Mechanism of Action of Isosorbide Dinitrate
Isosorbide dinitrate works by relaxing vascular smooth muscle through the release of nitric oxide, which activates guanylate cyclase to produce cyclic GMP, ultimately reducing intracellular calcium and causing vasodilation—this results in decreased preload through venous dilation and reduced afterload through arterial dilation, thereby lowering myocardial oxygen demand. 1
Primary Vascular Effects
Isosorbide dinitrate acts as an endothelium-independent vasodilator that primarily dilates capacitance vessels (the venous bed), increasing venous pooling and decreasing myocardial preload, which reduces left ventricular end-diastolic pressure and pulmonary capillary wedge pressure 2, 1
Arteriolar relaxation occurs with higher doses, reducing systemic vascular resistance, systolic arterial pressure, and mean arterial pressure (afterload) 1
Coronary artery dilation also occurs, improving oxygen supply to the myocardium, though the relative importance of preload reduction, afterload reduction, and coronary dilation in its therapeutic effect remains undefined 2, 1
Molecular Mechanism
The drug works by serving as an exogenous source of nitric oxide, replenishing or restoring the actions of endothelium-derived relaxing factor 3
Nitric oxide derived from isosorbide dinitrate stimulates soluble guanylate cyclase through metabolization catalyzed by enzymes such as glutathione S-transferase, cytochrome P-450, and possibly esterases 4
The cyclic GMP produced by guanylate cyclase acts via cGMP-dependent protein kinase, which ultimately lowers intracellular calcium through increased uptake to intracellular stores and decreased release from these stores 4
Hemodynamic Consequences
Decreased cardiac work and lower myocardial oxygen requirements result from the combined effects of preload and afterload reduction 3
The drug reduces right and left ventricular preload through peripheral vasodilation, which is particularly beneficial in conditions where myocardial oxygen demand exceeds supply 3
Pharmacokinetic Considerations
Isosorbide dinitrate undergoes extensive first-pass metabolism in the liver, with bioavailability of approximately 25%, though this increases progressively during chronic therapy 1
The drug is metabolized primarily by denitration to two active metabolites: the 2-mononitrate (15-25%) and the 5-mononitrate (75-85%), with the 5-mononitrate having an overall half-life of about 5 hours and significant biological activity 1
The parent compound has a serum half-life of about one hour, but the active metabolites contribute to a duration of action of up to 8 hours with standard oral formulations 2, 1
Important Clinical Caveat
Continuous therapy leads to tolerance development, as the anti-anginal efficacy is lost after 24 hours or less of continuous exposure; only after nitrates have been absent from the body for several hours (at least 10-14 hours) is their efficacy restored 2, 3, 1
The three-times-daily dosing regimen naturally provides the necessary nitrate-free interval to prevent tolerance, unlike once-daily or continuous formulations 5