Pharmacodynamic, Pharmacokinetic and Pharmacogenetic Aspects of Drugs Used in the Treatment of Alzheimer’s Disease

Abstract

With the aging population and its rapidly increasing prevalence, dementia has become an important public health concern in developed and developing countries. To date, the pharmacological treatment is symptomatic and based on the observed neurotransmitter disturbances. The four most commonly used drugs are donepezil, galantamine, rivastigmine and memantine. Donepezil, galantamine and rivastigmine are acetylcholinesterase inhibitors with different pharmacodynamic and pharmacokinetic profiles. Donepezil inhibits selectively the acetylcholinesterase and has a long elimination half-life (t(1/2)) of 70 h. Galantamine is also a selective acetylcholinesterase inhibitor, but also modulates presynaptic nicotinic receptors. It has a t(1/2) of 6-8 h. Donepezil and galantamine are mainly metabolised by cytochrome P450 (CYP) 2D6 and CYP3A4 in the liver. Rivastigmine is a so-called 'pseudo-irreversible' inhibitor of acetylcholinesterase and butyrylcholinesterase. The t(1/2) of the drug is very short (1-2 h), but the duration of action is longer as the enzymes are blocked for around 8.5 and 3.5 h, respectively. Rivastigmine is metabolised by esterases in liver and intestine. Memantine is a non-competitive low-affinity antagonist of the NMDA receptor with a t(1/2) of 70 h. Its major route of elimination is unchanged via the kidneys. Addressing the issue of inter-patient variability in treatment response might be of special importance for the vulnerable population taking anti-dementia drugs. Pharmacogenetic considerations might help to avoid multiple medication changes due to non-response and/or adverse events. Some pharmacogenetic studies conducted on donepezil and galantamine reported an influence of the CYP2D6 genotype on the pharmacokinetics of the drugs and/or on the response to treatment. Moreover, polymorphisms in genes of the cholinergic markers acetylcholinesterase, butyrylcholinesterase, choline acetyltransferase and paraoxonase were found to be associated with better clinical response to acetylcholinesterase inhibitors. However, confirmation studies in larger populations are necessary to establish evidence of which subgroups of patients will most likely benefit from anti-dementia drugs. The aim of this review is to summarize the pharmacodynamics and pharmacokinetics of the four commonly used anti-dementia drugs and to give an overview on the current knowledge of pharmacogenetics in this field.

Concentration of donepezil in the cerebrospinal fluid of AD patients: Evaluation of dosage sufficiency in standard treatment strategy

“…In the EU, the maximum recommended dose is 10 mg daily, and in the USA the FDAapproved dose is 23 mg daily (Doody et al 2008;Farlow et al 2010;Noetzli and Eap 2013).…”

“…Donepezil is well absorbed, with a bioavailability approaching 100 %. Peak plasma concentrations (Cmax) are achieved after 3-5 h in patients receiving immediaterelease (5-and 10-mg tablets) and 6 h in those receiving sustained-release (23-mg tablet) formulations (see Table 1; taken from Noetzli and Eap 2013). In the USA, the FDAapproved dose is higher at 23 mg daily.…”

Medication-Related Factors Affecting Discharge to Home

“…Drug therapy for patients with impaired cognitive and/or excretion is applied. 31) It is reported that patients receiving high doses of donepezil, a medication for Alzheimer's disease, developed urinary dis- 32,33) The involvement of pharmacists in the drug therapy of such patients would be beneficial and provide a better care environment for the patient.…”

Dementia of the Alzheimer type: current state of the problem

“…Учитывая предполагаемое влияние ИХЭС на амилои-догенез и прогрессирование дегенеративного процесса, ре-комендуется раннее начало терапии. Эффективность лече-ния напрямую зависит от дозы препарата и продолжитель-ности терапии, что в свою очередь непосредственно связано с наличием побочных эффектов и переносимости [48]. Для преодоления нежелательных явлений используют посте-пенное повышение дозы, малый шаг титрации дозы, разра-батывают безопасные лекарственные формы и новые спо-собы введения.…”

“…Кли-нические данные об эффективности Акатинола меманти-на ® показывают улучшение или сохранение (на более поздних стадиях) когнитивных и психомоторных функ-ций, обучаемости, повседневной деятельности, снижение зависимости от опекунов [49,50]. На метаболизм препа-рата не влияет система цитохрома Р450, поэтому вероят-ность возникновения лекарственных взаимодействий до-статочно низкая [48]. Эффективность мемантина зависит от дозы.…”