Explain antianginal drugs

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Antianginal Drugs

Angina pectoris occurs when myocardial oxygen demand exceeds supply. The three main patterns are: stable (effort-induced) angina from fixed atherosclerotic obstruction, unstable angina from plaque rupture/thrombosis, and Prinzmetal/vasospastic angina from coronary artery spasm. All antianginal drugs work by improving the O2 supply-demand balance.

The Four Drug Classes

Treatment algorithm for stable angina - sublingual nitroglycerin for acute relief, then beta-blocker as first-line, add calcium channel blocker or long-acting nitrate if inadequate, then ranolazine

Figure: Treatment algorithm for stable ischemic heart disease - Lippincott Pharmacology

1. Beta-Adrenergic Blockers (First-Line)

Mechanism: Block β1 receptors → decreased heart rate, contractility, and cardiac output → reduced myocardial O2 demand. Effective at rest and during exertion.

Key drugs:

Propranolol (prototype, non-selective β1+β2)
Metoprolol and atenolol (cardioselective β1 - preferred)
Carvedilol, labetalol (also have α-blocking effects)

Clinical use:

First-line for stable effort-induced angina
Reduce risk of death and MI in post-MI patients
Improve mortality in heart failure with reduced ejection fraction (HFrEF)

Contraindications and cautions:

Avoid in vasospastic (Prinzmetal) angina - can worsen coronary spasm
Avoid in severe bradycardia and AV block
Avoid non-selective agents in asthma (bronchospasm via β2 blockade)
Mask hypoglycemia symptoms in diabetics (except diaphoresis)
Agents with intrinsic sympathomimetic activity (ISA) like pindolol should be avoided in angina and post-MI
Never stop abruptly - taper over 2-3 weeks to prevent rebound angina, MI, and hypertension

2. Calcium Channel Blockers (CCBs)

Mechanism: Block L-type calcium channels in vascular smooth muscle and myocardium → arterial vasodilation (reduces afterload) + decreased heart rate and contractility (non-DHPs). Coronary vasodilation is the main benefit in vasospastic angina.

A. Dihydropyridines (DHPs) - Peripheral vasodilators

Amlodipine, nifedipine (ER), felodipine, nicardipine
Minimal cardiac conduction effects; mainly arteriolar vasodilators
Reflex tachycardia can occur (sympathetic activation from BP drop)
Amlodipine is preferred for vasospastic angina
Short-acting nifedipine is avoided in CAD (increased MI risk)

B. Non-Dihydropyridines - Central cardiac effects

Verapamil: Most negative inotropic; slows AV conduction and sinus rate; weak vasodilator. Contraindicated in preexisting AV conduction abnormalities.
Diltiazem: Intermediate profile - slows AV conduction + coronary vasodilator. Useful in variant angina.

Selectivity ranking (peripheral to central): Amlodipine > Diltiazem > Verapamil

Important: Non-DHPs (verapamil, diltiazem) can worsen HFrEF due to their negative inotropic effects - avoid in this population.

3. Organic Nitrates

Mechanism: Intracellularly converted to nitric oxide (NO) → activates guanylate cyclase → increased cGMP → dephosphorylation of myosin light chain → vascular smooth muscle relaxation.

Two main effects:

Venodilation (large veins) → reduces preload (venous return) → reduces myocardial O2 demand
Coronary artery dilation → increases O2 supply (major effect in variant angina)

Mechanism of nitrate action: NO → guanylate cyclase → cGMP → smooth muscle relaxation

Key formulations:

Drug	Route	Onset	Use
Nitroglycerin (NTG)	Sublingual tablet/spray	~1 min	Acute attack relief (all angina types)
NTG transdermal patch	Skin	Delayed	Prophylaxis (12h on, 12h off)
NTG IV	Intravenous	Rapid	Unstable angina/ACS
Isosorbide dinitrate	Oral	15-30 min	Prophylaxis
Isosorbide mononitrate	Oral	~30 min	Prophylaxis (better bioavailability, no first-pass)

Nitroglycerin undergoes extensive hepatic first-pass metabolism, so it is given sublingual or transdermally. Isosorbide mononitrate has better oral bioavailability.

Adverse effects:

Headache (most common - due to cerebral vasodilation)
Postural hypotension, flushing, reflex tachycardia at high doses
Dangerous hypotension with PDE-5 inhibitors (sildenafil, tadalafil) - combination is contraindicated

Tolerance: Develops rapidly due to vessel desensitization. Prevented by a 10-12 hour nitrate-free interval (usually overnight). Exception: in variant angina (which worsens in the morning), the free interval should be in the late afternoon instead.

4. Sodium Channel Blocker - Ranolazine (Newer Agent)

Mechanism: Inhibits the late inward Na+ current (late I-Na) → reduces intracellular Na+ → reduces Ca2+ overload via the Na+/Ca2+ exchanger → decreases diastolic wall tension, contractility, and myocardial O2 demand. Does not affect heart rate or blood pressure significantly.

Use: Add-on therapy for stable angina when other agents fail. Approved in the US.

Adverse effects / cautions:

Prolongs QT interval (but has not been associated with torsades de pointes in most patients)
Inhibits metabolism of digoxin and simvastatin
Less effective in women
Multiple drug interactions

5. Newer and Investigational Antianginals

Drug/Class	Mechanism
Ivabradine	Blocks If (funny current) in sinoatrial node → pure heart rate reduction without affecting contractility
Trimetazidine	pFOX inhibitor - inhibits fatty acid oxidation (LC-3KAT) → shifts metabolism to glucose oxidation, less O2 per ATP. Used in many countries (not USA)
Nicorandil	Potassium channel activator + nitrate-like → dual vasodilation
Perhexiline	Shifts cardiac metabolism (fatty acid → glucose); limited by CYP2D6-dependent toxicity
Fasudil	Rho-kinase inhibitor
L-arginine	Nitric oxide donor

Drug Selection by Angina Type and Comorbidities

Antianginal drug therapy considerations by medical condition - color coded: green = preferred, yellow = neutral, orange = caution, red = avoid

Figure: Antianginal Drug Therapy Considerations by Comorbidity - Lippincott Pharmacology

Condition	Preferred	Avoid
Stable angina	Beta-blocker (first-line) + CCB or long-acting nitrate	-
Vasospastic (Prinzmetal)	CCBs + nitrates	Beta-blockers (can worsen spasm)
Unstable angina/ACS	Antiplatelet + heparin + percutaneous intervention	-
Post-MI	Beta-blockers (reduce mortality)	-
HFrEF	Beta-blockers, dihydropyridine CCBs	Non-DHP CCBs (worsen HF)
Asthma	Selective CCBs; nitrates	Non-selective beta-blockers
Hypertension	Beta-blockers, CCBs (both lower BP)	-
Bradycardia/AV block	Nitrates, DHPs	Beta-blockers, verapamil, diltiazem

Key Points Summary

The primary mechanism of most antianginal drugs is reducing myocardial O2 demand (beta-blockers: reduce HR, contractility; nitrates: reduce preload; CCBs: reduce afterload/HR/contractility)
Increased O2 supply via coronary dilation is the main effect of nitrates and CCBs in vasospastic angina
Sublingual nitroglycerin is the drug of choice for acute anginal attacks for all patients
Beta-blockers are first-line for chronic stable angina and the only class with proven mortality benefit (in post-MI and HFrEF)
Nitrate tolerance is prevented by a 10-12 hour drug-free interval daily
PDE-5 inhibitors (sildenafil) + nitrates = absolutely contraindicated (severe hypotension)
Beta-blockers must be tapered when discontinuing, never stopped abruptly

Sources: Lippincott Illustrated Reviews Pharmacology, 7th Ed. | Goodman & Gilman's Pharmacological Basis of Therapeutics, 14th Ed. | Katzung's Basic and Clinical Pharmacology, 16th Ed.

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