Everything You Need to Know About Antihypertensive drug classes for Step 1

Hypertension questions on Step 1 love to test mechanisms (what receptor/enzyme is hit), physiology (preload/afterload/RAAS), and toxicities (the “classic” adverse effects and contraindications). If you can quickly map each drug class to where it acts + what it does to renin/aldosterone + the big side effects, you’ll convert a ton of pharm stems into easy points.

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Quick Definition + Why We Treat

Hypertension (HTN) = chronically elevated arterial blood pressure that increases risk of:

• Stroke (ischemic + hemorrhagic)
• MI, HF
• CKD
• Retinopathy
• Aortic dissection / aneurysm complications

Core hemodynamic idea:
$BP = CO \times SVR$
Most antihypertensives lower cardiac output (CO), systemic vascular resistance (SVR), or both.

First Aid cross-reference: Cardiovascular—Hypertension; Pharmacology—Autonomic drugs; Renal—RAAS; Endocrine—aldosterone physiology (exact page varies by edition).

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Pathophysiology (Step-Relevant)

Essential (Primary) HTN (most common)

Driven by a mix of:

• Increased SVR (arteriolar remodeling + endothelial dysfunction)
• RAAS overactivity (variable by patient)
• Sympathetic overactivity
• Salt sensitivity → volume expansion

Secondary HTN (high yield causes)

Think “when HTN is abrupt, severe, resistant, or in a young patient”:

• Renal artery stenosis (fibromuscular dysplasia in young women; atherosclerosis in older men)
• Primary hyperaldosteronism (Conn): HTN + hypokalemic metabolic alkalosis + low renin
• Pheochromocytoma: episodic headache, sweating, tachycardia
• Cushing syndrome
• OSA
• Coarctation of aorta: upper extremity HTN, diminished femoral pulses
• Thyroid disease
• Drug-induced: NSAIDs, OCPs, steroids, sympathomimetics, cocaine, calcineurin inhibitors

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Clinical Presentation + End-Organ Damage

Most patients are asymptomatic (“silent killer”). When symptomatic, it’s often end-organ:

• Neuro: headache, vision changes, focal deficits (stroke)
• Cardiac: chest pain, dyspnea (HF/MI)
• Renal: rising creatinine, proteinuria
• Eyes: AV nicking, cotton-wool spots, papilledema (severe)

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Diagnosis: How Step Questions Frame It

• Confirm elevated BP with repeat measurements (often on different days; ambulatory/home readings may be referenced).
• Evaluate for:
  • Diabetes, CKD, CAD
  • Secondary causes if resistant/early onset
• Basic workup you may see in stems:
  • BMP (K+, Cr)
  • Urinalysis (protein)
  • A1c/lipids
  • ECG (LVH)

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Big Picture: Drug Classes by Physiologic Target

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First-Line Therapy: What Step 1 Usually Expects

Common first-line options (especially in uncomplicated HTN):

• Thiazide diuretics
• ACE inhibitors or ARBs
• Calcium channel blockers (often DHPs)

Compelling indications are heavily tested (see table below).

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Thiazide Diuretics (HCTZ, chlorthalidone, indapamide)

Mechanism

• Inhibit NaCl reabsorption in distal convoluted tubule (DCT) → natriuresis
• Long-term BP reduction mainly from ↓ SVR (vascular effects)

High-yield effects

• ↑ Ca2+ reabsorption → can help calcium kidney stones (idiopathic hypercalciuria)
• Dilute urine (DCT is water-impermeable)

Adverse effects (memorize the classic)

• Hyponatremia
• Hypokalemic metabolic alkalosis
• Hyperuricemia (gout)
• Hyperglycemia
• Hyperlipidemia
• Hypercalcemia
• Sulfa allergy (less commonly emphasized for thiazides vs loops, but still testable)

Mnemonic-ish: “Thiazides make you HYPER GLUC + gout and keep Ca.”

Step-style associations

• Older patient with HTN + recurrent calcium stones → thiazide
• Patient with gout flare after starting new BP med → suspect thiazide

First Aid cross-reference: Renal—Diuretics; CV—HTN treatment.

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Loop Diuretics (furosemide, bumetanide, torsemide, ethacrynic acid)

Mechanism

• Inhibit Na-K-2Cl in thick ascending limb

Clinical role in HTN

• Not typical first-line for uncomplicated HTN
• Great in edema states (HF) and CKD with low GFR (where thiazides may be less effective)

Adverse effects (HIGH YIELD)

• Ototoxicity
• Hypokalemic metabolic alkalosis
• Dehydration
• Sulfa allergy (except ethacrynic acid)
• Nephritis
• Gout

Loops increase Ca2+ excretion → can worsen hypocalcemia.

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K-Sparing Diuretics

ENaC blockers: amiloride, triamterene

• Block epithelial Na+ channels in collecting tubule

Uses (very testable):

• Liddle syndrome (gain-of-function ENaC)
• Lithium-induced nephrogenic DI (amiloride)

Adverse: hyperkalemia, metabolic acidosis

Aldosterone antagonists: spironolactone, eplerenone

• Block mineralocorticoid receptor → ↓ Na+ reabsorption, ↓ K+ secretion

Uses:

• Primary hyperaldosteronism
• Resistant HTN
• HFrEF mortality benefit (RALES—often more Step 2, but concept matters)

Adverse:

• Hyperkalemia, metabolic acidosis
• Spironolactone: gynecomastia, impotence, menstrual irregularities (antiandrogen)
• Eplerenone: fewer endocrine side effects

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ACE Inhibitors (‑pril) and ARBs (‑sartan)

Mechanism (ACEi)

• ↓ Ang II (via ACE blockade) → ↓ aldosterone
• ↑ Bradykinin (ACE breaks down bradykinin)

Mechanism (ARB)

• Block AT1 receptor → ↓ aldosterone
• No bradykinin effect → less cough/angioedema (still possible, but lower)

High-yield physiologic effects

• Efferent arteriole dilation → ↓ intraglomerular pressure
  • Helpful in diabetic nephropathy (↓ proteinuria)
  • But can raise creatinine (expected modest bump)

Adverse effects (ACEi/ARB)

• Hyperkalemia
• Increased creatinine (especially with bilateral renal artery stenosis)
• ACEi: cough, angioedema (bradykinin-mediated)

Contraindications (very high yield)

• Pregnancy (teratogenic): classically causes fetal renal damage → oligohydramnios
• Bilateral renal artery stenosis: can precipitate acute kidney injury

Classic stem

• Patient started on ACEi → develops cough; switch to ARB
• Renal artery stenosis: ACEi causes abrupt rise in creatinine

First Aid cross-reference: Renal—RAAS; Pharm—antihypertensives.

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Direct Renin Inhibitor (aliskiren)

Mechanism

• Inhibits renin → ↓ Ang I → ↓ Ang II → ↓ aldosterone

Adverse/contraindications

• Similar to ACEi/ARB: hyperkalemia, teratogenicity
• Not a common exam favorite compared with ACEi/ARBs, but fair game.

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Calcium Channel Blockers (CCBs)

Dihydropyridines (amlodipine, nifedipine, felodipine, nicardipine, clevidipine)

“DHPs work on vessels.”

• Preferential arteriolar vasodilation → ↓ SVR

Adverse

• Peripheral edema (capillary hydrostatic pressure changes)
• Flushing, headache
• Reflex tachycardia (more with short-acting agents)

Key association

• Often used in Black patients as first-line (along with thiazides) in many guideline frameworks (Step may mention this).

Non-dihydropyridines (verapamil, diltiazem)

“Non-DHPs work on the heart.”

• ↓ HR, ↓ contractility, ↓ AV conduction

Adverse

• Bradycardia, AV block
• Worsen HFrEF (negative inotropy)
• Verapamil: constipation, gingival hyperplasia (can be asked)

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β-Blockers (metoprolol, atenolol, propranolol, carvedilol, labetalol, esmolol, etc.)

Mechanism (BP)

• ↓ HR/contractility → ↓ CO
• ↓ renin release from JG cells (β1 blockade) → ↓ RAAS

Who benefits (high yield)

• Post-MI
• Angina
• Certain arrhythmias
• HFrEF mortality benefit with select agents (carvedilol, metoprolol succinate, bisoprolol)
• Aortic dissection (reduce shear by lowering HR first)

Adverse effects

• Bradycardia, fatigue
• Sexual dysfunction
• Can mask hypoglycemia symptoms (tachycardia, tremor)
• Bronchospasm with nonselective agents (β2 block)

High-yield contraindications/cautions

• Severe asthma/COPD (esp nonselective)
• Acute decompensated HF (initiation can worsen)

Step pearls

• Esmolol = short-acting, IV (often used for acute rate control)
• Labetalol blocks α1 + β → useful in pregnancy-related HTN and emergencies (see below)

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α1-Blockers (prazosin, doxazosin, terazosin)

Mechanism

• Block α1 in vascular smooth muscle → vasodilation → ↓ SVR

Uses

• HTN with BPH (improves urinary symptoms)

Adverse (classic)

• Orthostatic hypotension
• First-dose syncope
• Dizziness

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Central α2-Agonists (clonidine, methyldopa)

Mechanism

• Stimulate α2 receptors in CNS → ↓ sympathetic outflow

Clonidine

• Adverse: sedation, dry mouth
• Key Step association: rebound hypertension if abruptly stopped

Methyldopa (pregnancy favorite)

• Converted to α-methylnorepinephrine → central α2 agonism

Adverse

• Coombs-positive hemolytic anemia
• Hepatotoxicity
• Hyperprolactinemia

High yield use: HTN in pregnancy

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Direct Vasodilators: Hydralazine and Minoxidil

Hydralazine

• ↑ cGMP → arteriolar smooth muscle relaxation → ↓ afterload

Adverse

• Reflex tachycardia, fluid retention
• Drug-induced lupus (anti-histone antibodies)
• Headache, flushing

Use

• HTN (including pregnancy, often with nitrates in HF regimens—more Step 2)

Minoxidil

• Opens KATP channels → arteriolar vasodilation

Adverse

• Reflex tachycardia, fluid retention
• Hypertrichosis
• Can cause/worsen pericardial effusion (less commonly tested)

Step association

• “Hair growth” clue → minoxidil

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High-Yield “Compelling Indications” Table

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Hypertensive Urgency vs Emergency (Step 1 framing)

Hypertensive emergency

Severe BP elevation with acute end-organ damage, e.g.:

• Encephalopathy, stroke
• Acute coronary syndrome
• Pulmonary edema
• Acute kidney injury
• Aortic dissection
• Papilledema

IV options you’ll see:

• Nicardipine / clevidipine (IV DHP CCBs)
• Labetalol
• Nitroprusside (older classic; still tested)
• Esmolol (especially dissection/ICU contexts)
• Hydralazine (pregnancy sometimes)

Nitroprusside toxicity (classic):

• Metabolizes to cyanide/thiocyanate
• Risk higher in renal failure (thiocyanate accumulation)

Hypertensive urgency

Severely elevated BP without end-organ damage → oral meds, gradual reduction.

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Step 1 “Gotchas” and Micro-Details That Earn Points

• ACEi/ARBs dilate efferent arteriole → ↓ GFR (mild rise in Cr expected); dangerous in bilateral RAS.
• Thiazides increase Ca2+ reabsorption; loops waste Ca2+.
• DHP CCBs: edema + reflex tachy; non-DHP: bradycardia/AV block + constipation (verapamil).
• Clonidine withdrawal → rebound HTN.
• Hydralazine → drug-induced lupus (anti-histone).
• Spironolactone → gynecomastia; eplerenone avoids it.
• β-blockers decrease renin; good post-MI; avoid in severe asthma (nonselective).

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Putting It Together: How to Approach a Pharm Stem Fast

1. Spot the patient type: pregnancy? CKD/diabetes? post-MI? BPH?
2. Identify the side effect clue: cough (ACEi), edema (DHP), lupus (hydralazine), gout (thiazide), gynecomastia (spironolactone), rebound HTN (clonidine).
3. Check contraindications: pregnancy (no ACEi/ARB/aliskiren), asthma (avoid nonselective β-blockers), HFrEF (avoid verapamil/diltiazem generally).

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Rapid Review Cheat Sheet (One-Liners)

• Thiazides: first-line; hyperCa, hypoK, gout, hyperglycemia.
• ACEi: cough/angioedema, hyperK; avoid pregnancy, bilateral RAS.
• ARB: like ACEi minus cough.
• DHP CCB: vasodilation → edema/flushing/headache.
• Verapamil/diltiazem: bradycardia/AV block; constipation (verapamil).
• β-blockers: post-MI, angina; ↓ renin; bronchospasm (nonselective).
• α1 blockers: BPH; orthostasis/first-dose syncope.
• Clonidine: rebound HTN if stopped.
• Methyldopa: pregnancy; Coombs+ hemolysis.
• Hydralazine: drug-induced lupus + reflex tachy.
• Minoxidil: hypertrichosis + fluid retention.
• Nitroprusside: cyanide/thiocyanate toxicity.