Explain me antianginal drugs its mechanism of action and side effects with diagrams
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nitrates mechanism of action angina nitric oxide vascular smooth muscle
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Antianginal Drugs: Mechanisms of Action & Side Effects
Angina pectoris results from an imbalance between myocardial oxygen demand and supply. Antianginal drugs work either by reducing oxygen demand (beta-blockers), increasing supply (nitrates, calcium channel blockers), or both.
Pathophysiology of Angina — The Basis of Drug Action
Three main types:
- Effort (stable) angina — atherosclerotic obstruction → ↑ demand exceeds fixed supply
- Vasospastic (Prinzmetal) angina — coronary vasospasm → ↓ supply
- Unstable angina (ACS) — plaque rupture + thrombus → ↓ supply acutely
Class 1: Organic Nitrates
Drugs: Nitroglycerin (GTN), Isosorbide dinitrate (ISDN), Isosorbide mononitrate (ISMN), Amyl nitrite
Mechanism of Action
Figure 12-1 — How vascular smooth muscle contraction and relaxation works (CCBs block Ca²⁺ influx; cGMP causes relaxation):
Figure 12-2 — The nitrate/NO mechanism in vascular smooth muscle:
Step-by-step:
- Nitrates undergo bioactivation via mitochondrial aldehyde dehydrogenase-2 (mtALDH2) → release free nitrite → converted to nitric oxide (NO)
- NO activates guanylyl cyclase → GTP → ↑ cGMP
- cGMP activates protein kinase G → dephosphorylates myosin light chains → vascular smooth muscle relaxation
- Endothelium also produces NO via eNOS from L-arginine
Hemodynamic effects in angina:
| Effect | Result |
|---|---|
| Venodilation (large veins) | ↓ Preload (venous return) → ↓ LVEDV → ↓ O₂ demand |
| Arterial dilation | ↓ Afterload → ↓ wall stress → ↓ O₂ demand |
| Coronary dilation | ↑ O₂ supply, ↑ collateral flow; prevents/relieves spasm |
| ↓ Cardiac output | ↓ O₂ demand overall |
The dominant antianginal mechanism is reduction of oxygen demand via decreased preload and afterload. In vasospastic angina, prevention of coronary artery spasm is paramount.
Side Effects
- Headache (most common — from cerebral vasodilation)
- Reflex tachycardia (baroreceptor response to ↓ BP)
- Postural hypotension / syncope
- Flushing
- Methemoglobinemia (rare, high doses)
- Nitrate tolerance — develops within 24h of continuous use; requires nitrate-free interval (8–12 h/day)
- Contraindicated with PDE-5 inhibitors (sildenafil, tadalafil) — severe refractory hypotension
- Contraindicated in hypertrophic obstructive cardiomyopathy, right ventricular infarction, severe aortic stenosis
Preparations & Routes
| Preparation | Route | Onset | Duration | Use |
|---|---|---|---|---|
| Nitroglycerin (sublingual) | SL | 1–3 min | 15–30 min | Acute relief |
| Nitroglycerin (IV) | IV | Immediate | During infusion | Unstable angina, HTN |
| ISDN | Oral/SL | 15–30 min | 4–6 h | Prophylaxis |
| ISMN | Oral | 30–60 min | 6–8 h | Prophylaxis (100% bioavailability) |
| GTN patch | Transdermal | 30–60 min | 24 h | Prophylaxis |
Class 2: Beta-Adrenoceptor Blockers (β-Blockers)
Drugs: Propranolol, Metoprolol, Atenolol, Bisoprolol, Carvedilol (also α-blocker), Nebivolol
Mechanism of Action
β-Blockers are not vasodilators (except carvedilol, nebivolol), but are the first-line prophylactic treatment for effort angina.
At β₁-receptors in the heart:
- ↓ Heart rate (negative chronotropy) → ↑ diastolic filling time → ↑ coronary perfusion time
- ↓ Myocardial contractility (negative inotropy)
- ↓ Conduction velocity (AV node)
Net effect: ↓ Myocardial oxygen demand at rest AND during exercise
β-Blockers reduce the "triple product" (HR × systolic BP × contractility), which is the main determinant of myocardial O₂ consumption.
Lower heart rate is particularly beneficial: coronary perfusion occurs mainly in diastole, so bradycardia prolongs perfusion time.
Side Effects
| Side Effect | Mechanism |
|---|---|
| Bradycardia / AV block | β₁ blockade |
| Fatigue, impaired exercise tolerance | ↓ Cardiac output |
| Bronchospasm | β₂ blockade (avoid non-selective in asthma/COPD) |
| Peripheral vasoconstriction | β₂ blockade → unopposed α |
| Worsening claudication | Peripheral vasoconstriction |
| Erectile dysfunction | |
| Masked hypoglycemia signs | (use with caution in diabetics on insulin) |
| Depression, insomnia, vivid dreams | CNS effects (lipophilic agents — propranolol) |
| Rebound angina on sudden withdrawal |
Contraindications
Acute decompensated heart failure, significant bradycardia, 2nd/3rd degree AV block, severe reactive airway disease, vasospastic (Prinzmetal) angina (may worsen spasm by unopposed α stimulation), cardiogenic shock.
Class 3: Calcium Channel Blockers (CCBs)
Drugs: Dihydropyridines: Nifedipine, Amlodipine, Felodipine | Non-DHPs: Verapamil, Diltiazem
Mechanism of Action
CCBs block voltage-gated L-type calcium channels — the dominant channel in cardiac and vascular smooth muscle.
Binding sites:
- Dihydropyridines (e.g., nifedipine) → bind α₁ subunit (one site)
- Verapamil & Diltiazem → bind related but distinct regions of α₁ subunit
The drugs bind from the inner side of the membrane, preferentially to open and inactivated channels (state-dependent block), reducing frequency of channel opening → ↓ Ca²⁺ influx.
Consequences by tissue:
| Tissue | Effect |
|---|---|
| Vascular smooth muscle | Relaxation → vasodilation → ↓ afterload |
| Coronary arteries | Dilation → relieves/prevents spasm |
| Heart (DHPs — minimal at therapeutic doses) | Modest ↓ contractility |
| Heart (verapamil/diltiazem) | ↓ SA node rate, ↓ AV conduction, ↓ contractility |
Dihydropyridines are predominantly vascular; verapamil and diltiazem have significant cardiac effects.
Side Effects
Dihydropyridines (nifedipine, amlodipine):
- Headache, flushing, dizziness (vasodilation)
- Ankle edema (arteriolar dilation without venodilation)
- Reflex tachycardia (especially short-acting nifedipine — dangerous in ACS)
- Gingival hyperplasia
Verapamil:
- Constipation (most common)
- Bradycardia, AV block
- ↓ Contractility (worsens heart failure)
- Raises digoxin levels (pharmacokinetic interaction)
Diltiazem:
- Bradycardia, AV block (less than verapamil)
- ↓ Contractility
- Relatively better tolerated
Class Contraindications:
- Verapamil/Diltiazem: severe LV dysfunction, bradycardia, AV block, concomitant β-blockers (additive AV block), cardiogenic shock
- Short-acting dihydropyridines: unstable angina / acute MI (↑ adverse cardiac events)
Class 4: Newer Antianginal Drugs
Ranolazine
- Mechanism: Inhibits the late inward sodium current (I_Na(late)) → prevents intracellular Na⁺ overload → prevents secondary Ca²⁺ overload (via Na⁺/Ca²⁺ exchanger) → ↓ diastolic wall tension and O₂ demand. Does not significantly lower HR or BP.
- Indications: Add-on therapy for chronic stable angina refractory to other agents (ACC/AHA Class I recommendation)
- Side effects: Dizziness, headache, constipation, nausea; prolongs QTc (contraindicated in pre-existing QT prolongation)
Ivabradine
- Mechanism: Selectively blocks the I_f (funny current) in SA node → reduces heart rate without affecting contractility or BP
- Indications: Symptomatic stable angina in patients with sinus rhythm and HR ≥70 bpm who cannot tolerate β-blockers. ACC/AHA notes it is potentially harmful as add-on to standard therapy in normal LV function.
- Side effects: Luminous phenomena (phosphenes — transient visual brightness), bradycardia, atrial fibrillation
Nicorandil
- Mechanism: Dual — activates K⁺-ATP channels (coronary dilation) + has nitrate-like component (venodilation)
- Used in Europe/Asia; not FDA-approved in USA
Trimetazidine
- Mechanism: Metabolic modulator — inhibits fatty acid β-oxidation → shifts myocardial metabolism to glucose → more O₂-efficient energy production
- Side effects: Extrapyramidal symptoms (parkinsonism), dizziness
- Not available in USA
Comparison of Antianginal Effects
| Parameter | Nitrates Alone | β-Blockers/CCBs Alone | Combined |
|---|---|---|---|
| Heart rate | ↑ (reflex) | ↓ | ↓ |
| Arterial pressure | ↓ | ↓ | ↓ |
| End-diastolic volume | ↓ | ↑ | None/↓ |
| Contractility | ↑ (reflex) | ↓ | None |
| Ejection time | ↓ | ↑ | None |
From Katzung's Basic and Clinical Pharmacology, 16th Ed., Table 12-3
Combination rationale: β-Blockers counteract the reflex tachycardia and increased contractility caused by nitrates; nitrates counteract the increased preload and end-diastolic volume caused by β-blockers. This complementary pharmacology makes them superior in combination.
Drug Selection by Angina Type
| Angina Type | First-Line | Second-Line | Avoid |
|---|---|---|---|
| Stable/Effort angina | β-Blockers + long-acting nitrates | CCBs | — |
| Vasospastic (Prinzmetal) | Nitrates + CCBs | — | β-Blockers |
| Unstable angina | IV nitroglycerin + β-blockers + antiplatelet | CCBs (add-on) | Short-acting DHPs |
| Refractory stable angina | Add ranolazine | Add ivabradine (if HR ≥70) | — |
Clinical Guidance Summary (Harrison's / ACC/AHA Guidelines)
Key Pearls
- Nitrates + PDE-5 inhibitors (sildenafil) → absolute contraindication (severe hypotension, potentially fatal). Wait ≥24 h after sildenafil, ≥48 h after tadalafil before giving nitrates.
- Never abruptly stop β-blockers in angina — rebound ischemia/MI risk.
- Short-acting nifedipine is contraindicated in ACS — causes reflex tachycardia and worsens outcomes.
- Verapamil + β-blockers → risk of complete heart block and severe LV depression — avoid combination.
- Tolerance to nitrates develops within 24 hours of continuous exposure. A nitrate-free interval of 8–12 hours is essential.
- Ranolazine is uniquely effective without hemodynamic effects — ideal for patients who cannot tolerate rate-lowering drugs.
Sources: Katzung's Basic and Clinical Pharmacology, 16th Ed. | Harrison's Principles of Internal Medicine, 21st Ed. | ACC/AHA 2023 Chronic Coronary Disease Guideline
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