Antianginal Drugs
Pharmacology · CVS · lean revision notes
Antianginal Drugs
Angina pectoris is chest pain arising from a mismatch between myocardial oxygen demand and supply. Antianginal drugs restore this balance either by reducing demand (preload, afterload, heart rate, contractility) or by improving supply (coronary vasodilation, relief of vasospasm). The three pillars — organic nitrates, beta-blockers, and calcium channel blockers (CCBs) — plus newer metabolic and pacemaker-current modulators dominate NEET PG pharmacology.
The oxygen demand–supply concept
Myocardial oxygen demand (MVO₂) is determined by heart rate, contractility, and wall tension (wall tension ∝ preload × afterload, by Laplace's law). Supply depends on coronary blood flow (mostly diastolic in the left ventricle) and arterial oxygen content. Every antianginal works on at least one of these levers.
High-yield: Coronary perfusion of the left ventricle occurs predominantly during diastole. Tachycardia shortens diastole and reduces perfusion time — this is why bradycardia-inducing drugs (beta-blockers, verapamil/diltiazem, ivabradine) are beneficial in stable angina.
Classification of angina
| Type | Mechanism | Typical trigger | Drug of choice |
|---|---|---|---|
| Stable (classic, exertional) | Fixed atheromatous stenosis; demand outstrips supply | Exertion, emotion, cold | Beta-blocker (first-line) |
| Unstable (crescendo, ACS) | Plaque rupture + non-occlusive thrombus | At rest, increasing frequency | Nitrates + antiplatelets + heparin; medical emergency |
| Variant / Prinzmetal (vasospastic) | Coronary artery spasm (supply problem) | At rest, often nocturnal/early morning; ST elevation | Calcium channel blocker |
| Microvascular (Syndrome X) | Small-vessel dysfunction, normal coronaries | Exertion | Beta-blocker / CCB |
High-yield: Beta-blockers are first-line in stable angina but contraindicated (or used with great caution) in Prinzmetal angina — unopposed alpha activity can worsen coronary spasm. CCBs are the drugs of choice in vasospastic angina.
1. Organic nitrates
Members and pharmacokinetics
- Glyceryl trinitrate (GTN / nitroglycerin) — sublingual for acute attack (onset 1–3 min), also IV, transdermal patch, ointment.
- Isosorbide dinitrate (ISDN) — sublingual and oral; active metabolite isosorbide-5-mononitrate.
- Isosorbide mononitrate (ISMN) — oral; 100% bioavailability (no first-pass metabolism), long acting, used for prophylaxis.
GTN and ISDN undergo extensive first-pass hepatic metabolism, hence the sublingual route bypasses the liver for the acute attack. ISMN escapes first-pass because it is already a metabolite.
Mechanism of action
Nitrates are prodrugs that release nitric oxide (NO). Bioactivation of GTN requires mitochondrial aldehyde dehydrogenase-2 (ALDH-2). NO activates soluble guanylyl cyclase → ↑ cyclic GMP → activates protein kinase G → dephosphorylation of myosin light chain → smooth-muscle relaxation (also via reduced intracellular calcium).
Flow: Nitrate prodrug → NO release → ↑ soluble guanylyl cyclase → ↑ cGMP → PKG activation → ↓ intracellular Ca²⁺ + myosin light-chain dephosphorylation → vascular smooth muscle relaxation.
High-yield: Nitrates dilate veins (capacitance vessels) more than arteries at therapeutic doses. The dominant antianginal effect is reduction of preload → ↓ venous return → ↓ ventricular wall tension → ↓ MVO₂. They also relieve coronary spasm and redistribute flow to ischaemic subendocardium.
Haemodynamic effects
- ↓ Preload (venodilation, dominant) → ↓ end-diastolic volume → ↓ wall tension.
- Mild ↓ afterload at higher doses.
- Reflex tachycardia and ↑ contractility — an undesirable effect that raises MVO₂; this is why nitrates are often combined with a beta-blocker, which blunts the reflex.
Nitrate tolerance
With continuous exposure (e.g., 24-hour patch or frequent dosing), the antianginal effect wanes within 24–48 hours.
High-yield: Tolerance is prevented by providing a nitrate-free (or low-nitrate) interval of 8–12 hours daily, usually overnight. Remove transdermal patches at night; with oral ISMN use an eccentric (asymmetric) dosing schedule.
Proposed mechanisms of tolerance: depletion of tissue sulfhydryl (–SH) groups, inhibition of ALDH-2, generation of reactive oxygen species/peroxynitrite, and neurohormonal counter-regulation (RAAS, sympathetic activation, plasma volume expansion).
Adverse effects
- Throbbing headache (meningeal artery dilation) — most common, often limits dosing.
- Postural hypotension, dizziness, flushing, reflex tachycardia.
- Monday disease — industrial workers exposed to nitrates develop tolerance over the week; weekend withdrawal causes rebound coronary spasm, headache and tachycardia on returning Monday.
- Methaemoglobinaemia with very high doses.
High-yield: Nitrates + phosphodiesterase-5 inhibitors (sildenafil, tadalafil, vardenafil) = absolutely contraindicated. PDE-5 inhibitors prevent cGMP breakdown; combined with nitrate-driven cGMP synthesis this causes life-threatening hypotension. Wait 24 h after sildenafil/vardenafil and 48 h after tadalafil before giving a nitrate.
2. Beta-adrenergic blockers
Rationale and members
Beta-blockers reduce heart rate, contractility, and blood pressure, lowering MVO₂; the slower heart rate also prolongs diastole, improving coronary perfusion.
- Cardioselective (β₁): atenolol, metoprolol, bisoprolol, nebivolol — preferred in asthma/COPD and diabetes.
- Non-selective: propranolol, nadolol, timolol.
- Vasodilating: carvedilol (also α₁-block), nebivolol (NO release).
High-yield: Beta-blockers are first-line for chronic stable angina and improve survival post-MI. They have no role and are potentially harmful in pure vasospastic (Prinzmetal) angina because blocking β₂-mediated coronary dilation leaves alpha-mediated vasoconstriction unopposed.
Adverse effects / cautions
- Bradycardia, AV block, fatigue, cold extremities, worsening of acute heart failure.
- Bronchospasm (non-selective) — avoid in asthma.
- Mask hypoglycaemia symptoms in diabetics (except sweating).
- Abrupt withdrawal → rebound tachycardia, hypertension, worsening angina/MI due to receptor upregulation — always taper.
3. Calcium channel blockers (CCBs)
CCBs block L-type voltage-gated calcium channels in vascular smooth muscle and myocardium, causing coronary and peripheral arterial dilation (↓ afterload, relief of spasm) and, for the non-dihydropyridines, negative chronotropic/dromotropic/inotropic effects.
| Feature | Dihydropyridines (DHP) | Non-DHP — Verapamil | Non-DHP — Diltiazem |
|---|---|---|---|
| Examples | Amlodipine, nifedipine, felodipine | Verapamil | Diltiazem |
| Main site | Vascular (arterioles) | Heart (SA/AV node) | Intermediate |
| Heart rate | Reflex ↑ (short-acting) | ↓↓ | ↓ |
| Use in angina | Yes; preferred in vasospasm + HTN | Yes (rate control) | Yes |
| Combine with beta-blocker? | Yes (amlodipine safe) | Avoid (heart block, bradycardia) | Caution |
High-yield: CCBs are the drugs of choice in Prinzmetal (vasospastic) angina — they directly relieve coronary spasm. Amlodipine and diltiazem are favoured.
High-yield: Short-acting nifedipine is avoided in angina/ACS — abrupt vasodilation causes reflex tachycardia and a coronary steal, increasing mortality. Use long-acting DHPs (amlodipine, sustained-release nifedipine).
High-yield: Verapamil + beta-blocker is a dangerous combination — additive depression of SA/AV node and contractility can cause severe bradycardia, complete heart block, or asystole. Verapamil is also the most constipating CCB and elevates digoxin levels (inhibits P-glycoprotein).
4. Newer / second-line antianginals
Ivabradine
- Selective inhibitor of the funny current (Iƒ) in the SA node → pure heart-rate reduction without affecting contractility or blood pressure.
- Used in stable angina (with/without beta-blocker if HR remains high) and in chronic HFrEF with sinus rhythm and HR ≥ 70/min.
- Characteristic adverse effect: phosphenes / luminous visual phenomena (it also blocks retinal Ih channels). Causes bradycardia. Contraindicated in atrial fibrillation.
Ranolazine
- Inhibits the late inward sodium current (late INa) → less Na⁺-driven Ca²⁺ overload → reduced diastolic wall tension and improved perfusion; a metabolic/anti-ischaemic action with no significant effect on heart rate or blood pressure.
- Adjunct in refractory chronic stable angina.
- Prolongs QT interval (avoid with other QT-prolongers); metabolised by CYP3A4 (avoid strong inhibitors). Mild HbA1c-lowering effect noted.
Nicorandil
- Dual action: K-ATP channel opener (arterial dilation) + nitrate moiety (NO release, venodilation). "Balanced" pre- and afterload reduction and ischaemic preconditioning.
- Adverse effect: oral, anal and gastrointestinal ulceration.
Trimetazidine
- Partial inhibitor of fatty-acid oxidation (3-ketoacyl-CoA thiolase), shifting myocardial metabolism to more oxygen-efficient glucose oxidation. Metabolic agent, no haemodynamic effect; can cause parkinsonism (avoid in Parkinson disease).
Combination therapy rationale
Drugs are combined for haemodynamic complementarity — each partner offsets the other's reflex disadvantage.
- Nitrate + beta-blocker: Nitrate ↓ preload but causes reflex tachycardia; the beta-blocker blocks that reflex and reduces HR/contractility. Beta-blocker may ↑ ventricular volume; nitrate offsets it. Classic synergistic pair.
- Nitrate + CCB (DHP) + beta-blocker: "Triple therapy" for severe stable angina; beta-blocker controls the reflex tachycardia from both nitrate and DHP.
- Avoid: beta-blocker + verapamil/diltiazem (excess cardiac depression).
Approach to chronic stable angina (stepwise):
- Lifestyle + risk-factor control (statin, antiplatelet, BP, glycaemic control, smoking cessation).
- Beta-blocker (first-line) or rate-limiting CCB.
- Add a long-acting nitrate or a DHP CCB if symptoms persist.
- Add ivabradine / ranolazine / nicorandil / trimetazidine for refractory symptoms.
- Sublingual GTN PRN for acute episodes throughout.
- Persistent symptoms / high-risk anatomy → revascularisation (PCI / CABG).
High-yield: Drugs proven to reduce mortality in coronary disease are antiplatelets, statins, beta-blockers (post-MI), and ACE inhibitors — not nitrates (purely symptomatic). Remember the "ABCD" of secondary prevention: Aspirin/Antiplatelet, Beta-blocker, Cholesterol (statin)/CCB, Diet + drugs (ACEi).
Investigations (clinical context)
For completeness: stable angina is evaluated with resting ECG, exercise (treadmill) stress testing, stress echocardiography or myocardial perfusion imaging, with coronary angiography (gold standard for anatomy) in high-risk or refractory cases. Vasospastic angina classically shows transient ST-segment elevation during pain and is confirmed by ergonovine/acetylcholine provocation testing. Pharmacology MCQs usually pivot from the diagnosis to the drug of choice.
Key differentials of drug effects (quick contrasts)
| Question stem clue | Answer |
|---|---|
| Pure heart-rate reduction, causes phosphenes | Ivabradine |
| Antianginal that prolongs QT, late Na current | Ranolazine |
| K-ATP opener causing mouth/anal ulcers | Nicorandil |
| Best for nocturnal rest pain with ST elevation | CCB (amlodipine/diltiazem) |
| Contraindicated with sildenafil | Nitrates |
| Dangerous with verapamil | Beta-blocker |
| Avoided as short-acting form in ACS | Nifedipine |
| ↑ digoxin level, most constipating | Verapamil |
Recently asked / exam angle
- Mechanism of nitrate action: "increases cGMP" — pick the soluble guanylyl cyclase / NO–cGMP pathway. Distinguish from PDE-5 inhibitors (prevent cGMP breakdown) — the basis of the lethal interaction.
- Nitrate tolerance prevention = daily nitrate-free interval (8–12 h) / eccentric dosing — a perennial favourite.
- Drug of choice in Prinzmetal angina = CCB, and beta-blockers contraindicated there.
- Ivabradine → phosphenes and SA-node Iƒ inhibition; ranolazine → late INa and QT prolongation; nicorandil → K-ATP opener + ulcers; trimetazidine → fatty-acid oxidation inhibitor (parkinsonism) — single-best-answer mechanism matches.
- Verapamil + beta-blocker combination causing heart block.
- ISMN having highest oral bioavailability among nitrates (no first-pass).
- Bioactivation enzyme of nitroglycerin = ALDH-2 (mitochondrial aldehyde dehydrogenase).
- Which antianginal does not reduce mortality (answer: nitrates).
- Monday disease in nitrate-industry workers.
Mnemonic for vasospastic angina management — "Spasm needs Calcium blocked": in spasm, give a CCB, avoid Beta-blockers (B for Bad in vasoSpasm). Mnemonic for nitrate effects — "VeNodilation reduces preload" (Nitrates → Veins → preload). Mnemonic for mortality-benefit drugs — "ABCD".
Rapid revision
- Antianginals work by ↓ demand (HR, contractility, wall tension) or ↑ supply (coronary dilation, relieving spasm).
- LV coronary perfusion is diastolic — slowing the heart helps angina.
- Nitrates → release NO → ↑ cGMP → mainly venodilation → ↓ preload.
- ISMN has the highest oral bioavailability (no first-pass); GTN bioactivated by ALDH-2.
- Prevent nitrate tolerance with a daily 8–12 h nitrate-free interval.
- Nitrates + PDE-5 inhibitors = contraindicated (fatal hypotension).
- Beta-blockers = first-line stable angina; contraindicated in Prinzmetal; taper to avoid rebound.
- CCBs = drug of choice in vasospastic (Prinzmetal) angina; avoid short-acting nifedipine in ACS.
- Verapamil + beta-blocker → severe bradycardia/heart block; verapamil raises digoxin and is most constipating.
- Ivabradine = SA-node Iƒ blocker → pure HR reduction, causes phosphenes.
- Ranolazine = late-INa inhibitor, prolongs QT; nicorandil = K-ATP opener causing mouth/anal ulcers; trimetazidine inhibits fatty-acid oxidation.
- Mortality benefit in CAD: antiplatelets, statins, beta-blockers, ACE inhibitors — nitrates are symptomatic only.