Tacrine,

Increases in alanine aminotransferase levels require dose decreases and more frequent monitoring of hepatic function. 

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Although controversy exists over the cholinergic involvement in AD dementia, as of 1993 the only AD therapy approved by the U.S. FDA was the cholinesterase inhibitor, tacrine [321-64-2] C 2H 4N2, sold as Cognex (Warner-Lambert). 

The anainoacridines, tacrine (19) and its 1-hydroxy metaboUte, velnacrine (20), are reversible inhibitors of AChE. Tacrine was synthesi2ed in the 1940s and has been used clinically for the treatment of myasthenia gravis and tardive dyskinesia (115). Placebo-controUed studies have indicated modest efficacy of tacrine to treat AD dementia (122,123) and in 1993 the dmg was recommended for approval by the PDA under the trade name Cognex. Tacrine (19) has been shown to interact with sites other than AChE, such as potassium channels (124) and muscarinic receptors. However, these interactions are comparatively weak and are not thought to contribute to the biological activity of the dmg at therapeutic levels (115). 

Serious hepatotoxicity of tacrine has been documented. More recent data suggest, however, that this toxicity can be reduced by carehiUy monitoring semm alanine aminotransferase levels (125). The side effects of tacrine also include gastrointestinal disturbances and emesis, and alternative AChE therapies are being advanced. Velnacrine (20), a metaboUte of tacrine, was expected to have reduced hepatotoxicity. However, its limited efficacy and side-effect profile, which includes dmg-related hematological changes, caused it to be dropped from further development. 

The acetylcholinesterase inhibitor tacrine (64) was approved for the treatment of mild-to-moderate SDAT in the United States in 1993 followed by several other countries. The acetylcholinesterase inhibitor galanthamine (65), which has long been in clinical use in Austria for the treatment of indications such as facial neuralgia and residual poliomyelitis paralysis, has also been approved for use in... 

Donepezil has the advantage of once-daily administration and appears to be better tolerated than tacrine. Tacrine is particularly harmful to the liver. The new dragp rivastigmine and galantamine, like the other two, are effective in treating mild-to-moderate dementia of AD. 

Tacrine is particularly damaging to the liver and can result in hepatotoxicity. Because tacrine is more likely to cause adverse reactions and drug interactions, it must be administered more frequently (4 times a day) and is rarely used in current therapy. Donepezil has fewer and milder side effects than tacrine It is considered the agent of first choice However, some patients may achieve a better response with one drug than another. Additional adverse reactions are listed in the Summary Drug Table Cholinesterase Inhibitors. 

When Hie cholinesterase inhibitors are administered with the anticholinergic drugp, there is a potential decrease in activity of the anticholinergic drug. There is an increased risk of toxicity of theophylline when the cholinesterase inhibitors are administered with tacrine There is a synergistic effect when tacrine is administered with succinyl-choline, cholinesterase inhibitors, or cholinergic agonists (eg, bethanechol). 

Tacrine is administered orally 3 or 4 times a day, preferably on an empty stomach 1 hour before or 2 hours after meals. For best results the drug should be administered around die clock. 

When administering tacrine, the nurse must monitor the patient for liver damage. This is best accomplished by monitoring alanine aminotransferase (AIT) levels. ALT is an enzyme found predominately in the liver. Disease or injury to the liver causes a release of tiiis enzyme into the bloodstream, resulting in elevated ALT levels, hi patients taking tacrine, ALT levels should be obtained weekly from at least week 4 to week 16 after die initiation of tiierapy. After week 16, transaminase levels are monitored every 3 months. 

Remember that during tacrine therapy the ALT level must be monitored at intervals prescribed by the primary health care provider. 

A patient is prescribed tacrine (Cognex) for mild dementia related to AD. The nurse has a meeting with the patient and family. What patient assessments would you need to make before discussing the drug regimen with the patient What would you include in a teaching plan for the patient and family ... 

C7HSN2 1885-29-6) see Bromazepam Tacrine 1,8-anthraquinonedisulfonic acid (C 4HsOjS2 82-48-4) see Dithranol anthrone... 

C H, 0 108-94-1) see Calusterone Clinofibrate Cyclobarbital Cyclobutyrol Cyclovalone Ethinamate Gabapentin Guanadrel Hexobarbital Levorphanol Orlistat Ramatroban Tacrine Tenylidone Venlafaxine 2-cyclohexen-l-one (CjHjO 930-68-7) see Carprofen... 

C H5N02 91-56-5) see Amfenac sodium Cinchocaine Oxyphenisatin acetate Tacrine iscthionic acid... 

The limited effectiveness of physostigmine did, however, encourage the development of longer-acting orally effective anticholinesterases such as tacrine (tetrahydroamino-acrydine), velnacrine and donepezil. 

The initial enthusiasm for tacrine and velnacrine, which are the anticholinesterases most studied clinically, has been tempered by the fact that not all patients respond. Most show the peripheral parasympathomimetic effects of cholinesterase inhibition, e.g. dyspepsia and diarrhoea, as well as nausea and vomiting, and about half of the patients develop hepatotoxicity with elevated levels of plasma alanine transaminase. While some peripheral effects can be attenuated with antimuscarinics that do not enter the brain, these add further side-effects and the drop-out rate from such trials is high (<75%) in most long-term studies. Donepezil appears to show less hepatotoxicity but its long-term value remains to be determined. 

Some of the cognitive improvements with tacrine, which is chemically related to amidopyridine, may be due to blockage of K+ channels. 

Yavich, L, Sirvio, J, Haapalinna, A, Puumala, T, Koivisto, E, Heinonen, E and Reikkinen, PJ (1996) The systemic administration of tacrine or selegiline facilitate spatial learning in aged Fisher 344 rats. J. Neural Trans. 103 619-626. 

Data from product Information for tacrine, donepezil, rivastigmine, galantamine, and memantine.34-38... 

Data from Product Information tacrine, donepezil, galantamine, memantine, and rivastigmine.34-38... 

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