Galantamine or galanthamine (trade names: Nivalin, Razadyne, Razadyne ER, Reminyl) is a chemical used for the treatment of mild to moderate Alzheimers disease and various memory impairments. It is an alkaloid that is obtained synthetically or from the bulbs and flowers of the Caucasian snowdrop Galanthus woronowii (Amaryllidaceae) and related genera like Narcissus (daffodil), Leucojum (snowflake) and Lycoris including Lycoris radiata (Red Spider Lily). The active ingredient was isolated by prof. Paskov 1959 (Sopharma, Bulgaria) from a species tradionally used as a popular medicine in Eastern Europe and thus the idea for developing a medicine from these species seems to be based on the local use (ie, an ethnobotany-driven drug discovery).^[1][2] It has been used for decades in Eastern Europe esp. in the symptomatic treatment of polio (poliomyelitis) and was later developed by Janssen Pharmaceutica into an Alzheimer medication. In the US it has been sold as a dietary supplement for memory and dream support prior to being approved as a drug by the FDA.

Pharmacology

Galantamine in its pure form is a white powder. Galantamine is a competitive and reversible cholinesterase inhibitor. It is believed it works by enhancing cholinergic function by increasing the concentration of acetylcholine in the brain. The atomic resolution 3D structure of the complex of galantamine and its target, acetylcholinesterase, was determined by X-ray crystallography in 1999 (PDB code: 1DX6; see complex).^[3] There is no evidence that galantamine alters the course of the underlying dementing process.^[4] Galantamine has also shown activity in modulating the nicotinic cholinergic receptors to increase acetylcholine release.^[5]

Pharmacokinetics

Absorption of galantamine is rapid and complete and shows linear pharmacokinetics. It is well absorbed with absolute oral bioavailability between 80 and 100%. It has a half-life of seven hours. Peak effect of inhibiting acetylcholinesterase was achieved about one hour after a single oral dose of 8 mg in some healthy volunteers.

Plasma protein binding of galantamine is about 18%, which is relatively low.

Metabolism

The major route of metabolism for galantamine is through the liver, this accounts for approximately 75% of the total metabolism of galantamine. Hepatic cytochrome P450 (CYP) isoenzymes are the active enzymes for this metabolic route. In vitro studies have shown that CYP2D6 and CYP3A4 are involved in galantamine metabolism.

For Razadyne ER (the once-a-day formulation), CYP2D6 poor metabolizers had drug exposures that were approximately 50% higher than for extensive metabolizers. About 7% of the population has this genetic mutation, however because the drug is individually titrated to tolerability, no specific dosage adjustment is necessary for this population.

Clinical use

Indications

Galantamine is indicated for mild to moderate Vascular Dementia and Alzheimer's.^[6][7]

Available forms

The product is supplied in twice-a-day tablets, once-a-day extended release capsules, and in oral solution. The tablets come in 4 mg, 8 mg, and 12 mg forms. The capsules come in 8 mg, 16 mg, and 24 mg forms.

Adverse events

In clinical trials, galantamine's side effect profile was very similar to that of other cholinesterase inhibitors, with gastrointestinal symptoms being the most notable and most commonly observed. In practice, some other cholinesterase inhibitors might be better tolerated; however, a careful and gradual titration over more than three months may lead to equivalent long-term tolerability.^[8]

Caution

The U.S. Food and Drug Administration (FDA) and international health authorities have published an alert based on data from two studies during the treatment by galantamine of mild cognitive impairment; higher mortality rates were seen in drug-treated patients.(14) On April 27, 2006, FDA approved labeling changes concerning all form of galantamine preparations (liquid, regular tablets,and extended release tablets) warning of the risk of bradycardia (and sometimes atrioventricular block,especially in predisposed persons). At the same time, the risk of syncope seems to be increased relative to placebo.^[15] These side effects have not been reported in any other studies except in mild cognitive impairment.

References