Nicorandil

Nicorandil is a vasodilator drug used to treat angina, which is chest pain that results from episodes of transient myocardial ischemia. Angina can be caused by diseases such as atherosclerosis, coronary artery disease, and aortic stenosis.^[2]

Nicorandil

Clinical data
Trade names	Ikorel, others
AHFS/Drugs.com	International Drug Names
Pregnancy category	AU: B3
Routes of administration	By mouth
ATC code	C01DX16 (WHO)
Legal status
Legal status	AU: S4 (Prescription only)[1] UK: POM (Prescription only)
Pharmacokinetic data
Bioavailability	75 to 80%
Protein binding	25%
Metabolism	Liver
Elimination half-life	1 hour
Excretion	Kidney (21%)
Identifiers
IUPAC name 2-[(pyridin-3-ylcarbonyl)amino]ethyl nitrate
CAS Number	65141-46-0 Y
PubChem CID	47528
IUPHAR/BPS	2411
DrugBank	DB09220 Y
ChemSpider	43240 Y
UNII	260456HAM0
KEGG	D01810 Y
ChEBI	CHEBI:31905 N
ChEMBL	ChEMBL284906 Y
CompTox Dashboard (EPA)	DTXSID8045692
ECHA InfoCard	100.059.541
Chemical and physical data
Formula	C8H9N3O4
Molar mass	211.177 g·mol−1
3D model (JSmol)	Interactive image
SMILES O=C(NCCO[N+]([O-])=O)c1cccnc1
InChI InChI=1S/C8H9N3O4/c12-8(7-2-1-3-9-6-7)10-4-5-15-11(13)14/h1-3,6H,4-5H2,(H,10,12) Y Key:LBHIOVVIQHSOQN-UHFFFAOYSA-N Y
NY (what is this?)  (verify)

It was patented in 1976 and approved for medical use in 1983.^[3]

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.^{[citation needed]}

Mechanism of action

Nicorandil is an anti-angina medication that has the dual properties of a nitrate and ATP-sensitive K⁺
channel opener.^[4] In humans, the nitrate action of nicorandil dilates the large coronary arteries at low plasma concentrations.^[4] At high plasma concentrations nicorandil reduces coronary vascular resistance, which is associated with increased ATP-sensitive K+ channel (K_ATP) opening.^[4]

Nicorandil stimulates guanylate cyclase to increase formation of cyclic GMP (cGMP).^[5] cGMP activates protein kinase G (PKG), which phosphorylates and inhibits GTPase RhoA and decreases Rho-kinase activity.^[5] Reduced Rho-kinase activity permits an increase in myosin phosphatase activity, decreasing the calcium sensitivity of the smooth muscle.^[5]

PKG also activates the sarcolemma calcium pump to remove activating calcium.^[6] PKG acts on K⁺
channels to promote K+ efflux and the ensuing hyperpolarization inhibits voltage-gated calcium channels.^[4] Overall, this leads to relaxation of the smooth muscle and coronary vasodilation.^{[citation needed]}

The effect of nicorandil as a vasodilator is mainly attributed to its nitrate property.^[4] Yet, nicorandil is effective in cases where nitrates, such as nitroglycerine, are not effective.^[4] Studies show that this is due to its K_ATP channel agonist action which causes pharmacological preconditioning and provides cardioprotective effects against ischemia.^[4] Nicorandil activates K_ATP channels in the mitochondria of the myocardium, which appears to relay the cardioprotective effects, although the mechanism is still unclear.^[7] In experimental animal models of the Long QT syndrome, Nicorandil normalizes the prolonged cardiac action potential duration and the QT interval.^[8]

Synthesis

Thieme Synthesis (original) patents:^[9][10][11]

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

Revised patents:^[12][13][14]

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.^{[citation needed]}