Pharmacology

Cholinesterase inhibitors with potential or established clinical effects can be classified as follows:

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.

Clinical trials

Galantamine has been evaluated in several clinical trials. Some trials are shown in Table 1.

Table 1. Clinical Trials with Galantamine

Indications

Galantamine is used for the treatment of mild-to-moderate Alzheimer disease. Based on its approval for the treatment of mild-to-moderately severe Alzheimer disease in both the United States and in Europe, with trials of its efficacy in other dementia types already yielding positive results, galantamine has been ranked as a first-line therapy for dementia.

Off-label uses

Contraindications

Galantamine is contraindicated in patients with severe hepatic or renal disease. It is not recommended for patients with gastrointestinal or urinary outflow disturbances.

Goals and duration of treatment

Therapy, if started early in the course of Alzheimer disease, may slow the progression of the disease and delay the need for full-time care, which may result in cost savings. Patients with mild-to-moderate Alzheimer disease who are apoE4 homozygous on genotyping studies are considered better responders to galantamine. A study on Alzheimer disease patients with aggression revealed increased regional cerebral blood flow on single photon emission computed tomography in the right prefrontal cortex, as compared with those without aggression and treatment with galantamine inhibited increases in the blood flow, indicating that responsiveness to galantamine may be related to aggression and dysfunction of the prefrontal cortex (19). Effectiveness of galantamine may be enhanced by combination with nonpharmacological therapies for Alzheimer disease. In a retrospective study, combination of galantamine with cognitive rehabilitation showed a superior benefit both on cognitive and affective functions as compared to galantamine only therapy in Alzheimer disease patients (32).

In an open study of patients with mild Alzheimer disease, galantamine was generally safe and well tolerated during the 3-year observation period (24). Improvement in cognition was maintained as compared to the general population.

Dosing

The recommended starting dose is 16 mg per day for 4 weeks. It is then increased up to the recommended maintenance dose of 24 mg per day, depending on the individual clinical benefit and tolerability. The drug is administered orally, twice daily, preferably with morning and evening meals. Extended release capsules of galantamine contain a rate-controlling membrane that allows the medication to be released gradually over a 24-hour period and allows for the convenience of once-daily dosing of 16 to 24 mg.

Special considerations

Pediatric. No relevant information.

Geriatric. Most of the patients on galantamine are elderly. In patients with mild hepatic impairment, smaller doses are used to start therapy (4 mg once daily) and may be increased slowly to a maximum dose (8 mg twice daily). Similar dose should be used in patients with moderately impaired hepatic function.

Pregnancy. No relevant information.

Anesthesia. Galantamine is likely to potentiate the effect of succinylcholine on muscle relaxation during anesthesia.

Interactions

Galantamine acts by inhibiting acetylcholinesterase. Thus, galantamine interacts with drugs that affect the cholinergic system. It may have a pharmacodynamic interaction with agents such as digoxin and beta-blockers that slow the heart rate.

Adverse effects

The most common adverse effects in patients treated with galantamine during clinical trials are cholinergic in nature and are dose related. Nausea, vomiting, abdominal pain, and diarrhea are reported in more than 5% of the patients. These events decrease in frequency as the treatment period progresses. A case of nightmares associated with galantamine has been reported (07).