Nicorandil

Last updated
Nicorandil
Nicorandil.svg
Clinical data
Trade names Ikorel, others
AHFS/Drugs.com International Drug Names
Pregnancy
category
  • AU:B3
Routes of
administration
By mouth
ATC code
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
  • 2-[(pyridin-3-ylcarbonyl)amino]ethyl nitrate
CAS Number
PubChem CID
IUPHAR/BPS
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.059.541 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C8H9N3O4
Molar mass 211.177 g·mol−1
3D model (JSmol)
  • O=C(NCCO[N+]([O-])=O)c1cccnc1
  • 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) Yes check.svgY
  • Key:LBHIOVVIQHSOQN-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (what is this?)    (verify)

Nicorandil is a vasodilator drug used to treat angina.

Contents

Angina is chest pain that results from episodes of transient myocardial ischemia. This can be caused by diseases such as atherosclerosis, coronary artery disease and aortic stenosis. 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. [2] Rho-kinase also decreases nitric oxide synthase activity, which reduces nitric oxide concentrations. [3] Lower levels of nitric oxide are present in spastic coronary arteries. [4] L-type calcium channel expression increases in spastic vascular smooth muscle cells, which could result in excessive calcium influx, and hypercontraction. [5]

It was patented in 1976 and approved for medical use in 1983. [6]

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 K+
channel
opener. [7] In humans, the nitrate action of nicorandil dilates the large coronary arteries at low plasma concentrations. [7] At high plasma concentrations nicorandil reduces coronary vascular resistance, which is associated with increased ATP-sensitive K+ channel (KATP) opening. [7]

Nicorandil stimulates guanylate cyclase to increase formation of cyclic GMP (cGMP). [8] cGMP activates protein kinase G (PKG), which phosphorylates and inhibits GTPase RhoA and decreases Rho-kinase activity. [8] Reduced Rho-kinase activity permits an increase in myosin phosphatase activity, decreasing the calcium sensitivity of the smooth muscle. [8]

PKG also activates the sarcolemma calcium pump to remove activating calcium. [9] PKG acts on K+
channels
to promote K+ efflux and the ensuing hyperpolarization inhibits voltage-gated calcium channels. [7] 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. [7] Yet, nicorandil is effective in cases where nitrates, such as nitroglycerine, are not effective. [7] Studies show that this is due to its KATP channel agonist action which causes pharmacological preconditioning and provides cardioprotective effects against ischemia. [7] Nicorandil activates KATP channels in the mitochondria of the myocardium, which appears to relay the cardioprotective effects, although the mechanism is still unclear. [10] In experimental animal models of the Long QT syndrome, Nicorandil normalizes the prolonged cardiac action potential duration and the QT interval. [11]

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, 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.

Synthesis

Thieme Synthesis (original) patents: Nicorandil synthesis.svg
Thieme Synthesis (original) patents:

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

Revised patents: Nicorandil synthesis (revised).svg
Revised patents:

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

Related Research Articles

<span class="mw-page-title-main">Angina</span> Chest discomfort that is generally brought on by inadequate blood flow to the cardiac muscle

Angina, also known as angina pectoris, is chest pain or pressure, usually caused by insufficient blood flow to the heart muscle (myocardium). It is most commonly a symptom of coronary artery disease.

<span class="mw-page-title-main">Smooth muscle</span> Involuntary non-striated muscle

Smooth (soft) muscle is an involuntary non-striated muscle, so-called because it has no sarcomeres and therefore no striations. It is divided into two subgroups, single-unit and multiunit smooth muscle. Within single-unit muscle, the whole bundle or sheet of smooth muscle cells contracts as a syncytium.

<span class="mw-page-title-main">Cyclic guanosine monophosphate</span> Chemical compound

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 response to the binding of membrane-impermeable peptide hormones to the external cell surface. Through protein kinases activation, cGMP can relax smooth muscle. cGMP concentration in urine can be measured for kidney function and diabetes detection.

<span class="mw-page-title-main">Vasodilation</span> Widening of blood vessels

Vasodilation, also known as vasorelaxation, is the widening of blood vessels. It results from relaxation of smooth muscle cells within the vessel walls, in particular in the large veins, large arteries, and smaller arterioles. Blood vessel walls are composed of endothelial tissue and a basal membrane lining the lumen of the vessel, concentric smooth muscle layers on top of endothelial tissue, and an adventitia over the smooth muscle layers. Relaxation of the smooth muscle layer allows the blood vessel to dilate, as it is held in a semi-constricted state by sympathetic nervous system activity. Vasodilation is the opposite of vasoconstriction, which is the narrowing of blood vessels.

Microvascular angina (MVA), previously known as cardiac syndrome X, also known as coronary microvascular dysfunction(CMD) or microvascular coronary disease is a type of angina (chest pain) with signs associated with decreased blood flow to heart tissue but with normal coronary arteries.

<span class="mw-page-title-main">Endothelium-derived relaxing factor</span> Nitric Oxide as an EDRF

The Endothelium-derived relaxing factor (EDRF) is a strong vasodilator produced by cardiac endothelial cells in response to stress signals such as high levels of ADP accumulation or hypoxia. Robert F. Furchgott is widely recognised for this discovery, even going so far as to be a co-recipient of the 1998 Nobel Prize in Medicine with his colleagues Louis J. Ignarro and Ferid Murad. Nitric oxide (NO) is a key component in any EDRF as these compounds either include NO or are structurally in the form of NO.

Vasospasm refers to a condition in which an arterial spasm leads to vasoconstriction. This can lead to tissue ischemia and tissue death (necrosis). Cerebral vasospasm may arise in the context of subarachnoid hemorrhage. Symptomatic vasospasm or delayed cerebral ischemia is a major contributor to post-operative stroke and death especially after aneurysmal subarachnoid hemorrhage. Vasospasm typically appears 4 to 10 days after subarachnoid hemorrhage.

<span class="mw-page-title-main">Variant angina</span> Medical condition

Variant angina, also known as Prinzmetal angina,vasospastic angina, angina inversa, coronary vessel spasm, or coronary artery vasospasm, is a syndrome typically consisting of angina. Variant angina differs from stable angina in that it commonly occurs in individuals who are at rest or even asleep, whereas stable angina is generally triggered by exertion or intense exercise. Variant angina is caused by vasospasm, a narrowing of the coronary arteries due to contraction of the heart's smooth muscle tissue in the vessel walls. In comparison, stable angina is caused by the permanent occlusion of these vessels by atherosclerosis, which is the buildup of fatty plaque and hardening of the arteries.

<span class="mw-page-title-main">Nitroglycerin (medication)</span> Medication

Nitroglycerin, also known as glyceryl trinitrate (GTN), is a vasodilator used for heart failure, high blood pressure (hypertension), anal fissures, painful periods, and to treat and prevent chest pain caused by decreased blood flow to the heart (angina) or due to the recreational use of cocaine. This includes chest pain from a heart attack. It is taken by mouth, under the tongue, applied to the skin, or by injection into a vein.

Coronary vasospasm refers to when a coronary artery suddenly undergoes either complete or sub-total temporary occlusion.

<span class="mw-page-title-main">Amrinone</span> Chemical compound

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high-gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high-gain CICR, which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.

An ATP-sensitive potassium channel is a type of potassium channel that is gated by intracellular nucleotides, ATP and ADP. ATP-sensitive potassium channels are composed of Kir6.x-type subunits and sulfonylurea receptor (SUR) subunits, along with additional components. KATP channels are widely distributed in plasma membranes; however some may also be found on subcellular membranes. These latter classes of KATP channels can be classified as being either sarcolemmal ("sarcKATP"), mitochondrial ("mitoKATP"), or nuclear ("nucKATP").

An atrial natriuretic peptide receptor is a receptor for atrial natriuretic peptide.

Fasudil (INN) is a potent Rho-kinase inhibitor and vasodilator. Since it was discovered, it has been used for the treatment of cerebral vasospasm, which is often due to subarachnoid hemorrhage, as well as to improve the cognitive decline seen in stroke patients. It has been found to be effective for the treatment of pulmonary hypertension. It has been demonstrated that fasudil could improve memory in normal mice, identifying the drug as a possible treatment for age-related or neurodegenerative memory loss.

<span class="mw-page-title-main">Nitrovasodilator</span> Drug that causes vasodilation by releasing nitric oxide

A nitrovasodilator is a pharmaceutical agent that causes vasodilation by donation of nitric oxide (NO), and is mostly used for the treatment and prevention of angina pectoris.

Biological functions of nitric oxide are roles that nitric oxide plays within biology.

<span class="mw-page-title-main">Rottlerin</span> Chemical compound

Rottlerin (mallotoxin) is a polyphenol natural product isolated from the Asian tree Mallotus philippensis. Rottlerin displays a complex spectrum of pharmacology.

<span class="mw-page-title-main">LY-215,840</span> Chemical compound

LY-215,840 is an ergoline derivative drug developed by Eli Lilly, which acts as a potent and selective antagonist at the serotonin 5-HT2 and 5-HT7 receptors. It has anti-hypertensive and muscle relaxant effects in animal studies.

Phosphodiesterases (PDEs) are a superfamily of enzymes. This superfamily is further classified into 11 families, PDE1 - PDE11, on the basis of regulatory properties, amino acid sequences, substrate specificities, pharmacological properties and tissue distribution. Their function is to degrade intracellular second messengers such as cyclic adenine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) which leads to several biological processes like effect on intracellular calcium level by the Ca2+ pathway.

Neointimal hyperplasia refers to proliferation and migration of vascular smooth muscle cells primarily in the tunica intima, resulting in the thickening of arterial walls and decreased arterial lumen space. Neointimal hyperplasia is the major cause of restenosis after percutaneous coronary interventions such as stenting or angioplasty. The term neointima is used because the cells in the hyperplastic regions of the vascular wall have histological characteristics of both intima and normal artery cells.

References

  1. "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  2. Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Kawano Y, Fukata Y, et al. (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. 101 (11): 1319–1323. doi: 10.1161/01.cir.101.11.1319 . PMID   10725293.
  3. Takemoto M, Sun J, Hiroki J, Shimokawa H, Liao JK (July 2002). "Rho-kinase mediates hypoxia-induced downregulation of endothelial nitric oxide synthase". Circulation. 106 (1): 57–62. doi: 10.1161/01.cir.0000020682.73694.ab . PMID   12093770.
  4. Kugiyama K, Yasue H, Okumura K, Ogawa H, Fujimoto K, Nakao K, et al. (August 1996). "Nitric oxide activity is deficient in spasm arteries of patients with coronary spastic angina". Circulation. 94 (3): 266–271. doi:10.1161/01.cir.94.3.266. PMID   8759065.
  5. Kuga T, Shimokawa H, Hirakawa Y, Kadokami Y, Arai Y, Fukumoto Y, et al. (May 2000). "Increased expression of L-type calcium channels in vascular smooth muscle cells at spastic site in a porcine model of coronary artery spasm". Journal of Cardiovascular Pharmacology. 35 (5): 822–828. doi: 10.1097/00005344-200005000-00021 . PMID   10813387.
  6. Fischer J, Ganellin CR (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 454. ISBN   9783527607495.
  7. 1 2 3 4 5 6 7 Nakae I, Matsumoto T, Horie H, Yokohama H, Omura T, Minai K, et al. (June 2000). "Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism". Journal of Cardiovascular Pharmacology. 35 (6): 919–925. doi: 10.1097/00005344-200006000-00014 . PMID   10836727.
  8. 1 2 3 Sauzeau V, Le Jeune H, Cario-Toumaniantz C, Smolenski A, Lohmann SM, Bertoglio J, et al. (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. 275 (28): 21722–21729. doi: 10.1074/jbc.M000753200 . PMID   10783386.
  9. Vrolix M, Raeymaekers L, Wuytack F, Hofmann F, Casteels R (November 1988). "Cyclic GMP-dependent protein kinase stimulates the plasmalemmal Ca2+ pump of smooth muscle via phosphorylation of phosphatidylinositol". The Biochemical Journal. 255 (3): 855–863. doi:10.1042/bj2550855. PMC   1135320 . PMID   2850801.
  10. Liu Y, Sato T, O'Rourke B, Marban E (June 1998). "Mitochondrial ATP-dependent potassium channels: novel effectors of cardioprotection?". Circulation. 97 (24): 2463–2469. doi: 10.1161/01.cir.97.24.2463 . PMID   9641699.
  11. Biermann J, Wu K, Odening KE, Asbach S, Koren G, Peng X, et al. (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. 650 (1): 309–316. doi:10.1016/j.ejphar.2010.10.016. PMC   2997896 . PMID   20959120.
  12. DE 2714713,issued 16 September 1993, assigned to Chugai Seiyaku Kabushiki Kaisha
  13. US 4200640,published 1980, assigned to Chugai Seiyaku Kabushiki Kaisha
  14. WO 2010000673,published 2010, assigned to Politechnika Lódzka, Uniwersytet Jagiellonski
  15. WO 2012089769,issued 2012, assigned to Procos S.P.A.
  16. CN 111269175,issued 2020, assigned to Zhangjiagang Jiuli New Material Technology Co Ltd.
  17. CN 110845403,issued 2020, assigned to Beijing Voban Pharmaceutical Co Ltd.

Further reading