trate or its metabolites are excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when isosorbide dinitrate is administered to a woman who is breast-feeding. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
MECHANISM OF ACTION
Similar to other nitrites and organic nitrates, isosorbide dinitrate is converted in vitro to the active intermediate compound nitric oxide (NO), a reactive free radical. Nitric oxide is also formed endogenously and is believed to be endothelial-derived growth factor. Among other properties, NO is believed to produce vasodilation. Nitric oxide activates the enzyme guanylate cyclase, thereby stimulating the synthesis of cyclic guanosine 3',5'-monophosphate (cGMP). This second messenger then activates a series of protein kinase-dependent phosphorylations in the smooth muscle cells, eventually resulting in the dephosphorylation of the myosin light chain of the smooth muscle fiber and the subsequent release, or extrusion, of calcium ions. The contractile state of smooth muscle is normally maintained by a phosphorylated myosin light chain (stimulated by an increase in calcium ions). Thus, the nitrite- or nitrate-induced dephosphorylation of the myosin light chain signals the cell to release calcium, thereby relaxing the smooth muscle cells and producing vasodilation.
It is believed that nitrates correct myocardial oxygen imbalances by reducing systemic and pulmonary arterial pressure (afterload) and decreasing cardiac output secondary to peripheral dilation rather than coronary artery dilation. Nitrates therefore relax peripheral venous vessels, causing a pooling of venous blood and decreased venous return to the heart, which decreases preload. Nitrates reduce both arterial impedance and venous filling pressures, resulting in a reduction of the left ventricular systolic wall tension, thereby decreasing afterload. Thus, nitrate-induced vasodilation increases venous capacitance and decreases arteriole resistance, thereby reducing both the preload and afterload and lowering the cardiac oxygen demand.
Total coronary blood flow may be increased by nitrites and nitrates in patients with normal hearts, but in patients with ischemia the drug does not increase total coronary blood flow but simply redistributes blood to ischemic areas. This effect is believed to be due to the drug's preferential dilation of the larger conductive vessels of the coronary circulation, which, in the presence of coronary atherosclerosis, redirects the distribution of the coronary blood supply to ischemic areas.
Nitrates cause a transient reflex compensatory increase in heart rate and myocardial contractility that would normally increase myocardial oxygen consumption, yet the nitrate-induced decrease in ventricular wall tension results in a net decrease in myocardial oxygen demand and amelioration of the pain of angina pectoris. In addition, isosorbide relaxes all other types of smooth muscle including bronchial, biliary, GI, ureteral, and uterine. Nitrites and nitrates are functional antagonists of acetylcholine, norepinephrine, and histamine.
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