Nicorandil is a vasodilatory
drug used to treat
angina.
Angina is chest pain that results from episodes of transient myocardial
ischemia. This can be caused by diseases such as
atherosclerosis
Atherosclerosis is a pattern of the disease arteriosclerosis in which the wall of the artery develops abnormalities, called lesions. These lesions may lead to narrowing due to the buildup of atheromatous plaque. At onset there are usually no s ...
,
coronary artery disease and
aortic stenosis
Aortic stenosis (AS or AoS) is the narrowing of the exit of the left ventricle of the heart (where the aorta begins), such that problems result. It may occur at the aortic valve as well as above and below this level. It typically gets worse ov ...
. Angina commonly arises from vasospasm of the coronary arteries. There are multiple mechanisms causing the increased smooth muscle contraction involved in coronary vasospasm, including increased
Rho-kinase activity. Increased levels of Rho-kinase inhibit
myosin phosphatase activity, leading to increased calcium sensitivity and hypercontraction. Rho-kinase also decreases
nitric oxide synthase
Nitric oxide synthases () (NOSs) are a family of enzymes catalyzing the production of nitric oxide (NO) from L-arginine. NO is an important cellular signaling molecule. It helps modulate vascular tone, insulin secretion, airway tone, and p ...
activity, which reduces nitric oxide concentrations. Lower levels of
nitric oxide are present in spastic coronary arteries.
L-type calcium channel expression increases in spastic vascular smooth muscle cells, which could result in excessive calcium influx, and hypercontraction.
It was patented in 1976 and approved for medical use in 1983.
Side effects
Side effects listed in the British National Formulary include flushing,
palpitations, weakness and vomiting. More recently,
perianal
The anus (Latin, 'ring' or 'circle') is an opening at the opposite end of an animal's digestive tract from the mouth. Its function is to control the expulsion of feces, the residual semi-solid waste that remains after food digestion, which, d ...
,
ileal
The ileum () is the final section of the small intestine in most higher vertebrates, including mammals, reptiles, and birds. In fish, the divisions of the small intestine are not as clear and the terms posterior intestine or distal intestine ma ...
and peristomal ulceration has been reported as a side effect. Anal ulceration is now included in the
British National Formulary
The ''British National Formulary'' (BNF) is a United Kingdom (UK) pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about many medicine ...
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 agonist.
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 (K
ATP) opening.
Nicorandil stimulates
guanylate cyclase
Guanylate cyclase (EC 4.6.1.2, also known as guanyl cyclase, guanylyl cyclase, or GC; systematic name GTP diphosphate-lyase (cyclizing; 3′,5′-cyclic-GMP-forming)) is a lyase enzyme that converts guanosine triphosphate (GTP) to cyclic guanos ...
to increase formation of
cyclic GMP
Cyclic guanosine monophosphate (cGMP) is a cyclic nucleotide derived from guanosine triphosphate (GTP). cGMP acts as a second messenger much like cyclic AMP. Its most likely mechanism of action is activation of intracellular protein kinases in r ...
(cGMP).
cGMP activates
protein kinase G
cGMP-dependent protein kinase or protein kinase G (PKG) is a serine/threonine-specific protein kinase that is activated by cGMP. It phosphorylates a number of biologically important targets and is implicated in the regulation of smooth muscle ...
(PKG), which phosphorylates and inhibits
GTPase
GTPases are a large family of hydrolase enzymes that bind to the nucleotide guanosine triphosphate (GTP) and hydrolyze it to guanosine diphosphate (GDP). The GTP binding and hydrolysis takes place in the highly conserved P-loop "G domain", a pro ...
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
The sarcolemma (''sarco'' (from ''sarx'') from Greek; flesh, and ''lemma'' from Greek; sheath) also called the myolemma, is the cell membrane surrounding a skeletal muscle fiber or a cardiomyocyte.
It consists of a lipid bilayer and a thin oute ...
calcium pump to remove activating calcium. PKG acts on
channels to promote K+ efflux and the ensuing
hyperpolarization inhibits
voltage-gated calcium channels
Voltage-gated calcium channels (VGCCs), also known as voltage-dependent calcium channels (VDCCs), are a group of voltage-gated ion channels found in the membrane of excitable cells (''e.g.'', muscle, glial cells, neurons, etc.) with a permeabi ...
.
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
Nitroglycerin (NG), (alternative spelling of nitroglycerine) also known as trinitroglycerin (TNG), nitro, glyceryl trinitrate (GTN), or 1,2,3-trinitroxypropane, is a dense, colorless, oily, explosive liquid most commonly produced by nitrating ...
, are not effective.
Studies show that this is due to its K
ATP channel agonist action which causes pharmacological preconditioning and provides cardioprotective effects against ischemia.
Nicorandil activates K
ATP 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
The cardiac action potential is a brief change in voltage ( membrane potential) across the cell membrane of heart cells. This is caused by the movement of charged atoms (called ions) between the inside and outside of the cell, through proteins c ...
duration and the
QT interval.
Society and culture
Brand names
Nicorandil is marketed under the brand names Ikorel (in the United Kingdom, Australia and most of Europe), Angedil (in
Romania
Romania ( ; ro, România ) is a country located at the crossroads of Central, Eastern, and Southeastern Europe. It borders Bulgaria to the south, Ukraine to the north, Hungary to the west, Serbia to the southwest, Moldova to the east, and ...
,
Poland
Poland, officially the Republic of Poland, is a country in Central Europe. It is divided into 16 administrative provinces called voivodeships, covering an area of . Poland has a population of over 38 million and is the fifth-most populou ...
), Dancor (in
Switzerland), Nikoran, PCA (in
India
India, officially the Republic of India (Hindi: ), is a country in South Asia. It is the seventh-largest country by area, the second-most populous country, and the most populous democracy in the world. Bounded by the Indian Ocean on the so ...
), Aprior (in the
Philippines
The Philippines (; fil, Pilipinas, links=no), officially the Republic of the Philippines ( fil, Republika ng Pilipinas, links=no),
* bik, Republika kan Filipinas
* ceb, Republika sa Pilipinas
* cbk, República de Filipinas
* hil, Republ ...
), Nitorubin (in
Japan), and Sigmart (in
Japan,
South Korea
South Korea, officially the Republic of Korea (ROK), is a country in East Asia, constituting the southern part of the Korean Peninsula and sharing a land border with North Korea. Its western border is formed by the Yellow Sea, while its eas ...
,
Taiwan
Taiwan, officially the Republic of China (ROC), is a country in East Asia, at the junction of the East and South China Seas in the northwestern Pacific Ocean, with the People's Republic of China (PRC) to the northwest, Japan to the nort ...
and
China). Nicorandil is not available in the United States.
Synthesis
Amide reaction between Nicotinoyl Chloride
0400-19-8& 2-Aminoethyl Nitrate
46-02-6
The reaction of N-(2-Hydroxyethyl)Nicotinamide
265-73-2with nitric acid gives nicorandil.
See also
*
Nitrovasodilator
A nitrovasodilator is a pharmaceutical agent that causes vasodilation (widening of blood vessels) by donation of nitric oxide (NO), and is mostly used for the treatment and prevention of angina pectoris.
This group of drugs includes nitrates (est ...
References
Further reading
*
*
{{Nitric oxide signaling
Antianginals
Vasodilators
Nitrate esters
Merck brands
3-Pyridyl compounds
Nicotinamides
Potassium channel openers