Galantamine

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Galantamine
Systematic (IUPAC) name
(4aS,6R,8aS)-4a,5,9,10,11,12- hexahydro-3-methoxy-11-methyl- 6H-benzofuro[3a,3,2-ef] [2]benzazepin-6-ol
Identifiers
CAS number	357-70-0
ATC code	N06 DA04
PubChem	9651
DrugBank	APRD00206
Chemical data
Formula	C₁₇H₂₁N O₃
Mol. weight	287.354 g/mol
Pharmacokinetic data
Bioavailability	80 to 100%
Protein binding	18%
Metabolism	Hepatic partially CYP450:CYP2D6/3A4 substrate
Half life	7 hours
Excretion	Renal (95%, of which 32% unchanged), fecal (5%)
Therapeutic considerations
Pregnancy cat.	B
Legal status	℞ Prescription only
Routes	Oral

Galantamine (trade names Razadyne®, Razadyne ER®, Reminyl®, Nivalin®) is a drug developed by Janssen Pharmaceutica, and used for the treatment of mild to moderate Alzheimer’s disease. It is an alkaloid that is obtained from the bulbs and flowers of Caucasian snowdrop (Voronov’snowdrop), Galanthus woronowii (Amaryllidaceae) and related species. The active ingredient was discovered accidentally by a Bulgarian pharmacologist in the 1950s.^[1]

1 Pharmacology
2 Pharmacokinetics
3 Metabolism
4 Clinical use
5 Total synthesis
6 References
7 External links

[edit] 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. There is no evidence that galantamine alters the course of the underlying dementing process.^[2] Galantamine has also shown activity in modulating the nicotinic cholinergic receptors to increase acetylcholine release.^[3]

[edit] 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 7 hours. Peak effect of inhibiting acetylcholinesterase was achieved about one hour after a single oral dose of 8 mg in healthy volunteers.

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

[edit] 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.

[edit] Clinical use

[edit] Indications

Galantamine is indicated for mild to moderate dementia of the Alzheimer’s type. It has been studied in Mild Cognitive Impairment (MCI) without demonstrating a statistically significant effect.

The U.S. Food and Drug Administration (FDA) sent out a warning indicating that the product should not be used in MCI patients because of increased mortality observed in trials for MCI with galantamine.^[4]

[edit] Available forms

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

[edit] 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.^[5]

[edit] Total synthesis

Main article: Galanthamine total synthesis

Galantamine is produced from a natural resource but many synthetic methods exist in total synthesis.

[edit] References

^ Scott LJ, Goa KL. Adis Review: Galantamine: a review of its use in Alzheimer's disease. Drugs 2000;60(5):1095-122 PMID 11129124
^ Ortho-McNeil Neurologics, “Razadyne ER US Product Insert”, May 2006. [1]
^ Woodruff-Pak DS, Vogel RW 3rd, Wenk GL, “Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning” Proc Natl Acad Sci U S A. 2001 Feb 13;98(4):2089-94. PMID 11172080
^ Alert for Healthcare Professionals on Galantamine
^ Birks J. “Cholinesterase inhibitors for Alzheimer's disease.” Cochrane Database Syst Rev. 2006 Jan 25;(1):CD005593. PMID 16437532