Vasodilator Therapy: Nitrates and Nicorandil

Abstract

Nitrates have been used to treat symptoms of chronic stable angina for over 135 years. These drugs are known to activate nitric oxide (NO)-cyclic guanosine-3′,-5′-monophasphate (cGMP) signaling pathways underlying vascular smooth muscle cell relaxation, albeit many questions relating to how nitrates work at the cellular level remain unanswered. Physiologically, the anti-angina effects of nitrates are mostly due to peripheral venous dilatation leading to reduction in preload and therefore left ventricular wall stress, and, to a lesser extent, epicardial coronary artery dilatation and lowering of systemic blood pressure. By counteracting ischemic mechanisms, short-acting nitrates offer rapid relief following an angina attack. Long-acting nitrates, used commonly for angina prophylaxis are recommended second-line, after beta-blockers and calcium channel antagonists. Nicorandil is a balanced vasodilator that acts as both NO donor and arterial K + ATP channel opener. Nicorandil might also exhibit cardioprotective properties via mitochondrial ischemic preconditioning. While nitrates and nicorandil are effective pharmacological agents for prevention of angina symptoms, when prescribing these drugs it is important to consider that unwanted and poorly tolerated hemodynamic side-effects such as headache and orthostatic hypotension can often occur owing to systemic vasodilatation. It is also necessary to ensure that a dosing regime is followed that avoids nitrate tolerance, which not only results in loss of drug efficacy, but might also cause endothelial dysfunction and increase long-term cardiovascular risk. Here we provide an update on the pharmacological management of chronic stable angina using nitrates and nicorandil.

The Role of Nitroglycerin and Other Nitrogen Oxides in Cardiovascular Therapeutics

“…Oral isosorbide mononitrate is completely absorbed and has 100% bioavailability as it avoids first pass metabolism. This leads to a more predictable dose-response and plasma levels with less variation when compared to other nitrates (53,59). Pentaerythrityl tetranitrate is a long-acting organic nitrate available in an oral formulation that acts within 10 to 20 minutes and has a duration of action of eight to 12 hours (55).…”

“…These compounds are prodrugs with a nitrooxy (-O-NO 2 ) moiety and are metabolized to produce bioactive metabolites (52,53). The bioactivation of organic nitrates causes liberation of NO, allowing them to serve as NO donors (53,54). Nitric oxide then causes vasodilation via its effect on vascular smooth muscle cells, and impairs platelet activation as previously discussed (12).…”

“…Nitrates are rapidly absorbed from mucous membranes, the gastrointestinal tract, and the skin (53). Thus, nitroglycerin is available in several preparations for delivery via several routes: oral tablets, sublingual tablets, buccal tablets, sublingual spray, transdermal ointment, and transdermal patch; it is also available in intravenous formulations, which are used in hospitalized patients with angina, hypertension, or heart failure (Figure 3, Table 1) (8,57).…”

“…Isosorbide dinitrate is rapidly absorbed and undergoes extensive first-pass metabolism by the liver, which results in low bioavailability (8,53). Sustained-release formulations have a slower rate of absorption and can provide therapeutic plasma concentrations of the drug for up to 12 hours (8).…”

“…Nicorandil is a nicotinamide-nitrate ester whose chemical structure consists of a nicotinamide derivative combined with a nitrate moiety (53). Nicorandil acts as both a NO donor and a K + ATP channel opener to provide anti-anginal effects (61).…”