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. It also acts as a histamine N-methyltransferase inhibitor.[1]

Tacrine
Clinical data
Trade namesCognex
AHFS/Drugs.comMonograph
MedlinePlusa693039
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    administration    		Oral, rectal
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only)
    • US: ℞-only
    Pharmacokinetic data
    Bioavailability2.4–36% (oral)
    Protein binding55%
    MetabolismHepatic (CYP1A2)
    Elimination half-life2–4 hours
    ExcretionRenal
    Identifiers
    CAS Number
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    ChEBI
    ChEMBL
    PDB ligand
    CompTox Dashboard (EPA)
    ECHA InfoCard100.005.721
    Chemical and physical data
    FormulaC13H14N2
    Molar mass198.269 g·mol−1
    3D model (JSmol)
    Melting point183 °C (361 °F)
    Boiling point358 °C (676 °F)
      (verify)

    Clinical use

    Tacrine was the prototypical cholinesterase inhibitor for the treatment of Alzheimer's disease. William K. Summers received a patent for this use.[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]

    Tacrine was also described as an analeptic agent used to promote mental alertness.[9]

    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][10]
    • 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[10]
    • 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[10]

    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.[10]

    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.[10]

    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 4816456, "Administration of monoamine acridines in cholinergic neuronal deficit states"
    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-for research 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. Elks, J.; Ganellin, C. R. (1990). Dictionary of Drugs. doi:10.1007/978-1-4757-2085-3. ISBN 978-1-4757-2087-7.
    10. Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Oct 8]. Greenwood Village, CO: Thomsen Healthcare; 2013.
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