ANTI-ANGINAL DRUGS

ANTI-ANGINAL DRUGS


Pathophysiology:

  • Major symptom – Chest pain.
    • Due to imbalance between oxygen supply & demand.
    • Due to fixed atherosclerotic narrowing of coronary arteries.

Aim of management:

  • Two major strategies for treatment & prevention of angina:
    • Decreasing oxygen requirement.
    • Increasing blood supply to ischemic region.
  • New strategy: By making efficient utilization of substrates by heart.

Anti-angina drugs:

  • Nitrates (GTN, isosorbide dinitrate), beta-blockers, CCB’s, fatty acid oxidation inhibitors, potassium channel opener (Nicorandil), metabolic modifiers (Trimetazidine) & newer drugs.

Classification of drugs:

  • To abort or terminate attack: GTN,lsosorbide dinitrate (sublingually).
  • For chronic prophylaxis: All other drugs.
  • For chronic resistant angina: Ranolazine (LC-3 KAT inhibitor & metabolic modifier-spares fatty acid oxidation).

Important drugs & description:

1. Nitrates:

  • Mainstay therapy for immediate angina relief.
  • MOA: Reduces preload & lowers end diastolic pressure.

Drugs:

  • Short acting: Glyceryl trinitrate (GTN, Nitroglycerine).
  • Long acting: Isosorbide dinitrate (short acting by sublingual route), Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritot tetranitrate

2. Calcium channel blockers & β-blockers:

  • For prophylaxis

CCB’s:

  • Phenyl alkylamine: Verapamil
  • Benzothiazepine: Diltiazem
  • Dihydropyridines: Nifedipine, Felodipine, Amlodipine, Nitrendipine, Nimodipine, Lacidipine, Lercanidipine, Benidipine.

MOA:

  • By vasodilation.
  • By decreasing heart rate & contractility.
  • Uses: Indicated only for unresponsive coronary spasm to nitrates.

3. β-Blockers:

  • Only anti-anginal drugs decreasing mortality in CAD patients (Post-MI).
  • Drugs: Propranolol, Metoprolol & Atenolol.

MOA: 

  • By reducing myocardial oxygen demand – 
  • Due to negative chronotropic effect (particularly during exercise), negative inotropic effect, & reduced arterial blood pressure (particularly systolic pressure) during exercise.
  • Decreased heart rate & contractility → Increases systolic ejection period & left ventricular end-diastolic volume → Increases O2 consumption.
  • Long-term β-blocker therapy – Total amount of “ischemic time”/day reduced.
  • Contra-indications: Variant angina.

4. Fatty acid oxidation inhibitors:

  • MOA: Alters myocardial metabolism.

5. Potassium channel opener:

  • Nicorandil.

MOA:

  • By coronary dilation – By activating myocardial ATP sensitive K+ channels.
  • Possess NO releasing property without tolerance property.

6. Metabolic modifier:

Trimetazidine:

  • MOA: Improves cellular tolerance to ischemia.
  • No effect on HR/BP.
  • Cause reversible parkinsonism.

7. Newer drugs:

7a. Ranolazine:

  • 1st new antianginal drug approved by FDA.
  • Approved as first-line agent for chronic angina.
  • Congener of trimetazidine.

MOA: 

  • LC3-KAT inhibitor.
  • Spares fatty acid oxidation & inhibits late INa+ current in myocardium indirectly facilitating Ca2+ entry.

Uses:

  • Chronic angina.
  • Erectile dysfunction.

Adverse effects:

  • QT prolongation.
  • Small decrease in HbA1C.

Contraindications:

  • Treatment of acute anginal episodes.
  • Liver & kidney disease.

7b. Ivabradine:

  • New drug.
  • A bradycardiac agent – Decreases heart rate without affecting conduction or contractility).

MOA: 

  • Acts by blocking hyperpolarization activated sodium channel (carries funny current).

Adverse effect:

  • Visual disturbances (most important)

7c. Fasudil:

  • Selective Rho A/Rho kinase (ROCK) inhibitor.
  • ROCK – An enzyme involved in vasoconstriction & cardiac remodeling.
  • ROCK enzyme inhibition –> Causes vasodilation.
  • Used in angina & cerebral vasospasm.

8. Other antianginal drugs:

  • Dipyridamole: Failure drug due to coronary steal phenomenon
  • Oxyphedrine.

Exam Important

  • Two major strategies for treatment & prevention of angina are decreasing oxygen requirement & increasing blood supply to ischemic region.
  • New strategy for development of anti-angina drug is by making efficient utilization of substrates by heart.
  • Anti-angina drugs include nitrates (GTN, isosorbide dinitrate), beta-blockers, CCB’s, fatty acid oxidation inhibitors, potassium channel opener (Nicorandil), metabolic modifiers (Trimetazidine) & newer drugs.
  • GTN, isosorbide dinitrate (sublingually) aborts or terminate acute anginal attack.
  • Ranolazine (LC-3 KAT inhibitor & metabolic modifier-spares fatty acid oxidation) is used for chronic resistant angina.
  • Glyceryl trinitrate (GTN, Nitroglycerine) are short-acting nitrates.
  • Isosorbide dinitrate (short-acting by sublingual route), Isosorbide mononitrate, Erythrityl tetranitrate, Pentaerythritol tetranitrate are all long-acting nitrates.
  • Nitrates are mainstay therapy for immediate angina relief.
  • Nitrates reduce preload & lowers end diastolic pressure.
  • CCB’s are indicated only for unresponsive coronary spasm to nitrates.
  • β-Blockers are only anti-anginal drugs decreasing mortality in CAD patients (Post-MI).
  • β-Blockers acts by reducing myocardial oxygen demand.
  • β-Blockers are contraindicated in variant angina.
  • Fatty acid oxidation inhibitors act by altering myocardial metabolism.
  • Nicorandil is a potassium channel opener.
  • Nicorandil acts by coronary dilation, by activating myocardial ATP sensitive K+ channels.
  • Trimetazidine is a metabolic modifier.
  • Ranolazine is a 1st new antianginal drug approved by FDA, approved as first-line agent for chronic angina.
  • Ranolazine is a congener of trimetazidine.
  • Ranolazine is LC3-KAT inhibitor, spares fatty acid oxidation & inhibits late INa+ current in myocardium indirectly facilitating Ca2+ entry.
  • Ivabradine is a bradycardiac agent.
  • Fasudil is a selective Rho A/Rho kinase (ROCK) inhibitor.
  • Fasudil is used in angina & cerebral vasospasm.
  • Dipyridamole is a failure drug due to coronary steal phenomenon.
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