Tacrine

Tacrine

Systematic (IUPAC) name
1,2,3,4-tetrahydroacridin-9-amine
Clinical data
Trade names	Cognex
AHFS/Drugs.com	monograph
MedlinePlus	a693039
Pregnancy category	AU: C US: C (Risk not ruled out)
Routes of administration	Oral, rectal
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	2.4–36% (oral)
Protein binding	55%
Metabolism	Hepatic (CYP1A2)
Biological half-life	2–4 hours
Excretion	Renal
Identifiers
CAS Number	321-64-2
ATC code	N06DA01 (WHO)
IUPHAR/BPS	6687
DrugBank	DB00382
ChemSpider	1859
UNII	4VX7YNB537
ChEBI	CHEBI:45980
ChEMBL	CHEMBL95
PDB ligand ID	THA (PDBe, RCSB PDB)
Chemical data
Formula	C13H14N2
Molar mass	198.264 g/mol
SMILES n1c3c(c(c2c1cccc2)N)CCCC3
InChI InChI=1S/C13H14N2/c14-13-9-5-1-3-7-11(9)15-12-8-4-2-6-10(12)13/h1,3,5,7H,2,4,6,8H2,(H2,14,15) Key:YLJREFDVOIBQDA-UHFFFAOYSA-N
Physical data
Melting point	183 °C (361 °F)
Boiling point	358 °C (676 °F)
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Tacrine is a centrally acting anticholinesterase and indirect cholinergic agonist (parasympathomimetic). It was the first centrally acting cholinesterase inhibitor approved for the treatment of Alzheimer's disease, and was marketed under the trade name Cognex. Tacrine was first synthesised by Adrien Albert at the University of Sydney. It also acts as a histamine N-methyltransferase inhibitor.^[1]

Clinical use

Tacrine was the prototypical cholinesterase inhibitor for the treatment of Alzheimer's disease. William K. Summers received a patent for this use (US Patent No. 4,816,456).^[2][3][4] Studies found that it may have a small beneficial effect on cognition and other clinical measures, though study data was limited and the clinical relevance of these findings was unclear.^[5][6]

Tacrine has been discontinued in the US^[7] in 2013, due to concerns over safety.^[8]

Adverse Effects

Very Common (>10% incidence) adverse effects include^[7]

• Increased LFTs
• Nausea
• Vomiting
• Diarrhea
• Headache
• Dizziness

Common (1-10% incidence) adverse effects include^[7][9]

• Indigestion
• Belching
• Abdominal pain
• Myalgia — muscle pain
• Confusion
• Ataxia — decreased control over bodily movements.
• Insomnia
• Rhinitis
• Rash
• Fatigue
• Weight loss
• Constipation
• Somnolence
• Tremor
• Anxiety
• Urinary incontinence
• Hallucinatons
• Agitation
• Conjunctivitis (a link to tacrine treatment has not been conclusively proven)
• Diaphoresis — sweating.

Uncommon/Rare (<1% incidence) adverse effects include^[9]

• Hepatotoxicity (that is toxic effects on the liver)
• Ototoxicity (hearing/ear damage; a link to tacrine treatment has not been conclusively proven)
• Seizures
• Agranulocytosis (a link between treatment and this adverse effect has not been proven) — a potentially fatal drop in white blood cells, the body's immune/defensive cells.
• Taste changes

Unknown incidence adverse effects include^[9]

• Urinary tract infection
• Delirium
• Other optic effects such as glaucoma, cataracts, etc. (also not conclusively linked to tacrine treatment)
• Depression
• Suicidal ideation and behaviour
• Hypotension
• Bradycardia

Overdose

As stated above, overdosage of tacrine may give rise to severe side effects such as nausea, vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Atropine is a popular treatment for overdose.^[9]

Pharmacokinetics

Major form of metabolism is in the liver via hydroxylation of benzylic carbon by CYP1A2. This forms the major metabolite 1-hydroxy-tacrine (velnacrine) which is still active.^[9]

References

1. Taraschenko, OD; Barnes, WG; Herrick-Davis, K; Yokoyama, Y; Boyd, DL; Hough, LB (April 2005). "Actions of tacrine and galanthamine on histamine-N-methyltransferase.". Methods and findings in experimental and clinical pharmacology 27 (3): 161–165. doi:10.1358/mf.2005.27.3.890872. PMID 15834447.
2. {US Patent No. 4,816,456} http://patft.uspto.gov/netacgi/nph-Parser?Sect1=PTO1&Sect2=HITOFF&d=PALL&p=1&u=%2Fnetahtml%2FPTO%2Fsrchnum.htm&r=1&f=G&l=50&s1=4,816,456.PN.&OS=PN/4,816,456&RS=PN/4,816,456
3. Waldholz M. A Psychiatrist’s work leads to a US study of Alzheimer’s drug: but Dr. Summers shuns test, seeks to widen his own; is Memory really aided; Fee-forresearch Furor. Wall Street Journal. Tuesday August 4, 1987 p A-1
4. Peacock D. New Mexico Doctor invents drugs, supplements for Alzheimer’s disease, Multiple Sclerosis. NM Bus Weekly. 25 MAR 2005
5. Qizilbash N, Whitehead A, Higgins J, et al. (1998). "Cholinesterase inhibition for Alzheimer disease: a meta-analysis of the tacrine trials". Journal of the American Medical Association 280 (20): 1777–82. doi:10.1001/jama.280.20.1777. PMID 9842955.
6. Rang HP, Dale MM, Ritter JM, Moore PK (2003). Pharmacology (5th ed.). Edinburgh: Churchill Livingstone. ISBN 978-0-443-07145-4..
7. "tacrine (Discontinued) - Cognex". Medscape Reference. WebMD. Retrieved 8 October 2013.
8. Tacrine at LiverTox
9. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Oct 8]. Greenwood Village, CO: Thomsen Healthcare; 2013.

External links

• Acetylcholinesterase: A gorge-ous enzyme QUite Interesting PDB Structure article at PDBe