Chemistry:Pilsicainide

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Short description: Chemical compound
Pilsicainide
Pilsicainide.svg
Clinical data
AHFS/Drugs.comInternational Drug Names
Routes of
administration		Oral, IV
ATC code
  • none
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
FormulaC17H24N2O
Molar mass272.392 g·mol−1
3D model (JSmol)
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Pilsicainide (INN) is an antiarrhythmic agent. It is marketed in Japan as サンリズム (Sunrythm). It was developed by Suntory Holdings Limited and first released in 1991.[1] The JAN applies to the hydrochloride salt, pilsicainide hydrochloride.

Medical uses

Pilsicainide is a drug used clinically in Japan to treat cardiac arrhythmias.

A cardiac arrhythmia includes any abnormal heartbeat and can be manifested as tachycardia, bradycardia, or other irregular rhythms. Pilsicainide has been proven successful in treating both ventricular[2] and supraventricular arrhythmias with few adverse effects.[3] It is especially effective in the treatment of atrial fibrillation.[4] Atrial fibrillation is the most common type of arrhythmia.[5] It may result from various heart abnormalities or may occur spontaneously in a seemingly healthy individual.[6] Atrial fibrillation is characterized by rapid, disorganized electrical impulses in the atria resulting in depolarization of only a small group of myocardial cells. This prevents the atria from undergoing coordinated contraction, instead resulting in small fibrillations of the heart muscle. Re-entry occurs when an impulse does not die after activating the heart but instead returns to the atria and causes re-excitation.[7] Simultaneous re-entry of multiple impulses with short wavelengths results in atrial fibrillation.[8] Impulse wavelength is the product of the conduction velocity and the effective refractory period. Pilsicainide suppresses atrial conduction velocity but also increases the effective refractory period.[9] Its effects on the refractory period are significantly more substantial, and therefore pilsicainide treatment results in an increased wavelength and termination of atrial fibrillation.[10] A single oral dose of pilsicainide effectively restores normal sinus rhythm in patients with recent-onset atrial fibrillation and a healthy left ventricle.[4] Long-term therapy with pilsicainide is successful in treating chronic atrial fibrillation).[11]

Pharmacology

It functions by blocking the fast inward movement of sodium ions through the Nav1.5 sodium channel[12] that contributes to the rapid depolarization characteristic of phase 0 in the cardiac action potential. Pilsicainide is a pure sodium channel blocker, meaning it does not significantly affect any other cardiac channels including potassium and calcium channels.[13] Pilsicainide binds to a common site on the sodium channel through either intracellular or extracellular application.[14] The affinity of pilsicainide for the sodium channel receptor and its rate of binding are dependent on the state of the channel. It has been proven to have a greater affinity for the receptor in its inactivated state as opposed to resting or open,[15] thereby following the modulated receptor hypothesis.[16] Binding of pilsicainide selectively inhibits the channel,[17] preventing the movement of sodium ions into the cardiac cell. This decreases the rate of depolarization of the cell membrane as well as the action potential amplitude, but has no effect on the overall duration of the action potential.[17] Suppression of the depolarization rate is use-dependent,[18] and therefore inhibition increases with increased stimulation. Pilsicainide also causes delayed impulse conduction through the myocardium in a dose-dependent manner.[19] The effects of pilsicainide have a slow rate of onset and offset resulting in a prolonged recovery time.[20] This contributes to its potent blocking activity and its classification as a class 1c antiarrhythmic agent.[21]

References

  1. ↑ "Company Timelines". Suntory. https://www.suntory.co.jp/company/history/timeline/index03.html. 
  2. ↑ "Effects of SUN-1165, N-(2,6-dimethylphenyl)-8-pyrrolizidine acetamide hydrochloride hemihydrate, a new class I antiarrhythmic drug, on ventricular arrhythmias, intraventricular conduction, and the refractory period in canine myocardial infarction". Journal of Cardiovascular Pharmacology 19 (3): 417–24. March 1992. doi:10.1097/00005344-199203000-00018. PMID 1378123. 
  3. ↑ "Electrophysiologic and hemodynamic effects of a single oral dose of pilsicainide hydrochloride, a new class 1c antiarrhythmic agent". Journal of Cardiovascular Pharmacology 31 (1): 157–64. January 1998. doi:10.1097/00005344-199801000-00021. PMID 9456290. 
  4. ↑ 4.0 4.1 "Conversion of recent-onset Atrial Fibrillation by a single oral dose of Pilsicainide (Pilsicainide Suppression Trial on atrial fibrillation).". The American Journal of Cardiology 78 (6): 694–7. September 1996. doi:10.1016/s0002-9149(96)00401-8. PMID 8831412. 
  5. ↑ "Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications". Archives of Internal Medicine 155 (5): 469–73. March 1995. doi:10.1001/archinte.1995.00430050045005. PMID 7864703. 
  6. ↑ "A review of atrial fibrillation". Journal of the National Medical Association 94 (12): 1036–48. December 2002. PMID 12510703. 
  7. ↑ "Atrial fibrillation: Mechanisms of disease". CMAJ 171 (7): 755–60. September 2004. doi:10.1503/cmaj.1031364. PMID 15451840. 
  8. ↑ "Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs". Circulation Research 62 (2): 395–410. February 1988. doi:10.1161/01.res.62.2.395. PMID 3338122. 
  9. ↑ "Postrepolarization refractoriness as a potential anti-atrial fibrillation mechanism of pilsicainide, a pure sodium channel blocker with slow recovery kinetics". Cardiovascular Drugs and Therapy 12 (5): 475–82. October 1998. doi:10.1023/a:1007758217189. PMID 9926279. 
  10. ↑ "Determination of refractory periods and conduction velocity during atrial fibrillation using atrial capture in dogs: direct assessment of the wavelength and its modulation by a sodium channel blocker, pilsicainide". Journal of the American College of Cardiology 35 (1): 246–53. January 2000. doi:10.1016/s0735-1097(99)00488-x. PMID 10636287. 
  11. ↑ "Pilsicainide for conversion and maintenance of sinus rhythm in chronic atrial fibrillation: a placebo-controlled, multicenter study.". Am Heart J 140 (3): 437–444. 2000. doi:10.1067/mhj.2000.107174. PMID 10966544. 
  12. ↑ "SUN 1165: a new antiarrhythmic Na current blocker in ventricular myocytes of guinea-pig". Comparative Biochemistry and Physiology. C, Comparative Pharmacology and Toxicology 87 (2): 237–43. 1987. doi:10.1016/0742-8413(87)90003-x. PMID 2443300. 
  13. ↑ "Uniqueness of pilsicainide in class Ic antiarrhythmics". Japanese Heart Journal 39 (3): 389–97. May 1998. doi:10.1536/ihj.39.389. PMID 9711190. 
  14. ↑ "Modes of the Na channel blocking action of pilsicainide, a new antiarrhythmic agent, in cardiac cells". Japanese Journal of Pharmacology 58 (4): 365–73. April 1992. doi:10.1254/jjp.58.365. PMID 1328732. 
  15. ↑ "Molecular determinants of state-dependent block of voltage-gated sodium channels by pilsicainide". British Journal of Pharmacology 160 (6): 1521–33. July 2010. doi:10.1111/j.1476-5381.2010.00816.x. PMID 20590641. 
  16. ↑ "Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction". The Journal of General Physiology 69 (4): 497–515. April 1977. doi:10.1085/jgp.69.4.497. PMID 300786. 
  17. ↑ 17.0 17.1 "Electrophysiological actions of N-(2,6-dimethylphenyl)-8-pyrrolizidine-acetamide hydrochloride hemihydrate (SUN 1165), a new antiarrhythmic agent". Journal of Cardiovascular Pharmacology 8 (5): 998–1002. 1986. doi:10.1097/00005344-198609000-00017. PMID 2429102. 
  18. ↑ "Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium". Journal of Molecular and Cellular Cardiology 12 (11): 1273–86. November 1980. doi:10.1016/0022-2828(80)90071-1. PMID 6777501. 
  19. ↑ "N-(2,6-Dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165): a new potent and long-acting antiarrhythmic agent". Arzneimittel-Forschung 35 (8): 1239–45. 1985. PMID 4074441. 
  20. ↑ "Effect of SUN 1165, a new potent antiarrhythmic agent, on the kinetics of rate-dependent block of Na channels and ventricular conduction of extrasystoles". Journal of Cardiovascular Pharmacology 11 (4): 407–12. April 1988. doi:10.1097/00005344-198804000-00005. PMID 2453743. 
  21. ↑ "Kinetics of onset of rate-dependent effects of Class I antiarrhythmic drugs are important in determining their effects on refractoriness in guinea-pig ventricle, and provide a theoretical basis for their subclassification". Cardiovascular Research 17 (6): 344–52. June 1983. doi:10.1093/cvr/17.6.344. PMID 6883410. 



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