Organic Nitrates

     The nitrates constitute one of the oldest treatments of angina pectoris. They are also used in acute ischemic syndromes and in heart failure. The main physiologic action of the nitrates is vasodilation, particularly of the systemic veins.

Mechanism of Action
     Nitrates produce vascular smooth muscle relaxation. The proposed mechanism involves the conversion of the administered drug to nitric oxide at or near the plasma membrane of vascular
smooth muscle cells. Nitric oxide, in turn, activates guanylate cyclase to produce cyclic guanosine monophosphate (cGMP), and the intracellular accumulation of cGMP leads to smooth muscle relaxation. This mechanism of vascular smooth muscle relaxation is similar to that associated with nitroprusside and endogenous endothelial-derived nitric oxide.

Hemodynamic Effects and Clinical Uses
     At low doses, nitroglycerin, the prototypical organic nitrate, produces greater dilation of veins than of arterioles. The venodilation results in venous pooling, diminished venous return, and hence decreased right and left ventricular filling. Systemic arterial resistance is generally unaffected, but cardiac output may fall because of the diminished preload, especially in patients with intravascular volume depletion. Arterial dilation occurs to some extent in the coronary arteries and may also occur in the facial vessels and the meningeal arterioles, giving rise to the side effects of flushing and headache, respectively.
     At high doses, nitrates can result in widespread arteriolar dilation, which may result in systemic hypotension and refl ex tachycardia. However, the increase in heart rate is not typically manifest in patients with heart failure, because decreasing afterload in that situation may actually improve cardiac output and reduce the sympathetic drive.
     The major use of nitrates is in the treatment of angina pectoris through venodilation leading to reduced left ventricular preload. The smaller left ventricular size lowers ventricular wall stress
and myocardial oxygen consumption, which alleviates the oxygen imbalance in ischemic states. Nitrates are also useful in patients with coronary artery spasm (Prinzmetal variant angina) by dilating
the coronary arterioles.

Agents and Pharmacokinetics
     Many formulations of nitrates are available. When the relief of acute angina is the objective, rapid onset of action is essential. However, in the long-term prevention of anginal attacks in a patient with chronic CAD, duration of action and predictability of effect are more crucial than the speed of drug effect.
     Sublingual nitroglycerin tablets or sprays are used in the treatment of acute angina attacks.
The peak action of these agents occurs within 3 minutes, because they are rapidly absorbed into the bloodstream via the oral mucosa; their effect, however, diminishes rapidly, falling off within 15 to 30 minutes, as the drug is deactivated in the liver. These forms of nitroglycerin are also effective when taken prophylactically, immediately before situations known by the patient to produce angina (e.g.,
before walking up a hill).
     Long-acting nitrates are used to prevent chest discomfort in the chronic management of CAD and must be given in suffi cient dosage to saturate the liver’s deactivating capacity. For this purpose, oral doses of sustained-release nitroglycerin, isosorbide dinitrate, or isosorbide mononitrate are used. These agents have a duration of action of 2 to 14 hours. Transdermal nitroglycerin patches or nitroglycerin
paste applied to the skin also deliver a sustained release of nitroglycerin. Of note, the effi cacy of long-acting nitrate therapy is attenuated by the rapid development of drug tolerance with continuous
use. For this reason, it is important that the dosing regimens allow a drug-free interval of several hours each day to maintain effi cacy. Intravenous nitroglycerin is administered by continuous infusion. This form is most useful in the treatment of hospitalized patients with unstable angina or acute heart failure.

Adverse Effects
     The most common adverse effects of the nitrates include hypotension, reflex tachycardia, headache, and flushing.