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15 Vasodilatorsto isosorbide 2-mononitrate and isosorbide 5-mononitrate (ISMN), both of which
probably confer the majority of the activity of ISDN. ISMN has a much longer half-
life (4.5 hours) and is used in its own right. It is not subject to hepatic first-pass
metabolism and has an oral bioavailability of 100%. Both are used in the prophylaxis
of angina.Potassium-channel activators
Nicorandil
Nicorandil (nicotinamidoethyl nitrate) is a potassium-channel activator with a
nitrate moiety and as such differs from other potassium-channel activators. It has
been used in Japan since 1984 and was launched in the UK in 1994.Presentation and uses
Nicorandil is available as tablets and the usual dose is 10–30 mg bd. It is used for the
treatment and prophylaxis of angina and in the treatment of congestive heart failure
and hypertension. It has been used experimentally via the intravenous route.Mechanism of action
ATP-sensitive K+channels are closed during the normal cardiac cycle but are open
(activated) during periods of ischaemia when intracellular levels of ATP fall. In the
open state K+passes down its concentration gradient out of the cell resulting in
hyperpolarization, which closes Ca^2 +channels resulting in less Ca^2 +for myocardial
contraction.
Nicorandil activates the ATP-sensitive K+channels within the heart and arterioles.
Inaddition, nicorandil relaxes venous capacitance smooth muscle by stimulating
guanylate cyclase via its nitrate moiety, leading to increased intracellular cGMP.Effects
Cardiovascular – nicorandil causes venodilation and arterial vasodilation result-
ing in a reduced pre- and afterload. The blood pressure falls. Left ventricular end-
diastolic pressure falls and there is an improved normal and collateral coronary
artery blood flow, partly induced by coronary artery vasodilation without a ‘steal’
phenomenon. An increase in cardiac output is seen in patients with ischaemic
heart disease and cardiac failure. It is effective at suppressing torsades de pointes
associated with a prolonged QT interval. High concentrations in vitro result in a
shortened action potential by accelerated repolarization. It also reduces the size
of experimentally induced ischaemia, the mechanism of which is uncertain, so
that an alternative, as yet undefined, cardioprotective mechanism has been pos-
tulated. Unlike nitrate therapy it is not associated with tolerance during prolonged
administration. Contractility and atrioventricular conduction is not affected.
Central nervous system – headaches, these usually clear with continued therapy.