Isordil Mechanism of Action

Pharmacologic Category: Organic Nitrate (Vasodilator).
Pharmacology: Pharmacodynamics: Animal Pharmacology: Isosorbide dinitrate, a direct-acting vasodilator, relaxes vascular smooth muscle. When administered intravenously to dogs, isosorbide dinitrate decreases systolic and diastolic blood pressure. Hind limb vascular resistance is decreased after femoral artery injection. Coronary blood flow increases secondary to vasodilation in the isolated rabbit heart. The parent drug was found to be a more potent vasodilator than its mononitrate metabolites.
Clinical Pharmacology: The exact mechanism of action of the nitrates in the relief of angina pectoris is not fully understood. They appear to relieve classic angina pectoris by reducing myocardial oxygen demand, i.e. by decreasing heart's "afterload" and "preload" through dilatation of peripheral venous capacitance and, to a lesser extent, arteriolar resistance vessels. Nitrates may cause a redistribution of coronary blood flow to ischemic areas by selectively dilating large coronary vessels or collateral vessels which may develop secondary to myocardial ischemia.
After therapeutic doses of the drug, systemic arterial pressure is usually decreased; heart rate is unchanged or undergoes slight compensatory increase. In the absence of heart failure, cardiac output transiently increases and then decreases. Pulmonary vascular resistance and pulmonary pressure are decreased.
The anti-anginal effects of isosorbide dinitrate generally occur within 2-5 minutes after administration and last 1-2 hours. The hemodynamic effects of oral tablets are observed from 20-60 minutes and last for 4-6 hours.
Pharmacokinetics: Gastrointestinal absorption of isosorbide dinitrate is rapid and complete. The drug undergoes an extensive first-pass effect with some interindividual variation. Isosorbide dinitrate is metabolized to two mononitrates which subsequently undergo glucoronidation. Less than 1% of isosorbide dinitrate is bound to plasma proteins. Plasma concentrations of isosorbide dinitrate and mononitrates were compared after administration of sublingual (2x5 mg) and oral (2x10 mg) tablets to volunteers. The sublingual dosage form was more rapidly absorbed than the oral formulation, as evidenced by earlier peak concentrations of the parent drug and the mononitrates. The half-life of the parent drug was 0.2-0.5 hours for the sublingual and oral tablets, respectively. For 2-isosorbide mononitrate, the half life was 2.0 hours for both dosage forms. For 5-isosorbide mononitrate, the half-life of the sublingual tablets was 5.8 hours while that of the oral tablets was 4.5 hours. With chronic administration, significant plasma accumulation of the parent compound occurs, presumably the result of the saturation of the intrahepatic biotransformation process.
The elimination phase after both acute and chronic administration of isosorbide dinitrate appears to be biexponential. Essentially all of the drug is eliminated by the kidneys, principally as isosorbide glucuronide.