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Pharmacology: Heart Failure & Angina — Exam-Oriented Notes

Source: Katzung's Basic and Clinical Pharmacology, 16th Edition

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PART 1: DRUGS USED IN HEART FAILURE

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Overview

• 5-year mortality ~50% — highly lethal
• Most common cause: coronary artery disease + hypertension
• Two major types:
  • HFrEF (Systolic HF): ↓ contractility, ↓ EF (<40%)
  • HFpEF (Diastolic HF): stiff ventricle, impaired relaxation, EF preserved (≥50%)

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Pathophysiology (Key Exam Points)

• Primary defect in HFrEF = excitation-contraction coupling failure
• Compensatory mechanisms activated: baroreceptor reflex, SNS, RAAS, aldosterone, ADH
• These compensatory mechanisms worsen the heart over time
• Apoptosis of cardiac cells contributes to progression

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Drug Classes for HF — Overview Table

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1. Diuretics

• Furosemide (loop diuretic) — first-line for fluid overload; acts on thick ascending loop of Henle
• Thiazides — for mild congestion; synergistic with loop diuretics in refractory cases
• Aldosterone antagonists (spironolactone, eplerenone) — K⁺-sparing; potent neurohormonal blockade (see below)

Exam tip: Diuretics relieve symptoms but do NOT reduce mortality alone (except aldosterone antagonists)

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2. ACE Inhibitors (ACEi)

• ↓ Mortality in HFrEF (landmark: CONSENSUS, SOLVD trials)
• ↓ Hospitalizations
• Reduce ventricular hypertrophy (reverse remodeling)

Exam tip: Cough → switch to ARB. Angioedema → absolute contraindication

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3. Angiotensin Receptor Blockers (ARBs)

• Used when ACEi not tolerated (cough, angioedema)
• Do NOT combine ACEi + ARB (↑ risk of renal failure, hyperkalemia)

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4. ARNI — Sacubitril/Valsartan (Entresto)

• Neprilysin inhibition → ↑ natriuretic peptides (ANP, BNP) → vasodilation, ↓ fluid retention
• Valsartan → AT₁ blockade

Exam tip: Sacubitril/valsartan is now preferred over ACEi in chronic HFrEF in patients who tolerate it

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5. β-Blockers

• ↓ Mortality significantly in HFrEF (trials: COPERNICUS, MERIT-HF)
• Reverse ventricular remodeling over months

• Carvedilol = non-selective β + α₁ blocker (also vasodilates)

Exam tip: β-blockers are used in stable HFrEF — not during acute decompensation

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6. Aldosterone Antagonists (MRAs)

• Spironolactone → gynecomastia (anti-androgen effect)
• Eplerenone → selective (no gynecomastia)
• Both → hyperkalemia (monitor K⁺, especially with ACEi)

Exam tip: "K⁺-sparing + mortality benefit" → aldosterone antagonist

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7. SGLT2 Inhibitors

• EMPEROR-Reduced (empagliflozin)
• DAPA-HF (dapagliflozin)
• Both showed ↓ CV death + HF hospitalization in HFrEF regardless of diabetes status
• Also benefit in HFpEF (EMPEROR-Preserved)

Exam tip: Only class with proven benefit in both HFrEF and HFpEF; newest pillar of HF therapy

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8. Cardiac Glycosides — Digoxin

1. Positive inotrope: Inhibits Na⁺/K⁺-ATPase → ↑ intracellular Na⁺ → Na⁺/Ca²⁺ exchanger reverses → ↑ intracellular Ca²⁺ → ↑ contractility
2. Negative chronotrope: Vagomimetic effect → ↓ SA node rate, ↓ AV conduction (used in AF + HF)

• Narrow therapeutic index: therapeutic level 0.5–0.9 ng/mL
• Renal excretion — dose adjust in renal failure
• Long half-life ~36 hours

• Cardiac: AV block, ventricular arrhythmias (↑ with hypokalemia, hypomagnesemia)
• GI: Nausea, vomiting, anorexia (early signs)
• Visual: Yellow-green halos (xanthopsia)
• Precipitated by: Hypokalemia (most important!), hypomagnesemia, hypercalcemia, renal failure, amiodarone, quinidine, verapamil (all ↑ digoxin levels)

Exam tip: Digoxin does NOT reduce mortality but reduces hospitalizations. Hypokalemia is the #1 precipitant of toxicity.

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9. Vasodilators

• Used when ACEi/ARB/ARNI not tolerated (e.g., renal failure, hyperkalemia)
• BiDil trial: showed mortality benefit specifically in Black patients with HFrEF
• Hydralazine = arteriolar dilator (↓ afterload); ISDN = venodilator (↓ preload)

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10. Inotropes for Acute Decompensated HF

Exam tip: Dobutamine/milrinone = "positive inotropes + vasodilators" — short-term use only (↑ arrhythmia risk, ↑ mortality with chronic use)

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The 4 Pillars of Chronic HFrEF (Current Guidelines — GDMT)

All 4 classes independently reduce mortality — all should be used together unless contraindicated

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PART 2: DRUGS USED IN ANGINA

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Types of Angina

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Determinants of Myocardial O₂ Supply vs. Demand

• Heart rate (most important)
• Contractility (inotropic state)
• Wall stress = Preload (LVEDV) + Afterload (aortic pressure)

• Coronary blood flow (depends on diastolic pressure + duration of diastole)
• Heart extracts ~75% of available O₂ at rest → must ↑ flow to meet demand

Exam tip: Drugs reduce angina by either ↓ O₂ demand (β-blockers) or ↑ O₂ supply + ↓ demand (nitrates, Ca²⁺-blockers)

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Drug Classes for Angina

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1. Nitrates (Organic Nitrates)

• Converted to nitric oxide (NO) → activates guanylyl cyclase → ↑ cGMP → dephosphorylation of myosin light chains → smooth muscle relaxation (vasodilation)
• Predominant effect: Venodilation (↓ preload) at low doses
• Arteriolar dilation (↓ afterload) at high doses

• ↓ Preload → ↓ LVEDV → ↓ wall stress → ↓ O₂ demand
• ↓ Afterload → ↓ LV work
• ↑ Coronary blood flow (redistributes to ischemic subendocardium)

• Direct coronary vasodilation → relieves vasospasm

• Prevention: Nitrate-free interval of 8–12 hours/day (remove patch at night)

• Headache (most common — meningeal vasodilation)
• Reflex tachycardia
• Hypotension, flushing
• Methemoglobinemia (high doses)

Exam tip: SL NTG = drug of choice for acute angina attack. Tolerance = major limitation of long-acting nitrates.

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2. β-Blockers

• ↓ Heart rate → prolongs diastole → ↑ coronary filling time → ↑ myocardial perfusion

• ↓ Frequency of stable angina attacks
• Reduce exercise-induced angina
• No benefit in vasospastic angina (may worsen — unopposed α causes spasm)

• Stable angina
• Post-MI angina (also cardioprotective)
• Angina + hypertension
• Angina + HF (special dosing)

Exam tip: β-blockers = mainstay of stable angina prevention; contraindicated in vasospastic angina

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3. Calcium Channel Blockers (CCBs)

• In vascular smooth muscle → vasodilation (↓ afterload, coronary vasodilation)
• In cardiac myocytes → ↓ contractility
• In SA/AV node (non-DHPs) → ↓ HR, ↓ AV conduction

• ↓ O₂ demand (↓ afterload, ↓ HR with non-DHPs)
• ↑ O₂ supply (coronary vasodilation)
• Drug of choice for vasospastic (Prinzmetal) angina — all CCBs effective

• DHP: Peripheral edema, flushing, reflex tachycardia (nifedipine short-acting — avoid!)
• Non-DHP: Bradycardia, AV block, constipation, negative inotropy

• Verapamil/diltiazem: AV block, HF with ↓ EF, sick sinus syndrome
• Do NOT combine verapamil + β-blocker → complete heart block risk

Exam tip: CCBs = drug of choice for Prinzmetal/vasospastic angina. Verapamil + β-blocker = dangerous combination.

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4. Ranolazine

• Does NOT significantly affect HR or BP — purely anti-ischemic

Exam tip: Ranolazine = unique MOA (late Na⁺ current), no hemodynamic effect, QT prolongation is key SE

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5. Ivabradine

Exam tip: Ivabradine = only drug that reduces HR without affecting contractility — pure heart rate reducer

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Drug Choices by Angina Type (Summary)

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Comparison: Nitrates vs β-Blockers vs CCBs

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High-Yield Exam Points — Quick Fire

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