Alzime Mechanism of Action

Pharmacology: Pharmacodynamics: Mechanism of Action: Donepezil hydrochloride, a piperidine derivative, is a centrally active, reversible inhibitor of acetylchlolinesterase. The drug is structurally unrelated to other cholinesterase agents (e.g. tacrine, physostigmine).
The precise mechanism of action of donepezil in patients with dementia of the Alzheimer's type (Alzheimer's disease) has not been fully elucidated. The drug is an anticholinesterase agent that binds reversibly with and inactivates cholinesterase (e.g. acetylcholinesterase), thus inhibiting hydrolysis of acetylcholine. As a result, the concentration of acetylcholine increases at cholinergic synapses. In vitro data and data in animals indicate that the anticholinesterase activity of donepezil is relatively specific for acetylchlolinesterase in the brain compared with butyrylcholinesterase inhibition in peripheral tissues.
A deficiency of acetylcholine caused by selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis and hippocampus is recognized as one of the early pathophysiologic features of Alzheimer's disease associated with memory loss and cognitive deficits. Because the resultant cortical deficiency of this neurotransmitter is believed to account for some of the clinical manifestations of mild to moderate dementia, enhancement of cholinergic function with an anticholinesterase agent, such as tacrine or donepezil, is one of the pharmacologic approaches to treatment.
Alzheimer's disease: Donepezil hydrochloride is used for the palliative treatment of mild to moderate dementia of the Alzheimer's disease, presenile or senile dementia. The rationale for use of donepezil in this condition is to potentially increase CNS acetylcholine concentrations, which can be deficient in patients with Alzheimer's disease. The current indication is based principally on 2 short-term (15 or 30 weeks), double-blind, placebo-controlled studies in patients with a diagnosis of Alzheimer's disease of mild to moderate severity. Both studies demonstrated clinically important but modest and variable improvement in cognitive function and clinician-rated global assessment of observed clinical change.
The specific role of donepezil in the management of Alzheimer's disease, particularly long-term or in patients with severe disease remains to be fully elucidated. In patients who received therapy with donepezil for at least 2 years in uncontrolled studies following their participation in placebo-controlled studies of the drug, improvement in cognitive function was maintained for an average of at least 40 weeks, with some benefit still evident after 2 years of follow-up.
In the 15 and 30 week, placebo-controlled studies upon which the current indication principally is based, donepezil therapy was associated with improvement in cognitive and overall functioning (e.g. as assessed by results of neuropsychological tests and clinicians impression of change, respectively). Age, race, or gender did not predict response to donepezil therapy in this study. Cognitive function was evaluated with the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS cog), a multiple-item instrument that has been extensively validated in longitudinal cohort of patients with Alzheimer's disease. ADAS cog measures elements of memory, orientation, attention, reasoning, language and praxis. Scores on the ADAS cog range from 0-70, with increasing scores being indicative of increasing cognitive impairment. Although normal geriatric adults may have scores of 0 or 1, slightly higher scores are not unusual in adults without dementia. Patients recruited into the 2 controlled studies of donepezil had initial scores of approximately 26 (range 4-61) on the ADAS cog. Longitudinal studies of ambulatory patients with mild to moderate Alzheimer's disease suggest that scores on the ADAS cog will increase (i.e. indicating a decline in cognitive function) by 6-12 points each year in such patients. A smaller annual change in score is observed in patients with either very mild or very advanced Alzheimer's disease because the ADAS cog does not uniformly reflect cognitive change over the course of the disease. In clinical trials of donepezil, ADAS cog scores increases by approximately 2-4 points per year in patients who received placebo.
Overall clinical change in patients receiving donepezil or placebo was evaluated with a Clinician's Interview Based Impression of Change (CIBIC) that required use of information from caregivers (CIBIC plus). A variety of CIBIC formats have been used in clinical studies, and the various CIBIC formats may differ in terms of depth and structure. The CIBIC plus used in the studies of donepezil was a subjective, semistructured instrument intended to measure the patient's ability to function generally, cognitively , behaviorally, and in activities of daily living. Scores of 1, 4, or 7 on the CIBIC plus denote marked improvement, no change, or markedly worse, respectively.
In the 15- and 30-week controlled studies of donepezil, the treatments were administered for 12 or 24 weeks, respectively, followed by placebo washout periods of 3 or 6 weeks, respectively, to determine whether rebound effects would occur following discontinuance of the drug . Patients received 5 or 10 mg of donepezil hydrochloride or placebo once daily in these studies; patients who were assigned to receive the 10-mg dosage of donepezil hydrochloride initially received 5 mg daily for 7 days to minimize the likelihood of adverse cholinergic effects. In the 15-week study, the improvement from baseline in the ADAS cog scores with donepezil compared with placebo averaged 2.7 or 3 points after 12 weeks of treatment with donepezil hydrochloride 5 or 10 mg daily, respectively; the difference in ADAS cog scores for the 2 dosages was not statistically significant. In this study, and improvement of 7 points in the ADAS cog scores was attained at 12 weeks by a cumulative 14, 21, or 36% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively, while an improvement of 4 points was attained at 12 weeks by a cumulative 30, 49, or 57% of patients in these respective groups. Cognitive function was maintained (i.e., no change in ADAS cog scores from baseline) at 12 weeks in a cumulative 72, 83, or 87% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. In the 30-week study, improvement from baseline in ADAS cog scores with donepezil compared with placebo averaged 2.8 or 3.1 points after 24 weeks of treatment with 5 or 10mg daily, respectively, of donepezil hydrochloride; the difference in ADAS cog scores for the 2 dosages was not statistically significant. An improvement of 7 points from baseline in the ADAS cog scores was attained at 24 weeks by a cumulative 8, 15, or 26% of patients who received placebo, 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. Improvement of 4 points from baseline in the ADAS cog scores was attained at 24 weeks by a cumulative 28, 40, or 58% of patients who received placebo. 5 mg of donepezil hydrochloride, or 10 mg of donepezil hydrochloride once daily, respectively. Cognitive function was maintained (i.e., no change in ADAS cog scores from baseline) at 24 weeks in a cumulative 59, 83, or 82% of patients who received placebo, donepezil hydrochloride 5 mg, or donepezil hydrochloride 10 mg once daily, respectively.
Overall clinical improvement (as determined by the CIBIC plus assessment) also was observed in patients treated with donepezil in these 2 controlled studies. CIBIC plus scores attained in patients receiving 5 or 10 mg of donepezil hydrochloride once daily differed from placebo by 0.36 or 0.38 points, respectively, after 12 weeks of treatment in the 15-week study and by 0.35 or 0.39 points, respectively, after 24 weeks of treatment in the 30-week study. As with the ADAS cog scores, a dose-related effect of donepezil on overall clinical change in these studies was not established. Following the 6-week placebo washout period in the 30-week study, scores on the ADAS cog scores for patients treated with donepezil or placebo were indistinguishable, indicating no evidence of an effect of donepezil on the underlying disease process in dementia. Results of neuropsychologic test (i.e., ADAS cog scores, CIBIC plus, Mini-Mental State Examination [MMSE], and Clinical Dementia Rating {CDR}) performed 6 weeks after discontinuance of donepezil therapy did not show evidence of a rebound deterioration in cognitive symptoms.
Vascular dementia: Donepezil may be effective in treatment of vascular dementia. Results from a randomized, controlled study have shown an improvement in cognition and global function in patients with probably or possible vascular dementia. A systemic review also concluded that donepezil improved mild to moderate vascular cognitive impairment in the short term (treatment for 6 months). The manufacturer has reported that out of a total of 3 studies of donepezil in vascular dementia, one (Study 319) showed an apparently increased mortality compared with placebo: 1.7% and 0%, respectively. In a combined analysis of the other 2 studies, the mortality rate was1.7% in the donepezil group and 2 % in the placebo group. Combined analysis of all 3 studies showed no statistically significant difference in the mortality rates between the donepezil (1.7%) and placebo (1.1%) groups; the risk of vascular events such as stroke and myocardial infarction was also similar for each group. The unexpected low mortality rate with placebo in Study 319 was unusual given the age and pathology of the subjects. An increased risk of death has also been reported with another acetylcholinesterase inhibitors, galantamine, when used in patients who did not have Alzheimer's disease.
Pharmacokinetics: Pharmacokinetics parameters: Absorption: Donepezil is well absorbed with a relative oral bioavailability of 100% and reaches peak plasma concentrations in 3 to 4 hours. Pharmacokinetics are linear over a dose range of 1 to 10 mg given once daily. Neither food nor time of administration (morning vs evening dosing) influences the rate or extent of absorption.
Distribution: Following multiple-dose administration, donepezil accumulates in plasma by 4-to 7-fold and steady state is reached within 15 days. The steady-state volume of distribution is 12 L/kg. Donepezil is approximately 96% bound to human plasma proteins, mainly to albumins (approximately 75%) and alpha-1 acid glycoprotein (approximately 21%) over the concentration range of 2 to 1,000 ng/mL.
Metabolism: Donepezil is excreted in the urine intact and extensively metabolized to 4 major metabolites (2 of which are known to be active) and a number of minor metabolites, not all of which have been identified. Donepezil is metabolized by the CYP-450 isoenzymes 2D6 and 3A4, and undergoes glucuronidation. Following administration of ¹⁴C-labeled donepezil, plasma radioactivity, expressed as a percent of the administered dose, was present primarily as intact donepezil (53%) and as 6-O-desmethyl donepezil (11%), which has been reported to inhibit AChE to the same extent as donepezil in vitro and was found in plasma at concentrations equal to approximately 20% of donepezil.
Excretion: The elimination half-life of donepezil is approximately 70 hours and the mean apparent plasma is 0.13 L/h/kg. Approximately 57% and 15% of the total dose was recovered in urine and faces, respectively, over a period of 10 days, while 28% remained unrecovered, with approximately 17% of the donepezil dose recovered in the urine as unchanged drug.