Galantamine

Abstract

Currently, acetylcholinesterase (AChE) inhibitors are the most promising class of drugs for the treatment of Alzheimer’s disease (AD). Galantamine is a reversible, competitive, tertiary alkaloid AChE inhibitor. The drug is selective for AChE rather than butyrylcholinesterase. In addition to inhibition of AChE galantamine interacts allosterically with nicotinic acetylcholine receptors to potentiate the action of agonists at these receptors. Recipients of galantamine 16 or 24 mg/day achieved significant improvements in cognitive and global symptoms relative to placebo recipients in large (n = 285 to 978 patients with mild to moderate AD) well-designed trials of 3 to 6 months’ duration. Galantamine also improved activities of daily living in these patients and significantly reduced the requirement for caregiver assistance with activities of daily living. Moreover, galantamine recipients achieved significantly better outcomes on behavioural symptoms than placebo recipients. In a long term study (12 months), galantamine 24 mg/day slowed the progression of symptoms of the disease and maintained cognitive function and activities of daily living in patients with mild to moderate AD. Galantamine was generally well tolerated with the majority of adverse events being mild to moderate in intensity and transient. Predictably, adverse events were cholinergic in nature and generally related to the gastrointestinal system. These effects were reduced in patients receiving the recommended dose escalation regimen. Galantamine had no clinically relevant effects on vital signs, haematological or biochemical laboratory parameters and, importantly, there were no reports of hepatotoxicity. The incidence of serious adverse events was similar between galantamine (8 to 32 mg/day) and placebo groups (6 to 16% of patients across all treatment groups). Conclusions: Galantamine is an effective well tolerated symptomatic treatment for AD which improves cognition, function and activities of daily living in the short term (up to 6 months) in patients with mild to moderate AD. In addition, it delays the development of behavioural disturbances and psychiatric symptoms, and reduces caregiver burden (as measured by caregiver time). In the long term (up to 1 year), galantamine maintains cognition and activities of daily living. Adverse events associated with galantamine are mainly cholinergic, usually mild to moderate in intensity and transient. Galantamine has been evaluated in several large well-designed studies and, given the relative lack of established treatment options, it may be considered as one of the first-line pharmacological treatments in patients with mild to moderate AD. Galantamine, a tertiary alkaloid, is a selective, competitive inhibitor of acetylcholinesterase (AChE). The inhibitor affinity (K_i) of galantamine for AChE in rat striatal tissue was 0.015 μmol/L. In postmortem brain tissue from patients without evidence of psychiatric disorder and fresh cortical brain biopsies from patients undergoing neurosurgery, galantamine inhibited AChE activity in a concentration-dependent manner. In postmortem samples, the concentrations of drug required to inhibit AChE activity by 50% were 3.2 and 2.8 μmol/L for the frontal cortex and hippocampal region, respectively. Tacrine and physostigmine exhibited a higher degree of AChE inhibition than galantamine in these regions of the brain. Galantamine was 10-fold less potent at inhibiting AChE from fresh brain cortex biopsies than from erythrocytes, whereas tacrine exhibited similar enzymatic inhibition levels in tissue from both sources. In 5 patients with possible or probable Alzheimer’s disease (AD) receiving oral galantamine 5mg 3 times daily for 2 to 3 months, erythrocyte AChE activity was inhibited by 21 to 41% 2 hours after the morning dose. Recovery of AChE activity occurred within ≈30 hours of the final dose of the drug. There was no detectable inhibition of butyrylcholinesterase in galantamine-treated patients for the duration of the study. Galantamine selectively inhibited AChE rather than butyrylcholinesterase in human plasma and erythrocytes. The drug showed a 53-fold selectivity for AChE over butyrylcholinesterase. In addition to inhibition of AChE, galantamine interacts directly with nicotinic acetylcholine receptors (nAChRs) and potentiates their action. Galantamine binds allosterically to the α-subunit of nAChRs. In cultured cell lines expressing nAChRs, galantamine modulated ion channel activity and potentiated the actions of the receptors in the presence of agonists. Galantamine attenuated drug- and lesion-induced cognitive deficits in animal models of learning and memory. The beneficial effects of galantamine on scopolamine-induced deficit in rats were similar to those observed with tacrine. Galantamine is rapidly absorbed following oral administration. Mean maximum plasma drug concentrations (C_max) after a single oral (tablet) 10mg dose ranged considerably from 49.2 to 1150 μg/L and were reached in a mean of 0.88 or 2 hours in healthy volunteers in 2 studies. At steady state, mean C_max and trough plasma concentrations (C_min) of galantamine fluctuated between 42 to 137 μg/L and 29 to 97 μg/L, respectively, following 12 or 16mg twice daily doses. In clinical trials, C_max values were 30 to 40% higher in patients with AD than those observed in healthy young volunteers. The mean absolute oral bioavailability of galantamine was 100% in healthy volunteers. Galantamine has a large volume of distribution following oral administration, confirming the high non-specific absorption of this drug. Although intravenous administration of galantamine in mice resulted in a rapid accumulation of the drug in tissues, patients receiving 12 or 16mg twice daily showed no evidence of accumulation of the drug after 2 to 6 months of therapy. Plasma protein binding of...