Explain me antianginal drugs with its mechanism of action and side effects with diagrams
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antianginal drugs mechanism of action diagram
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Here is a comprehensive guide to antianginal drugs — their mechanisms of action and side effects.
Antianginal Drugs
Pathophysiology Overview
Angina pectoris results from an imbalance between myocardial oxygen demand and supply. Antianginal drugs work by either:
- Reducing demand (↓ heart rate, contractility, wall tension)
- Increasing supply (coronary/peripheral vasodilation)
Overall Mechanism Summary
1. Organic Nitrates
Drugs: Nitroglycerin (GTN), Isosorbide dinitrate (ISDN), Isosorbide mononitrate (ISMN), Amyl nitrite
Mechanism of Action
Nitroglycerin must be bioactivated enzymatically:
- ALDH2 (mitochondrial aldehyde dehydrogenase isoform 2) and glutathione S-transferase denitrate nitroglycerin → releases nitric oxide (NO)
- NO combines with the heme group of soluble guanylyl cyclase (sGC) → activates it
- sGC converts GTP → cGMP (cyclic GMP)
- cGMP activates protein kinase G (PKG)
- PKG dephosphorylates myosin light chains → smooth muscle relaxation → vasodilation
Net hemodynamic effects:
| Effect | Result |
|---|---|
| Venodilation (dominant) | ↓ Venous return → ↓ Preload → ↓ Wall tension → ↓ O₂ demand |
| Arterial dilation | ↓ Afterload → ↓ Cardiac work |
| Coronary redistribution | Improves flow to ischemic subendocardium |
| Weak negative inotropy | via NO |
Pharmacokinetics:
- Oral bioavailability is low (<10–20%) due to extensive hepatic first-pass metabolism
- Sublingual route preferred for rapid effect (onset 1–3 min, duration 15–30 min)
- Isosorbide mononitrate has 100% bioavailability (oral)
Side Effects
| Side Effect | Mechanism |
|---|---|
| Headache (most common) | Cerebral vasodilation |
| Flushing | Cutaneous vasodilation |
| Hypotension / syncope | Excessive vasodilation |
| Reflex tachycardia | Baroreceptor response to hypotension |
| Tolerance | Depletion of sulfhydryl groups needed for ALDH2; requires nitrate-free interval (8–12 h/day) |
| Severe hypotension with PDE-5 inhibitors | Both increase cGMP — dangerous combination; wait ≥6 h between use |
| Methemoglobinemia (with large doses) | Rare |
2. Beta-Adrenoceptor Blockers (β-Blockers)
Drugs: Metoprolol, Atenolol (cardioselective β₁); Propranolol (non-selective β₁/β₂)
Mechanism of Action
By blocking β₁-adrenoceptors on the heart:
- ↓ Heart rate (negative chronotropy)
- ↓ Contractility (negative inotropy)
- ↓ AV conduction velocity
→ All three reduce myocardial oxygen demand, especially during exertion (the main trigger for effort angina)
Hemodynamic effects:
- ↓ Heart rate × ↓ Systolic pressure = reduced rate-pressure product (key determinant of O₂ demand)
- Prolonged diastolic filling time → improved coronary perfusion
- Not vasodilators; do not benefit vasospastic/Prinzmetal angina (may worsen it by allowing unopposed α-vasoconstriction)
Side Effects
| Side Effect | Notes |
|---|---|
| Bradycardia / heart block | Especially non-selective agents |
| Bronchospasm | β₂ blockade — contraindicated in asthma |
| Fatigue, lethargy | CNS effects |
| Cold extremities | ↓ peripheral perfusion |
| Impotence | Peripheral vascular effect |
| Masking of hypoglycemia | Blocks tachycardia warning sign in diabetics |
| Rebound angina | On abrupt withdrawal — must taper |
| Negative inotropy | Worsens decompensated heart failure |
3. Calcium Channel Blockers (CCBs)
Drugs:
- Dihydropyridines (DHPs): Amlodipine, Nifedipine, Felodipine
- Non-dihydropyridines (Non-DHPs): Verapamil (phenylalkylamine), Diltiazem (benzothiazepine)
Mechanism of Action
Block voltage-gated L-type calcium channels (Ca²⁺ channels):
| Drug Class | Primary Target | Effect |
|---|---|---|
| Dihydropyridines | Vascular smooth muscle >> heart | Peripheral arterial vasodilation → ↓ afterload |
| Verapamil | Heart > vessels | ↓ HR, ↓ contractility, ↓ AV conduction; less vasodilation |
| Diltiazem | Heart and vessels equally | Intermediate effects |
How it helps angina:
- DHPs: ↓ afterload → ↓ O₂ demand; first-line for vasospastic (Prinzmetal) angina
- Non-DHPs: ↓ HR + contractility → ↓ O₂ demand (similar to β-blockers)
- All: coronary vasodilation → ↑ O₂ supply
Side Effects
Dihydropyridines:
| Side Effect | Cause |
|---|---|
| Peripheral edema | Vasodilation causing precapillary dilation > postcapillary |
| Flushing, headache | Vasodilation |
| Reflex tachycardia | With short-acting nifedipine (less with amlodipine) |
| Gingival hyperplasia | (especially nifedipine) |
Non-dihydropyridines (Verapamil/Diltiazem):
| Side Effect | Cause |
|---|---|
| Bradycardia / AV block | Direct cardiac effect |
| Constipation | (especially verapamil — smooth muscle relaxation in GI) |
| Negative inotropy | May worsen systolic heart failure |
| Contraindicated with β-blockers | Risk of complete heart block |
Side Effects Comparison
4. Newer / Second-Line Antianginal Agents
Ranolazine
- Mechanism: Inhibits the late sodium current (late I_Na) → ↓ intracellular Na⁺ → ↓ Na⁺/Ca²⁺ exchanger activity → ↓ intracellular Ca²⁺ → reduces diastolic tension and cardiac work
- Does not affect heart rate or blood pressure significantly
- Side effects: QT prolongation (though no torsades reported), dizziness, constipation, nausea; may inhibit metabolism of digoxin and simvastatin
Ivabradine
- Mechanism: Selectively blocks the hyperpolarization-activated I_f ("funny") current in the SA node → ↓ heart rate only
- No negative inotropic or vasodilator effects
- Similar efficacy to CCBs and β-blockers for angina
- Side effects: Visual disturbances (phosphenes — flickering lights), bradycardia
Nicorandil
- Mechanism: Dual — K⁺ channel activator (hyperpolarizes smooth muscle) + nitrate-like NO donor → vasodilation of coronary and peripheral vessels
- Side effects: Headache (like nitrates), hypotension, oral/GI ulceration
Trimetazidine (metabolic agent)
- Mechanism: Partially inhibits fatty acid oxidation (inhibits LC-3KAT enzyme) → myocardium shifts to glucose oxidation which consumes less oxygen per ATP → metabolic efficiency in ischemia
- Not approved in the USA; available in Europe and Asia
- Side effects: Parkinsonism-like symptoms, GI effects
Summary Table
| Drug Class | Key Mechanism | Reduces | Angina Type | Key Side Effect |
|---|---|---|---|---|
| Organic Nitrates | NO → cGMP → vasodilation | Preload (primarily) | Effort + Vasospastic | Headache, tolerance |
| β-Blockers | ↓ HR, contractility | O₂ demand | Effort only | Bronchospasm, bradycardia |
| DHP CCBs | Block L-Ca²⁺ in vessels | Afterload | Effort + Vasospastic | Edema, flushing |
| Non-DHP CCBs | Block L-Ca²⁺ in heart | HR + contractility | Effort + Vasospastic | AV block, constipation |
| Ranolazine | Block late I_Na | Diastolic tension | Effort (add-on) | QT prolongation |
| Ivabradine | Block I_f in SA node | HR only | Effort (add-on) | Visual phosphenes |
| Nicorandil | K⁺ activation + NO | Pre/afterload | Effort + Vasospastic | Headache, ulcers |
Key Clinical Point: β-blockers and short-acting dihydropyridine CCBs should not be combined (risk of severe bradycardia). However, β-blockers + long-acting DHPs (amlodipine) is a safe and effective combination. Never combine nitrates + PDE-5 inhibitors (sildenafil, tadalafil) due to severe hypotension risk.
Source: Katzung's Basic and Clinical Pharmacology, 16th Edition, Chapter 12: Vasodilators & the Treatment of Angina Pectoris
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