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Nicorandil

An Updated Review of its Use in Ischaemic Heart Disease with Emphasis on its Cardioprotective Effects

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Summary

Abstract

Nicorandil is a drug with both nitrate-like and ATP-sensitive potassium-channel (K+ATP) activating properties. By virtue of this dual mechanism of action, the drug acts as a balanced coronary and peripheral vasodilator and reduces both preload and afterload.

The K+ATP channel has been shown to be involved in the phenomenon of myocardial preconditioning, and studies in animal models of ischaemia-reperfusion-induced myocardial stunning or infarction indicate that nicorandil has cardioprotective effects. Studies in patients undergoing percutaneous transluminal coronary angioplasty (PTCA) have shown that the administration of nicorandil reduces ST-segment elevation during ischaemia.

Nicorandil significantly improved the results of exercise tolerance tests versus baseline in patients with stable effort angina pectoris in early noncomparative trials. The drug also improved the results of exercise tolerance tests relative to placebo in early randomised, double-blind, placebo-controlled trials.

In randomised, double-blind comparative studies in patients with angina pectoris, nicorandil has demonstrated equivalent efficacy, as measured by exercise tolerance testing, to isosorbide di- and mononitrate, metoprolol, propranolol, atenolol, diltiazem, amlodipine and nifedipine.

The effects of nicorandil on various aspects of myocardial recovery from ischaemic damage caused by acute myocardial infarction have been investigated in the short term. Regional left ventricular (LV) wall motion, a marker of myocardial function, was significantly improved in nicorandil recipients relative to control.

The main adverse event associated with nicorandil as treatment for angina pectoris is headache. This can be minimised by commencing nicorandil at a low dose in patients prone to headache. There have been infrequent case reports of mouth ulcers in patients receiving nicorandil; causality has not been conclusively established, but product prescribing information indicates that an alternative treatment should be considered if persistent aphthous or severe mouth ulceration occurs.

Thus, nicorandil remains a useful background therapy for patients with angina pectoris. The drug has also demonstrated potential cardioprotective effects when used as part of an intervention strategy directly after acute myocardial infarction in high-risk patients. Further large scale longer term studies of nicorandil in this latter indication are awaited with interest.

Pharmacological Properties

Nicorandil has both nitrate-like and ATP-sensitive potassium-channel (K+ATP) activating properties. By virtue of this dual mechanism of action, the drug acts as a balanced coronary and peripheral vasodilator and reduces both preload and afterload. Nicorandil decreases ventricular volume, coronary vascular resistance and mean arterial pressure. Heart rate and coronary blood flow have been shown to either increase or remain unchanged.

Nicorandil has been shown to significantly increase poststenotic quantitative coronary blood flow after intracoronary injection (0.5mg) and significantly reduce exercise-induced increases in mean systemic arterial pressure and left ventricular (LV) filling pressure without altering cardiac stroke volume index or heart rate after oral administration (20mg). Nicorandil improved myocardial perfusion during exercise in patients with previous myocardial infarction or angina pectoris.

Tolerance to nicorandil does not develop in patients with congestive heart failure; findings from limited investigations in patients with ischaemic heart disease are inconclusive.

Several studies in various animal models of ischaemia-reperfusion-induced myocardial stunning or infarction indicate that nicorandil has cardioprotective effects, which have also been shown in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). Nicorandil was associated with less isch-aemia according to measurements of ST-segment elevation: in the larger of 2 studies this effect was significant at 30 and 60 seconds relative to control but at 120 seconds the extent of ischaemia was similar in the control and nicorandil groups. Conversely, the extent of ischaemia in an active control group given isosorbide dinitrate was similar to that in the control group at all time-points measured.

A study of the effects of nicorandil on myocardial energy metabolism demonstrated that myocardial extraction ratios of hypoxanthine and ammonia — indirect markers of cellular energy metabolism — were significantly higher in nicorandil versus placebo recipients, as was the myocardial extraction ratio of lactate, indicating improved myocardial energy metabolism with nicorandil.

Pharmacokinetic Properties

Orally administered nicorandil is rapidly absorbed with peak plasma concentrations (Cmax) occurring 0.5 to 1 hour after administration of a single dose. Cmax rises in proportion with oral doses of between 5 and 40mg. During repeated administration of nicorandil 20mg twice daily, steady-state plasma concentrations of ≈250 to 300 μg/L occur within 4 days of the first dose. The bioavailability of oral nicorandil is >75%. Food delays the rate of absorption of nicorandil but this has minimal effect on bioavailability or Cmax.

The apparent volume of distribution of nicorandil was 1 to 1.4 L/kg after either a 20mg oral dose or a 5mg intravenous dose. The drug was 19 and 24% bound to albumin and total plasma protein, respectively.

A single dose of nicorandil is almost entirely eliminated from plasma within 8 hours. The half-life of the first rapid phase of elimination (t1/2β) was ≈45 minutes after oral or intravenous administration of nicorandil to volunteers or patients with ischaemic heart disease.

In healthy volunteers, ≤60% of the cumulative total of nicorandil metabolites is excreted in the urine within 24 hours of administration of the drug. Only ≈1% of single or repeated 20mg oral doses is recovered from the urine as unchanged nicorandil. The mean total body clearance of nicorandil is between 52 and 69 L/h.

Pharmacokinetic studies in patients with hepatic or renal impairment suggest that dosage adjustment of nicorandil is not required in these patient groups. The pharmacokinetic properties of nicorandil are not influenced by age.

Therapeutic Efficacy

In early noncomparative trials, nicorandil significantly improved the results of exercise tolerance tests versus baseline in patients with stable effort angina pectoris. The drug also improved the results of exercise tolerance tests relative to placebo in early randomised, double-blind, placebo-controlled trials.

Nicorandil has demonstrated equivalent efficacy, as measured by exercise tolerance testing, to isosorbide di- and mononitrate, metoprolol, propranolol, atenolol, diltiazem, amlodipine and nifedipine in well-designed comparative trials of up to 12 weeks’ duration in patients with stable angina pectoris.

Fewer episodes of ischaemia or arrhythmia occurred during 48 hours’ treatment with nicorandil compared with placebo in patients with unstable angina pectoris.

The effects of nicorandil on various aspects of myocardial recovery from ischaemic damage caused by acute myocardial infarction have been investigated in the short (≈1 month) term. In most studies nicorandil was administered as an intravenous or intracoronary injection before reperfusion was attempted. Studies were usually small, with all but 1 enrolling fewer than 50 patients per group.

Regional LV wall motion assessed by echocardiograph was significantly improved in nicorandil recipients relative to control in all studies that measured this parameter, indicating functional improvement. The proportion of patients with no-reflow phenomenon was lower with nicorandil than control in 2 studies but was similar to control in another.

Administration of nicorandil was not associated with significant changes in LV ejection fraction or cardiac index relative to control. The drug significantly decreased end-diastolic volume index versus control in 1 study but not versus baseline in another.

Tolerability

During the European clinical development programme, the total incidence of adverse events among nicorandil recipients was similar to that in patients who received comparator drugs. Mild to moderate headache was the most frequently reported adverse event, occurring in 36% of patients with angina pectoris treated with oral nicorandil. The incidence of headache was highest during initial treatment with the drug but generally resolved within a few days. Headache was the most frequent reason for treatment withdrawal in the European clinical development programme, accounting for 5% of all withdrawals in nicorandil recipients, and was less frequent with a lower dosage (5mg twice daily) than a higher dosage (10mg twice daily).

A later prescription-event monitoring study involving 13 260 patients also reported that headache was the most frequent adverse event reported during nicorandil treatment (9.4 events per 1000 patient-months during the treatment period).

Other than headache, the most frequently reported adverse events were dizziness, nausea and malaise.

There have been case reports of mouth ulcers developing during nicorandil treatment, but there is at present no clear evidence of a causal relationship.

Dosage and Administration

According to UK guidelines, the recommended initial dosage of nicorandil is 10mg orally twice daily; however, a 5mg starting dose may be used in patients particularly susceptible to headache. The dosage should be titrated to effect, up to a maximum of 30mg twice daily; most patients respond to a dosage of between 10 and 20mg twice daily. Dosage adjustment is not necessary in elderly patients. Paediatric studies have not been conducted and the use of nicorandil in this patient group is not recommended.

Nicorandil is contraindicated in patients with cardiogenic shock, LV failure with low filling pressures, and in hypotension. The drug is also contraindicated in patients who have demonstrated an idiosyncratic response or hypersensitivity. Alternative treatment should be considered if patients develop persistent aphthous or severe mouth ulceration during treatment with nicorandil.

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  1. Adis International Limited, 41 Centorian Drive, Private Bag 65901, Mairangi Bay, Auckland 10, New Zealand

    Anthony Markham, Greg L. Plosker & Karen L. Goa

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  1. Anthony Markham
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Correspondence to Karen L. Goa.

Additional information

Various sections of the manuscript reviewed by: N. Dunn, Drug Safety Research Unit, Bursledon Hall, Bursledon, Southampton, England; H. Fujiwara, 2nd Department of Internal Medicine, Gifu University School of Medicine, Gifu, Japan; G. J. Gross, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA; H. Kambara, Cardiovascular Center, Osaka Red Cross Hospital, Osaka, Japan; S. T. O’Rourke, Department of Pharmaceutical Sciences, College of Pharmacy, North Dakota State University, Fargo, North Dakota, USA; S. Saito, Cardiology Division of 2nd Department Medicine, Nihon University School of Medicine, Tokyo, Japan; S. Sen, Klinik für Innere Medizin, Abteiling II, Stadtische Klinken Höchst, Frankfurt, Germany;M.Yokota, Cardiovascular Section, Department of Clinical Pathophysiology, Nagoya University, Graduate School of Medicine, Nagoya, Japan.

Data Selection

Sources: Medical literature published in any language since 1992 on Nicorandil, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International, Auckland, New Zealand). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘Nicorandil’ or ‘SG-75’. EMBASE search terms were ‘Nicorandil’ or ‘SG-75’. AdisBase search terms were ‘Nicorandil’ or ‘SG 75’. Searches were last updated 12 Sep 2000.

Selection: Studies in patients with angina pectoris or myocardial infarction who received nicorandil. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: nicorandil, angina pectoris, cardioprotection, pharmacodynamics, pharmacokinetics, therapeutic use.

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Markham, A., Plosker, G.L. & Goa, K.L. Nicorandil. Drugs 60, 955–974 (2000). https://doi.org/10.2165/00003495-200060040-00007

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