7.4 Antianginals
Antianginal drugs relieve chest pain (angina) caused by myocardial ischemia. They work by decreasing myocardial oxygen demand or increasing oxygen supply, restoring the supply-demand balance.
Angina Pathophysiology
Oxygen Supply-Demand Mismatch
O₂ Demand: HR, contractility, wall tension (preload/afterload)
O₂ Supply: Coronary blood flow (diastolic time, coronary perfusion pressure, vessel diameter)
Angina occurs when demand exceeds supply (ischemia)
Types of Angina
Stable angina: Predictable, exertional, relieved by rest/nitroglycerin
Unstable angina: At rest or increasing frequency/severity (ACS)
Variant (Prinzmetal's): Coronary vasospasm, often at rest/night
Nitrates
Mechanism of Action
Converted to nitric oxide (NO) → activates guanylate cyclase → ↑ cGMP → smooth muscle relaxation
Venodilation >> arteriodilation (dose-dependent)
↓ Preload (venous pooling) → ↓ wall tension → ↓ O₂ demand (primary effect)
↑ Coronary flow (dilate epicardial vessels, collaterals, relieve spasm)
Nitroglycerin (NTG)
Sublingual: Rapid onset (1-3 min), acute angina relief
Patient instruction: 1 tablet q5min × 3; if no relief → call 911 (possible MI)
Transdermal patch: Long-acting prophylaxis (12h on, 12h off to prevent tolerance)
IV: Unstable angina, acute MI, hypertensive emergencies
Isosorbide Dinitrate & Mononitrate
Longer-acting oral nitrates for chronic angina prophylaxis
Dosing: BID/TID with nitrate-free interval (8-12h) to prevent tolerance
Mononitrate: active form, 100% bioavailability
Adverse Effects
Headache (most common): cerebral vasodilation—tolerance develops
Orthostatic hypotension: venous pooling, reflex tachycardia
Tolerance: Develops with continuous use—require nitrate-free interval
Contraindication: Phosphodiesterase-5 inhibitors (sildenafil, etc.)—severe hypotension
Beta-Blockers
Mechanism in Angina
β₁ blockade → ↓ HR, ↓ contractility, ↓ BP → ↓ O₂ demand
↓ HR → ↑ diastolic time → ↑ coronary perfusion (coronaries fill during diastole)
Blunt exercise-induced tachycardia—↑ exercise tolerance
Clinical Use
First-line for chronic stable angina (with aspirin/statin)
Especially post-MI—mortality benefit
Agents: Metoprolol, atenolol, carvedilol, bisoprolol
Titrate to resting HR ~55-60 bpm
Limitations
NOT for variant angina (may worsen—α-mediated vasospasm unopposed)
Side effects: Fatigue, erectile dysfunction, bronchospasm
Contraindications: Severe bradycardia, AV block, reactive airway disease
Calcium Channel Blockers (CCBs)
Mechanism in Angina
Block L-type Ca²⁺ channels → vasodilation + ↓ contractility (non-DHP)
↓ Afterload (arterial dilation) → ↓ O₂ demand
↑ Coronary blood flow (especially variant angina—relieve spasm)
Non-Dihydropyridines (Verapamil, Diltiazem)
↓ HR, ↓ contractility, ↓ AV conduction + vasodilation
Similar efficacy to β-blockers for stable angina
Alternative when β-blockers contraindicated (asthma, COPD)
Avoid combination with β-blockers (additive cardiac depression)
Dihydropyridines (Amlodipine, Nifedipine)
Vascular-selective—minimal cardiac effects
Can be added to β-blockers (no cardiac depression)
Reflex tachycardia with short-acting nifedipine—use extended-release
First-line for variant angina (vasospasm)
Ranolazine
Mechanism
Inhibits late Na⁺ current (INa-late) in cardiomyocytes
↓ Intracellular Na⁺ accumulation → ↓ Ca²⁺ overload (via Na⁺/Ca²⁺ exchanger)
Improves diastolic relaxation, ↓ wall tension → ↓ O₂ demand
NO effect on HR or BP—metabolic antianginal
Clinical Use
Add-on therapy for chronic angina inadequately controlled by β-blockers/CCBs/nitrates
↓ Angina frequency, ↑ exercise tolerance
NO mortality benefit (not for ACS)
Adverse Effects & Interactions
QT prolongation (modest)—avoid with other QT-prolonging drugs
Constipation, dizziness, nausea
CYP3A4 substrate—many drug interactions (avoid strong inhibitors/inducers)
Other Antianginal Agents
Ivabradine
If channel inhibitor in SA node
Pure HR reduction (no ↓ BP/contractility)
Alternative if β-blockers not tolerated
Requires sinus rhythm, resting HR ≥70
Not widely available for angina in US (more common in Europe)
Trimetazidine
Metabolic modulator—shifts metabolism from fatty acids to glucose
More efficient O₂ use, ↓ lactate production
Used in Europe/Asia, not FDA-approved in US
Adjunctive Therapy for CAD/Angina
Aspirin
Antiplatelet—↓ MI, stroke, CV death in CAD patients
75-162 mg/day (low dose)
All patients with stable CAD unless contraindicated
Statins
HMG-CoA reductase inhibitors—↓ LDL cholesterol
Plaque stabilization, ↓ inflammation, ↓ CV events
High-intensity statin (atorvastatin 40-80mg, rosuvastatin 20-40mg) for CAD
ACE Inhibitors / ARBs
For CAD with hypertension, diabetes, LV dysfunction, or CKD
↓ CV events, vascular protection
Treatment Strategy Summary
Chronic Stable Angina
All patients: Aspirin, statin, lifestyle modification, risk factor control
First-line antianginal: β-blocker (or non-DHP CCB if contraindicated)
Add if inadequate: Long-acting nitrate or DHP CCB (amlodipine)
Refractory: Add ranolazine, consider revascularization (PCI/CABG)
Acute relief: Sublingual nitroglycerin PRN
Variant (Prinzmetal's) Angina
First-line: CCBs (DHP or non-DHP) + long-acting nitrates
Avoid: Non-selective β-blockers (may worsen vasospasm)