 | |
 | |
| Clinical data | |
|---|---|
| Trade names | Razadyne, others |
| AHFS/Drugs.com | Monograph |
| MedlinePlus | a699058 |
| License data | |
| Pregnancy category | |
| Routes of administration | By mouth |
| Drug class | Acetylcholinesterase inhibitor |
| ATC code | |
| Legal status | |
| Legal status | |
| Pharmacokinetic data | |
| Bioavailability | 80–100% |
| Protein binding | 18% |
| Metabolism | Liver partiallyCYP450:CYP2D6/3A4 substrate |
| Eliminationhalf-life | 7 hours |
| Excretion | Kidney (95%, of which 32% unchanged), fecal (5%) |
| Identifiers | |
| |
| CAS Number |
|
| PubChemCID | |
| IUPHAR/BPS | |
| DrugBank |
|
| ChemSpider |
|
| UNII | |
| KEGG |
|
| ChEBI | |
| ChEMBL | |
| PDB ligand | |
| CompTox Dashboard(EPA) | |
| ECHA InfoCard | 100.118.289 |
| Chemical and physical data | |
| Formula | C17H21NO3 |
| Molar mass | 287.359 g·mol−1 |
| 3D model (JSmol) | |
| Melting point | 126.5 °C (259.7 °F) |
| |
| |
| (verify) | |
Galantamine is a type ofacetylcholinesterase inhibitor. It is analkaloidextracted from the bulbs and flowers ofGalanthus nivalis (common snowdrop),Galanthus caucasicus (Caucasian snowdrop),Galanthus woronowii (Voronov's snowdrop), and other members of the familyAmaryllidaceae, such asNarcissus (daffodil),Leucojum aestivum (snowflake), andLycoris includingLycoris radiata (red spider lily).[5] It can also beproduced synthetically.
Galantamine is primarily known for its potential to slowcognitive decline. It is used clinically for treating early-stageAlzheimer's disease andmemory impairments, although it has had limited success with the more advanced condition ofdementia.[6][7][8][9]
The mechanism of action is via the increase of theneurotransmitteracetylcholine by inhibiting the activity ofacetylcholinesterase, the enzyme that catalyzes thebreakdown of acetylcholine. This elevates and prolongs acetylcholine levels boosting acetylcholine'sneuromodulatory functionality, subsequently enhancing functionality of the variouscognitions that acetylcholine is involved in, such as memory processing,reasoning, andthinking.[6] Galantamine may cause seriousadverse effects, such as stomach bleeding, liver injury or chest pain.[6][8]
Galantamine was isolated for the first time from bulbs ofGalanthus nivalis (common snowdrop) in the Soviet Union in the 1940s.[10] The active ingredient was extracted, identified, and studied, in particular in relation toacetylcholinesterase (AChE)-inhibiting properties.[11][12] The first industrial process was developed in 1959.[13][14] However, it was not until the 1990s when full-scale synthesis was upscaled and optimized.[15]
Galantamine, sold under the brand nameRazadyne among others, isindicated for the treatment of mild to moderatevascular dementia and Alzheimer's disease.[6][7] The first person to extract galantamine and theorize its usefulness in medicine, was the Bulgarian chemistDimitar Paskov in 1959. In the United States, it is approved by theFood and Drug Administration (FDA) for the treatment of mild to moderate dementia.[8][16] Galantamine may not be effective for treating mild cognitive impairment.[17]
Alzheimer's disease is characterized by the impairment ofcholinergic function.[6][8] One hypothesis is that this impairment contributes to the cognitive deficits caused by the disease. This hypothesis forms the basis for use of galantamine as a cholinergic enhancer in the treatment of Alzheimer's.[6][8] Galantamine inhibits acetylcholinesterase, an enzyme whichhydrolyzes acetylcholine.[6][8] As a result of acetylcholinesterase inhibition, galantamine increases the availability of acetylcholine for synaptic transmission.[8] Additionally, galantamine binds to theallosteric sites ofnicotinic receptors, which causes a conformational change.[18] This allosteric modulation increases the nicotinic receptor's response to acetylcholine.[8] The activation of presynaptic nicotinic receptors increases the release of acetylcholine, further increasing the availability of acetylcholine.[8] Galantamine's competitive inhibition of acetylcholinesterase and allosteric nicotinic modulation serves as a dual mechanism of action.[18]
To reduce the prevalence of negative side effects associated with galantamine, such asnausea andvomiting, a dose-escalation scheme may be used.[19] The use of a dose-escalation scheme has been well accepted in countries where galantamine is used.[19] A dose-escalation scheme for Alzheimer's treatment involves a recommended starting dosage of 4 mg galantamine tablets given twice a day (8 mg/day).[6] After a minimum of 4 weeks, the dosage may then be increased to 8 mg given twice a day (16 mg/day).[6] After a minimum of 4 weeks at 16 mg/day, the treatment may be increased to 12 mg given twice a day (24 mg/day).[6] Dosage increases are based upon the assessment of clinical benefit as well as tolerability of the previous dosage.[6] If treatment is interrupted for more than three days, the process is usually restarted, beginning at the starting dosage, and re-escalating to the current dose.[6] It has been found that a dosage between 16–24 mg/day is the optimal dosage.[20]
In December 2023, the FDA approved aNew Drug Application (NDA) for a pro-drug of galantamine called ALPHA-1062.[21] In July 2024, The FDA approvedbenzgalantamine (Zunveyl, a derivative of galantamine), previously known as ALPHA-1062, to treat mild-to-moderate Alzheimer's disease.[22]
Theadverse effect profile of galantamine includes potential forallergic reaction, includinghives, swelling of the face or throat, and skin rash.[6][23] Using galantamine may cause chest pain, bloody urine, stomach bleeding, and liver injury, among other side effects.[6][23] Nausea, vomiting, diarrhea, dizziness, and headache are considered common side effects.[6]
A gradual titration over more than three months may enable long-term tolerability in some people.[24]
Galantamine has a wide spectrum ofinteractions with other medications and medical disorders, requiring close assessment between the physician and patient.[23]
Galantamine's chemical structure contains a tertiaryamine. At a neutralpH, this tertiary amine will often bond to a proton, and appear mostly as an ammonium ion.[6]
Galantamine is a potentallosteric potentiatingligand of humannicotinic acetylcholine receptors (nAChRs)α4β2,α3β4, andα6β4, and chicken/mouse nAChRsα7/5-HT3 in certain areas of the brain.[6][25] By binding to the allosteric site of the nAChRs, a conformational change occurs which increases the receptors response to acetylcholine.[8] This modulation of thenicotinic cholinergic receptors on cholinergic neurons in turn causes an increase in the amount of acetylcholine released.[26]However, recent studies suggest that Galantamine does not functionally act at human nAChRsα4β2 orα7 as a positive allosteric modulator.[27][28]
Galantamine also works as a weakcompetitive andreversiblecholinesterase inhibitor in all areas of the body.[6] By inhibiting acetylcholinesterase, it increases the concentration and thereby action ofacetylcholine in certain parts of the brain. Galantamine's effects on nAChRs and complementary acetylcholinesterase inhibition make up a dual mechanism of action. 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 byX-ray crystallography in 1999 (PDB code:1DX6;see complex).[29] There is no evidence that galantamine alters the course of the underlying dementing process.[30]
Absorption of galantamine is rapid and complete and shows linear pharmacokinetics. It is well absorbed with absolute oralbioavailability between 80 and 100%. It has a terminal elimination half-life of seven hours. Peak effect of inhibitingacetylcholinesterase 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.[18]
Plasma protein binding of galantamine is about 18%, which is relatively low.
Approximately 75% of a dose of galantamine is metabolised in the liver. In vitro studies have shown that hepaticCYP2D6 andCYP3A4 are involved in galantamine metabolism. Within 24 hours of intravenous or oral administration approximately 20% of a dose of galantamine will be excreted unreacted in the urine.[18]
In humans, several metabolic pathways for galantamine exist.[25] These pathways lead to the formation of a number of different metabolites.[25] One of the metabolites that may result can be formed through theglucuronidation of galantamine.[25] Additionally, galantamine may undergooxidation ordemethylation at its nitrogen atom, forming two other possible metabolites.[25] Galantamine can undergo demethylation at its oxygen atom, forming an intermediate which can then undergo glucuronidation or sulfate conjugation.[25] Lastly, galantamine may be oxidized and then reduced before finally undergoing demethylation or oxidation at its nitrogen atom, or demethylation and subsequent glucuronidation at its oxygen atom.[25]
Since galantamine is metabolized by CYP2D6 and CYP3A4, inhibiting either of theseisoenzymes will increase the cholinergic effects of galantamine.[18] Inhibiting these enzymes may lead to adverse effects.[18] It was found thatparoxetine, an inhibitor of CYP2D6, increased thebioavailability of galantamine by 40%.[18] The CYP3A4 inhibitorsketoconazole anderythromycin increased thebioavailability of galantamine by 30% and 12%, respectively.[18]
Since the alkaloid is isolated from botanical sources containing low amounts (0.1%) by weight, extraction yields are low.[31] Although galantamine can be produced from natural resources, it also has many industrial syntheses, such as byJanssen,Ortho-McNeil Pharmaceutical,Shire, andTakeda Pharmaceutical Company.[32]
The toxicity oforganophosphates results primarily from their action as irreversible inhibitors of acetylcholinesterase.[33] Inhibiting acetylcholinesterase causes an increase in acetylcholine, as the enzyme is no longer available to catalyze its breakdown.[33] In the peripheral nervous system, acetylcholine accumulation can cause an overstimulation of muscarinic receptors followed by a desensitization of nicotinic receptors.[33] This leads to severe skeletal muscle fasciculations (involuntary contractions).[33] The effects on the central nervous system includeanxiety, restlessness,confusion,ataxia,tremors,seizures, cardiorespiratory paralysis, andcoma.[33] As a reversible acetylcholinesterase inhibitor, galantamine has the potential to serve as an effective organophosphate poisoning treatment by preventing irreversible acetylcholinesterase inhibition.[33] Additionally, galantamine hasanticonvulsant properties which may make it even more desirable as an antidote.[33]
Research supported in part by theUS Army has led to aUS patent application for the use of galantamine and/or its derivatives for treatment oforganophosphate poisoning.[33] The indications for use of galantamine in the patent application include poisoning bynerve agents "including but not limited tosoman,sarin, andVX,tabun, andNovichok agents". Galantamine was studied in the research cited in the patent application for use along with the well-recognized nerve agent antidoteatropine. 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.[34]
Galantamine given in addition torisperidone to autistic children has been shown to improve some of the symptoms of autism such as irritability, lethargy, and social withdrawal.[35] Additionally, the cholinergic and nicotinic receptors are believed to play a role in attentional processes.[36] Some studies have noted that cholinergic and nicotinic treatments have improved attention in autistic children.[36] As such, it is hypothesized that galantamine's dual action mechanism might have a similar effect in treating autistic children and adolescents.[36]
Galantamine may have some limited use in reducing the side-effects of anestheticsketamine anddiazepam. In one study, a control group of patients were givenketamine anddiazepam and underwentanesthesia and surgery.[37] The experimental group was givenketamine,diazepam, and nivalin (of which the active ingredient is galantamine).[37] The degree of drowsiness and disorientation of the two groups was then assessed 5, 10, 15, 30 and 60 minutes after surgery.[37] The group that had taken nivalin were found to be more alert 5, 10, and 15 minutes after the surgery.[37]
Galantamine is known to haveoneirogenic properties. Research has demonstrated its potential to increasedream recall, dream self-awareness and dream vividness. The enhancement of suchdream properties can facilitate the induction oflucid dreams.[38][39]
