Pilsicainide

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.

Pilsicainide
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
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC17H24N2O
Molar mass272.392 g·mol−1
3D model (JSmol)
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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.
  2. Hashimoto H, Satoh N, Nakashima M (March 1992). "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. doi:10.1097/00005344-199203000-00018. PMID 1378123.
  3. Ino T, Atarashi H, Kuruma A, Onodera T, Saitoh H, Hayakawa H (January 1998). "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. doi:10.1097/00005344-199801000-00021. PMID 9456290.
  4. Atarashi H, Inoue H, Hiejima K, Hayakawa H, et al. (The PSTAF Investigators) (September 1996). "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. doi:10.1016/s0002-9149(96)00401-8. PMID 8831412.
  5. Feinberg WM, Blackshear JL, Laupacis A, Kronmal R, Hart RG (March 1995). "Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications". Archives of Internal Medicine. 155 (5): 469–73. PMID 7864703.
  6. Dang D, Arimie R, Haywood LJ (December 2002). "A review of atrial fibrillation". Journal of the National Medical Association. 94 (12): 1036–48. PMC 2568400. PMID 12510703.
  7. Veenhuyzen GD, Simpson CS, Abdollah H (September 2004). "Atrial fibrillation: Mechanisms of disease". CMAJ. 171 (7): 755–60.
  8. Rensma PL, Allessie MA, Lammers WJ, Bonke FI, Schalij MJ (February 1988). "Length of excitation wave and susceptibility to reentrant atrial arrhythmias in normal conscious dogs". Circulation Research. 62 (2): 395–410. doi:10.1161/01.res.62.2.395. PMID 3338122.
  9. Kanki H, Mitamura H, Takatsuki S, Sueyoshi K, Shinagawa K, Sato T, Ogawa S (October 1998). "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. doi:10.1023/a:1007758217189. PMID 9926279.
  10. Shinagawa K, Mitamura H, Takeshita A, Sato T, Kanki H, Takatsuki S, Ogawa S (January 2000). "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. doi:10.1016/s0735-1097(99)00488-x. PMID 10636287.
  11. Okishige K, Nishizaki M, Azegami K, Igawa M, Yamawaki N, Aonuma K (2000). "Pilsicainide for conversion and maintenance of sinus rhythm in chronic atrial fibrillation: a placebo-controlled, multicenter study". Am Heart J. 140 (3): e13. doi:10.1067/mhj.2000.107174.
  12. Inomata N, Ishihara T, Akaike N (1987). "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. doi:10.1016/0742-8413(87)90003-x. PMID 2443300.
  13. Yamashita T, Murakawa Y, Sezaki K, Hayami N, Inoue M, Fukui E, Omata M (May 1998). "Uniqueness of pilsicainide in class Ic antiarrhythmics". Japanese Heart Journal. 39 (3): 389–97. doi:10.1536/ihj.39.389. PMID 9711190.
  14. Hattori Y, Inomata N (April 1992). "Modes of the Na channel blocking action of pilsicainide, a new antiarrhythmic agent, in cardiac cells". Japanese Journal of Pharmacology. 58 (4): 365–73. doi:10.1254/jjp.58.365. PMID 1328732.
  15. Desaphy JF, Dipalma A, Costanza T, Bruno C, Lentini G, Franchini C, George A, Conte Camerino D (July 2010). "Molecular determinants of state-dependent block of voltage-gated sodium channels by pilsicainide". British Journal of Pharmacology. 160 (6): 1521–33. doi:10.1111/j.1476-5381.2010.00816.x. PMC 2938822. PMID 20590641.
  16. Hille B (April 1977). "Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction". The Journal of General Physiology. 69 (4): 497–515. doi:10.1085/jgp.69.4.497. PMC 2215053. PMID 300786.
  17. Hattori Y, Inomata N, Aisaka K, Ishihara T (1986). "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. doi:10.1097/00005344-198609000-00017. PMID 2429102.
  18. Courtney KR (November 1980). "Interval-dependent effects of small antiarrhythmic drugs on excitability of guinea-pig myocardium". Journal of Molecular and Cellular Cardiology. 12 (11): 1273–86. doi:10.1016/0022-2828(80)90071-1. PMID 6777501.
  19. Aisaka K, Hidaka T, Inomata N, Hamasaki S, Ishihara T, Morita M (1985). "N-(2,6-Dimethylphenyl)-8-pyrrolizidineacetamide hydrochloride hemihydrate (SUN 1165): a new potent and long-acting antiarrhythmic agent". Arzneimittel-Forschung. 35 (8): 1239–45. PMID 4074441.
  20. Hattori Y, Hidaka T, Aisaka K, Satoh F, Ishihara T (April 1988). "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. doi:10.1097/00005344-198804000-00005. PMID 2453743.
  21. Campbell TJ (June 1983). "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. doi:10.1093/cvr/17.6.344. PMID 6883410.
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