Tacrine

198.26

198.26

206-291-2

4VX7YNB537

DTXSID1037272

N - Nervous system

2933990090

38.9

2.2

Solid

1.3±0.1 g/cm3

183.5 °C

353.8±42.0 °C at 760 mmHg

167.8±27.9 °C

1.682

1.36e-01 g/L

9.95(at 20 °C)

9.95 (at 20 °C)

R25

P201, P202, P261, P264, P270, P271, P280, P281, P301+P310, P302+P352, P304+P340, P305+P351+P338, P308+P313, P311, P312, P321, P322, P330, P332+P313, P337+P313, P361, P362, P363, P403+P233, P405, P501

H301

Overdosage with cholinesterase inhibitors can cause a cholinergic crisis characterized by severe nausea/vomiting, salivation, sweating, bradycardia, hypotension, collapse, and convulsions. Increasing muscle weakness is a possibility and may result in death if respiratory muscles are involved. The estimated median lethal dose of tacrine following a single oral dose in rats is 40 mg/kg, or approximately 12 times the maximum recommended human dose of 160 mg/day.

Strikingly, therapy with tacrine was associated with serum aminotransferase elevations in almost half of patients. These elevations usually arose within 6 to 8 weeks of starting therapy and rapidly resolved when therapy was stopped. Elevations above 3 times the upper limit of the normal range (ULN) occurred in 25%, above 10 times ULN in 6% and above 20 times ULN in 2% of patients. Accompanying elevations in alkaline phosphatase and bilirubin were rare, and the ALT abnormalities were usually asymptomatic and resolved rapidly when therapy was stopped or with dose reduction. Monitoring of serum aminotransferase levels during tacrine therapy was recommended, with dose modification for ALT elevations above 3 times the ULN and discontinuation if levels rose above 5 times the ULN. In prelicensure studies, no instances of clinically apparent acute liver injury with jaundice were reported. Subsequently, however, several cases of acute hepatocellular injury with jaundice attributed to tacrine were reported, generally arising within 2 to 8 weeks of starting therapy and usually resolving rapidly with discontinuation. Eosinophilia often accompanied the hepatic injury due to tacrine, but rash and fever were uncommon as were autoantibodies. Rechallenge often led to recurrence of the hepatic injury with a somewhat shorter latency but similar or milder course. In many patients, the serum aminotransferase elevations resolved even without drug discontinuation or dose modification. Nevertheless, fatal cases of liver injury attributed to tacrine were reported to the sponsor. Routine monitoring of serum aminotransferase levels for the first six months of therapy was recommended. However, the availability of other oral anticholinesterase inhibitors that are given only once or twice daily, do not require ALT monitoring and only rarely cause liver enzyme elevations has led to the withdrawal of tacrine from clinical use in the United States.

55%

For the palliative treatment of mild to moderate dementia of the Alzheimer's type.

Tacrine is an oral acetylcholinesterase inhibitor previously used for therapy of Alzheimer disease. Tacrine therapy is associated with a very high rate of serum aminotransferase elevations during therapy and has been linked to several instances of clinically apparent, acute liver injury.

Alzheimer Disease Agents

Tacrine is a parasympathomimetic- a reversible cholinesterase inhibitor that is indicated for the treatment of mild to moderate dementia of the Alzheimer's type. An early pathophysiological feature of Alzheimer's disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus. Tacrine is postulated to exert its therapeutic effect by enhancing cholinergic function. This is accomplished by increasing the concentration of acetylcholine at cholinergic synapses through reversible inhibition of its hydrolysis by acetylcholinesterase. If this proposed mechanism of action is correct, tacrine's effect may lessen as the disease progresses and fewer cholinergic neurons remain functionally intact. There is no evidence that tacrine alters the course of the underlying dementing process.

Drugs used to specifically facilitate learning or memory, particularly to prevent the cognitive deficits associated with dementias. These drugs act by a variety of mechanisms. (See all compounds classified as Nootropic Agents.)|Drugs that mimic the effects of parasympathetic nervous system activity. Included here are drugs that directly stimulate muscarinic receptors and drugs that potentiate cholinergic activity, usually by slowing the breakdown of acetylcholine (CHOLINESTERASE INHIBITORS). Drugs that stimulate both sympathetic and parasympathetic postganglionic neurons (GANGLIONIC STIMULANTS) are not included here. (See all compounds classified as Parasympathomimetics.)|Drugs that inhibit cholinesterases. The neurotransmitter ACETYLCHOLINE is rapidly hydrolyzed, and thereby inactivated, by cholinesterases. When cholinesterases are inhibited, the action of endogenously released acetylcholine at cholinergic synapses is potentiated. Cholinesterase inhibitors are widely used clinically for their potentiation of cholinergic inputs to the gastrointestinal tract and urinary bladder, the eye, and skeletal muscles; they are also used for their effects on the heart and the central nervous system. (See all compounds classified as Cholinesterase Inhibitors.)

Tacrine is rapidly absorbed. Absolute bioavailability of tacrine is approximately 17%.|349 ± 193 L

Hepatic. Cytochrome P450 1A2 is the principal isozyme involved in tacrine metabolism. The major metabolite, 1-hydroxy-tacrine (velnacrine), has central cholinergic activity.|Tacrine has known human metabolites that include 2-Hydroxytacrine, 4- Hydroxytacrine, 7-Hydroxytacrine, and N4-hydroxylamine.

2 to 4 hours

The mechanism of tacrine is not fully known, but it is suggested that the drug is an anticholinesterase agent which reversibly binds with and inactivates cholinesterases. This inhibits the hydrolysis of acetylcholine released from functioning cholinergic neurons, thus leading to an accumulation of acetylcholine at cholinergic synapses. The result is a prolonged effect of acetylcholine.

1,2,3,4-Tetrahydro-9-acridinamine

Human Drugs -> FDA Approved Drug Products with Therapeutic Equivalence Evaluations (Orange Book) -> Active Ingredients