Tacrine

Tacrine is a centrally acting acetylcholinesterase inhibitor 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 in 1949. It also acts as a histamine N-methyltransferase inhibitor.^[2]

Tacrine

Clinical data
Trade names	Cognex
AHFS/Drugs.com	Monograph
MedlinePlus	a693039
Pregnancy category	AU: C
Routes of administration	Oral, rectal
ATC code	N06DA01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) BR: Class C1 (Other controlled substances)[1] UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	2.4–36% (oral)
Protein binding	55%
Metabolism	Hepatic (CYP1A2)
Elimination half-life	2–4 hours
Excretion	Renal
Identifiers
IUPAC name 1,2,3,4-Tetrahydroacridin-9-amine
CAS Number	321-64-2 Y
IUPHAR/BPS	6687
DrugBank	DB00382 Y
ChemSpider	1859 Y
UNII	4VX7YNB537
ChEBI	CHEBI:45980 Y
ChEMBL	ChEMBL95 Y
PDB ligand	THA (PDBe, RCSB PDB)
CompTox Dashboard (EPA)	DTXSID1037272
ECHA InfoCard	100.005.721
Chemical and physical data
Formula	C13H14N2
Molar mass	198.269 g·mol−1
3D model (JSmol)	Interactive image
Melting point	183 °C (361 °F)
Boiling point	358 °C (676 °F)
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) Y Key:YLJREFDVOIBQDA-UHFFFAOYSA-N Y
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Clinical use

Tacrine was the prototypical cholinesterase inhibitor for the treatment of Alzheimer's disease. William K. Summers received a patent for this use in 1989.^[3][4][5] 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.^[6][7]

Tacrine has been discontinued in the US^[8] in 2013, due to concerns over safety.^[9]

Tacrine was also described as an analeptic agent used to promote mental alertness.^[10]

Adverse effects

Very common (>10% incidence) adverse effects include^[8]

• Increased liver function tests (LFT), with 49% of patients displaying elevated ALA^[11]
• Diarrhea
• Dizziness
• Headache
• Nausea
• Vomiting

Common (1-10% incidence) adverse effects include^[8][12]

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

Uncommon/rare (<1% incidence) adverse effects include^[12]

• 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.
• Hepatotoxicity (that is toxic effects on the liver)
• Ototoxicity (hearing/ear damage; a link to tacrine treatment has not been conclusively proven)
• Seizures
• Taste changes

Unknown incidence adverse effects include^[12]

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

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.^[12]

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.^[12]