Galantamine

{{Short description|Chemical compound}} {{Use mdy dates|date=August 2024}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Infobox drug | Watchedfields = changed | caption2 = 3D representation of a galantamine molecule | class = Acetylcholinesterase inhibitor | verifiedrevid = 461118063 | image = Galantamine.svg | image_class = skin-invert-image | alt = | caption = Molecular structure of galantamine | image2 = Galantamine 3D.png | image_class2 = bg-transparent | alt2 =  | tradename = Razadyne, others | Drugs.com = {{drugs.com|monograph|galantamine-hydrobromide}} | MedlinePlus = a699058 | DailyMedID = Razadyne | pregnancy_AU = B1 | pregnancy_AU_comment = <ref name="Drugs.com pregnancy">{{cite web | title=Galantamine Use During Pregnancy | website=Drugs.com | date=February 18, 2019 | url=https://www.drugs.com/pregnancy/galantamine.html | access-date=February 24, 2020 | archive-date=February 25, 2020 | archive-url=https://web.archive.org/web/20200225040154/https://www.drugs.com/pregnancy/galantamine.html | url-status=live }}</ref> | pregnancy_category = | routes_of_administration = By mouth | ATC_prefix = N06 | ATC_suffix = DA04

| legal_AU =  | legal_BR = C1 | legal_BR_comment = <ref>{{Cite web |author=Anvisa |author-link=Brazilian Health Regulatory Agency |date=March 31, 2023 |title=RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial |trans-title=Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control|url=https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |url-status=live |archive-url=https://web.archive.org/web/20230803143925/https://www.in.gov.br/en/web/dou/-/resolucao-rdc-n-784-de-31-de-marco-de-2023-474904992 |archive-date=August 3, 2023 |access-date=August 16, 2023 |publisher=Diário Oficial da União |language=pt-BR |publication-date=April 4, 2023}}</ref> | legal_CA =  | legal_DE =  | legal_NZ =  | legal_UK =  | legal_US = Rx-only | legal_US_comment = <ref name="Razadyne FDA label">{{cite web | title=Razadyne- galantamine hydrobromide tablet, film coated | website=DailyMed | date=November 11, 2010 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e62efb5a-d2cc-4e11-9e61-10e65ef3d897 | access-date=August 5, 2024 | archive-date=April 26, 2023 | archive-url=https://web.archive.org/web/20230426034728/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e62efb5a-d2cc-4e11-9e61-10e65ef3d897 | url-status=live }}</ref> | legal_EU = Rx-only | legal_EU_comment = <ref>{{cite web | title = Active substance: galantamine | work = List of nationally authorised medicinal products, Human Medicines Evaluation Division | publisher = European Medicines Agency | date = November 12, 2020 | url = https://www.ema.europa.eu/documents/psusa/galantamine-list-nationally-authorised-medicinal-products-psusa/00001512/202003_en.pdf | access-date = December 19, 2020 | archive-date = October 31, 2021 | archive-url = https://web.archive.org/web/20211031194913/https://www.ema.europa.eu/en/documents/psusa/galantamine-list-nationally-authorised-medicinal-products-psusa/00001512/202003_en.pdf | url-status = live }}</ref> | legal_status = Rx-only

| IUPHAR_ligand = 6693 | CAS_number_Ref = {{cascite|correct|??}} | CAS_number = 357-70-0 | PubChem = 9651 | DrugBank_Ref = {{drugbankcite|correct|drugbank}} | DrugBank = DB00674 | ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}} | ChemSpiderID = 9272 | UNII_Ref = {{fdacite|correct|FDA}} | UNII = 0D3Q044KCA | KEGG_Ref = {{keggcite|correct|kegg}} | KEGG = D04292 | ChEBI_Ref = {{ebicite|correct|EBI}} | ChEBI = 42944 | ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL = 659 | PDB_ligand = GNT

| IUPAC_name = (4a''S'',6''R'',8a''S'')-5,6,9,10,11,12-Hexahydro-3-methoxy-11-methyl-4a''H''-[1]benzofuro[3a,3,2-''ef''][2]benzazepin-6-ol | C = 17 | H = 21 | N = 1 | O = 3 | smiles = O(c2c1O[C@H]4C[C@@H](O)/C=C\[C@@]43c1c(cc2)CN(C)CC3)C | StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI = 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 | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey = ASUTZQLVASHGKV-JDFRZJQESA-N | melting_point = 126.5 }}

'''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).<ref>{{cite web | vauthors = Theodorou M | url = http://www.nnfcc.co.uk/publications/nnfcc-project-factsheet-sustainable-production-of-the-natural-product-galanthamine-defra-nf0612 | archive-url = https://web.archive.org/web/20120314175551/http://www.nnfcc.co.uk/publications/nnfcc-project-factsheet-sustainable-production-of-the-natural-product-galanthamine-defra-nf0612 | archive-date = March 14, 2012 | work = NNFCC Project Factsheet | publisher = The National Non-Food Crops Centre (NNFCC) | title = Sustainable Production of the Natural Product Galanthamine (Defra), NF0612 }}</ref> 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.<ref name="drugs">{{cite web|title=Galantamine|url=https://www.drugs.com/mtm/galantamine.html|publisher=Drugs.com|date=August 8, 2023|access-date=March 26, 2024|archive-date=October 14, 2018|archive-url=https://web.archive.org/web/20181014091614/https://www.drugs.com/mtm/galantamine.html|url-status=live}}</ref><ref name="birks">{{cite journal | vauthors = Birks J | title = Cholinesterase inhibitors for Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | issue = 1 | article-number = CD005593 | date = January 2006 | volume = 2016 | pmid = 16437532 | doi = 10.1002/14651858.CD005593 | pmc = 9006343 | veditors = Birks JS }}</ref><ref name=kalola/><ref name="battle">{{cite journal |vauthors=Battle CE, Abdul-Rahim AH, Shenkin SD, Hewitt J, Quinn TJ |title=Cholinesterase inhibitors for vascular dementia and other vascular cognitive impairments: a network meta-analysis |journal=The Cochrane Database of Systematic Reviews |volume=2021 |issue=2 |article-number=CD013306 |date=February 2021 |pmid=33704781 |pmc=8407366 |doi=10.1002/14651858.CD013306.pub2}}</ref>

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.<ref name=":0">{{cite journal | vauthors = Lim AW, Schneider L, Loy C | date = November 2024 | title = Galantamine for dementia due to Alzheimer's disease and mild cognitive impairment | journal = The Cochrane Database of Systematic Reviews | volume = 11 | issue = 11 | article-number = CD001747 | doi = 10.1002/14651858.CD001747.pub4 | pmc = 11536474 | pmid = 39498781 }}</ref> Galantamine inhibits the activity of acetylcholinesterase, an enzyme that catalyzes the breakdown of the neurotransmitter acetylcholine.<ref name=":0" /> This action elevates and prolongs synaptic acetylcholine concentrations, increasing the availability of acetylcholine to its receptors.<ref name=":0" /> The cholinergic system is involved in a variety of functions relevant to Alzheimer's symptomology, such as memory processing, reasoning, and thinking.<ref name=drugs/><ref>{{cite journal | vauthors = Chen ZR, Huang JB, Yang SL, Hong FF | date = March 2022 | title = Role of Cholinergic Signaling in Alzheimer's Disease | journal = Molecules | volume = 27 | issue = 6 | page = 1816 | doi = 10.3390/molecules27061816 | pmc = 8949236 | pmid = 35335180 | doi-access = free }}</ref> Galantamine may cause serious adverse effects, such as stomach bleeding, liver injury or chest pain.<ref name=drugs/><ref name="kalola">{{cite web | vauthors = Kalola UK, Nguyen H | date = March 12, 2023 | title = Galantamine | publisher = StatPearls Publishing, US National Library of Medicine | pmid = 34662060 | url = https://www.ncbi.nlm.nih.gov/books/NBK574546/ | access-date = March 26, 2024 | archive-date = December 26, 2023 | archive-url = https://web.archive.org/web/20231226163656/https://www.ncbi.nlm.nih.gov/books/NBK574546/ | url-status = live }}</ref>

Galantamine was isolated for the first time from bulbs of ''Galanthus nivalis'' (common snowdrop) in the Soviet Union in the 1940s.<ref>Proskurnina NF, Areshknina LY. J. Chim. Gen. USSR. Chem. Abst. 1947;1948;1742(1595h):1216. No title available.</ref> The active ingredient was extracted, identified, and studied, in particular in relation to acetylcholinesterase (AChE)-inhibiting properties.<ref>{{cite journal | title=Snowdrops: The heralds of spring and a modern drug for Alzheimer's disease | vauthors=Heinrich M | journal=Pharmaceutical Journal | year=2004 | volume=273 | issue=7330 | pages=905–6 | oclc=98892008 | url=http://www.pharmaceutical-journal.com/pj-online-christmas-2004-snowdrops-the-heralds-of-spring-and-a-modern-drug-for-alzheimer8217s-disease/20013614.article | access-date=July 30, 2015 | archive-date=October 23, 2018 | archive-url=https://web.archive.org/web/20181023160656/https://www.pharmaceutical-journal.com/pj-online-christmas-2004-snowdrops-the-heralds-of-spring-and-a-modern-drug-for-alzheimer8217s-disease/20013614.article }}</ref><ref>{{cite journal | title=On the pharmacology of the new alkaloid galantamine | vauthors = Mashkovsky MD, Kruglikova-Lvova RP | journal=Farmakologia Toxicologia | year=1951 | volume=14 | pages=27–30 }}</ref> The first industrial process was developed in 1959.<ref>{{cite journal | vauthors = Heinrich M, Lee Teoh H | title = Galanthamine from snowdrop--the development of a modern drug against Alzheimer's disease from local Caucasian knowledge | journal = Journal of Ethnopharmacology | volume = 92 | issue = 2–3 | pages = 147–162 | date = June 2004 | pmid = 15137996 | doi = 10.1016/j.jep.2004.02.012 }}</ref><ref>{{cite journal | vauthors = Scott LJ, Goa KL | title = Galantamine: a review of its use in Alzheimer's disease | journal = Drugs | volume = 60 | issue = 5 | pages = 1095–1122 | date = November 2000 | pmid = 11129124 | doi = 10.2165/00003495-200060050-00008 | s2cid = 250305879 }}</ref> However, it was not until the 1990s when full-scale synthesis was upscaled and optimized.<ref>{{Cite web|url=https://www.alzforum.org/therapeutics/galantamine|title=Galantamine|website=alzforum|access-date=November 17, 2019|archive-date=November 17, 2019|archive-url=https://web.archive.org/web/20191117153220/https://www.alzforum.org/therapeutics/galantamine|url-status=live}}</ref>

== 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.<ref name=drugs/><ref name=birks/> The first person to extract galantamine and theorize its usefulness in medicine, was the Bulgarian chemist Dimitar Paskov in 1959. In the United States, it is approved by the Food and Drug Administration (FDA) for the treatment of mild to moderate dementia.<ref name=kalola/><ref>{{cite web|title=Galantamine hydrobromide (trademark)|url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021615lbl.pdf|publisher=US Food and Drug Administration|access-date=December 17, 2017|date=2004|archive-date=July 13, 2020|archive-url=https://web.archive.org/web/20200713225426/https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/021615lbl.pdf|url-status=live}}</ref> Galantamine may not be effective for treating mild cognitive impairment.<ref>{{cite journal | vauthors = Tricco AC, Soobiah C, Berliner S, Ho JM, Ng CH, Ashoor HM, Chen MH, Hemmelgarn B, Straus SE | title = Efficacy and safety of cognitive enhancers for patients with mild cognitive impairment: a systematic review and meta-analysis | journal = CMAJ | volume = 185 | issue = 16 | pages = 1393–401 | date = November 2013 | pmid = 24043661 | pmc = 3826344 | doi = 10.1503/cmaj.130451 }}</ref>

===Alzheimer's disease=== Alzheimer's disease is characterized by the impairment of cholinergic function.<ref name=drugs/><ref name=kalola/> 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.<ref name=drugs/><ref name=kalola/> Galantamine inhibits acetylcholinesterase, an enzyme which hydrolyzes acetylcholine.<ref name=drugs/><ref name=kalola/> As a result of acetylcholinesterase inhibition, galantamine increases the availability of acetylcholine for synaptic transmission.<ref name=kalola/> Additionally, galantamine binds to the allosteric sites of nicotinic receptors, which causes a conformational change.<ref name="springer">{{cite journal | vauthors = Farlow MR | title = Clinical pharmacokinetics of galantamine | journal = Clinical Pharmacokinetics | volume = 42 | issue = 15 | pages = 1383–92 | year = 2003 | pmid = 14674789 | doi = 10.2165/00003088-200342150-00005 | s2cid = 36855768 }}</ref> This allosteric modulation increases the nicotinic receptor's response to acetylcholine.<ref name=kalola/> The activation of presynaptic nicotinic receptors increases the release of acetylcholine, further increasing the availability of acetylcholine.<ref name=kalola /> Galantamine's competitive inhibition of acetylcholinesterase and allosteric nicotinic modulation serves as a dual mechanism of action.<ref name="springer" />

To reduce the prevalence of negative side effects associated with galantamine, such as nausea and vomiting, a dose-escalation scheme may be used.<ref name="direct">{{cite journal | vauthors = Erkinjuntti T, Kurz A, Gauthier S, Bullock R, Lilienfeld S, Damaraju CV | title = Efficacy of galantamine in probable vascular dementia and Alzheimer's disease combined with cerebrovascular disease: a randomised trial | journal = Lancet | volume = 359 | issue = 9314 | pages = 1283–90 | date = April 2002 | pmid = 11965273 | doi = 10.1016/S0140-6736(02)08267-3 | s2cid = 1172847 }}</ref> The use of a dose-escalation scheme has been well accepted in countries where galantamine is used.<ref name="direct" /> 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).<ref name=drugs/> After a minimum of 4 weeks, the dosage may then be increased to 8 mg given twice a day (16 mg/day).<ref name="drugs" /> 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).<ref name="drugs" /> Dosage increases are based upon the assessment of clinical benefit as well as tolerability of the previous dosage.<ref name="drugs" /> 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.<ref name="drugs" /> It has been found that a dosage between 16–24 mg/day is the optimal dosage.<ref name="pmid24591834">{{cite journal | vauthors = Hager K, Baseman AS, Nye JS, Brashear HR, Han J, Sano M, Davis B, Richards HM | title = Effects of galantamine in a 2-year, randomized, placebo-controlled study in Alzheimer's disease | journal = Neuropsychiatric Disease and Treatment | volume = 10 | pages = 391–401 | date = 2014 | pmid = 24591834 | pmc = 3937252 | doi = 10.2147/NDT.S57909 | doi-access = free }}</ref>

In December 2023, the FDA approved a New Drug Application (NDA) for a pro-drug of galantamine called ALPHA-1062.<ref>{{cite press release | title=Alpha Cognition Announces FDA Acceptance of New Drug Application for ALPHA-1062 for Mild-to-Moderate Alzheimer's Disease | publisher=Alpha Cognition | via=Business Wire | date=December 7, 2023 | url=https://www.businesswire.com/news/home/20231207840612/en/Alpha-Cognition-Announces-FDA-Acceptance-of-New-Drug-Application-for-ALPHA-1062-for-Mild-to-Moderate-Alzheimer%E2%80%99s-Disease | access-date=August 5, 2024 | archive-date=April 16, 2024 | archive-url=https://web.archive.org/web/20240416023157/https://www.businesswire.com/news/home/20231207840612/en/Alpha-Cognition-Announces-FDA-Acceptance-of-New-Drug-Application-for-ALPHA-1062-for-Mild-to-Moderate-Alzheimer%E2%80%99s-Disease | url-status=live }}</ref> 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.<ref>{{cite press release | title=Alpha Cognition's Oral Therapy Zunveyl Receives FDA Approval to Treat Alzheimer's Disease | publisher=Alpha Cognition | via=Business Wire | date=July 29, 2024 | url=https://www.businesswire.com/news/home/20240729327804/en/ | access-date=August 4, 2024 | archive-date=August 4, 2024 | archive-url=https://web.archive.org/web/20240804193100/https://www.businesswire.com/news/home/20240729327804/en/ | url-status=live }}</ref>

== Side effects == The adverse effect profile of galantamine includes potential for allergic reaction, including hives, swelling of the face or throat, and skin rash.<ref name=drugs/><ref name=mayo/> Using galantamine may cause chest pain, bloody urine, stomach bleeding, and liver injury, among other side effects.<ref name=drugs/><ref name=mayo/> Nausea, vomiting, diarrhea, dizziness, and headache are considered common side effects.<ref name="drugs" />

A gradual titration over more than three months may enable long-term tolerability in some people.<ref>{{cite journal | vauthors = Birks J | title = Cholinesterase inhibitors for Alzheimer's disease | journal = The Cochrane Database of Systematic Reviews | issue = 1 | article-number = CD005593 | date = January 2006 | volume = 2016 | pmid = 16437532 | doi = 10.1002/14651858.CD005593 | pmc = 9006343 | veditors = Birks J }}</ref>

Galantamine has a wide spectrum of interactions with other medications and medical disorders, requiring close assessment between the physician and patient.<ref name="mayo">{{cite web |title=Galantamine |url=https://www.mayoclinic.org/drugs-supplements/galantamine-oral-route/precautions/drg-20067458?p=1 |publisher=Mayo Clinic |access-date=March 26, 2024 |date=2024 |archive-date=March 26, 2024 |archive-url=https://web.archive.org/web/20240326145046/https://www.mayoclinic.org/drugs-supplements/galantamine-oral-route/precautions/drg-20067458?p=1 |url-status=live }}</ref>

== 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.<ref name=drugs/>

Galantamine is a potent allosteric potentiating ligand of human nicotinic acetylcholine receptors (nAChRs) α4β2, α3β4, and α6β4, and chicken/mouse nAChRs α7/5-HT3 in certain areas of the brain.<ref name=drugs/><ref name="metabolism">{{cite journal | vauthors = Mannens GS, Snel CA, Hendrickx J, Verhaeghe T, Le Jeune L, Bode W, van Beijsterveldt L, Lavrijsen K, Leempoels J, Van Osselaer N, Van Peer A, Meuldermans W | title = The metabolism and excretion of galantamine in rats, dogs, and humans | journal = Drug Metabolism and Disposition | volume = 30 | issue = 5 | pages = 553–63 | date = May 2002 | pmid = 11950787 | doi = 10.1124/dmd.30.5.553 | s2cid = 6795456 }}</ref> By binding to the allosteric site of the nAChRs, a conformational change occurs which increases the receptors response to acetylcholine.<ref name=kalola/> This modulation of the nicotinic cholinergic receptors on cholinergic neurons in turn causes an increase in the amount of acetylcholine released.<ref>{{cite journal | vauthors = Woodruff-Pak DS, Vogel RW, Wenk GL | title = Galantamine: effect on nicotinic receptor binding, acetylcholinesterase inhibition, and learning | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 98 | issue = 4 | pages = 2089–94 | date = February 2001 | pmid = 11172080 | pmc = 29386 | doi = 10.1073/pnas.031584398 | bibcode = 2001PNAS...98.2089W | jstor = 3055005 | doi-access = free }}</ref> However, recent studies suggest that Galantamine does not functionally act at human nAChRs α4β2 or α7 as a positive allosteric modulator.<ref>{{cite journal | vauthors = Moerke MJ, McMahon LR, Wilkerson JL | title = More than Smoke and Patches: The Quest for Pharmacotherapies to Treat Tobacco Use Disorder | journal = Pharmacological Reviews | volume = 72 | issue = 2 | pages = 527–557 | date = April 2020 | pmid = 32205338 | pmc = 7090325 | doi = 10.1124/pr.119.018028 | url = https://pharmrev.aspetjournals.org/content/72/2/527/tab-article-info | access-date = October 24, 2020 | archive-date = October 8, 2021 | archive-url = https://web.archive.org/web/20211008220759/https://pharmrev.aspetjournals.org/content/72/2/527/tab-article-info | url-status = live }}</ref><ref name="pmid29669164">{{cite journal |vauthors=Kowal NM, Ahring PK, Liao WY, Indurti DC, Harvey BS, O'Connor SM, Chebib M, Olafsdottir ES, Balle T |title=Galantamine is not a positive allosteric modulator of human α4β2 or α7 nicotinic acetylcholine receptors |journal=British Journal of Pharmacology |volume=175 |issue=14 |pages=2911–2925 |date=July 2018 |pmid=29669164 |pmc=6016680 |doi=10.1111/bph.14329 |url= |issn=}}</ref>

Galantamine also works as a weak competitive and reversible cholinesterase inhibitor in all areas of the body.<ref name="drugs" /> By inhibiting acetylcholinesterase, it increases the concentration and thereby action of acetylcholine 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.

thumb|center|class=skin-invert-image|Galantamine's dual mechanism of action

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: [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DX6 1DX6]; [http://www.proteopedia.org/wiki/index.php/1dx6 see complex]).<ref>{{cite journal | vauthors = Greenblatt HM, Kryger G, Lewis T, Silman I, Sussman JL | title = Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 A resolution | journal = FEBS Letters | volume = 463 | issue = 3 | pages = 321–6 | date = December 1999 | pmid = 10606746 | doi = 10.1016/S0014-5793(99)01637-3 | s2cid = 573270 | doi-access = free | bibcode = 1999FEBSL.463..321G }}</ref> There is no evidence that galantamine alters the course of the underlying dementing process.<ref>{{Cite web |url=http://www.ortho-mcneilneurologics.com/ortho-mcneilneurologics/shared/pi/razadyne.pdf |title=Ortho-McNeil Neurologics, "Razadyne ER US Product Insert", May 2006 |access-date=December 21, 2009 |archive-url=https://web.archive.org/web/20091222071643/http://www.ortho-mcneilneurologics.com/ortho-mcneilneurologics/shared/pi/razadyne.pdf |archive-date=December 22, 2009 }}</ref>

=== 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.<ref name="springer" />

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. Within 24 hours of intravenous or oral administration approximately 20% of a dose of galantamine will be excreted unreacted in the urine.<ref name="springer" />

In humans, several metabolic pathways for galantamine exist.<ref name=metabolism/> These pathways lead to the formation of a number of different metabolites.<ref name=metabolism/> One of the metabolites that may result can be formed through the glucuronidation of galantamine.<ref name=metabolism/> Additionally, galantamine may undergo oxidation or demethylation at its nitrogen atom, forming two other possible metabolites.<ref name=metabolism/> Galantamine can undergo demethylation at its oxygen atom, forming an intermediate which can then undergo glucuronidation or sulfate conjugation.<ref name=metabolism/> 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.<ref name=metabolism/>

thumb|center|class=skin-invert-image|Metabolic pathways of galantamine

==Drug interactions== Since galantamine is metabolized by CYP2D6 and CYP3A4, inhibiting either of these isoenzymes will increase the cholinergic effects of galantamine.<ref name="springer" /> Inhibiting these enzymes may lead to adverse effects.<ref name="springer" /> It was found that paroxetine, an inhibitor of CYP2D6, increased the bioavailability of galantamine by 40%.<ref name="springer" /> The CYP3A4 inhibitors ketoconazole and erythromycin increased the bioavailability of galantamine by 30% and 12%, respectively.<ref name="springer" />

== Extraction and synthesis == {{main|Galantamine total synthesis}} Since the alkaloid is isolated from botanical sources containing low amounts (0.1%) by weight, extraction yields are low.<ref name="pmid28337117">{{cite journal | vauthors = Kim JK, Park SU | title = Pharmacological aspects of galantamine for the treatment of Alzheimer's disease | journal = EXCLI Journal | volume = 16 | pages = 35–39 | date = 2017 | pmid = 28337117 | pmc = 5318685 | doi = 10.17179/excli2016-820 }}</ref> 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.<ref>{{cite journal | vauthors = Mucke HA | title = The case of galantamine: repurposing and late blooming of a cholinergic drug | journal = Future Science OA | volume = 1 | issue = 4 | pages = FSO73 | date = November 2015 | pmid = 28031923 | pmc = 5137937 | doi = 10.4155/fso.15.73 }}</ref>

==Research==

===Organophosphate poisoning=== The toxicity of organophosphates results primarily from their action as irreversible inhibitors of acetylcholinesterase.<ref name = "organo" /> Inhibiting acetylcholinesterase causes an increase in acetylcholine, as the enzyme is no longer available to catalyze its breakdown.<ref name = "organo" /> In the peripheral nervous system, acetylcholine accumulation can cause an overstimulation of muscarinic receptors followed by a desensitization of nicotinic receptors.<ref name = "organo" /> This leads to severe skeletal muscle fasciculations (involuntary contractions).<ref name = "organo" /> The effects on the central nervous system include anxiety, restlessness, confusion, ataxia, tremors, seizures, cardiorespiratory paralysis, and coma.<ref name = "organo" /> As a reversible acetylcholinesterase inhibitor, galantamine has the potential to serve as an effective organophosphate poisoning treatment by preventing irreversible acetylcholinesterase inhibition.<ref name = "organo" /> Additionally, galantamine has anticonvulsant properties which may make it even more desirable as an antidote.<ref name = "organo" />

Research supported in part by the US Army has led to a US patent application for the use of galantamine and/or its derivatives for treatment of organophosphate poisoning.<ref name = "organo">{{cite journal | vauthors = Albuquerque EX, Pereira EF, Aracava Y, Fawcett WP, Oliveira M, Randall WR, Hamilton TA, Kan RK, Romano JA, Adler M | title = Effective countermeasure against poisoning by organophosphorus insecticides and nerve agents | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 103 | issue = 35 | pages = 13220–5 | date = August 2006 | pmid = 16914529 | pmc = 1550772 | doi = 10.1073/pnas.0605370103 | bibcode = 2006PNAS..10313220A | doi-access = free }}</ref> 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 LD50).<ref name="Albuquerque_patent">{{cite web |url=http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090023706.PN.&OS=PN/20090023706&RS=PN/20090023706 |title=United States Patent Application 20090023706 |publisher=US Patent and Trademark Office |date=January 22, 2009 |access-date=May 27, 2016 |vauthors=((Albuquerque, Edson X)), ((Adler, Michael)), ((Pereira, Edna F.R.)) |archive-date=July 13, 2020 |archive-url=https://web.archive.org/web/20200713225511/http://appft.uspto.gov/netacgi/nph-Parser?p=1&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=1&f=G&l=50&d=PG01&s1=20090023706.PN.&OS=PN%2F20090023706&RS=PN%2F20090023706 }}</ref>

===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.<ref>{{cite journal | vauthors = Ghaleiha A, Ghyasvand M, Mohammadi MR, Farokhnia M, Yadegari N, Tabrizi M, Hajiaghaee R, Yekehtaz H, Akhondzadeh S | title = Galantamine efficacy and tolerability as an augmentative therapy in autistic children: A randomized, double-blind, placebo-controlled trial | journal = Journal of Psychopharmacology | volume = 28 | issue = 7 | pages = 677–85 | date = July 2014 | pmid = 24132248 | doi = 10.1177/0269881113508830 | s2cid = 206491732 }}</ref> Additionally, the cholinergic and nicotinic receptors are believed to play a role in attentional processes.<ref name="aut">{{cite journal | vauthors = Nicolson R, Craven-Thuss B, Smith J | title = A prospective, open-label trial of galantamine in autistic disorder | journal = Journal of Child and Adolescent Psychopharmacology | volume = 16 | issue = 5 | pages = 621–9 | date = October 2006 | pmid = 17069550 | doi = 10.1089/cap.2006.16.621 }}</ref> Some studies have noted that cholinergic and nicotinic treatments have improved attention in autistic children.<ref name="aut" /> As such, it is hypothesized that galantamine's dual action mechanism might have a similar effect in treating autistic children and adolescents.<ref name="aut" />

===Anesthesia=== Galantamine may have some limited use in reducing the side-effects of anesthetics ketamine and diazepam. In one study, a control group of patients were given ketamine and diazepam and underwent anesthesia and surgery.<ref name="anesth">{{cite journal | vauthors = Chakalova E, Marinova M, Srebreva M, Anastasov D, Ploskov K | title = [Attempt to eliminate residual somnolence and disorientation with nivaline after anesthesia with ketalar and diazepam for minor obstetrical and gynecologic surgery] | language = bg | journal = Akusherstvo I Ginekologiia | volume = 26 | issue = 3 | pages = 28–31 | date = 1987 | pmid = 3631427 }}</ref> The experimental group was given ketamine, diazepam, and nivalin (of which the active ingredient is galantamine).<ref name="anesth" /> The degree of drowsiness and disorientation of the two groups was then assessed 5, 10, 15, 30 and 60 minutes after surgery.<ref name="anesth" /> The group that had taken nivalin were found to be more alert 5, 10, and 15 minutes after the surgery.<ref name="anesth" />

=== Oneirogen ===

Galantamine is known to have oneirogenic properties. Research has demonstrated its potential to increase dream recall, dream self-awareness and dream vividness. The enhancement of such dream properties can facilitate the induction of lucid dreams.<ref name="Tan Fan 2023 p. ">{{cite journal | vauthors = Tan S, Fan J | title = A systematic review of new empirical data on lucid dream induction techniques | journal = Journal of Sleep Research | volume = 32 | issue = 3 | article-number = e13786 | date = June 2023 | pmid = 36408823 | doi = 10.1111/jsr.13786 | doi-access = free }}</ref><ref name="Sparrow Hurd Carlson Molina 2018 pp. 74–88">{{cite journal | vauthors = Sparrow G, Hurd R, Carlson R, Molina A | title = Exploring the effects of galantamine paired with meditation and dream reliving on recalled dreams: Toward an integrated protocol for lucid dream induction and nightmare resolution | journal = Consciousness and Cognition | volume = 63 | pages = 74–88 | date = August 2018 | pmid = 29960246 | doi = 10.1016/j.concog.2018.05.012 | publisher = Elsevier BV }}</ref>

== References == {{Reflist}}

{{Antidementia}} {{Acetylcholine metabolism and transport modulators}} {{Nicotinic acetylcholine receptor modulators}} {{Portal bar | Medicine}}

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