Galantamine is a type of acetylcholinesterase inhibitor. It is an alkaloid extracted from the bulbs and flowers of Galanthus nivalis (common snowdrop), Galanthus caucasicus (Caucasian snowdrop), Galanthus woronowii (Voronov's snowdrop), and other members of the family Amaryllidaceae, such as Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (red spider lily). It can also be produced synthetically.
Galantamine is used clinically for treating early-stage Alzheimer's disease and memory impairments, although it has had limited success with the more advanced condition of dementia.
While the exact mechanism of galantamine in treating Alzheimer's disease is unknown, it is hypothesized to exert its therapeutic effects by enhancing cholinergic function. Galantamine inhibits the activity of acetylcholinesterase, an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine. Galantamine may cause serious adverse effects, such as stomach bleeding, liver injury or chest pain.
Galantamine was isolated for the first time from bulbs of Galanthus nivalis (common snowdrop) in the Soviet Union in the 1940s. The active ingredient was extracted, identified, and studied, in particular in relation to acetylcholinesterase (AChE)-inhibiting properties. The first industrial process was developed in 1959. However, it was not until the 1990s when full-scale synthesis was upscaled and optimized.
Medical uses
Galantamine, sold under the brand name Razadyne among others, is indicated for the treatment of mild to moderate vascular dementia and Alzheimer's disease. Galantamine may not be effective for treating mild cognitive impairment.
Alzheimer's disease
Alzheimer's disease is characterized by the impairment of cholinergic function. This allosteric modulation increases the nicotinic receptor's response to acetylcholine. The use of a dose-escalation scheme has been well accepted in countries where galantamine is used.
In December 2023, the FDA approved a New Drug Application (NDA) for a pro-drug of galantamine called ALPHA-1062. In July 2024, The FDA approved benzgalantamine (Zunveyl, a derivative of galantamine), previously known as ALPHA-1062, to treat mild-to-moderate Alzheimer's disease.
Side effects
The adverse effect profile of galantamine includes potential for allergic reaction, including hives, swelling of the face or throat, and skin rash.
Galantamine has a wide spectrum of interactions with other medications and medical disorders, requiring close assessment between the physician and patient.
Pharmacology
Galantamine's chemical structure contains a tertiary amine. At a neutral pH, this tertiary amine will often bond to a proton, and appear mostly as an ammonium ion. By binding to the allosteric site of the nAChRs, a conformational change occurs which increases the receptors response to acetylcholine.
However, recent studies suggest that Galantamine does not functionally act at human nAChRs α<sub>4</sub>β<sub>2</sub> or α<sub>7</sub> as a positive allosteric modulator.
Galantamine also works as a weak competitive and reversible cholinesterase inhibitor in all areas of the body. There is no evidence that galantamine alters the course of the underlying dementing process.
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 terminal elimination 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.
The coadministration of food delays the rate of galantamine absorption, but does not affect the extent of absorption. Although galantamine can be produced from natural resources, it also has many industrial syntheses, such as by Janssen, Ortho-McNeil Pharmaceutical, Shire, and Takeda Pharmaceutical Company.
Research
Organophosphate poisoning
The toxicity of organophosphates results primarily from their action as irreversible inhibitors of acetylcholinesterase. The indications for use of galantamine in the patent application include poisoning by nerve agents "including but not limited to soman, sarin, and VX, tabun, and Novichok agents". Galantamine was studied in the research cited in the patent application for use along with the well-recognized nerve agent antidote atropine. According to the investigators, an unexpected synergistic interaction occurred between galantamine and atropine in an amount of 6 mg/kg or higher. Increasing the dose of galantamine from 5 to 8 mg/kg decreased the dose of atropine needed to protect experimental animals from the toxicity of soman in dosages 1.5 times the dose generally required to kill half the experimental animals (Median lethal dose, also called LD<sub>50</sub>).
Autism
Galantamine given in addition to risperidone to autistic children has been shown to improve some of the symptoms of autism such as irritability, lethargy, and social withdrawal. Additionally, the cholinergic and nicotinic receptors are believed to play a role in attentional processes. Some studies have noted that cholinergic and nicotinic treatments have improved attention in autistic children. The experimental group was given ketamine, diazepam, and nivalin (of which the active ingredient is galantamine).