Tacrine

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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.<ref>Template:Cite journal</ref>

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.<ref>Template:Cite patent</ref><ref>Template:Cite report</ref><ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> 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.<ref name="Qizilbash1998">Template:Cite journal</ref><ref name="Rang2003">Template:Cite book.</ref>

Tacrine has been discontinued in the US<ref name=MSR>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref> in 2013, due to concerns over safety.<ref>{{#invoke:citation/CS1|citation |CitationClass=web }}</ref>

Tacrine was also described as an analeptic agent used to promote mental alertness.<ref name="ElksGanellin1990">Template:Cite book</ref>

Adverse effects

Very common (>10% incidence) adverse effects include<ref name = MSR />

• Increased liver function tests (LFT), with 49% of patients displaying elevated ALA<ref>Template:Cite journal</ref>
• Diarrhea
• Dizziness
• Headache
• Nausea
• Vomiting

Common (1-10% incidence) adverse effects include<ref name = MSR /><ref name = DD />

• 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<ref name = DD />

• 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<ref name = DD />

• 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.<ref name = DD />

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.<ref name = DD>Truven Health Analytics, Inc. DRUGDEX® System (Internet) [cited 2013 Oct 8]. Greenwood Village, CO: Thomsen Healthcare; 2013.</ref>

External links

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