Nicorandil

Side effects

Side effects listed in the British National Formulary include flushing, palpitations, weakness and vomiting. More recently, perianal, ileal, and peristomal ulceration has been reported as a side effect. Anal ulceration is now included in the British National Formulary as a reported side effect. Other side effects include severe migraine, toothache, and nasal congestion.

Mechanism of action

Nicorandil is an anti-angina medication that has the dual properties of a nitrate and ATP-sensitive channel opener. In humans, the nitrate action of nicorandil dilates the large coronary arteries at low plasma concentrations. At high plasma concentrations nicorandil reduces coronary vascular resistance, which is associated with increased ATP-sensitive channel (KATP) opening.

Nicorandil stimulates guanylate cyclase to increase formation of cyclic GMP (cGMP). cGMP activates protein kinase G (PKG), which phosphorylates and inhibits GTPase RhoA and decreases Rho-kinase activity. Reduced Rho-kinase activity permits an increase in myosin phosphatase activity, decreasing the calcium sensitivity of the smooth muscle.

PKG also activates the sarcolemma calcium pump to remove activating calcium. PKG acts on channels to promote K+ efflux and the ensuing hyperpolarization inhibits voltage-gated calcium channels. Overall, this leads to relaxation of the smooth muscle and coronary vasodilation.

The effect of nicorandil as a vasodilator is mainly attributed to its nitrate property. Yet, nicorandil is effective in cases where nitrates, such as nitroglycerine, are not effective. Studies show that this is due to its KATP channel agonist action which causes pharmacological preconditioning and provides cardioprotective effects against ischemia. Nicorandil activates KATP channels in the mitochondria of the myocardium, which appears to relay the cardioprotective effects, although the mechanism is still unclear. In experimental animal models of the Long QT syndrome, Nicorandil normalizes the prolonged cardiac action potential duration and the QT interval.

Synthesis

Amide reaction between Nicotinoyl Chloride [10400-19-8] & 2-Aminoethyl Nitrate [646-02-6].

The reaction of N-(2-Hydroxyethyl)Nicotinamide [6265-73-2] with nitric acid gives nicorandil.

Names

Brand names

Nicorandil is marketed under the brand names Ikorel (in the United Kingdom, Australia and most of Europe), Cordinic (in Russia), Angedil (in Romania, Poland), Dancor (in Switzerland), Nikoran, PCA (in India), Aprior (in the Philippines), Nitorubin (in Japan), and Sigmart (in Japan, South Korea, Taiwan and China). Nicorandil is not available in the United States.

References

References

1. (21 June 2022). "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017".
2. (March 2000). "Inhibition of myosin phosphatase by upregulated rho-kinase plays a key role for coronary artery spasm in a porcine model with interleukin-1beta". Circulation.
3. (2006). "Analogue-based Drug Discovery". John Wiley & Sons.
4. (June 2000). "Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism". Journal of Cardiovascular Pharmacology.
5. (July 2000). "Cyclic GMP-dependent protein kinase signaling pathway inhibits RhoA-induced Ca2+ sensitization of contraction in vascular smooth muscle". The Journal of Biological Chemistry.
6. (November 1988). "Cyclic GMP-dependent protein kinase stimulates the plasmalemmal Ca2+ pump of smooth muscle via phosphorylation of phosphatidylinositol". The Biochemical Journal.
7. (June 1998). "Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection?". Circulation.
8. (January 2011). "Nicorandil normalizes prolonged repolarisation in the first transgenic rabbit model with Long-QT syndrome 1 both in vitro and in vivo". European Journal of Pharmacology.
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