Abstract
Cholinergic adverse effects of acetylcholinesterase inhibitors (AChEIs) are caused by their central and peripheral pharmacological actions on a variety of organ tissues. Gastrointestinal adverse effects predominate and these were relatively common in the phase II and III randomised clinical trials of AChEIs for the treatment of probable Alzheimer’s disease. However, in these studies forced and rapid titration of drugs was used, which is not the case in clinical practice. Although there is a risk of pharmacodynamic interactions with other drugs leading to enhanced cholinergic adverse effects, very few of these interactions have proven to be clinically significant. Unresolved issues include the mechanism of syncope and neuromuscular weakness, which should be resolved through structured pharmacovigilance programmes and clinical studies. Loss of bodyweight may prove to be a long term significant complication. As a class, the AChEIs have proven to be well tolerated in the symptomatic treatment of Alzheimer’s disease in its mild-to-moderately severe stages. The incidence and clinical significance of cholinergic adverse events will need to be carefully studied if the drugs are used for indications other than Alzheimer’s disease.
Similar content being viewed by others
References
Ormrod D, Spencer C. Metrifonate: a review of its use in Alzheimer’s disease. CNS Drugs 2000; Jun 13(6): 443–67
Giacobini E. Cholinesterase inhibitors for Alzheimer’s disease therapy: from tacrine to future applications. Neurochem Int 1998; 32: 413–9
Pepeu G. Preclinical pharmacology of cholinesterase inhibitors. In: Giacobini E, editor. Cholinesterases and cholinesterase inhibitors. London: Martin Dunitz Publisher, 2000: 145–55
Giacobini E. Cholinesterase inhibitors: from the Calabar bean to Alzheimer therapy. Giacobini E, editor. Cholinesterases and cholinesterase inhibitors. London: Martin Dunitz Publisher, 2000: 181–226
Doody RS, Geldmacher DS, Pratt RD, et al. Optimal donepezil efficacy in Alzheimer’s disease is dependant on continued administration. Presented at the 9th Meeting of the European Neurological Society; 1999 Jun 5–9; Milan.
Friedman JH. ’Drug holiday’ in the treatment of Parkinson’s disease: a brief review. Arch Intern Med 1985; 145: 913–5
Gauthier S. Acetylcholinesterase inhibitors in the treatment of Alzheimer’s disease. Exp Opin Invest Drugs 1999; 8: 1511–20
Nordberg A, Svensson AL. Cholinesterase inhibitors in the treatment of Alzheimer’s disease. Drug Saf 1998; Dec 19(6): 465–80
Crimson ML. Pharmacokinetics and drug interactions of cholinesterase inhibitors administered in Alzheimer’s disease. Pharmacotherapy 1998; 18: 47–54
Schachter AS, Davis KL. Guidelines for the appropriate use of cholinesterase inhibitors in patients with Alzheimer’s disease. CNS Drugs 2000; Apr 11(4): 281–8
Samuels SC. Alzheimer disease treatment: a focus on cholinesterase inhibitors. Primary Psychiatry 2000; 7: 62–6
VanDenBerg CM, Kazmi Y, Jann MW. Cholinesterase inhibitors for the treatment of Alzheimer’s disease in the elderly. Drugs Aging 2000; Feb 16(2): 123–38
Folstein MF, Folstein SE, McHugh PR. Mini Mental State: a practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975; 12: 189–98
Cutler NR, Sramek JJ. Tolerability profiles of AchEIs: a critical component of care for Alzheimer’s disease patients. Int J Geriatr Psychopharmacol 1998; 1Suppl. 1: S20–5
Corey-Bloom J, Anand R, Veach J, for the ENA713 B352 Study Group. A randomized trial evaluating the efficacy and safety of ENA 713 (rivastigmine tartrate), a new acetylcholinesterase inhibitor, in patients with mild-to-moderately severe Alzheimer’s disease. Int J Geriatr Psychopharmacol 1998; 1: 55–65
Rösier M, Anand R, Cicin-Sain A, et al., on behalf of the B303 Exelon Study Group. Efficacy and safety of rivastigmine in patients with Alzheimer’s disease: results of an international, 26-week, multicentre, randomised, placebo-controlled trial. BMJ 1999; 318: 633–8
Cummings JL, Cyrus PA, Bieber F, et al. Metrifonate treatment of the cognitive deficits of Alzheimer’s disease. Neurology 1998; 50: 1214–21
Morris JC, Cyrus PA, Orazem J, et al. Metrifonate benefits cognitive, behavioral and global function in patients with Alzheimer’s disease. Neurology 1998; 50: 1222–30
Dubois B, McKeith I, Orgogozo JM, et al. A multicentre, randomized, double-blind, placebo-controlled study to evaluate the efficacy, tolerability and safety of two doses of metrifonate in patients with mild-to-moderate Alzheimer’s disease: the MALT study. Int J Geriatr Psychiatry 1999; 14: 973–82
Rogers SL, Friedhoff T, and the Donepezil Study Group. The efficacy and safety of donepezil in patients with Alzheimer’s disease: results of a US multicentre, randomized, double-blind, placebo-controlled trial. Dementia 1996; 7: 293–303
Rogers SL, Doody R, Mohs RC, Donepezil Study Group, et al. Donepezil improves cognition and global function in Alzheimer disease. Arch Intern Med 1998; 158: 1021–31
Rogers SL, Farlow MR, Doody RS, Donepezil Study Group, et al. A 24-week, double-blind, placebo-controlled trial of donepezil in patients with Alzheimer’s disease. Neurology 1998; 50: 136–45
Burns A, Rossor M, Hecker J, Donepezil Study Group, et al. Donepezil in the treatment of Alzheimer’s disease: results from a multinational clinical trial. Dement Geriatr Cogn Disord 1999; 10: 237-44
Tariot PN, Solomon PR, Morris JC, Galantamine USA-10 Study Group, et al. A 5-month, randomized, placebo-controlled trial of galantamine in AD. Neurology 2000; 54: 2269–76
Raskind MA, Peskind ER, Wessel T, Galantamine USA-1 Study Group, et al. Galantamine in AD: a 6-month randomized, placebo-controlled trial with a 6-month extension. Neurology 2000; 54: 2261–8
Wilcock GK, Lilienfeld S, Gaens E, on behalf of the Galantamine International-1 Study Group. Efficacy and safety of galantamine in patients with mild-to-moderate Alzheimer’s disease: multicentre randomised controlled trial. BMJ 2000; 321: 1–7
Cutler NR, Anand R, Hartman RD, et al. Antiemetic therapy for Alzheimer’s patients receiving the cholinesterase inhibitor SDZ ENA 713 [abstract]. Clin Pharmacol Ther 1998; 63: 188
Medina A, Bodick N, Goldberger A, et al. Effects of central muscarinic-1 receptor stimulation on blood pressure regulation. Hypertension 1997; 29: 828–34
Sramko CA, Berger F, Calabrese P, et al. Tolerability and safety of donepezil in the treatment of Alzheimer’s disease: results from a post marketing surveillance study [abstract]. Eur Neuropsychopharmacol 2000; 10Suppl. 3: S368
Feldman H, Gauthier S, Hecker J, et al. A 24-week randomised, double-blind study of donepezil in moderate to severe Alzheimer’s disease. Neurology 2001; 57: 613–20
Mohs R, Doody R, Morris J, et al. A 1-year placebo-controlled preservation of function survival study of donepezil in AD patients. Neurology 2001; 57: 481–8
Winblad B, Engedal K, Soininen H, et al. A 1-year, randomised, placebo-controlled study of donepezil in patients with mild to moderate AD. Neurology 2001; 57: 489–95
Dear Healthcare Professional letter [online]. Available from URL: http://www.fda.gov/medwatch/safety/2001/exelon.htm [Accessed 2001 Nov 29]
McKeith I, Del Ser T, Spano PF, et al. Efficacy of rivastigmine in dementia with Lewy bodies: a randomized double-blind, placebo-controlled international study. Lancet 2001; 356: 2031–6
Aarsland D, Larsen JP, Janvin C, et al. Donepezil treatment in Parkinson’s disease with dementia: a double-blind, placebo-controlled crosss-over study [abstract]. Neurology 2001; 56Suppl. 3: A128
Wilkinson DG, Passmore P, Smith R, et al. Comparison of the tolerability, ease of use, and efficacy of donepezil and rivastigmine in Alzheimer’s disease patients: a 12-week multinational study [abstract]. Neurology 2001: 56Suppl. 3: A456–7
Acknowledgements
The author’s research is funded by the Canadian Institutes for Health Research, the Fonds de la Recherche en Santé du Québec, the National Institute of Aging. Special thanks to Professor Ezio Giacobini for reviewing the manuscript. The author is or has been a consultant to Bayer, Eisai/Pfizer, Janssen-Cilag and Novartis, sponsors of the drugs discussed in this review, but has received no funding for the current work.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Gauthier, S. Cholinergic Adverse Effects of Cholinesterase Inhibitors in Alzheimer’s Disease. Drugs Aging 18, 853–862 (2001). https://doi.org/10.2165/00002512-200118110-00006
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002512-200118110-00006