Cholinesterase inhibitors with potential or established clinical effects can be classified as follows:
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(1) Reversible inhibitors: donepezil, galantamine.
(2) Pseudoreversible inhibitors (carbamate derivatives): physostigmine, rivastigmine.
(3) Irreversible inhibitors: eg, metrifonate.
Pharmacodynamics. In addition to being a reversible, competitive cholinesterase inhibitor, galantamine allosterically modulates nicotinic acetylcholine receptors (16). Stimulation of nicotinic receptors can increase the release of neurotransmitters such as acetylcholine and glutamate. Chronic low-level stimulation of nicotinic receptors protects against beta-amyloid toxicity by increasing the release of the terminally truncated form of beta-amyloid precursor protein. The neuroprotective mechanism of galantamine in Alzheimer disease is explained by its targeting neuronal-type alpha7 nicotinic acetylcholine receptors (α7nAChRs) on the cell surface, which are impaired early in the course of the disease and inhibit amyloid beta-induced neurotoxicity by acting as a cargo carrier for binding to autophagosomal marker protein LC3 during engulfing of amyloid beta1-42 (17).
In addition to its action as modulator of neurotransmitter release, galantamine is a neuroprotective agent through an antiapoptotic action. In clinical trials, galantamine shows the greatest benefits when treatment is started early, indicating that these benefits may result from an effect on the underlying disease process. Such an effect might be mediated by the concomitant action of galantamine on nicotinic receptors. In a placebo-controlled PET study galantamine caused sustained in vivo cortical acetylcholinesterase inhibition and (11)C-nicotine binding for up to 12 months, which were correlated positively with the results of a cognitive test of attention (13). Another evidence for disease modifying effect is that galantamine inhibits beta-amyloid aggregation and cytotoxicity in experimental cell systems (18). Galantamine treatment has been shown to facilitate beta-amyloid clearance in brains of rodent models of Alzheimer disease (30). A functional MRI (fMRI) study has shown that treatment with galantamine enhances processing of stimuli along the dorsal visual system, which may be useful as a biomarker of treatment effects (03).
A crosslinked dimer of galantamine, Gal-2, modulates P-glycoprotein-mediated efflux mechanism at the blood-brain barrier by competing for the substrate binding sites indicating that it has potential to augment the treatment of neurodegenerative disorders (20).
A prospective placebo-controlled study studied the long-term effects of galantamine on default mode connectivity, which is impaired in patients with mild to moderate Alzheimer disease (02). Functional connectivity significantly increased in the posterior cingulate cortex and in the precuneus as demonstrated by fMRI in patients treated with galantamine indicating that this is a more sensitive biomarker of the drug effect than cognitive testing, which remained stable throughout the study period.
Pharmacokinetics. Galantamine is rapidly absorbed following oral administration. Peak plasma concentration after a single dose of 10 mg is 180 ng/ml and is reached in approximately 2 hours in healthy adult volunteers. The bioavailability is 100%. In clinical trials of Alzheimer disease patients, doses of 15 to 55 mg resulted in steady-state peak plasma concentrations of 32 to 182 ng/ml. The major route of metabolism of galantamine is via cytochrome P450 isozymes in the liver, and about 75% of the dose is metabolized. The elimination half-life of galantamine is about 7 to 8 hours, and approximately 20% to 25% of the galantamine dose administered is excreted unchanged in urine (12).
Pharmacogenetics. Polymorphisms of the CYP2D6 gene significantly influence galantamine plasma concentrations and, hence, treatment efficacy and tolerability (21).
Therapeutic drug monitoring. A simple, rapid, and selective liquid chromatography method coupled with tandem mass spectrometry has been developed and validated for the quantification of galantamine in human plasma using a commercially available compound, glimepiride, as an internal standard (22). The lower limit of quantification of galantamine by this method is 4 ng/mL.
Formulations. Galantamine is currently administered via the oral route and may cause nausea, vomiting, and gastrointestinal disturbances. A transdermal patch with reservoir and controlled release of galantamine has been constructed and is undergoing investigation for use in Alzheimer disease patients (34). It is not approved for clinical use.