Nicorandil

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Nicorandil
Clinical data
Trade namesIkorel, others
AHFS/Drugs.comInternational 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
Bioavailability75 to 80%
Protein binding25%
MetabolismLiver
Elimination half-life1 hour
ExcretionKidney (21%)
Identifiers
  • 2-[(pyridin-3-ylcarbonyl)amino]ethyl nitrate
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) checkY
  • Key:LBHIOVVIQHSOQN-UHFFFAOYSA-N checkY
 ☒NcheckY (what is this?)  (verify)

Nicorandil is a

vasodilator drug used to treat angina
.

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,

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

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

voltage-gated calcium channels.[7]
Overall, this leads to relaxation of the smooth muscle and coronary vasodilation.

The effect of nicorandil as a

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:[12][13][14]

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

Revised patents:[15][16][17]

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

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. PMID 10725293
    .
  3. PMID 12093770
    .
  4. PMID 8759065
    .
  5. PMID 10813387
    .
  6. ISBN 9783527607495
    .
  7. ^
    PMID 10836727
    .
  8. ^
    PMID 10783386
    .
  9. PMID 2850801
    .
  10. PMID 9641699
    .
  11. 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