Angina pectoris ( pharmacology)
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angina pectoris pharmacological treatment
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Angina Pectoris — Pharmacology
Overview
Angina pectoris results from an imbalance between myocardial oxygen supply and demand, most commonly due to atherosclerotic coronary artery disease. Three classic forms exist:
| Type | Trigger | Mechanism |
|---|---|---|
| Stable (effort) angina | Physical exertion | Fixed atheromatous plaque → fixed flow limitation |
| Unstable angina | Rest or minimal exertion | Plaque rupture / dynamic obstruction |
| Variant (Prinzmetal) angina | Often at rest | Coronary artery vasospasm |
Pharmacotherapy works by reducing myocardial O₂ demand (↓ heart rate, preload, afterload, contractility) and/or increasing O₂ supply (coronary vasodilation, relief of spasm).
Drug Groups
1. Organic Nitrates & Nitrites
Prototype: Nitroglycerin (glyceryl trinitrate)
Mechanism of Action:
Nitrates are converted intracellularly (via mitochondrial aldehyde dehydrogenase-2, mtALDH2) to nitric oxide (NO). NO activates guanylyl cyclase → ↑ cGMP → dephosphorylation of myosin light chains → smooth muscle relaxation and vasodilation.
Hemodynamic effects:
- Venodilatation (dominant): ↓ venous return → ↓ preload → ↓ wall tension → ↓ O₂ demand
- Arteriolar dilation: ↓ afterload (at higher doses)
- Coronary artery dilation: Relieves vasospasm (variant angina); preferentially dilates epicardial coronary vessels
Pharmacokinetics & Preparations:
| Drug | Route | Onset | Duration | Use |
|---|---|---|---|---|
| Nitroglycerin (sublingual) | SL | 1–3 min | 10–30 min | Acute attack |
| Isosorbide dinitrate (SL) | SL | 5 min | 10–60 min | Acute attack |
| Nitroglycerin (IV) | IV | Minutes | Brief (stops with infusion) | Severe rest/unstable angina |
| Nitroglycerin (oral sustained) | Oral | 30 min | 6–8 h | Prophylaxis |
| Nitroglycerin (transdermal patch) | Transdermal | Slow | 8–12 h | Prophylaxis |
| Isosorbide mononitrate | Oral | — | 6–10 h | Prophylaxis (100% bioavailability) |
Note: Oral nitrates have very low bioavailability (<10–20%) due to high hepatic first-pass metabolism. Isosorbide mononitrate (active metabolite) has 100% bioavailability.
Toxicity:
- Orthostatic hypotension, reflex tachycardia
- Throbbing headache (meningeal vessel dilation)
- Tolerance: Develops with continuous exposure; prevented by providing a nitrate-free interval (8–12 h/day, usually overnight)
Key Drug Interaction: Synergistic, potentially fatal hypotension with PDE-5 inhibitors (sildenafil, tadalafil) — absolutely contraindicated combination.
2. Beta-Adrenoceptor Blockers (β-Blockers)
Prototype: Propranolol (non-selective); Atenolol, Metoprolol (β₁-selective)
Mechanism: Competitive antagonism at β-adrenoceptors → ↓ heart rate, ↓ myocardial contractility, ↓ blood pressure → reduced myocardial O₂ demand
Effects on determinants of O₂ demand:
- ↓ Heart rate (most important)
- ↓ Contractility (inotropy)
- ↓ Systolic blood pressure
Clinical Use:
- First-line prophylaxis for stable (effort) angina — shown to increase exercise time to angina/ST depression
- Protective post-MI; reduce mortality
- Not effective for variant angina (may worsen coronary spasm)
Pharmacokinetics: Oral and IV; duration varies by agent (propranolol 4–6 h; atenolol longer)
Toxicity:
- Bronchospasm (avoid in asthma — use β₁-selective agents)
- AV block, acute heart failure
- Fatigue, cold extremities
- Do not abruptly discontinue — rebound angina/tachycardia
3. Calcium Channel Blockers (CCBs)
Mechanism: Block voltage-gated L-type calcium channels on cardiac and vascular smooth muscle. Drugs bind to the α₁ subunit of the channel, reducing frequency of channel opening in response to depolarization → ↓ intracellular Ca²⁺.
Two pharmacological subgroups:
| Subgroup | Drugs | Primary Action |
|---|---|---|
| Non-dihydropyridines | Verapamil, Diltiazem | Cardiac > vascular: ↓ HR, ↓ AV conduction, ↓ contractility + vasodilation |
| Dihydropyridines | Nifedipine, Amlodipine, Felodipine | Vascular > cardiac: Potent vasodilation, less cardiac depression |
Effects on angina:
- Reduce myocardial O₂ demand (all agents)
- Dilate coronary arteries — particularly effective in variant angina (relieve spasm)
- Amlodipine/nifedipine: potent peripheral arteriolar dilation → ↓ afterload
Clinical Use:
- Stable angina: All CCBs used for prophylaxis
- Variant (Prinzmetal) angina: Drug of choice (along with nitrates)
- Verapamil/diltiazem: also used for rate control in SVT
Toxicity:
- Verapamil/diltiazem: AV block, bradycardia, acute heart failure, constipation (verapamil)
- Nifedipine/dihydropyridines: Flushing, headache, peripheral edema, reflex tachycardia (especially with immediate-release nifedipine — contraindicated in ACS)
- Amlodipine: long half-life (30–50 h), once-daily dosing, less tachycardia
4. Newer & Adjunct Antianginal Drugs
Ranolazine
- Mechanism: Inhibits the late inward Na⁺ current (late I_Na) → ↓ Na⁺-dependent Ca²⁺ overload via Na⁺/Ca²⁺ exchanger → ↓ diastolic tension and O₂ demand
- Does not affect heart rate or blood pressure significantly
- Approved in the USA for chronic stable angina refractory to other agents
- Prolongs QT interval but not associated with torsades de pointes
- Inhibits metabolism of digoxin and simvastatin
Ivabradine
- Mechanism: Selectively inhibits the hyperpolarization-activated I_f (funny) current (If/HCN channels) in the sinoatrial node → reduces heart rate without affecting contractility or blood pressure
- Efficacy similar to β-blockers and CCBs in stable angina
- Useful when β-blockers are contraindicated (e.g., asthma)
- Approved in the USA for stable symptomatic heart failure with reduced EF (also used off-label for angina)
Nicorandil
- Mechanism: Potassium channel activator + nitrate component → dual vasodilation (venous and arterial)
- Available in Europe/Asia; not approved in the USA
Trimetazidine
- Mechanism: Metabolic modulator — inhibits long-chain 3-ketoacyl thiolase (LC-3KAT), partially blocking fatty acid oxidation → shifts myocardium to more O₂-efficient glucose oxidation
- Effective in stable angina; not approved in the USA
Summary: Drug Choice by Angina Type
| Angina Type | First-Line | Alternatives |
|---|---|---|
| Stable (effort) | β-Blockers + long-acting nitrates | CCBs (all types), ranolazine, ivabradine |
| Unstable angina (ACS) | IV nitrates + heparin + antiplatelet therapy | PCI/stenting preferred; aspirin, statins |
| Variant (Prinzmetal) | CCBs (nifedipine, amlodipine) + nitrates | Avoid β-blockers |
| Stable + asthma | CCBs or long-acting nitrates | Ivabradine |
| Refractory stable | Add ranolazine | Trimetazidine (where available) |
Key Determinants of Myocardial O₂ Demand
The three drug classes reduce these determinants:
| Determinant | Nitrates | β-Blockers | CCBs |
|---|---|---|---|
| Preload (ventricular volume) | ↓↓ | ↓ | ↓ |
| Afterload (systemic BP) | ↓ | ↓ | ↓↓ (DHPs) |
| Heart rate | ↑ (reflex) | ↓↓ | ↓ (non-DHPs) |
| Contractility | ↑ (reflex) | ↓↓ | ↓ (non-DHPs) |
| Coronary spasm relief | ✓ | ✗ | ✓✓ |
Combining β-blockers with nitrates is logical: β-blockers blunt the reflex tachycardia caused by nitrates, while nitrates offset the increased preload (ventricular volume) that can result from β-blocker-induced bradycardia.
Source: Katzung's Basic and Clinical Pharmacology, 16th Edition, pp. 304–325
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