Antihypertensive Drugs
A Step 1-focused tour of the antihypertensive classes — thiazides, ACE-Is/ARBs, calcium channel blockers, beta-blockers, and the second-line vasodilators and sympatholytics — organized around each agent's mechanism, first-line indications, and the signature toxicities the boards love to test.
The Big Picture
Blood pressure = cardiac output × total peripheral resistance, and every antihypertensive lowers one or both. On Step 1, the classes proven to reduce cardiovascular mortality and used first-line for essential hypertension are thiazide diuretics, ACE inhibitors, angiotensin II receptor blockers (ARBs), and calcium channel blockers (CCBs). Beta-blockers, alpha-blockers, central sympatholytics, and direct vasodilators are second-line or reserved for specific compelling indications.
Anchor the mechanisms to two systems the exam loves: the nephron (where diuretics act, segment by segment) and the renin–angiotensin–aldosterone system (RAAS) (where ACE-Is, ARBs, aliskiren, and aldosterone antagonists act). Most questions are not "which drug lowers BP" but "which drug caused this signature toxicity" or "which agent fits this specific patient." Learn each drug by its one or two unforgettable adverse effects.
- First-line for uncomplicated HTN: thiazide, ACE-I/ARB, or dihydropyridine CCB. Beta-blockers are no longer first-line for uncomplicated HTN.
- Diabetic nephropathy / proteinuria: ACE-I or ARB — they dilate the efferent arteriole, lowering intraglomerular pressure and slowing progression.
- ACE-I signature triad: dry cough and angioedema (both bradykinin-mediated) + hyperkalemia; also teratogenic.
- ARBs do everything ACE-Is do except cough (no bradykinin effect) and carry much lower angioedema risk — still hyperkalemic and teratogenic.
- Never give ACE-I/ARB in pregnancy or bilateral renal artery stenosis (precipitates acute kidney injury).
- Dihydropyridine CCBs (-dipine): vasoselective → peripheral edema, flushing, reflex tachycardia. Non-dihydropyridines (verapamil, diltiazem): cardiac-acting (act on the heart) → bradycardia, AV block, constipation (verapamil).
- Thiazides: hypokalemic metabolic alkalosis + hyperGlycemia, hyperLipidemia, hyperUricemia (gout), hyperCalcemia, and hyponatremia.
- Spironolactone → hyperkalemia + gynecomastia; eplerenone avoids the gynecomastia.
- Pregnancy-safe agents: hydralazine, labetalol, methyldopa, nifedipine.
- Hypertensive emergency (IV): nitroprusside, labetalol, nicardipine/clevidipine, fenoldopam.
Class-by-Class: MOA · Use · Signature Toxicity
| Class (example) | Mechanism | Key clinical use | Signature toxicity |
|---|---|---|---|
| Thiazide (HCTZ, chlorthalidone) | Blocks Na⁺/Cl⁻ cotransporter in DCT | First-line HTN; Ca²⁺ stones; nephrogenic DI | HypoK⁺ alkalosis; hyperGLUC (Glucose, Lipids, Uric acid, Ca²⁺); hyponatremia; sulfa allergy |
| Loop (furosemide) | Blocks Na⁺-K⁺-2Cl⁻ (NKCC2) in thick ascending limb | HTN in CKD; pulmonary edema / HF | Ototoxicity, hypoK⁺, hypocalcemia, gout, sulfa allergy |
| K⁺-sparing (spironolactone, eplerenone) | Aldosterone-receptor antagonist (collecting duct) | HF, hyperaldosteronism, ascites | HyperK⁺; gynecomastia (spironolactone only) |
| ACE inhibitor (-pril) | Blocks ACE → ↓angiotensin II, ↑bradykinin | HTN, HF, diabetic nephropathy, post-MI | Cough, angioedema, hyperK⁺, teratogen, ↑Cr |
| ARB (-sartan) | Blocks AT₁ receptor | Same as ACE-I; used if cough intolerable | HyperK⁺, teratogen (no cough) |
| Dihydropyridine CCB (-dipine) | Blocks L-type Ca²⁺ channels in vessels | HTN, angina, Raynaud | Peripheral edema, flushing, reflex tachycardia, gingival hyperplasia |
| Non-DHP CCB (verapamil, diltiazem) | Blocks L-type Ca²⁺ channels in heart | HTN, angina, rate control in AF/SVT | Bradycardia, AV block, constipation (verapamil) |
| Beta-blocker (-olol) | ↓Cardiac output, ↓renin | Compelling: HF, post-MI, angina, arrhythmia | Bradycardia, AV block, bronchospasm, masks hypoglycemia |
| α₁-blocker (prazosin, -osin) | Blocks vascular α₁ | HTN + BPH; PTSD nightmares (prazosin) | First-dose orthostatic hypotension |
| α₂-agonist (clonidine, methyldopa) | ↓Central sympathetic outflow | Resistant HTN; methyldopa in pregnancy | Clonidine: rebound HTN; methyldopa: Coombs⁺ hemolysis |
| Hydralazine | ↑cGMP → arteriolar dilation | Severe HTN, pregnancy, HF (+ isosorbide) | Reflex tachycardia, drug-induced lupus |
| Minoxidil | Opens K⁺ channels → hyperpolarizes vessel | Refractory HTN; alopecia (topical) | Hypertrichosis, pericardial effusion |
| Nitroprusside | Releases NO → ↑cGMP (artery + vein) | Hypertensive emergency | Cyanide toxicity |
| Fenoldopam | Dopamine D₁ agonist | Hypertensive emergency (↑renal perfusion) | Hypotension, reflex tachycardia |
RAAS Blockers in Depth
Renin (from juxtaglomerular cells) cleaves angiotensinogen to angiotensin I; ACE (largely in lung endothelium) converts it to angiotensin II, which raises BP by vasoconstriction and by driving aldosterone (Na⁺/water retention) and ADH release. ACE inhibitors block that conversion, so angiotensin II and aldosterone fall — but ACE also degrades bradykinin, so inhibiting it lets bradykinin accumulate, producing the classic dry cough and angioedema. ARBs block the AT₁ receptor downstream and spare bradykinin — hence no cough and only rare angioedema.
Both classes preferentially dilate the efferent arteriole, dropping intraglomerular pressure. This protects the kidney long-term in diabetic nephropathy (less hyperfiltration and proteinuria) but is dangerous in bilateral renal artery stenosis, where GFR depends on efferent tone — removing it causes acute kidney injury. A modest creatinine rise (up to ~30%) is expected and acceptable; a steep rise suggests underlying stenosis. Because they raise K⁺ and are teratogenic (fetal renal dysgenesis, oligohydramnios), avoid them in pregnancy and combine cautiously with K⁺-sparing diuretics. Aliskiren (direct renin inhibitor) blocks the top of the cascade but should not be combined with an ACE-I/ARB in diabetics (hyperkalemia, renal failure).
- A man on a new BP pill develops a persistent dry cough; switching to a "-sartan" resolves it. → ACE inhibitor (bradykinin) → switch to an ARB.
- Lips and tongue swell hours after the first dose of an antihypertensive. → ACE-inhibitor angioedema (higher risk in Black patients) — stop immediately.
- A hypertensive diabetic with albuminuria needs BP control that also protects the kidneys. → ACE inhibitor or ARB.
- New ankle edema and facial flushing after starting amlodipine, with normal JVP and clear lungs. → Dihydropyridine CCB (not heart failure).
- A young woman on hydralazine develops arthralgias, malar rash, and anti-histone antibodies. → Drug-induced lupus (also procainamide, isoniazid).
- A patient on an IV drip for malignant HTN develops altered mental status and lactic (anion-gap) acidosis. → Nitroprusside → cyanide toxicity.
- A man started on a nonselective beta-blocker for HTN has an asthma exacerbation. → Bronchospasm — switch to a β₁-selective agent.
- A patient who abruptly stopped his clonidine returns with severe rebound hypertension and tachycardia. → Clonidine withdrawal.
- ACE-inhibitor toxicities — "CAPTOPRIL": Cough, Angioedema, Pregnancy problem (teratogen), Taste changes, Orthostatic hypotension, Potassium excess (hyperkalemia), Renal failure (in renal artery stenosis), Increased renin, Leukopenia.
- Thiazide metabolic toxicities — "hyperGLUC": hyper-Glycemia, hyper-Lipidemia, hyper-Uricemia (gout), hyper-Calcemia.
- Pregnancy-safe antihypertensives — "Hypertensive Moms Love Nifedipine": Hydralazine, Methyldopa, Labetalol, Nifedipine.
- "-dipine dilates": the dihydropyridine CCBs act on vessels; verapamil/diltiazem act on the heart.
- Suffix shortcuts: -pril = ACE-I · -sartan = ARB · -osin = α₁-blocker · -olol = beta-blocker.
- Heart failure (reduced EF): ACE-I/ARB + beta-blocker (carvedilol, metoprolol succinate, bisoprolol) + aldosterone antagonist + loop diuretic for congestion — the first three carry a mortality benefit (the loop is for symptom control).
- Post-MI: beta-blocker + ACE-I.
- Diabetes / CKD with proteinuria: ACE-I or ARB first.
- Black patients (no CKD) and the elderly: thiazide or CCB work better as monotherapy; ACE-Is are less effective and carry higher angioedema risk.
- BPH + HTN: an α₁-blocker (doxazosin) treats both — but is not first-line for BP alone.
- Osteoporosis: a thiazide helps (retains Ca²⁺). Migraine / tremor / hyperthyroid symptoms: a beta-blocker helps.
- Avoid non-DHP CCB (verapamil/diltiazem) with a beta-blocker → additive AV block / bradycardia.
- Pheochromocytoma: establish α-blockade (phenoxybenzamine) before β-blockade to avoid unopposed α-vasoconstriction — the same rule applies to cocaine-associated hypertension.
- Gynecomastia in a man on a diuretic → spironolactone (switch to eplerenone).
- Excess hair growth (hypertrichosis), also marketed for baldness → minoxidil.
- Gingival hyperplasia (shared with phenytoin & cyclosporine) → calcium channel blocker (classically a dihydropyridine, e.g., nifedipine, amlodipine).
- Coombs-positive hemolytic anemia in a pregnant patient on BP meds → methyldopa.
- Reflex tachycardia + fluid retention + lupus-like syndrome → hydralazine.
- Improves renal perfusion during a hypertensive emergency via D₁ receptors → fenoldopam.
- First-dose syncope / orthostasis → prazosin (α₁-blocker); also used for PTSD nightmares.
- Prevents cerebral vasospasm after subarachnoid hemorrhage → nimodipine (a dihydropyridine CCB).
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