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Renin Angiotensin Mechanism.

AntiAnginal Drugs

  • The Drugs used in treatment of Angina pectoris are called as antianginal drugs.

Classification:

  1. Nitrates:
  • a) Short acting (10 minutes): Glyceryl tri nitrate. (Nitroglycerine, GTN)
  • b) Long Acting (1 hour): Isosorbide di nitrate, Isosorbide mono nitrate.
      2. Calcium channel blockers:
  • a) Phenyl alkyl amine: Verapamil.
  • b) Benzothiazepin: Diltiazem.
  • c) Dihydropyridines: Nifedipine, Amlodipine, Nimodipine, felodipine.
       3. Beta Adrenergic Blockers:  Propranolol, Atenolol, Metoprolol, Alprenolol.
       4. Potassium Channel Openers: Nicorandil.
       5. Miscellaneous: Dipyridamole, Trimetazidine, Ranolazine, Oxyphedrine etc.

Nitrates

1) Glyceryl Tri Nitrate:

  • It is heavy colorless explosive liquid.
  • It as an organic nitrate compound and is synthesized by nitration of glycerin.
  • Nitroglycerine was first used in treatment of angina pectoris by William Murrell in 1878.
IUPAC Name: 1,3-dinitrooxypropan-2-yl nitrate.

Mechanism of Action:

  • Nitroglycerin is converted into nitric oxide (NO) in smooth muscle and activates guanylyl cyclase, thereby increasing cGMP concentration, and resulting in smooth muscle relaxation.
  • Dilatation of the veins results in decreased venous return to the heart, thereby decreasing left ventricular volume (reduced preload) and decreasing myocardial oxygen requirements.
  • Arteriolar relaxation reduces arteriolar resistance (reduced afterload), thereby decreasing myocardial oxygen demands. In addition, nitroglycerine causes coronary artery dilatation, thereby improving myocardial blood distribution.

Therapeutic Uses:

  1. In treatment of angina attacks.
  2. As a tocolytic agent (Used in prevention of premature abortion)

Side effects / Toxic effects:

  1. Tachycardia.
  2. Orthostatic Hypotension.
  3. Throbbing headache.
  4. Can react with Sildenafil citrate and a like drugs to induce profound hypotension leading to death.

2) Isosorbide Mono Nitrate:

IUPAC Name: [(3S,3aR,6R,6aS)-3-hydroxy-2,3,3a,5,6,6a-hexahydrofuro[3,2-b]furan-6-yl] nitrate
  • Isosorbide-5-mononitrate, the long-acting metabolite of isosorbide dinitrate, is used as a vasodilatory agent in the management of angina pectoris.
  • By dilating the vessels, it lowers the blood pressure and reduces the left ventricular preload and afterload, therefore, leads to a reduction of myocardial oxygen requirement.

Calcium Channel Blockers.

  • The drugs which block calcium ion channels and are employed as vasodilators are called as Calcium Channel blockers.

Mechanism of Action:

  • These class of drugs block the voltage gated “L Type” of calcium ion channels and hence reduce intracellular calcium concentration and muscle contractility.

1) Verapamil:

  • It belongs to the “Phenyl Alkyl Amines” class of the calcium ion channel blockers.
IUPAC Name:  2-(3,4-dimethoxyphenyl)-5-[2-(3,4-dimethoxyphenyl)ethyl-methylamino]-2-propan-2-ylpentanenitrile;hydrochloride

Mechanism of Action:

  • Verapamil inhibits the transmembrane influx of extracellular calcium ions into myocardial and vascular smooth muscle cells, causing dilatation of the main coronary and systemic arteries and decreasing myocardial contractility.

 

  • This class of drug has following essential chemical features,
  1. The benzene ring,
  2. A tertiary amino nitrogen charged at physiological pH.
  3. The isopropyl group and other ring substituents are not found essential for the activity.

Therapeutic Uses:

  1. Angina pectoris.
  2. Management of hypertension.
  3. AV nodal cardiac arrhythmia.

Side Effects / Toxic effects:

  1. Heart failure.
  2. AV node depression.
  3. SA node depression.

2) Amlodipine:

  • Amlodipine is a synthetic “dihydropyridine” and a calcium channel blocker with antihypertensive and antianginal properties.
IUPAC Name: 3-O-ethyl 5-O-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate.

Mechanism of Action:

  • Amlodipine inhibits the transmembrane influx of extracellular calcium ions into myocardial and vascular smooth muscle cells, causing dilatation of the main coronary and systemic arteries and decreasing myocardial contractility.

Essential structural features for  activity:1-4 dihydropyridines

  1. The 1-4 dihydropyridine ring.
  2. The secondary nitrogen remaining uncharged at physiological pH.
  3. A bulky substituent at 4 position of the 1-4 dihydropyridine ring.
  4. NO2 and other ester moieties are not essential.

Therapeutic Uses:

  1. Angina pectoris.
  2. Management of hypertension.
  3. In certain cardiac arrhythmias.

Side Effects / Toxic effects:

  1. Hypotension.
  2. Swelling of ankles.
  3. Vertigo.

3) Diltiazem:

  • It belongs to the “Benzothiazepin” class of Calcium ion channel blockers.
IUPAC Name: [(2S,3S)-5-[2-(dimethylamino)ethyl]-2-(4-methoxyphenyl)-4-oxo-2,3-dihydro-1,5-benzothiazepin-3-yl] acetate;hydrochloride.

Mechanism of Action:

  • Diltiazem hydrochloride inhibits the transmembrane influx of extracellular calcium ions into select myocardial and vascular smooth muscle cells, causing dilatation of coronary and systemic arteries and decreasing myocardial contractility.

Structure Activity Relationship:

  1. The tertiary basic nitrogen is essential for action.
  2. N demethylation and quaternarization of nitrogen reduces the activity or abolishes the activity.

Side effects/ Toxic effects:

  1. Hypotension.
  2. Bradycardia.
  3. Dizziness.

Therapeutic Uses:

  1. Stable angina.
  2. Unstable angina.
  3. Variant angina.
  4. Supraventricular tachycardia.
  5. Atrial fibrillation.
  6. Atrial flutter.

Adrenergic Beta Blockers.

1) Atenolol:

  • It is well known beta blocker used in several cardiac conditions.
IUPAC Name:  2-[4-[2-hydroxy-3-(propan-2-ylamino)propoxy]phenyl]acetamide

Mechanism of Action:

  • Atenolol acts as a peripheral, cardio selective beta blocker specific for beta-1 adrenergic receptors, without intrinsic sympathomimetic effects.
  • It reduces exercise heart rates and delays atrioventricular conduction, with overall oxygen requirements decreasing.

Therapeutic uses:

  1. Hypertension.
  2. Angina.
  3. Myocardial infraction.
  4. Supraventricular Tachycardia.
  5. Ventricular tachycardia.
  6. Alcohol withdrawal symptoms.

Side effects / Toxic Effects:

  1. Hypotension.
  2. Bradycardia.
  3. Hypoglycemia.

Potassium channel openers:

1) Nicorandil:
  • Its a potassium channel opener drug used in treatment of angina pectoris.
IUPAC Name: 2-(pyridine-3-carbonylamino)ethyl nitrate.

Mechanism of action:

  • Nicorandil is a potassium channel opener with nitro vasodilator (NO donor) actions, making it both an arterial and a venous dilator.
  • It causes sustained dilation of both the arterial resistance and conductive vessels that increases coronary blood flow.

Therapeutic Uses:

  • In treatment of various angina.

Side effects / Toxic effects:

  1. Flushing.
  2. Palpitations.
  3. Perianal ulcerations.
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