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🩺 Antihypertensive Drugs — Detailed Exam-Oriented Notes

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📌 OVERVIEW

1. Diuretics
2. ACE Inhibitors (ACEIs)
3. Angiotensin Receptor Blockers (ARBs)
4. Calcium Channel Blockers (CCBs)
5. Beta-Blockers (BBs)

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1️⃣ DIURETICS

A. Thiazide Diuretics

• Hyponatremia
• Hypokalemia (↑ K⁺ loss in collecting duct)
• Hyperglycemia
• Hyperuricemia (gout) → contraindicated in gout
• Hyperlipidemia (↑ LDL, TG)
• Hypercalcemia (↑ Ca²⁺ reabsorption)
• Hypomagnesemia
• Sexual dysfunction (↑ ED)

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B. Loop Diuretics

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C. Potassium-Sparing Diuretics

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2️⃣ ACE INHIBITORS (ACEIs)

Mechanism of Action

• ↓ Angiotensin II → vasodilation (↓ TPR), ↓ aldosterone → natriuresis, ↓ ADH → diuresis
• ↓ Bradykinin breakdown (ACE = kininase II) → ↑ bradykinin → vasodilation + dry cough + angioedema
• ↓ Cardiac and vascular remodeling (anti-fibrotic)

Compelling Indications (Choose ACEIs here):

• Diabetic nephropathy — reduce proteinuria independently of BP
• Heart failure with reduced EF (HFrEF)
• Post-MI (cardioprotection)
• CKD with proteinuria
• Left ventricular dysfunction

Pharmacokinetics

• Most are prodrugs (except Captopril, Lisinopril) → activated by hepatic esterases
• Captopril: short-acting, thrice daily; others once daily
• Excreted renally → dose-reduce in CKD

Side Effects (mnemonic: "CAPTOPRIL")

• Cough (most common, dry, non-productive — due to ↑ bradykinin; ~10–15%)
• Angioedema (rare but life-threatening; more common in Black patients)
• Potassium increase (hyperkalemia)
• Teratogenic — absolutely contraindicated in pregnancy (fetal renal agenesis, oligohydramnios, renal tubular dysgenesis in 2nd/3rd trimester — "ACE fetopathy")
• Orthostatic hypotension (first-dose effect, esp. with diuretics)
• Proteinuria initially may ↑ before ↓
• Rash and taste disturbance (esp. Captopril — contains sulfhydryl group)
• Increase in serum creatinine (acceptable up to 30% rise; stop if >30%)
• Low BP (hypotension)

Contraindications:

• Pregnancy (Category D/X — absolute contraindication)
• Bilateral renal artery stenosis / unilateral with single kidney (→ acute renal failure)
• Hyperkalemia
• Prior angioedema with ACEI

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3️⃣ ANGIOTENSIN RECEPTOR BLOCKERS (ARBs)

Mechanism

Key Differences: ARBs vs ACEIs

Indications: Same as ACEIs — prefer ARBs when patient cannot tolerate ACEI cough

• Diabetic nephropathy (Losartan/Irbesartan — landmark RENAAL/IDNT trials)
• Heart failure (Valsartan — Val-HeFT; Candesartan — CHARM)
• Post-MI (Valsartan)
• Hypertension + CKD

Side Effects: Same as ACEIs except NO cough

• Hyperkalemia
• Teratogenic (same contraindication in pregnancy)
• Hypotension, ↑ creatinine
• Dizziness

Special: Losartan

• Also blocks uric acid reabsorption → uricosuric → useful in hypertensive patients with gout
• Metabolized by CYP2C9 to active metabolite E-3174

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4️⃣ CALCIUM CHANNEL BLOCKERS (CCBs)

Classification:

MOA

• DHPs → vascular smooth muscle → vasodilation → ↓ TPR → ↓ BP; also coronary vasodilation
• Verapamil/Diltiazem → cardiac (SA node, AV node) → ↓ HR, ↓ conduction; also some vasodilation

Clinical Uses:

Side Effects:

Contraindications:

• Verapamil/Diltiazem: Avoid in HFrEF (↓ contractility worsens failure), WPW + AF (block AV node → accessory pathway conduction → VF), 2°/3° AV block
• Short-acting nifedipine: Avoid in acute MI (reflex tachycardia → ↑ O₂ demand)

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5️⃣ BETA-BLOCKERS (BBs)

• Non-selective: Propranolol, Carvedilol (α+β), Labetalol (α+β), Nadolol, Timolol
• Cardioselective (β₁): Atenolol, Metoprolol, Bisoprolol, Esmolol, Acebutolol
• Intrinsic sympathomimetic activity (ISA): Acebutolol, Pindolol (less bradycardia at rest)

MOA

• ↓ Renin release from juxtaglomerular cells (↓ RAS activation)
• Central ↓ sympathetic outflow (propranolol)
• ↓ Peripheral norepinephrine release (presynaptic β₂ block)

Compelling Indications for Beta-Blockers in HTN:

• Post-MI (reduce mortality — especially propranolol, metoprolol, carvedilol)
• Heart failure (carvedilol, bisoprolol, metoprolol succinate — "CBS" for HFrEF)
• Angina pectoris
• Atrial fibrillation (rate control)
• Hypertension with essential tremor
• Hypertension with hyperthyroidism (propranolol — blocks peripheral T4→T3 conversion)
• Pheochromocytoma: ONLY after alpha-blockade is established first (avoid unopposed α → hypertensive crisis)
• Migraine prophylaxis (propranolol)
• Hypertensive emergency during surgery (esmolol, labetalol)
• Pregnancy-related HTN (labetalol — safe in pregnancy)

Side Effects (mnemonic: "BRAD HIPS"):

• Bradycardia
• Raynaud's exacerbation (peripheral vasoconstriction)
• AV block
• Depression, fatigue, sexual dysfunction
• Hyperglycemia (mask signs of hypoglycemia in T1DM — blunt tachycardia)
• Impotence
• Pulmonary bronchospasm (non-selective BBs — avoid in asthma/COPD)
• Suddenly stopping → rebound hypertension, angina, MI (taper gradually!)

Contraindications:

• Asthma / reactive airways (non-selective BBs)
• 2°/3° AV block
• Decompensated heart failure (relative)
• Cocaine-induced HTN (unopposed α → worse vasospasm) — use labetalol or phentolamine
• Pheochromocytoma (without prior α-blockade)

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6️⃣ ALPHA-BLOCKERS

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7️⃣ CENTRAL SYMPATHOLYTICS

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8️⃣ DIRECT VASODILATORS

Hydralazine

Minoxidil

Sodium Nitroprusside (SNP)

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9️⃣ DIRECT RENIN INHIBITOR

• MOA: Binds renin directly → blocks conversion of angiotensinogen → Angiotensin I
• Use: Hypertension (limited use due to side effects and drug interactions)
• Side effects: Diarrhea, hyperkalemia, angioedema, hypotension
• Contraindicated: In combination with ACEIs/ARBs in patients with diabetes or CKD (↑ adverse events — ALTITUDE trial)
• Contraindicated: Pregnancy

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🔟 HYPERTENSIVE EMERGENCIES — IV Drugs

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1️⃣1️⃣ SPECIAL CLINICAL SITUATIONS — Drug of Choice

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1️⃣2️⃣ HIGH-YIELD EXAM FACTS (Quick Recall)

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1️⃣3️⃣ RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM (RAAS) — Summary Diagram

Angiotensinogen (liver)
         ↓  [Renin — released by JG cells: stimulated by ↓ BP, ↓ Na⁺, SNS]
         ↓  ← BLOCKED BY: Aliskiren (direct renin inhibitor)
    Angiotensin I
         ↓  [ACE — in lung endothelium]
         ↓  ← BLOCKED BY: ACE Inhibitors
    Angiotensin II
         ↓
    AT₁ Receptor ← BLOCKED BY: ARBs
         ↓
    • Vasoconstriction (↑ BP)
    • Aldosterone release (Na⁺ retention, K⁺ loss)
    • ADH release
    • Sympathetic activation
    • Cardiac/vascular remodeling

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1️⃣4️⃣ STEPWISE APPROACH — JNC 8 / ACC/AHA Guidelines

1. Non-black patients: Start with ACEI or ARB or CCB or Thiazide (all equally preferred)
2. Black patients: Start with CCB or Thiazide (ACEIs/ARBs less effective as monotherapy)
3. CKD with proteinuria (any race): ACEI or ARB preferred
4. If target not achieved: Combine agents — most powerful combo is ACEI/ARB + CCB + Thiazide
5. If still uncontrolled (≥3 drugs at max dose): Add spironolactone (4th agent) → "resistant HTN"
6. Never combine ACEI + ARB (↑ hyperkalemia/renal failure — ONTARGET trial)

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