Cholinesterase Inhibitors

The “cholinergic hypothesis” proposes that part of age-related cognitive decline is caused by reduced cerebral cholinergic function. This theory has been used as a rationale for testing drug therapies that restore cholinergic function in patients with Alzheimer’s disease (AD) and related dementias. Interest in the use of cholinesterase inhibitors to manage the symptoms of AD rose dramatically following the 1986 publication of a clinical trial of tacrine by Summers and colleagues. Several further positive industry-sponsored clinical trials of tacrine were published. Trials without industry sponsorship, however, failed to document similar benefits with this medication. Ultimately, the potential for serious hepatotoxicity and high rates of intolerable adverse effects weakened enthusiasm for tacrine. While tacrine was approved for use in the United States and in some European countries, evaluation by the Canadian Health Protection Branch led to its rejection on the grounds that the benefits did not translate into sufficient functional improvement to offset its potential risks. This opinion was strengthened by an assessment that concluded that tacrine showed no clear evidence of efficacy or effectiveness.

Other cholinesterase inhibitors that initially appeared to have benefits in the management of AD have also been abandoned due to adverse effects. For example, metrifonate, velnacrine, and physostigmine never received approval for use in Canada. The drugrelated adverse events associated with this class of medications includes a variety of gastrointestinal symptoms (such as nausea, diarrhea and weight loss), muscle weakness, and bradyarrhythmias.

Over the past few years, newer cholinesterase inhibitors have been introduced and are perceived as having fewer adverse effects. In August 1997, donepezil became the first cholinesterase inhibitor to receive approval for use in Canada. Subsequently, rivastigmine and galantamine were also given approval for use (in June 2000 and February 2001, respectively). Numerous randomized controlled trials (RCTs) of these cholinesterase inhibitors have demonstrated their small but significant and consistent benefits in delaying the progressive cognitive decline associated with AD. Aside from their efficacy, the cholinesterase inhibitors are generally perceived to be safe. In contrast to tacrine, the newer medications do not appear to have any significant risk of hepatotoxicity.

Nonetheless, even the cholinesterase inhibitors that have been approved in Canada are
subject to controversy. Many clinicians are divided over the likely real-world benefits of these medications. The effectiveness of the cholinesterase inhibitors in most patients is modest at best. Furthermore, the cognitive benefits wash out rapidly once the drugs are discontinued. Roe and colleagues have suggested that adherence rates are low: 13.9% of patients on donepezil for more than six months had gaps in treatment of six weeks or more. Several cost-benefit analyses examining the cholinesterase inhibitors have been presented. A recent publication suggests that donepezil may delay time to institutionalization (which is a key assumption in the cost effectiveness models).On the other hand, several critical systematic reviews have argued that the finding of cost effectiveness with these drugs is still not clear.

These controversies may have contributed to delays in the addition of cholinesterase inhibitors to provincial drug plans that provide reimbursement for medication costs to older patients and those on social assistance. For example, although donepezil was approved for use in Canada in 1997, it was not covered by provincial formularies until much later. In some provinces (e.g., British Columbia), the provincial health plan still does not provide reimbursement for any cholinesterase inhibitor. These regional differences in coverage for a medication that typically costs $150 Canadian per month have led to dramatic differences in the rates of cholinesterase inhibitor use across the country. The Ontario Drug Benefit Program decided to cover donepezil in June 1999. Coverage is provided under “Limited Use” criteria: the prescribing physician must verify that patients prescribed this drug have mild to moderate probable AD in order for them to qualify for reimbursement. Rivastigmine and galantamine are also covered as Limited Use products under the Ontario Drug Benefit program.



Sudeep Singh Gill. Patterns of Use and Adverse Events Associated with Cholinesterase Inhibitors in Older Adults with Dementia