Tocainide

Last updated

Tocainide
Tocainide.svg
Clinical data
Trade names Tonocard
Other namesTocainamide
AHFS/Drugs.com Micromedex Detailed Consumer Information
MedlinePlus a601248
ATC code
Pharmacokinetic data
Bioavailability 0.9-1 (oral)
Protein binding 10-20%
Metabolism glucuronidation (primary)
Elimination half-life 9-14 R, 13-20 S
Excretion 30-50% urine (unchanged)
Identifiers
  • N-(2,6-dimethylphenyl)alaninamide
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.050.441 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C11H16N2O
Molar mass 192.262 g·mol−1
3D model (JSmol)
  • O=C(Nc1c(cccc1C)C)C(N)C
  • InChI=1S/C11H16N2O/c1-7-5-4-6-8(2)10(7)13-11(14)9(3)12/h4-6,9H,12H2,1-3H3,(H,13,14) Yes check.svgY
  • Key:BUJAGSGYPOAWEI-UHFFFAOYSA-N Yes check.svgY
   (verify)

Tocainide (Tonocard) is a class Ib antiarrhythmic agent. It is no longer sold in the United States.

Contents

Synthesis

Tocainide synthesis: Tocainide synthesis.png
Tocainide synthesis:

Pharmacokinetics

Tocainide is a lidocaine derivative, that undergoes very less first pass metabolism. It occurs as two enantiomers. The R isomer is three times more potent than the S isomer. [5] Tocainide's oral bioavailability is almost 100%. [6] Plasma half-life generally lasts for 11.5-15.5 hours (13.5 ± 2 hours [7] ). In the blood, tocainide is 10-20% protein bound. [8] [6] The volume of distribution is 2.8-3.2 L/kg. [8] 31-45% is excreted unchanged in the urine. [8] The more active R-isomer is cleared faster in anephric patients (without kidneys) or those with severe kidney dysfunction. The main metabolite is tocainide carbamoyl ester glucuronlde. [9]

Drug interactions

Rifampicin increases conversion of tocainide into its main metabolite, tocainide carbamoyl ester glucuronlde, [9] by inducing the glucuronosyl transferase enzyme that catalyzes glucuronidation of tocainide to produce that metabolite. Rifampicin also increases elimination rate and decreases oral clearance of tocainide. [10] Tocainide decreases plasma clearance of theophylline. [11]

Pharmacokinetics

Oral bioavailability is high (near complete), with low protein binding (≈10–20%) and renal excretion of a substantial unchanged fraction; metabolism proceeds largely via glucuronidation. Reported plasma half-life values are roughly in the 9–20 hour range, with known stereoselective differences between enantiomers. [12] [13]

History and status

Tocainamide (tocainide) emerged in the 1970s as an orally effective alternative to lidocaine for ventricular arrhythmias, with early uncontrolled and controlled studies in refractory patients. [14] [15] Accumulating reports of bone-marrow toxicity and other serious adverse events led to declining use and eventual withdrawal from some markets; in the United States, tocainide products were removed in 2003. [16] [17]

See also

References

  1. ↑ DE 2235745,Boyes RN, Byrnes EW,"Antiarrhythmisch Wirksame Verbindung, Verfahren zu Deren Herstellung und Deren Verwendung",issued 1972, assigned to Astra Pharmaceutical Products Inc.
  2. ↑ GB 1461602,"Primary Amino Acylanilides Methods of Making the Same and Use as Antiarrhythmic Drugs",issued 1974, assigned to Astra Pharmaceutical Products Inc.
  3. ↑ DE 2400540,Boyes RN, Duce BR, Smith EM, Byrnes EW,"Primaeraminoacylanilide, Verfahren zu Deren Herstellung und Sie Enthaltende Arzneimittel",issued 1974, assigned to Astra Pharmaceutical Products Inc.
  4. ↑ Byrnes EW, McMaster PD, Smith ER, Blair MR, Boyes RN, Duce BR, et al. (October 1979). "New antiarrhythmic agents. 1. Primary alpha-amino anilides". Journal of Medicinal Chemistry. 22 (10): 1171–1176. doi:10.1021/jm00196a005. PMID   513064.
  5. ↑ Tricarico D, Fakler B, Spittelmeister W, Ruppersberg JP, Stützel R, Franchini C, et al. (April 1991). "Stereoselective interaction of tocainide and its chiral analogs with the sodium channels in human myoballs". Pflügers Archiv. 418 (3): 234–237. doi:10.1007/BF00370521. PMID   1649990. S2CID   24456292.
  6. 1 2 Kutalek SP, Morganroth J, Horowitz LN (September 1985). "Tocainide: a new oral antiarrhythmic agent". Annals of Internal Medicine. 103 (3): 387–391. doi:10.7326/0003-4819-103-3-387. PMID   3927807.
  7. ↑ Winkle RA, Meffin PJ, Fitzgerald JW, Harrison DC (December 1976). "Clinical efficacy and pharmacokinetics of a new orally effective antiarrhythmic, tocainide". Circulation. 54 (6): 885–889. doi: 10.1161/01.CIR.54.6.885 . PMID   791536.
  8. 1 2 3 "Kidney Disease Program (KDP)". University of Louisville. Archived from the original on 2023-12-12. Retrieved 2023-12-12.
  9. 1 2 Kwok DW (1987). Studies on the metabolism of tocainide in humans (Thesis). doi: 10.14288/1.0096967 . hdl: 2429/26428 .[ page needed ]
  10. ↑ Rice TL, Patterson JH, Celestin C, Foster JR, Powell JR (March 1989). "Influence of rifampin on tocainide pharmacokinetics in humans". Clinical Pharmacy. 8 (3): 200–205. PMID   2495879.
  11. ↑ Loi CM, Wei X, Parker BM, Korrapati MR, Vestal RE (April 1993). "The effect of tocainide on theophylline metabolism". British Journal of Clinical Pharmacology. 35 (4): 437–440. doi:10.1111/j.1365-2125.1993.tb04163.x. PMC   1381557 . PMID   8485025.
  12. ↑ Roden DM, Woosley RL (3 July 1986). "Flecainide". New England Journal of Medicine. 315 (1): 36–41. doi:10.1056/NEJM198607033150106. PMID   3520324.
  13. ↑ Carocci A, Corbo F, Lentini G, Cavalluzzi MM, Franchini C, Catalano A (6 February 2019). "A Focus on the Synthesis and Pharmacokinetics of Tocainide and its Analogues". Current Medicinal Chemistry. 25 (42): 5822–5834. doi:10.2174/0929867325666180327104320. PMID   29589531.
  14. ↑ Podrid PJ, Lown B (April 1982). "Tocainide for refractory symptomatic ventricular arrhythmias". The American Journal of Cardiology. 49 (5): 1279–1286. doi:10.1016/0002-9149(82)90056-X. PMID   6801955.
  15. ↑ Hohnloser SH, Lange HW, Raeder EA, Podrid PJ, Lown B (January 1986). "Short- and long-term therapy with tocainide for malignant ventricular tachyarrhythmias". Circulation. 73 (1): 143–149. doi:10.1161/01.cir.73.1.143. PMID   3079677.
  16. ↑ "Tocainide". Drugs and Lactation Database (LactMed®). National Institute of Child Health and Human Development. 2006. PMID   30000176.
  17. ↑ Hogan E (2015). "The Treatment of Trigeminal Neuralgia". Nerves and Nerve Injuries. pp. 81–97. doi:10.1016/B978-0-12-802653-3.00055-5. ISBN   978-0-12-802653-3.

Further reading

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