Progress in Clinical Neurosciences: Treatment of Alzheimer’s Disease and Other Dementias - Review and Comparison of the Cholinesterase Inhibitors

Abstract

306Alzheimer's disease (AD) is the most common type of dementia encountered in older patients.1,2 To date, the most successful pharmacological approach to the treatment of AD has been with cholinesterase inhibitors (ChEIs) which are felt to increase acetylcholine (ACh) levels in the central nervous system (CNS) by interfering with the hydrolysis of ACh by acetylcholinesterase (AChE) and/or butyrylcholinesterase (BuChE). In this paper we will review the ChEIs approved by the Therapeutics Products Program of Health Canada for the symptomatic treatment of AD. We will compare these three agents (listed in order of approval -donepezil, rivastigmine, and galantamine) and give guidance as to who should be treated with what and how. A B S T R A C T: B a c k g r o u n d :A l z h e i m e r's disease (AD) is the most common cause of dementia in older adults. Acceptance of the c h o l i n e rgic hypothesis led to a search for medications which could enhance central cholinergic activity in this condition. There are now three cholinesterase inhibitors available for the treatment of AD in Canada. O b j e c t i v e s : To review the currently available cholinesterase inhibitors approved for the treatment of AD in Canada and to provide guidance on who and how to treat with these agents. R e s u l t s : D o n e p e z i l , rivastigmine, and galantamine are approved for the treatment of AD in Canada. In clinical trails, patients with mild to moderate AD treated with these agents experienced modest improvements in cognition, function, behaviour, and/or global clinical state. The magnitude of benefits seen with each agent appeared to be similar. While to date, there is no convincing evidence that one is more efficacious or effective, they do differ in their pharmacokinetics, additional mechanisms of action, and side effect profiles. Therefore, the selection of agent will be based on considerations such as side effect profiles, ease of administration, personal familiarity/experience, and beliefs about the importance of the noted differences in their pharmacokinetics and additional mechanisms of action. Conclusion: We believe that these agents should be offered to all individuals with a mild to moderate dementia where Alzheimer's pathology is felt to be a contributing factor. We view all three available cholinesterase inhibitors as first-line drugs. RÉSUMÉ: Traitement de la maladie d'Alzheimer-Revue et comparaison des inhibiteurs de la cholinestérase. I n t r o d u c t i o n :La maladie d'Alzheimer (MA) est la cause la plus fréquente de démence chez les personnes âgées. L'acceptation de l'hypothèse cholinergique a mené à la recherche de médicaments qui pourraient augmenter l'activité cholinergique centrale dans cette maladie. Il y a maintenant trois inhibiteurs de la cholinestérase qui sont disponibles au Canada pour le traitement de la maladie d'Alzheimer. O b j e c t i f s : Revoir les inhibiteurs de la cholinestérase qui sont actuellement disponibles et approuvés pour le traitement de la MAau Canada et fournir des conseils sur le t...

Cholinesterase Inhibitor Therapies and Neuropsychiatric Manifestations of Alzheimer’s Disease

“…These agents work by blocking acetylcholinesterase activity, thus preventing the hydrolysis of acetylcholine to choline and acetate in the synaptic cleft [5]. AD is characterized by specific pathological changes, which lead to cholinergic deficits.…”

Chronic Infusion of Amyloid-β Peptide and Sustained Attention Altered α7 Nicotinic Receptor Density in the Rat Brain

“…In some degenerative processes, like Alzheimer's disease (AD), the cholinergic transmission is critically affected, which currently makes the anticholinesterase agents the pharmacological therapy of choice throughout the world [12][13][14]. Some studies have shown that activation of the cholinergic system in the hippocampus or in the amygdala maylead to cognitive adjustments related to emotional situations [15,16].…”

A 12-Month Study of the Efficacy of Rivastigmine in Patients with Advanced Moderate Alzheimer’s Disease

“…To date, the most successful pharmacological approach to the treatment of AD has been with cholinesterase inhibitors (ChEIs), which are felt to increase acetylcholine (ACh) levels in the central nervous system by interfering with the hydrolysis of ACh by acetylcholinesterase (AChE) and/or butyrylcholinesterase [9,10].…”

“…Clinical use of tacrine has been limited by the high rate of side effects and need of serial blood monitoring for hepatotoxicity [12]. More recently, clinical trials of donepezil [13][14][15], rivastigmine [16][17][18][19] and galantamine [9,20] have demonstrated benefits on cognitive and global measures. The randomized controlled trials supporting these claims have involved patients with mild to moderately severe AD [Mini-Mental State Examination (MMSE) score of 5-26, or stages 3-6 on the Global Deterioration Scale (GDS)], but unfortunately, there is little information about the effects of these agents on advanced AD, especially regarding the long-term effects.…”