Abstract
Summary
Tacrine, a centrally acting, reversible acetylcholinesterase inhibitor, is effective in the treatment of Alzheimer’s disease. However, a major adverse effect of the drug is hepatotoxicity, which affects about one-half of patients treated.
The pathogenic mechanisms of this hepatotoxicity are poorly understood, but probably involve reactive metabolites. The liver injury is predominantly that of hepatocellular necrosis, and manifests as an increase in serum alanine aminotransferase (ALT) levels; 25 and 2% of patients will experience ALT levels greater than 3 times and 20 times the upper limit of the normal range, respectively.
Although hepatotoxicity is generally asymptomatic and has not led to death, severe reactions have been reported, and careful monitoring of ALT levels is mandatory in all patients, especially during initiation of therapy and following dose escalation. An ALT level exceeding 3 times the upper limit of the normal range should prompt withdrawal of the drug.
Following cessation of tacrine, ALT levels generally decrease rapidly and usually normalise within 6 weeks. Rechallenge can be safely attempted once ALT levels are near normal, except in patients whose ALT levels were markedly increased or in whom a moderate increase of ALT levels was associated with features of hypersensitivity (e.g. rash, fever, eosinophilia). Approximately 90% of those patients rechallenged with tacrine will tolerate the drug and continue with therapy on a long term basis. Minimisation of morbidity and maximisation of the number of patients treated in the long term can be achieved by following sensible guidelines and by the early recognition of danger signs.
Similar content being viewed by others
References
Summers WK, Viesselman JO, Marsh GM, et al. Use of THA in Alzheimer-like dementia: pilot study in 12 patients. Bioi Psychiatry 1981; 16: 145–53
Summers WK, Majowski IV, Marsh GM, et al. Oral tetrahydroaminoacridine in long term treatment of senile dementia, Alzheimer type. N Engl J Med 1986; 315: 1241–5
Marx lL. Alzheimer’s drug trial put on hold. Science 1987; 238: 1041–2
Wagstaff AJ, McTavish D. Tacrine: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic efficacy in Alzheimer’s disease. Drugs Aging 1994; 4 (6): 510–40
Knapp Ml, Knopman OS, Solomon PR, et al. A 30 week randomized controlled trial of high dose tacrine in patients with Alzheimer’s disease. lAMA 1994; 271 (13): 985–91
Farlow M, Gracon SI, Hershey LA, et al. A controlled trial of tacrine in Alzheimer’s disease. JAMA 1992; 268 (18): 2523–9
Chatellier G, LaComblez L. Tacrine (tetrahydroaminoacridine; THA) and lecithin in senile dementia of the Alzheimer type: a multicentre trial. BMJ 1990; 300: 495–9
Gauthier S, Bouchard R, Lamontagne A, et al. Tetrahydroaminoacridine- Iecithin combination treatment in patients with intermediate-stage Alzheimer’s disease. N Engl J Med 1990; 322: 1272–6
Ahlin A, Nyback H, Junthe T, et al. Tetrahydroaminoacridine in Alzheimer’s dementia: clinical and biomedical results of a double-blind crossover trial. Hum Psychopharmacol 1991; 6: 109–18
Eagger SA, Levy R, Sahakian Bl. Tacrine in Alzheimer’s disease. Lancet 1991; 337: 989–92
Wilcox GK, Sumon DJ, Scott M, et al. An evaluation of the efficacy and safety of tetrahydroaminoacridine (THA) without lecithin in the treatment of Alzheimer’s disease. Age Ageing 1993; 22: 316–24
Davis KL, Thal LJ, Gamzu ER, et al. A double blind, placebocontrolled multicenter study of tacrine for Alzheimer’s disease. N Engl J Med 1992; 327: 1253–9
Eagger SA, Morant NJ, Levy R. Parallel group analysis of the effects of tacrine versus placebo in Alzheimer’s disease. Dementia 1991; 2: 207–11
Maltby N, Broe GA, Creasey H, et al. Efficacy of tacrine and lecithin in mild to moderate Alzheimer’s disease; double blind trial. BMI 1994; 308: 879–83
Fitten LJ, Perryman KM, Gross PL, et al. Treatment of Alzheimer’s disease with short and long term oral THA and lecithin: a double blind study. Am J Psychiatry 1990; 147: 239–42
Minthon L, Gustafson L, Dalfelt G, et al. Oral tetrahydroaminoacridine treatment of Alzheimer’s disease evaluated clinically and by regional cerebral blood flow and EEG. Dementia 1993; 4: 32–42
Molloy OW, Guyatt GH, Wilson DB, et al. Effect of tetrahydroaminoacridine on cognition, function and behaviour in Alzheimer’s disease. Can Med Assoc J 1994; 144: 29–34
Weinstein HC, Teunisse S, van Gool WA. Tetrahydroaminoacridine and lecithin in the treatment of Alzheimer’s disease. Effect on cognition, functioning in daily life, behavioural disturbances and burden experienced by carers. J Neurol 1991; 238: 34–8
Bowen D. The cholinergic system and the excitatory amino acids in Alzheimer’s disease. Acta Neurol Scand 1990; 80 Suppl.: 15–6
Adem A. Putative mechanisms of action of tacrine in Alzheimer’s disease. Acta Neurol Scand 1992; 82 Suppl.139: 69–74
Coyle JT, Price DL, De Long MR. Alzheimer’s disease: a disorder of cortical cholinergic innervation. Science 1983; 219: 1184–90
Mesulam M-M, Geula C. Shifting patterns of cortical cholinesterases in Alzheimer’s disease: implications for treatment, diagnosis, and pathogenesis. Adv Neurol 1990; 51: 235–40
Nordberg A. Neuroreceptor changes in Alzheimer’s disease. Cerebrovasc Brain Metab Rev 1992; 4: 303–28
Nordberg A. Clinical studies in Alzheimer’s patients with position emission tomography. Behav Brain Res 1993; 57: 215–24
Freeman SE, Dawson RM. Tacrine: a pharmacological review. Prog Neurobiol 1991; 36: 257–77
Adem A, Mohammed AK, Winblad B. Multiple effects of tetrahydroaminoacridine on the cholinergic system: biochemical and behavioural aspects. J Neurol Transm 1990; 2: 113–28
Nilsson-Hakansson L, Lai Z, Nordberg A. Tetrahydroaminoacridine induces opposite changes in muscarinic and nicotinic receptors in rat brain. Eur J Pharmacol 1990; 186: 301–5
Nishibon M, Oishi R, Itoh Y, et al. 9 amino-I,2,3,4 tetrahydroaminoacridine is a potent inhibitor of histamine N methyltransferase. Jap J Pharmacol 1991; 55: 539–46
Drukarch B, Leysen lE, Stoof JC. Further analysis of the neuropharmacological profile of 9 amino-I,2,3,4 tetrahydroaminoacridine (THA), an alleged drug for the treatment of Alzheimer’s disease. Life Sci 1988; 42: 1011–7
Jossan SS, Adem A, Winblad B, et al. Characterisation of dopamine and serotonin uptake inhibitory effects of tetrahydroaminoacridine in rat brain. Pharmacol Toxicol 1992; 71: 213–5
Adem A, Jossan SS, Oreland L. Tetrahydoraminoacridine inhibits human and rat brain monoamine oxidase. Neurosci Lett 1989; 107: 313–7
Forsyth DR, Wilcock SK, Morgan RA, et al. Pharmacokinetics oftacrine hydrochloride in Alzheimer’sdisease. Clin Pharmacol Ther 1989; 46: 634–41
Selen A, Balough L, Siedlik P, et al. Pharmacokinetics oftacrine in healthy subjects [abstract no. PPI477]. Pharmaceutical Res 1988; 5: 5–218
Ahlin A, Adem A, Junthe T. Pharmacokinetics of tetrahydroaminoacridine: relations to clinical and biochemical effects in Alzheimer’s patients. Int Clin Psychopharmacol 1992; 7: 29–36
Makela PM, Truman CA, Ford JM, et al. What effect do ageing and disease have on the in vitro plasma protein binding of tacrine hydrochloride (THA)? Br J Clin Pharmacol 1994; 37: 117P–118P
McNally W, Roth M, Young R, et al. Quantitative whole body autoradiographic determination of tacrine tissue distribution in rats following intravenous or oral dose. Pharmaceutical Res 1989; 6: 924–30
Woolf TF, Pool WF, Kukura M, et al. Characterization of tacrine metabolism and bioactivation using heterologous expression systems and inhibition studies: evidence for CYPIA2 involvement. In ISSX Proceeding, Fifth North American ISSX Meeting; 1993 Oct 17-21; Tuscon
Madden S, Woolf TF, Pool WF, et al. An investigation into the formation of stable protein-reactive cytotoxic metabolites from tacrine in vitro: studies with human and rat liver microsomes. Biochem Pharmacol 1993; 46: 13–20
Park BK, Madden S, Spaldin V, et al. Tacrine transaminitis: potential mechanisms. Alz Dis Assoc Disord 1994; 8 (2): S39–49
Doglerom P, Nagelkerke JF, Mulder GJ. Hepatotoxicity of tetrahydroaminoacridine in isolated rat hepatocytes: effects of glutathione and vitamin E. Biochem Pharmacol 1988; 37: 2311–3
Ford JM, Truman CA, Wilcock G, et al. Serum concentrations of tacrine hydrochloride predict its adverse effects in Alzheimer’s disease. Clin Pharmacol Ther 1993; 53: 691–5
Watkins PB, Zimmerman HJ, Knapp MJ, et al. Hepatotoxic effects of tacrine administration in patients with Alzheimer’s disease. JAMA 1994; 271 (13): 992–8
Watkins PB. Tacrine and transaminases. Alz Dis Assoc Disord 1994; 8 (2): 532–8
Hammel P, Larrey D, Bemuau J, et al. Acute hepatitis after tetrahydroaminoacridine administration for Alzheimer’s disease. J Clin Gastroenterol 1990; 12 (3): 329–31
Ames DJ, Bhathal PS, Davies BM, et al. Heterogeneity of adverse hepatic reactions to tetrahydroaminoacridine. Aust NZ J Med 1990; 20: 193–5
Watkins PB. Role of cytochromes P450 in drug metabolism and hepatotoxicity. Sem Liver Dis 1990; 10: 235–42
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Balson, R., Gibson, P.R., Ames, D. et al. Tacrine-Induced Hepatotoxicity. CNS Drugs 4, 168–181 (1995). https://doi.org/10.2165/00023210-199504030-00002
Published:
Issue Date:
DOI: https://doi.org/10.2165/00023210-199504030-00002