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Nicorandil belongs to the class of compounds known as potassium channel activators which are characterised by their arterial vasodilator properties. In addition, nicorandil has venodilating properties which are attributable to a nitrate group in its chemical structure. Therefore, by combining these two vasodilator mechanisms, nicorandil represents a novel type of compound for use in the treatment of angina pectoris. Furthermore, increasing experimental evidence suggests that potassium channel activation may also exert a direct cytoprotective effect by augmenting normal physiological processes which protect the heart against ischaemic events.
Comparative studies of up to 3 months’ duration suggest that nicorandil is equivalent in efficacy to isosorbide dinitrate, propranolol, atenolol, nifedipine or diltiazem in the treatment of stable angina. Preliminary evidence suggests that an improvement of anginal and ischaemic symptoms is maintained for up to 1 year. Whilst the efficacy of nicorandil in other types of angina has not been extensively studied, preliminary results indicate that intravenous nicorandil is as effective as isosorbide dinitrate in the treatment of unstable angina and is also effective in patients with variant angina. In addition, the limited data available indicate that nicorandil may be effective in patients with unstable and variant angina who are refractory to therapy with conventional antianginal agents, a potentially important area for further study.
Headache, mostly of mild to moderate intensity was the most commonly reported adverse event, occurring in one-third of patients receiving the recommended therapeutic regimen of nicorandil 10 to 20mg twice daily. In comparative trials involving a total of 84 patients who received nicorandil, the incidence of headache was similar to that produced by isosorbide mononitrate and isosorbide dinitrate. Headache was most frequent on initiating therapy but declined with continued treatment. To date, approximately 5% of patients participating in European trials have withdrawn due to headache, although this rate may be reduced by using a lower starting dose of nicorandil (5mg twice daily).
In summary, clinical experience thus far indicates that nicorandil, with its novel combination of two distinct vasodilator mechanisms, offers an effective alternative to established vasodilator therapy with conventional nitrates and calcium antagonists in the long term treatment of stable angina pectoris. Further studies are warranted to establish whether the unique pharmacodynamic profile of nicorandil is advantageous for the treatment of other types of angina and/or the ischaemic myocardium.
In patients with cardiovascular disease, the haemodynamic effects of nicorandil which are attributable to its nitrate-like properties include dilation of large coronary arteries (by 10 to 20%) and a spasmolytic action. In addition, as a result of potassium channel activation, intravenous administration of nicorandil (2mg; 0.1 or 0.2 mg/kg) decreased coronary vascular resistance (by 24 to 53%), resulting in an increase in coronary blood flow (of 26 to 93%) in resting subjects. Orally administered nicorandil 15 to 40mg produced a similar but nonsignificant decrease in coronary vascular resistance (by 10 to 32%) and increase in coronary sinus blood flow (⩽32%), although significant effects were measured during exercise in patients with evidence of old myocardial infarction.
At rest, administration of nicorandil intravenously (2 to 8 mg; 0.1 or 0.2 mg/kg) or as a single oral dose (5 to 80mg) decreased systemic vascular resistance (by 5 to 36%) and mean arterial pressure (by 5 to 24%), as well as indicators of venous return such as pulmonary capillary wedge pressure (by 14 to 45%) and left ventricular end-diastolic pressure (by 10 to 143%). Systemic vasodilation was occasionally associated with a transient increase in resting heart rate of up to 18%, although this was not observed in patients with congestive heart failure. Oral nicorandil 15 to 60mg did not consistently affect the systolic blood pressure response to exercise, although a decrease in preload is still evident (33%) and a transient increase in exercise heart rate may be apparent 30 minutes post dose (20 to 30mg).
The haemodynamic effects of nicorandil reach a peak within 1 to 2 minutes of intravenous administration or 30 to 60 minutes after a single oral dose (20 to 40 mg) and persist for up to 8 hours (40 to 60mg).
Several placebo-controlled studies in patients with stable effort angina have indicated that 2 hours after a single oral dose of nicorandil 5 to 60mg there is a significant improvement in anginal symptoms, including an increase in total exercise duration (by 12 to 36%), time to onset of angina (by 20 to 78%) and time to ST segment depression (by 25 to 94%); significant changes in these parameters have been reported 6 hours after a single dose of nicorandil (20 or 60mg) and for up to 12 hours following repeated twice daily administration (10 to 20mg).
In both animal and clinical studies, nicorandil has demonstrated a more prominent effect on systemic vascular resistance (afterload) and coronary blood flow than conventional nitrates. Furthermore, in contrast to nitroglycerin (glyceryl trinitrate), continuous intravenous infusion of nicorandil does not appear to be associated with the development of haemodynamic tolerance over a period of 24 hours, an effect also attributable to its nitrate-independent vasodilator activity as a potassium channel activator. Patients do not appear to develop a significant degree of tolerance to the antianginal effect of nicorandil 10 to 40mg twice daily during long term therapy (⩽ 1 year), although the issue of whether cross-tolerance can develop between nicorandil and conventional nitrates has yet to be resolved.
Thus, nicorandil may improve the balance between myocardial oxygen supply and demand through a combination of coronary vasodilation as well as a balanced decrease in systemic pre-and afterload. In addition, the direct effect of potassium channel activation on cardiac myocytes may account for the cardioprotective effect of nicorandil in animal models of myocardial infarction and ischaemia-reperfusion injury, as well as an anti-ischaemic effect in patients subjected to brief coronary artery occlusion during percutaneous transluminal coronary angioplasty.
Although the standard pharmacokinetic parameters of nicorandil have been measured in healthy volunteers, there are limited data in patients with cardiovascular disease. A single oral dose of nicorandil 5 to 20mg is rapidly absorbed, reaching peak plasma concentrations in 0.5 to 1 hours, corresponding with the peak systemic haemodynamic effect. Food significantly decreases the rate, but not the extent, of absorption. After a single oral dose (20mg) or intravenous injection (5mg) of nicorandil, the apparent distribution volume is 1 to 1.4 L/kg. In healthy volunteers, oral bio-availability of nicorandil following a 5mg oral dose was generally greater than 75%, suggesting that nicorandil is not subject to extensive ‘first-pass’ hepatic metabolism.
Nicorandil is rapidly eliminated from the plasma with a half-life of about 50 minutes and the plasma concentrations are reduced to 4% of peak values after 8 hours, although very low plasma concentrations are maintained for up to 24 hours due to a further disposition process, possibly involving release of the drug from the endothelium wall of blood vessels.
The main route of elimination from the plasma appears to be denitration by the liver to the pharmacologically inactive alcohol metabolite A -(2-hydroxyethyl)-nicotinamide, followed by urinary excretion. In addition, N-(2-hydroxyethyl)-nicotinamide may be further degraded into nicotinic acid and related metabolites, some of which may become incorporated into cellular pools of these naturally occurring endogenous nucleotides. This latter metabolic pathway may underlie the observation that plasma concentrations of nicorandil appear to show a circadian rhythm, whilst saturable entry into these endogenous pools may also contribute to the small but significant plasma accumulation of the drug following repeated twice daily administration (10 to 20mg).
As a result of extensive hepatic metabolism, renal clearance of the unchanged drug is low (<1% of the original dose) and the pharmacokinetic profile of nicorandil does not appear to be significantly altered in the elderly or in patients with renal impairment (creatinine clearance <1.2 L/h). It is currently unclear whether the pharmacokinetics of nicorandil are affected to a clinically significant degree in patients with hepatic impairment.
Nicorandil has been most extensively investigated in the treatment of effort-induced angina pectoris. In comparative trials (n ⩽140 patients) lasting up to 3 months, twice daily dosage with nicorandil 10 to 20mg was as effective as standard therapy with isosorbide mononitrate, isosorbide dinitrate, propranolol, atenolol, nifedipine or diltiazem. An open-label dose titration study involving 106 patients with coronary artery disease demonstrated that twice daily regimens of nicorandil 10 to 40mg maintained an improvement in objective and subjective indicators of angina and myocardial ischaemia throughout the year-long treatment period. Few trials have investigated the efficacy of nicorandil in other types of angina, although a single short term (⩽9 days) comparative trial indicated that intravenous nicorandil (2 to 6 mg/h for 3 to 9 hours) was of equivalent efficacy to isosorbide dinitrate (2 to 6 mg/h for 3 to 9 hours) in unstable angina. In addition, nicorandil may be effective in improving the symptoms of unstable and variant angina in patients who are refractory to conventional therapy with a combination of nitrates, β- blockers and calcium antagonists. Likewise, in a 3-day noncomparative trial, nicorandil 5 to 10mg 4 times daily markedly reduced anginal attack frequency and ST segment elevation in patients with variant angina pectoris. However, as yet, no comparative studies with nitrates and/or calcium channel antagonists have been published.
The tolerability of nicorandil has been assessed in more than 1680 European patients. Overall, the qualitative as well as quantitative pattern of adverse events are those typically associated with vasodilator therapy; mild to moderate headache was the most frequently reported adverse event, occurring in 20 to 50% of patients treated with the recommended therapeutic dose (10 to 20mg twice daily). In comparative trials, the incidence of headache was similar to that associated with the conventional nitrate vasodilators, isosorbide mononitrate and isosorbide dinitrate. Headaches were most frequently reported during the first few days of nicorandil treatment, although they usually resolved with continued therapy. To date, headache has caused approximately 5% of patients to withdraw during European clinical trials, although the withdrawal rate may be reduced, particularly in patients prone to headache, using a starting dose (5mg twice daily) lower than the recommended therapeutic dose.
Other less common adverse events associated with nicorandil treatment include dizziness, palpitations and gastrointestinal disturbances (gastralgia, nausea and vomiting); postural hypotension leading to dizziness and syncope has been associated with high starting doses (⩾40 mg).
Heart rate was not significantly affected in long-term studies using nicorandil 10 to 80 mg/ day and there is no evidence of a proarrhythmogenic effect in patients with coronary heart disease or heart failure. Similarly, there have been no reports of unexpected drug interactions during concomitant therapy with other classes of antianginal drugs.
The tolerability profile of nicorandil appears to have been confirmed by a 6-year postmarketing surveillance study involving 14 530 Japanese patients treated with nicorandil (5 to 10mg 3 times daily), which validated that headache, gastrointestinal disturbances and dizziness were the most commonly reported adverse events.
Dosage and Administration
Nicorandil dosage should be individually titrated in order to provide acceptable relief from anginal symptoms, whilst causing minimum adverse vasodilator-related effects such as headache and postural hypotension. Clinical results indicate that an initial oral dose of 10mg twice daily, increasing to a maximum of 40mg twice daily, is effective in improving the symptoms of effort-induced angina in patients with coronary artery disease. In patients particularly prone to headache, a lower starting dose of nicorandil 5mg twice daily (for as little as 2 days) can subsequently reduce the incidence and severity of headache.
KeywordsNicorandil Pinacidil Cardiovascular Pharmacology Isosorbide Dinitrate Variant Angina
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