Chemical formula: C₈H₉N₃O₄ Molecular mass: 211.177 g/mol PubChem compound: 47528
Nicorandil, a nicotinamide ester, is a vasodilator agent with a dual mechanism of action, which leads to relaxation of smooth tonic vascular muscles in both venous and arterial part of vessels.
It possesses a potassium channel opening effect. This activation of potassium channels induces vascular cell membrane hyperpolarisation with an arterial muscle relaxant effect, thereby leading to arterial dilation and afterload reduction. In addition, the activation of the potassium channel leads to cardioprotective effects mimicking ischemic preconditioning.
Due to its nitrate moiety, nicorandil also relaxes vascular smooth muscle, particularly in the venous system via an increase in intracellular cyclic guanosine monophosphate (cGMP). This results in an increased pooling in capacitance vessels with a decrease in preload.
Nicorandil has been shown to exert a direct effect on coronary arteries, both on normal and stenotic segments, without leading to a steal phenomenon. Furthermore, the reduction of end-diastolic pressure and wall tension decreases the extravascular component of vascular resistance. Ultimately, this results in an improved oxygen balance in the myocardium and improved blood flow in the post-stenotic areas of the myocardium.
Furthermore, nicorandil has demonstrated a spasmolytic activity in both in vitro and in vivo studies and reverses coronary spasm induced by methacholine or noradrenalin.
Nicorandil pharmacokinetics are linear from 5 mg to 40 mg.
After oral administration, nicorandil is absorbed rapidly and completely from the gastrointestinal tract, independent from food intake. The absolute bioavailability is about 75%. There is no significant hepatic first pass effect. Maximum plasma concentrations (Cmax) are reached after about 30 to 60 minutes. The plasma concentration (and the area under the curve (AUC)) shows a linear proportionality to the dose.
Steady state is rapidly achieved (within 4 to 5 days) during repeated oral administration (bid regimen). At steady state, the accumulation ration (based on AUC) is around 2 for 20 mg bid tablet and 1.7 for 10 mg bid tablet.
Distribution of the product throughout the body remains stable, irrespective of dose, within the therapeutic range.
The volume of distribution of nicorandil after intravenous (iv) dosing is 1.04 L/kg of body weight. Nicorandil is only slightly bound to human plasma proteins (bound fraction estimated at about 25%).
Nicorandil is principally metabolised in the liver by denitration into a series of compounds without cardiovascular activity. In plasma unchanged nicorandil accounted for 45.5% of the radioactive AUC and the alcohol metabolite, N-(20hydroxyethyl)-nicotinamide for 40.5%. The other metabolites accounted for the remaining 20% of the radioactive AUC.
Nicorandil is mainly eliminated in urine as metabolites since parent product is less than 1% of the administered dose in human urine (0–48 hours). N-(2-hydroxyethyl)-nicotinamide is the most abundant metabolite (about 8.9% of the administered dose within 48 hours) followed by nicotinuric acid (5.7%), nicotinamide (1.34%), N-methyl-nicotinamide (0.61%) and nicotinic acid (0.40%). These metabolites represent the major route of transformation of nicorandil.
Decrease in plasma concentrations occurs in two phases:
After 4–5 mg intravenous dosing (5 min infusion), the total body clearance was approximately 40–55 L/hour.
Nicorandil and its metabolites are mainly excreted by urinary route, faecal excretion being very low.
No clinically relevant modifications of the nicorandil pharmacokinetic profile is evidenced in population at risk such as elderly people, liver disease patients and chronic renal failure patients.
The metabolism of nicorandil appears not to be significantly modified by cimetidine or rifampicin, respectively an inhibitor and an inducer of liver microsomal mixed-function oxidases.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential.
Fertility studies showed no effects on mating ability in either male or female rats, decreases in the number of live foetuses and implantation sites were noted at high doses. Histopathological changes of the testes (diminished spermatogenic cells) were determined in repeated dose toxicity studies. Additional investigative studies for testicular toxicity revealed decreased blood flow in the testis and decreased blood levels of testosterone. These results suggest that testicular toxicity by nicorandil is related to a sustained decrease in blood flow caused by reduction of cardiac output. Upon cessation of treatment, recovery from nicorandil-induced testicular toxicity was observed after 4 weeks; which indicates that the observed changes are reversible.
Radioactivity passed through the placenta in pregnant rats after administration of radioactively marked nicorandil.
Following exposure to nicorandil at doses that were maternally toxic, embryotoxicity was observed in the rat and rabbit. There was no evidence of teratogenicity (rat and rabbit), or abnormal pre- or post-natal physical or behavioural development (rat).
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