium nitroprusside injection — FDA label: metabolism, cyanide treatment — FDA / DailyMed
- Tenormin (atenolol) — clinical pharmacology, renal elimination (FDA label) — FDA / DailyMed
- Losartan — AT1 selectivity, effects blocked beyond vasoconstriction, E-3174, Marfan syndrome — StatPearls (NCBI)
- Resistant Hypercalcemia — StatPearls (NCBI)
- Drug-Induced Lupus Erythematosus — hydralazine, acetylator status, antihistone antibodies — StatPearls (NCBI)
- Amiloride HCl tablets — FDA label — FDA / DailyMed
- Norvasc (amlodipine) — pharmacokinetics, no negative inotropy (FDA label) — FDA / DailyMed
- Metoprolol — mechanism, IV use and ECG monitoring, withdrawal syndrome, contraindications — StatPearls (NCBI)
- Indapamide tablets — clinical pharmacology (FDA label) — FDA / DailyMed
- Esmolol — cardioselective IV agent, use in active bronchospasm — StatPearls (NCBI)
- Captopril — StatPearls (NCBI)
Each class page compared lists its full sources; this page reuses facts verified there.
By LearnDrugs
Educational summary for medical students. Always verify against current prescribing information and guidelines. Not medical advice.