Tacrine is a centrally acting

acetylcholinesterase inhibitor Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and ...

and indirect

cholinergic Cholinergic agents are compounds which mimic the action of acetylcholine and/or butyrylcholine. In general, the word "choline" describes the various quaternary ammonium salts containing the ''N'',''N'',''N''-trimethylethanolammonium cation. F ...

agonist (

parasympathomimetic A parasympathomimetic drug, sometimes called a cholinomimetic drug or cholinergic receptor stimulating agent, is a substance that stimulates the parasympathetic nervous system (PSNS). These chemicals are also called cholinergic drugs because acet ...

). It was the first centrally acting cholinesterase inhibitor approved for the treatment of

Alzheimer's disease Alzheimer's disease (AD) is a neurodegeneration, neurodegenerative disease that usually starts slowly and progressively worsens. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in short-term me ...

, and was marketed under the trade name Cognex. Tacrine was first synthesised by

Adrien Albert Adrien Albert (19 November 1907 – 29 December 1989) was a leading authority in the development of medicinal chemistry in Australia. Albert also authored many important books on chemistry, including one on selective toxicity. His father, J ...

at the

University of Sydney The University of Sydney (USYD), also known as Sydney University, or informally Sydney Uni, is a public research university located in Sydney, Australia. Founded in 1850, it is the oldest university in Australia and is one of the country's si ...

in 1949. It also acts as a

histamine N-methyltransferase Histamine ''N''-methyltransferase (HNMT, HMT) is an enzyme involved in the metabolism of histamine. It is one of two enzymes involved in the metabolism of histamine in mammals, the other being diamine oxidase (DAO). HNMT catalyzes the methylation o ...

inhibitor.

Clinical use

Tacrine was the prototypical

cholinesterase inhibitor Cholinesterase inhibitors (ChEIs), also known as anti-cholinesterase, are chemicals that prevent the breakdown of the neurotransmitter acetylcholine or butyrylcholine. This increases the amount of the acetylcholine or butyrylcholine in the syn ...

for the treatment of

. William K. Summers received a patent for this use in 1989. 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.. Tacrine has been discontinued in the US in 2013, due to concerns over safety.Tacrine
t LiverTox Tacrine was also described as an

analeptic An analeptic, in medicine, is a central nervous system stimulant. The term "analeptic" typically refers to respiratory analeptics (for example, doxapram). Analeptics are central nervous system (CNS) stimulants that include a wide variety of medica ...

agent used to promote mental alertness.

Adverse Effects

;Very common (>10% incidence) adverse effects include * Increased

liver function tests Liver function tests (LFTs or LFs), also referred to as a hepatic panel, are groups of blood tests that provide information about the state of a patient's liver. These tests include prothrombin time (PT/INR), activated partial thromboplastin ti ...

(LFT) * Nausea * Vomiting * Diarrhea * Headache * Dizziness ;Common (1-10% incidence) adverse effects include * 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 * Hallucinations * Agitation *

Conjunctivitis Conjunctivitis, also known as pink eye, is inflammation of the conjunctiva, outermost layer of the white part of the eye and the inner surface of the eyelid. It makes the eye appear pink or reddish. Pain, burning, scratchiness, or itchiness may ...

(a link to tacrine treatment has not been conclusively proven) * Diaphoresis — sweating. ;Uncommon/rare (<1% incidence) adverse effects include * Hepatotoxicity (''that is'' toxic effects on the liver) * Ototoxicity (hearing/ear damage; a link to tacrine treatment has not been conclusively proven) * Seizures *

Agranulocytosis Agranulocytosis, also known as agranulosis or granulopenia, is an acute condition involving a severe and dangerous lowered white blood cell count (leukopenia, most commonly of neutrophils) and thus causing a neutropenia in the circulating blood. ...

(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 *

Urinary tract infection A urinary tract infection (UTI) is an infection that affects part of the urinary tract. When it affects the lower urinary tract it is known as a bladder infection (cystitis) and when it affects the upper urinary tract it is known as a kidney ...

* Delirium * Other optic effects such as

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...

cataracts A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble w ...

, etc. (also not conclusively linked to tacrine treatment) * Depression * Suicidal ideation and behaviour * Hypotension *

Bradycardia Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...

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 Atropine is a tropane alkaloid and anticholinergic medication used to treat certain types of nerve agent and pesticide poisonings as well as some types of slow heart rate, and to decrease saliva production during surgery. It is typically given i ...

is a popular treatment for overdose.

Pharmacokinetics

Major form of metabolism is in the liver via hydroxylation of benzylic carbon by

CYP1A2 Cytochrome P450 1A2 (abbreviated CYP1A2), a member of the cytochrome P450 mixed-function oxidase system, is involved in the metabolism of xenobiotics in the human body. In humans, the CYP1A2 enzyme is encoded by the ''CYP1A2'' gene. Function ...

. This forms the major metabolite 1-hydroxy-tacrine (velnacrine) which is still active.Truven Health Analytics, Inc. DRUGDEX® System (Internet) ited 2013 Oct 8 Greenwood Village, CO: Thomsen Healthcare; 2013.

References

External links

Acetylcholinesterase: A gorge-ous enzyme
QUite Interesting PDB Structure article a
PDBe
{{Monoamine metabolism modulators Acetylcholinesterase inhibitors Antidementia agents