Galantamine

Galantamine

Systematic (IUPAC) name
(4aS,6R,8aS)- 5,6,9,10,11,12- hexahydro- 3-methoxy- 11-methyl- 4aH- [1]benzofuro[3a,3,2-ef] [2] benzazepin- 6-ol
Clinical data
Trade names	Razadyne
AHFS/Drugs.com	monograph
MedlinePlus	a699058
Pregnancy category	B
Legal status	℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	80 to 100%
Protein binding	18%
Metabolism	Hepatic partially CYP450:CYP2D6/3A4 substrate
Biological half-life	7 hours
Excretion	Renal (95%, of which 32% unchanged), fecal (5%)
Identifiers
CAS Number	357-70-0 Y
ATC code	N06DA04 (WHO)
PubChem	CID: 9651
IUPHAR/BPS	6693
DrugBank	DB00674 Y
ChemSpider	9272 Y
UNII	0D3Q044KCA Y
KEGG	D04292 Y
ChEBI	CHEBI:42944 Y
ChEMBL	CHEMBL659 Y
PDB ligand ID	GNT (PDBe, RCSB PDB)
Chemical data
Formula	C17H21NO3
Molecular mass	287.354 g/mol
SMILES O(c2c1O[C@H]4C[C@@H](O)/C=C\[C@@]43c1c(cc2)CN(C)CC3)C
InChI InChI=1S/C17H21NO3/c1-18-8-7-17-6-5-12(19)9-14(17)21-16-13(20-2)4-3-11(10-18)15(16)17/h3-6,12,14,19H,7-10H2,1-2H3/t12-,14-,17-/m0/s1 Y Key:ASUTZQLVASHGKV-JDFRZJQESA-N Y
Physical data
Melting point	126.5 °C (259.7 °F)
(verify)

Galantamine (Nivalin, Razadyne, Razadyne ER, Reminyl, Lycoremine) is used for the treatment of mild to moderate Alzheimer's disease and various other memory impairments, in particular those of vascular origin. It is an alkaloid that is obtained synthetically or from the bulbs and flowers of Galanthus caucasicus (Caucasian snowdrop, Voronov's snowdrop), Galanthus woronowii (Amaryllidaceae) and related genera like Narcissus (daffodil), Leucojum aestivum (snowflake), and Lycoris including Lycoris radiata (Red Spider Lily).

Studies of usage in modern medicine began in the Soviet Union in the 1950s. The active ingredient was extracted, identified, and studied, in particular in relation to its acetylcholinesterase (AChE)-inhibiting properties. The bulk of the work was carried out by Soviet pharmacologists M. D. Mashkovsky and R. P. Kruglikova–Lvova, beginning in 1951. The work of Mashkovsky and Kruglikova-Lvova was the first published work that demonstrated the AChE-inhibiting properties of galantamine.

The first industrial process was developed in Bulgaria by prof. Paskov in 1959 (Nivalin, Sopharma) from a species traditionally 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 (i.e., an ethnobotany-driven drug discovery).

Galantamine has been used for decades in Eastern Europe and Russia for various indications such as treatment of myasthenia, myopathy, and sensory and motor dysfunction associated with disorders of the central nervous system. In the US, it is FDA approved for the treatment of Alzheimer's disease.

It is available in both a prescription form and as an over the counter supplement.

Medical uses

Galantamine

Uses
treatment of dementia caused by Alzheimer's disease
Who might take
adults who have mid-to-moderate Alzheimer's disease as indicated by the Mini–mental state examination
Precautions
give fluids - drug can cause dehydration, diarrhea, or vomiting watch for Slow heart rate and fainting can cause bladder blockage can cause seizures can cause bleeding in stomach or intestines do not combine with other sleep aid medications do not combine alcohol use with this drug people with Chronic obstructive pulmonary disease should be cautious people with sleep apnea should be cautious
Other options
donepezil and rivastigmine are comparable drugs behavioral, physical, or social therapy may be useful

Galantamine is indicated for the treatment of mild to moderate vascular dementia and Alzheimer's.

Available forms

The product is supplied in both a prescription form as well as an over the counter supplement. in twice-a-day tablets, in once-a-day extended-release capsules, and in oral solution.

Side effects

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.

The U.S. Food and Drug Administration (FDA) and international health authorities have published an alert of galantamine based on data from two studies during the treatment for mild cognitive impairment (MCI); higher mortality rates were seen in drug-treated patients. 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 (slow resting heart rate), and sometimes atrioventricular block, especially in predisposed persons. At the same time, the risk of syncope (fainting) seems to be increased relative to placebo. "In randomized controlled trials, bradycardia was reported more frequently in galantamine-treated patients than in placebo-treated patients, but was rarely severe and rarely led to treatment discontinuation" These side effects have not been reported in Alzheimer's Disease related studies.

Pharmacology

Galantamine is a potent allosteric potentiating ligand of human nicotinic acetylcholine receptors (nAChRs) α₄β₂, α₇/5-HT₃, α₃β₄, and α₆β₄ in certain areas of the brain, as well as a weak competitive and reversible cholinesterase inhibitor in all areas of the body. It increases the concentration and thereby action of acetylcholine in certain parts of the brain. It has shown activity in modulating the nicotinic cholinergic receptors on cholinergic neurons to increase acetylcholine release. It is hypothesized that this action might relieve some of the symptoms of Alzheimer's.

Galantamine in its pure form is a white powder. 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). 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 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

Approximately 75% of a dose of galantamine is metabolised in the liver. In vitro studies have shown that Hepatic 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.

Synthesis

Main article: Galantamine total synthesis

Galantamine is produced from natural resources and a patented total synthesis process. Many other synthetic methods exist but have not been implemented on an industrial scale.

Research

Autism

Galantamine given in addition to risperidone to autistic children has been shown to improve some of the symptoms of autism (irritability, lethargy, and social withdrawal).

External links

• Razadyne ER (manufacturer's website)
• Proteopedia 1dx6
• AChE inhibitors and substrates (Part II)
• Acetylcholinesterase: A gorge-ous enzyme PDB Structure article at PDBe