Module 3 - Anticonvulsants and Other Centrally Acting Drugs

Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. QJM 1998;325-332(Fulltext)
Clinical effects and toxicokinetic evaluation following massive topiramate ingestion. Lynch MJ, Pizon AF, Siam MG, Krasowski MD. J Med Toxicol 2010;6(2):135-8
Treatment of severe intravenous phenytoin overdose with hemodialysis and hemoperfusion. Eyer F, Felgenhauer N, Pfab R, Thürmel K, Zilker T. Med Sci Monit 2008;14(12):CS145-8
Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations.
Ferrell PB Jr, McLeod HL. Pharmacogenomics 2008;9(10):1543-6
Chronic valproic acid intoxication: reversal by naloxone. Thanacoody HK. Emerg Med J 2007;24(9):677-8 PMID17711961Free PMC Article
Possible bioactivation pathways of lamotrigine. Lu W, Uetrecht JP. Drug Metab Dispos 2007;35(7):1050-6 Epub 2007 Apr 4
Toxicology case of the month: Carbamazepine overdose. Soderstrom J, Murray L, Little M, Daly FF. Emerg Med J 2006;23(11):869-71
Science review: carnitine in the treatment of valproic acid-induced toxicity - what is the evidence? Lheureux PE, Penaloza A, Zahir S, Gris M. Crit Care 2005;9(5):431-40 Epub 2005 Jun 10. Review

Valproate
Isbister GK, Balit CR, Whyte IM, Dawson A. Valproate overdose: a comparative cohort study of self poisonings.Br J Clin Pharmacol 2003;55(4):398-404
Sikma MA, Mier JC, Meulenbelt J.Massive valproic acid overdose, a misleading case. Am J Emerg Med 2008;26(1):110.e3-6.

See: Problems for Discussion

• Understand the complex pharmacokinetics of phenytoin and how these influence the risk for phenytoin toxicity.
• Compare and contrast the differences between oral and intravenous phenytoin toxicity.

Phenytoin
Privitera MD, Welty T.Severe intoxication after phenytoin infusion: a preventable pharmacogenetic adverse reaction. Neurology 2004;62(1):161; author reply 161
Mamiya K, Kojima K, Yukawa E, Higuchi S, Ieiri I, Ninomiya H, Tashiro N.Phenytoin intoxication induced by fluvoxamine.Ther Drug Monit 2001;23(1):75-7

See: Problems for Discussion

• Understand the mechanisms of toxicity and the clinical effects seen in carbamazepine poisoning.
• Realise the potential importance and methods of GI decontamination following massive carbamazepine overdose
• Understand the methods of enhanced elimination that may be used to increase carbamazepine clearance in severe poisoning.

Carbamazepine
LaRoche SM, Helmers SL.The new antiepileptic drugs: scientific review. JAMA 2004;291(5):605-14

See: Problems for Discussion

• To be able to discuss the important adverse effects of chloroquine and quinine in therapeutic doses.
• To be able to perform a risk assessment following acute deliberate self-poisoning and accidental paediatric ingestion of quinine, chloroquine and hydroxychloroquine.
• To be able to discuss the clinical manifestations of quinine intoxication, including cinchonism, CNS effects, cardiovascular effects and quinine blindness (amblyopia).
• To be able to discuss the clinical manifestations of chloroquine and hydroxychloroquine intoxication.
• To be able to discuss the role of gastrointestinal decontamination and intravenous diazepam in antimalarial poisoning.

Quinine and chloroquine
Wilkinson R, Mahatane J, Wade P, Pasvol G.Chloroquinine poisoning.BMJ 1993;307(6902):504
Wyte IM. Chapter 94: Antimalarial agents. In: Dart RC et al (Eds). MedicalToxicology. Third Edition. Philadelphia: Lippincott Williams and Wilkins; 2004. p.466-474

See: Problems for Discussion

• To understand the differences in antihistamine toxicity
• To review the effects of P450 metabolism on drug toxicity
• To review the effects of the potassium efflux pump (ie, potassium channel)

• To understand the diagnostic features of the anticholinergic syndrome
• To understand the role of cholinergic agents in its treatment and the background to the controversy

Anticholinergics and Antihistamines
Isbister GK, Oakley P, Whyte I, Dawson A.Treatment of anticholinergic-induced ileus with neostigmine. Ann Emerg Med 2001;38(6):689-93
Suchard JR. Assessing physostigmine's contraindication in cyclic antidepressant ingestions. J Emerg Med 2003;25(2):185-91
Oakley P. Physostigmine versus diazepines for anticholinergic poisoning. Ann Emerg Med 2001;37(2):239-41
Francis PD, Clarke CF. Angel trumpet lily poisoning in five adolescents: clinical findings and management. J Paediatr Child Health 1999 Feb;35(1):93-5
Craig-McFeely PM, Freemantle SL, Pearce GL, Shakir SA.QT lengthening and life-threatening arrhythmias associated with fexofenadine. Br J Gen Pract 2000;50(451):148
Eller MG, Walker BJ, Westmark PA, Ruberg SJ, Antony KK, McNutt BE, Okerholm RA.Pharmacokinetics of terfenadine in healthy elderly subjects. J Clin Pharmacol 1992;32(3):267-71
de Abajo FJ, Rodríguez LA.Risk of ventricular arrhythmias associated with nonsedating antihistamine drugs. Br J Clin Pharmacol 1999;47(3):307-13
Gupta S, Banfield C, Kantesaria B, Marino M, Clement R, Affrime M, Batra V. Pharmacokinetic and safety profile of desloratadine and fexofenadine when coadministered with azithromycin: a randomized, placebo-controlled, parallel-group study. Clin Ther 2001;23(3):451-66

See: Problems for Discussion

• Understand the mechanism of toxicity and clinical effects.
• Understand treatment of theophylline overdose, in particular the theory behind the use of multi-dose charcoal.

Xanthines
Okada S, Teramoto S, Matsuoka R.Recovery from theophylline toxicity by continuous hemodialysis with filtration. Ann Intern Med 2000;133(11):922

See: Problems for Discussion