Galantamine
4 sources
Collated from PsychonautWiki, Pharmacology, DrugCentral, DailyMed. Where sources differ (e.g. dosing), Compare shows them side by side.
Also known as GalantaminePW
Oral
Route dataPsychonautWiki
| Threshold | Light | Common | Strong | Heavy |
|---|---|---|---|---|
| 1 mg | 4–8 mg | 8–16 mg | 16–24 mg | 24 mg+ |
| Onset | 20–60 minutes |
|---|---|
| Total | 6–12 hours |
Bioavailability: 90 %
🧬 Receptor activityPHDC
| Target | Action | Affinity | Source | |
|---|---|---|---|---|
| Acetylcholinesterase | — | Ki 61.9 nM | CHEMBL | TargetAcetylcholinesterase Action— AffinityKi 61.9 nM SourceCHEMBL |
| Cholinesterase | — | Ki 192.47 nM | CHEMBL | TargetCholinesterase Action— AffinityKi 192.47 nM SourceCHEMBL |
| Butyrylcholinesterase | — | Ki 8000 nM | CHEMBL | TargetButyrylcholinesterase Action— AffinityKi 8000 nM SourceCHEMBL |
| Unchecked | — | Ki 10000 nM | CHEMBL | TargetUnchecked Action— AffinityKi 10000 nM SourceCHEMBL |
| Glutamate receptor ionotropic, NMDA 2B | — | Ki 100000 nM | CHEMBL | TargetGlutamate receptor ionotropic, NMDA 2B Action— AffinityKi 100000 nM SourceCHEMBL |
| Acetylcholinesterase (ACHE) | Inhibitor | 7.21 Ki | DRUGCENTRAL | TargetAcetylcholinesterase (ACHE) ActionInhibitor Affinity7.21 Ki SourceDRUGCENTRAL |
| Acetylcholinesterase (ache) | — | 6.44 IC50 | DRUGCENTRAL | TargetAcetylcholinesterase (ache) Action— Affinity6.44 IC50 SourceDRUGCENTRAL |
| Butyrylcholinesterase (BCHE) | — | 5.1 Ki | DRUGCENTRAL | TargetButyrylcholinesterase (BCHE) Action— Affinity5.1 Ki SourceDRUGCENTRAL |
| Butyrylcholinesterase; Protein Bche (Bche) | — | 5.23 IC50 | DRUGCENTRAL | TargetButyrylcholinesterase; Protein Bche (Bche) Action— Affinity5.23 IC50 SourceDRUGCENTRAL |
| Cholinesterase (BCHE) | — | 6.72 Ki | DRUGCENTRAL | TargetCholinesterase (BCHE) Action— Affinity6.72 Ki SourceDRUGCENTRAL |
Mechanism of actionPHDM
Alzheimer’s disease is characterized by progressive, irreversible degeneration of acetylcholine-producing neurons, cognitive impairment, and the accumulation of neurofibrillary tangles and amyloid plaques. The cholinergic system plays a critical role in memory, alongside other important neural functions such as attention, learning, stress response, wakefulness and sleep, and sensory information. Studies show that acetylcholine (ACh) is involved in the modulation of acquisition, encoding, consolidation, reconsolidation, extinction, and retrieval of memory. The gradual loss of cholinergic neurons in Alzheimer’s disease (AD) may, therefore, contribute to the memory loss exhibited by AD patients. Acetylcholinesterase is secreted by cholinergic neurons to rapidly hydrolyze ACh at the synaptic cleft to release acetate and choline. Choline is later recycled back into the presynaptic cholinergic neuron via reuptake by the high-affinity choline transporter. There is some evidence demonstrating the potential involvement of the acetylcholinesterase enzyme in the formation of amyloid fibrils. Galantamine competitively and reversibly inhibits the anticholinesterase enzyme in the CNS (namely in the frontal cortex and hippocampal regions) by binding to the choline-binding site and acyl-binding pocket of the enzyme active site. By blocking the breakdown of ACh, galantamine enhances ACh levels in the synaptic cleft. Nicotinic acetylcholine receptors (nAChR) in the CNS are mostly expressed at the presynaptic neuronal membrane to control the release of multiple neurotransmitters, such as ACh, glutamate, GABA, dopamine, serotonin, norepinephrine. Agonists of nAChRs improve performance in cognitive tasks, while antagonists of nAChR impair cognitive processes. Some studies show a decrease in the expression and activity of nAChRs in patients with AD, which may explain the reduction in central cholinergic neurotransmission in these patients. Galantamine binds to nAChRs at the allosteric site, leading to a conformational change of the receptor, increased ACh release, and increased activity of neighbouring glutaminergic and serotoninergic neurons. The modulation of nAChRs facilitates both excitatory and inhibitory cholinergic transmissions in brain tissues and increases receptor sensitivity. The modulated release of other neurotransmitters by galantamine may also contribute to the upregulation of nAChRs and amelioration of behavioural symptoms in AD.
Galantamine, a tertiary alkaloid, is a competitive and reversible inhibitor of acetylcholinesterase. While the precise mechanism of galantamine's action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by cholinesterase. If this mechanism is correct, galantamine's effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. There is no evidence that galantamine alters the course of the underlying dementing process.
The cause of cognitive impairment in Alzheimer's Disease is not fully understood, it has been shown that acetylcholine producing neurons degenerate. The cholinergic loss has been correlated with cognitive impairment and a density of amyloid plaques. Galantamine is a tertiary alkaloid and it competes with and is a reversible inhibitor of acetylcholinesterase. The exact mechanism of galantamine is not known, but it is believed to enhance cholinergic function.
PharmacodynamicsPH
Galantamine is a competitive and reversible inhibitor of acetylcholinesterase that works to increase acetylcholine levels. Galantamine acts both centrally and peripherally to inhibit both muscle and brain acetylcholinesterase, thereby increasing cholinergic tone. Galantamine is also a positive allosteric modulator of neuronal nicotinic acetylcholine receptors. As dementia is a progressive neurodegenerative disease, galatamine has a negligible effect in altering the course of the underlying process of dementia and may exert its therapeutic effectiveness for a short period of time. However, galantamine promoted improvements in cognition, global function, activities of daily living, and behavioural symptoms in clinical studies of Alzheimer’s disease. Galantamine exhibited therapeutic efficacy in studies of vascular dementia and Alzheimer’s disease with cerebrovascular disease. In one study, galantamine reversed scopolamine-induced acute anticholinergic syndrome that was characterized by drowsiness, disorientation, and delirium.
Pharmacokinetics
Half-lifePH
Galantamine has a terminal half-life of about 7 hours.
Elimination half-life: 7 hours
AbsorptionPHDM
Over a dose range of 8-32 mg/day, galantamine exhibits a dose-linear pharmacokinetic profile. The oral bioavailability of galantamine ranges from 90-100%. Following oral administration, the Tmax is about 1 hour. Following 10 hours of administration, the mean galantamine plasma concentrations were 82–97 µg/L for the 24 mg/day dose and 114–126 µg/L for the 32 mg/day dose.
Renal clearance accounts for about 20–25% of total plasma clearance of the drug in healthy individuals: the elimination of galantamine has been shown to be decreased in subjects with renal impairment. Following oral or intravenous administration, approximately 20% of the dose is excreted as unchanged in the urine within 24 h. In a radiolabelled drug study, about 95% and 5% of the total radioactivity was recovered in the urine and feces, respectively. Of the dose recovered in the urine, about 32% was in the unchanged parent compound, and 12% was in the glucuronide form.
The mean volume of distribution is 175 L. About 52.7% of galantamine is distributed to blood cells, the blood to plasma concentration ratio of galantamine is 1.2. Galantamine penetrates the blood–brain barrier.
The renal clearance is 65 mL/min and the total plasma clearance is about 300 mL/min.
Protein binding: Low (18%)
Mean volume of distribution is 175 L.
MetabolismPH
_In vitro_ study findings suggest that about 75% of the drug is metabolized by CYP2D6 and CYP3A4. CYP2D6 promotes O-demethylation of the drug to form O-desmethyl-galantamine and the CYP3A4-mediated pathway forms the galantamine-N-oxide. Important metabolic pathways also include N-demethylation, epimerization, and sulfate conjugation. Other metabolites include norgalantamine, O-desmethyl-galantamine, O-desmethyl-norgalantamine, epigalantamine and galantaminone, which do not retain clinically significant pharmacology activities. Galantamine can also undergo glucuronidation: in one oral radiolabeled drug study in poor and extensive CYP2D6 metabolizers, about 14-24% of the total radioactivity was identified as galantamine glucuronide 8 hours post-dose. O-demethylation by CYP2D6 becomes prominent in patients with who are extensive metabolizers of CYP2D6, but unchanged galatamine (39-77%) and its glucuronide metabolite (14-24%) predominated in the plasma of both poor and extensive metabolizers of CYP2D6 in a radiolabelled drug study. The total plasma clearance, or nonrenal clearnace, accounts for 20–25% of drug elimination.
In studies of oral 3(H)-galantamine, unchanged galantamine and its glucuronide, accounted for most plasma radioactivity in poor and extensive CYP2D6 metabolizers. Up to 8 hours post-dose, unchanged galantamine accounted for 39-77% of the total radioactivity in the plasma, and galantamine glucuronide for 14-24%. By 7 days, 93- 99% of the radioactivity had been recovered, with about 95% in urine and about 5% in the feces. Total urinary recovery of unchanged galantamine accounted for, on average, 32% of the dose and that of galantamine glucuronide for another 12% on average.
Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine. In vitro studies indicate that cytochrome CYP2D6 and CYP3A4 were the major cytochrome P450 isoenzymes involved in the metabolism of galantamine, and inhibitors of both pathways increase oral bioavailability of galantamine modestly. O-demethylation, mediated by CYP2D6 was greater in extensive metabolizers of CYP2D6 than in poor metabolizers. In plasma from both poor and extensive metabolizers, however, unchanged galantamine and its glucuronide accounted for most of the sample radioactivity.
Galantamine is metabolized by hepatic cytochrome p450 enzymes.
Galantamine has known human metabolites that include [(1S,12S,14R)-14-hydroxy-4-methyl-11-oxa-4-azatetracyclo[8.6.1.01,12.06,17]heptadeca-6(17),7,9,15-tetraen-9-yl] hydrogen sulfate, Galantamine N-oxide, N-desmethylgalantamine, and O-Desmethylgalantamine.
Route of Elimination: Galantamine is metabolized by hepatic cytochrome P450 enzymes, glucuronidated, and excreted unchanged in the urine.
Half Life: 7 hours
Protein bindingPH
The plasma protein binding of galantamine is 18% at therapeutically relevant concentrations.
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External links
Fact-sheets from PsychonautWiki. Harm-reduction reference only — not medical advice.