Pharmacology and Drug Treatment of Heart Failure & Angina

PART I: HEART FAILURE

Pathophysiology Overview

• Sympathetic activation → ↑ heart rate, ↑ contractility (short-term compensation), but chronic activation causes cardiac remodeling, β-receptor downregulation, and arrhythmias
• RAAS activation → angiotensin II → vasoconstriction, aldosterone secretion → sodium/water retention, fibrosis
• Natriuretic peptides (BNP, ANP) → beneficial counter-regulatory vasodilation and natriuresis

Drug Treatment of Chronic Systolic HF (HFrEF)

Treatment Principle I — Neurohumoral Modulation

1. ACE Inhibitors (ACEIs)

• Mechanism: Block conversion of angiotensin I → angiotensin II, reducing vasoconstriction, aldosterone secretion, and cardiac remodeling; ↓ preload and afterload
• Key drugs: Enalapril, lisinopril, ramipril, captopril
• Evidence: CONSENSUS trial (enalapril, ~40% mortality reduction in NYHA IV); SOLVD Treatment trial (~16% mortality reduction, NYHA II–III, EF <35%)
• Side effects: Cough (bradykinin-mediated), hyperkalemia, renal impairment, angioedema (rare)

2. Angiotensin Receptor Blockers (ARBs)

• Mechanism: Block AT₁ receptors directly; equivalent hemodynamic effects to ACEIs; no bradykinin-related cough
• Key drugs: Valsartan, losartan, candesartan
• Use: As alternative when ACEIs are not tolerated; not recommended to combine with ACEIs

3. Angiotensin Receptor–Neprilysin Inhibitor (ARNI)

• Drug: Sacubitril/valsartan (LCZ696)
• Mechanism: Sacubitril inhibits neprilysin (the enzyme that degrades natriuretic peptides), augmenting BNP and ANP; combined with valsartan (ARB)
• Evidence: PARADIGM-HF trial (2014) — sacubitril/valsartan reduced all-cause mortality by ~16% vs. enalapril in 8,442 patients with HFrEF
• Current guideline position: Preferred over ACEIs/ARBs in patients who tolerate it
• Contraindication: Do NOT combine with ACEI; must allow 36-hour washout period

4. β-Adrenergic Receptor Blockers (β-Blockers)

• Mechanism: Block chronic sympathetic activation; reduce heart rate, reverse cardiac remodeling (β₁-receptor upregulation), reduce arrhythmias, and reduce sudden cardiac death
• Approved agents for HF: Carvedilol (non-selective β + α₁ blocker), metoprolol succinate CR/XL (selective β₁), bisoprolol
• Evidence: MERIT-HF (metoprolol CR/XL, ~34% mortality reduction vs. placebo in NYHA II–IV)
• Key caveat: Must be started at low doses and uptitrated slowly; avoid in acute decompensation
• Paradox: Although β-blockers are negative inotropes acutely, their long-term effect on remodeling improves EF

5. Mineralocorticoid Receptor Antagonists (MRAs)

• Drugs: Spironolactone, eplerenone
• Mechanism: Block aldosterone's effects on the kidney (↓ Na retention, ↓ K excretion) and heart (antifibrotic)
• Evidence: RALES trial (spironolactone, ~30% mortality reduction vs. placebo in NYHA III–IV, EF <35%); 2024 meta-analysis (PMID: 39232490) confirmed individual patient-level benefit
• Monitoring: Risk of hyperkalemia; check K⁺ and renal function regularly
• Eplerenone: More selective (fewer gynecomastia side effects); indicated post-MI with HF

Treatment Principle II — Preload Reduction

Diuretics

• Loop diuretics (furosemide, bumetanide, torsemide): Block Na⁺/K⁺/2Cl⁻ cotransporter in loop of Henle → most potent natriuresis; first-line for symptom relief of fluid overload
• Thiazides (metolazone, hydrochlorothiazide): Block distal tubule NaCl cotransporter; used as adjuncts for diuretic resistance
• Use: Essential for congestion; no proven mortality benefit, but reduce hospitalizations
• IV furosemide: Preferred in acute decompensation; also has venodilatory effect at high doses

Treatment Principle III — Afterload Reduction (Vasodilators)

• Hydralazine + Isosorbide Dinitrate (H-ISDN):
  • The V-HeFT I trial (Cohn et al., 1986) showed ~34% mortality reduction vs. placebo
  • Particularly recommended in Black patients with HFrEF who cannot tolerate ACEIs/ARBs (BiDil trial)
  • Mechanism: Hydralazine = arteriodilator; ISDN = venodilator (preload ↓) + coronary vasodilator

Treatment Principle IV — Increasing Cardiac Contractility

Digoxin (Cardiac Glycoside)

• Mechanism: Inhibits Na⁺/K⁺-ATPase → ↑ intracellular Na⁺ → ↑ intracellular Ca²⁺ via Na⁺/Ca²⁺ exchanger → positive inotropy; also vagomimetic → ↓ AV conduction (rate control in AF)
• Evidence: DIG trial — no mortality benefit; reduces HF hospitalizations by ~27%
• Narrow therapeutic index: Monitor serum levels (0.5–0.9 ng/mL target in HF); toxicity → nausea, visual disturbances, arrhythmias
• Current role: HF with AF for rate control; symptomatic HFrEF refractory to standard therapy

Inotropes for Acute Decompensation

• Dobutamine: Selective β₁ agonist → ↑ contractility and ↑ heart rate; first-line inotrope in cardiogenic shock
• Dopamine: Dose-dependent effects — D₂ agonism at low doses (splanchnic/renal vasodilation), β₁ at intermediate (2–5 μg/kg/min), α₁ at high doses (vasoconstriction); second/third-line due to complex profile
• Norepinephrine: β₁ + α₁ agonist; used in persistent hypotension; increases afterload
• Milrinone (PDE3 inhibitor): "Inodilator" — ↑ cAMP → ↑ contractility + vasodilation; useful in patients on β-blockers or with high pulmonary resistance; loading dose 25–75 μg/kg, infusion 0.375–0.75 μg/kg/min
• Levosimendan (calcium sensitizer, not available in US): ↑ myofilament sensitivity to Ca²⁺; approved in Europe/Asia for acute HF decompensation

Treatment Principle V — Heart Rate Reduction

• Ivabradine: Selective I_f (hyperpolarization-activated Na⁺ channel) inhibitor in SA node; reduces heart rate without negative inotropy or other hemodynamic effects
• Approved in the US for HFrEF (EF ≤35%) in sinus rhythm with HR ≥70 bpm, on maximally tolerated β-blocker; also used off-label for angina

Treatment Principle VI — SGLT2 Inhibition

• Drugs: Dapagliflozin, empagliflozin
• Mechanism: Originally antidiabetic agents; reduce glucose and sodium reabsorption in the proximal tubule (osmotic diuresis), reduce cardiac preload and afterload, improve myocardial energetics
• Evidence: DAPA-HF trial (2019) — dapagliflozin reduced mortality by ~17% vs. placebo in NYHA II–IV with EF ≤40%, including non-diabetic patients
• Current status: Now guideline-recommended as a "pillar" of HFrEF therapy alongside ACEIs/ARNIs, β-blockers, and MRAs (the "Fantastic Four")

Drug Treatment of Acutely Decompensated HF

Summary Table: Evidence-Based HFrEF Drug Therapy

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics, Harrison's Principles of Internal Medicine 22E

PART II: ANGINA

Types of Angina and Pathophysiology

• ↓ Demand: Reduce HR, contractility, preload, afterload
• ↑ Supply: Coronary vasodilation, improve collateral flow

Drug Classes for Angina Treatment

1. Organic Nitrates

• Drugs: Nitroglycerin (GTN), isosorbide dinitrate (ISDN), isosorbide mononitrate (ISMN)
• Mechanism: Converted intracellularly to NO → activates guanylyl cyclase → ↑ cGMP → vascular smooth muscle relaxation; venodilation at low doses (↓ preload), arteriodilation at higher doses (↓ afterload); also coronary vasodilation and antithrombotic effects
• Pharmacokinetics: Sublingual GTN — onset 1–3 min, duration 20–30 min; absorbed rapidly through mucous membranes
• Formulations:
  • Sublingual GTN (0.4 mg): Acute angina relief; also prophylactically 5 min before triggering activity
  • Long-acting oral nitrates (ISDN, ISMN): Prevention of chronic angina; require eccentric dosing (nitrate-free interval of 8–12 hours/day) to prevent tolerance
  • Transdermal GTN patches: Convenient, but nitrate-free interval essential
• Hemodynamic effects: ↓ preload → ↓ ventricular wall tension → ↓ O₂ demand; ↓ LV end-diastolic pressure → better subendocardial perfusion
• Side effects: Headache (↑ meningeal venous dilation), reflex tachycardia, hypotension, tolerance with continuous use
• Contraindication: PDE5 inhibitors (sildenafil, tadalafil) — potentially fatal hypotension

2. β-Adrenergic Blockers

• Drugs: Metoprolol, atenolol, bisoprolol, propranolol (non-selective), carvedilol (β + α₁)
• Mechanism: Block cardiac β₁ receptors → ↓ HR, ↓ contractility (↓ O₂ demand); prolong diastole (↑ coronary filling time); attenuate exercise-induced tachycardia
• Effects on Hemodynamics:

• First-line therapy for stable angina and post-MI ischemia; proven to reduce mortality after MI
• Side effects: Fatigue, depression, bradycardia, AV block, bronchoconstriction (avoid in asthma/COPD with non-selective), masking of hypoglycemia, cold extremities
• Contraindications: Severe bradycardia, second/third-degree AV block, decompensated HF (short-term), severe asthma

3. Calcium Channel Blockers (CCBs)

• Mechanism: Block L-type voltage-gated Ca²⁺ channels in vascular smooth muscle and cardiac muscle → vasodilation, ↓ afterload, ↓ contractility
• Two subclasses:

• Amlodipine (5–10 mg OD), nifedipine (slow release), felodipine
• Potent vasodilation → ↓ afterload → ↓ O₂ demand
• Minimal cardiac conduction effects; may cause reflex tachycardia (especially short-acting nifedipine — avoid in angina)
• Side effects: Headache, peripheral edema, flushing

• Verapamil (80–160 mg TID/SR 120–480 mg OD), diltiazem (30–80 mg QID/SR 120–320 mg OD)
• ↓ HR, ↓ AV conduction, ↓ contractility, vasodilation
• Preferred for vasospastic (Prinzmetal's) angina and in patients where β-blockers are contraindicated
• Combination with β-blockers: Avoid verapamil/diltiazem + β-blocker (risk of severe bradycardia/AV block)
• Special indication: CCBs (particularly verapamil, diltiazem, and long-acting DHPs) are first-line for vasospastic angina

4. Combination Therapy

• β-Blocker + long-acting nitrate: Complementary — β-blocker prevents reflex tachycardia from nitrate; nitrate offsets β-blocker-induced preload increase
• β-Blocker + DHP-CCB: Effective combination for refractory angina
• Triple therapy: Nitrate + β-Blocker + CCB for refractory cases

5. Ivabradine (Adjunct for Angina)

• Selective I_f inhibitor → ↓ sinus node firing rate → ↓ heart rate with no effect on contractility or vasomotor tone
• Efficacy comparable to CCBs/β-blockers for reducing anginal episodes
• No bronchospasm, no peripheral vascular effects
• Approved in Europe for stable angina; off-label in US (approved for HF only in US); useful when β-blockers are contraindicated or not tolerated

6. Ranolazine

• Mechanism: Late sodium current (late I_Na) inhibitor → ↓ intracellular Na⁺ overload → ↓ secondary Ca²⁺ overload → ↓ myocardial O₂ demand without affecting HR or BP
• Indications: Chronic stable angina refractory to other agents; second-line or adjunctive
• Unique feature: Minimal hemodynamic effect, making it suitable in patients with low BP or HR
• Side effects: QTc prolongation (mild), constipation, nausea, dizziness

7. Antiplatelet and Statin Therapy (Modification of Disease)

• Aspirin (75–100 mg/day): All patients with stable angina/CAD unless contraindicated — reduces platelet aggregation at sites of atherosclerotic plaque
• P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel): Dual antiplatelet therapy (DAPT) for ACS and after PCI
• Statins: Stabilize plaques, reduce LDL, anti-inflammatory; proven to reduce cardiac events in all forms of CAD; target LDL <70 mg/dL in high-risk angina
• ACE Inhibitors: Reduce adverse cardiac events in high-risk CAD patients (independent of BP lowering)

Drug Treatment by Angina Type

Recent Evidence Alert

• PMID 39232490 (Lancet, 2024): Individual patient-level meta-analysis confirms MRA benefit across HFrEF spectrum — use spironolactone/eplerenone broadly in HFrEF unless hyperkalemia/renal impairment prohibits
• PMID 40159279 (Nature Medicine, 2025): IV iron therapy (ferric carboxymaltose) in HF with iron deficiency reduces hospitalizations — adjunct consideration

Key Takeaway: The "Fantastic Four" of HFrEF

1. ARNI (sacubitril/valsartan) — or ACEI/ARB if ARNI not tolerated
2. β-Blocker (carvedilol, metoprolol succinate, bisoprolol)
3. MRA (spironolactone or eplerenone)
4. SGLT2 inhibitor (dapagliflozin or empagliflozin)

Sources: Goodman & Gilman's The Pharmacological Basis of Therapeutics (9781264258079); Katzung's Basic and Clinical Pharmacology, 16th Ed. (9781260463309); Harrison's Principles of Internal Medicine 22E (9781265977061)You've run out of free credits. Sign up for a free account to continue using Orris.