10.1 Antihypertensives, Heart Failure & Antiarrhythmics

10.1 Antihypertensives, Heart Failure & Antiarrhythmics

Quick Answer: Antihypertensive and HF drugs act on volume (diuretics), RAAS tone (ACEI/ARB/ARNI, aldosterone antagonists), cardiac output/heart rate (beta-blockers, non-DHP CCBs), and vascular resistance (DHP CCBs, hydralazine, nitrates, minoxidil). Antiarrhythmics are organized by Vaughan Williams ion-channel effects; exam stems pair a clinical scenario with a mechanism or toxicity (for example, amiodarone multi-organ effects, digoxin toxicity with hypokalemia, class Ic use after structural heart disease, adenosine AV-node block).

Cardiovascular drugs on the CBSE reward mechanism-first thinking. A stem may show hyperkalemia after starting an ACE inhibitor, cough after lisinopril, bradycardia after verapamil plus a beta-blocker, or QT prolongation after a class III agent. Link each drug class to its molecular target, physiologic effect (preload, afterload, inotropy, chronotropy, dromotropy), and predictable adverse effects.

Diuretics: Classes, Transporters, and Sites

Diuretics reduce extracellular volume and, for some classes, lower peripheral resistance with chronic use. Know the nephron segment and the transporter blocked.

Loop diuretics inhibit NKCC2, dissipating the medullary osmotic gradient and impairing free-water reabsorption capacity. They remain effective at lower GFRs than thiazides and are first-line for volume overload in decompensated HF. Thiazides are preferred in many primary hypertension regimens when GFR is adequate; they also reduce urinary calcium excretion (useful conceptually in calcium stone formers). Carbonic anhydrase inhibitors (acetazolamide) act mainly in the proximal tubule and are weak diuretics for HTN but high-yield for other uses (altitude, metabolic alkalosis, glaucoma).

Exam pearl: combining a loop or thiazide with an ACEI/ARB and an MRA multiplies hyperkalemia risk and requires electrolyte monitoring—classic polypharmacy traps.

ACE Inhibitors, ARBs, and ARNI

Angiotensin-converting enzyme inhibitors (ACEIs) block conversion of angiotensin I → angiotensin II and reduce degradation of bradykinin. Less angiotensin II means less AT1-mediated vasoconstriction, less aldosterone release, and lower afterload/preload over time. Bradykinin accumulation contributes to dry cough and risk of angioedema. ACEIs also preferentially dilate the efferent arteriole, lowering intraglomerular pressure—renoprotective in diabetic nephropathy but can raise creatinine and cause hyperkalemia, especially in bilateral renal artery stenosis or volume depletion.

ARBs (for example, losartan, valsartan) block AT1 receptors directly. They share many hemodynamic and potassium effects with ACEIs but do not raise bradykinin, so cough/angioedema rates are lower (angioedema is still possible but less frequent). Do not combine ACEI + ARB chronically for routine HTN/HF because dual blockade increases adverse renal and potassium events without proportional outcome gains.

ARNI (sacubitril/valsartan) pairs an ARB with neprilysin inhibition. Neprilysin degrades natriuretic peptides (ANP/BNP) and other vasoactive peptides; inhibiting it increases natriuretic peptide signaling → vasodilation, natriuresis, and favorable remodeling signals. Used in HFrEF with mortality benefit when replacing ACEI/ARB in appropriate patients. Washout from ACEI is required before ARNI to reduce angioedema risk (both pathways can increase bradykinin-related effects).

Calcium Channel Blockers: Dihydropyridine vs Non-Dihydropyridine

All clinically used CCBs block L-type voltage-gated calcium channels, but tissue selectivity differs.

Dihydropyridines (DHPs) — amlodipine, nifedipine, felodipine — preferentially relax vascular smooth muscle, lowering systemic vascular resistance (afterload). Reflex tachycardia can occur with short-acting agents. Common effects: peripheral edema (arteriolar dilation → capillary pressure imbalance), flushing, headache. DHPs are useful antihypertensives and antianginals (↓ afterload, coronary vasodilation) but do not meaningfully slow AV nodal conduction at usual doses.

Non-dihydropyridines — verapamil (more cardiac) and diltiazem (intermediate) — reduce heart rate, AV nodal conduction (negative dromotropy), and contractility (negative inotropy) in addition to vasodilation. They treat rate control in atrial fibrillation/flutter and some SVTs, and can help angina by lowering myocardial O2 demand. Avoid in decompensated systolic HF and use caution with beta-blockers (additive bradycardia/AV block). Verapamil is more associated with constipation and stronger negative inotropy than diltiazem.

Beta-Blockers: Selective vs Nonselective

Beta-blockers antagonize catecholamine effects at β-adrenergic receptors.

• β1-selective (cardioselective) agents (metoprolol, atenolol, bisoprolol, nebivolol at usual doses) reduce heart rate, contractility, and renin release with relatively less β2 blockade.
• Nonselective agents (propranolol, nadolol, carvedilol also has α1 blockade) block β1 and β2; β2 blockade can worsen bronchospasm and mask hypoglycemia recovery signals.
• Combined α1/β blockers (carvedilol, labetalol) add vasodilation via α1 antagonism—useful in HF (carvedilol) or hypertensive urgency/pregnancy contexts (labetalol conceptually).
• ISA (intrinsic sympathomimetic activity) agents are less emphasized clinically for outcome-driven HF care.

Evidence-based HF beta-blockers classically include carvedilol, metoprolol succinate, and bisoprolol. Mechanisms of benefit: reduced myocardial O2 demand, improved diastolic filling time, blunted arrhythmogenic catecholamine effects, and reverse remodeling over time—not acute inotropy.

Adverse effects high-yield for exams: bradycardia, AV block, fatigue, erectile dysfunction, dyslipidemia/glucose effects with some agents, exacerbation of decompensated HF if started aggressively, and nonselective agents in reactive airway disease.

Alpha-Blockers and Direct Vasodilators

α1-antagonists (prazosin, doxazosin, terazosin) reduce arteriolar and venous tone → lower BP; useful also for BPH symptoms. First-dose orthostatic hypotension is classic. They are not first-line monotherapy for primary HTN in modern outcome-driven algorithms but remain mechanistically testable.

Hydralazine is a direct arterial vasodilator (reduces afterload). Compensatory sympathetic activation and fluid retention often require co-therapy with a beta-blocker and diuretic. Associated with drug-induced lupus-like syndrome (hydralazine, procainamide classic pair). Nitrates (nitroglycerin, isosorbide dinitrate) primarily increase NO → cGMP → venous capacitance (↓ preload) with arterial effects at higher doses; combine with hydralazine in selected HF regimens (for example, self-identified Black patients with HFrEF historically studied). Minoxidil opens K+ channels in vascular smooth muscle → hyperpolarization and arterial dilation; potent afterload reduction with marked reflex tachycardia and fluid retention; hypertrichosis is a signature side effect.

Heart Failure: Neurohormonal Targets

Chronic HFrEF is driven by maladaptive activation of the sympathetic nervous system and RAAS, plus other pathways. Disease-modifying pillars target these axes:

1. ACEI / ARB / ARNI — reduce afterload and aldosterone-driven remodeling.
2. Beta-blockers (evidence-based) — blunt catecholamine toxicity and lower heart rate.
3. Mineralocorticoid receptor antagonists — block residual aldosterone effects (fibrosis, Na+ retention, K+ loss).
4. SGLT2 inhibitors (for example, dapagliflozin, empagliflozin) — originally antihyperglycemics; reduce HF hospitalization/mortality via natriuresis/osmotic diuresis, hemodynamic and metabolic effects, and cardiorenal protection even in many patients without diabetes. For basic-science exams, remember SGLT2 blockade in the proximal tubule increases urinary glucose and Na+ excretion and has become a high-yield HF concept beyond pure glucose control.

Acute decompensated HF still uses loop diuretics for congestion; inotropes and vasodilators appear in selected shock/afterload scenarios but are not chronic mortality pillars. Digoxin may help symptoms/rate control in selected patients without reducing overall mortality the way the neurohormonal quartet does.

Antiarrhythmics: Vaughan Williams I–IV

Organize by dominant ion-channel / autonomic effect:

Amiodarone is predominantly class III but multi-channel (Na+, Ca2+, β effects). High-yield toxicities: pulmonary fibrosis, thyroid dysfunction (hyper- or hypo- because iodine-rich structure and peripheral conversion effects), hepatotoxicity, corneal deposits, blue-gray skin, photosensitivity, bradycardia/AV block. Long half-life and extensive tissue distribution.

Digoxin inhibits Na+/K+-ATPase → ↑ intracellular Na+ → reduced Na+/Ca2+ exchange → ↑ intracellular Ca2+ (positive inotropy). Increases vagal tone → slows AV nodal conduction (useful in AF rate control). Toxicity: GI symptoms, visual changes (xanthopsia), arrhythmias including bidirectional VT; hypokalemia potentiates toxicity because digoxin and K+ compete at the pump site.

Adenosine activates A1 receptors on AV nodal cells → opens K+ channels and inhibits Ca2+ currents → transient AV block. Diagnostic/therapeutic for SVT involving the AV node. Extremely short half-life; brief asystole, flushing, chest discomfort expected. Effects antagonized by methylxanthines (theophylline, caffeine); potentiated by dipyridamole.

Class Ic caveat: strong use-dependent Na+ channel blockade can promote reentry and ventricular proarrhythmia in damaged myocardium—classic reason to avoid flecainide/propafenone when coronary disease or reduced EF is present, while they remain options in carefully selected structurally normal hearts (for example, some AF "pill-in-pocket" contexts).

Integration: Mechanism Maps for Exam Stems

When a stem describes a patient with HFrEF, map drugs to remodeling and load reduction rather than "BP pills." When a stem shows hyperkalemia, think ACEI/ARB/ARNI/MRA/ENaC blockers and renal impairment. When a stem shows cough after HTN therapy, prefer ACEI-induced bradykinin over ARB. When bradycardia and constipation appear with rate control, consider verapamil. When multi-organ toxicity appears after long-term arrhythmia therapy, amiodarone leads the differential. When a wide-complex tachycardia treatment discussion involves post-MI patients, class Ic agents are the classic "avoid" answer.

Mastery is the ability to move from clinical vignette → molecular target → expected ECG/lab change → toxicity pattern without memorizing isolated brand lists.