Tacrine Cholinergics

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). 

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). 

Chopin P, Briley M. (1992). Effects of four non-cholinergic cognitive enhancers in comparison with tacrine and galanthamine on scopolamine-induced amnesia in rats. Psychopharmacoiogy (Beriin). 106(1) 26-30. 

Tacrine is not without its problems. It produces typical cholinergic side effects (nansea, cramping, loss of appetite, rnnny nose, and diarrhea). In addition, tacrine can be toxic to the liver in some patients. If liver problems develop while taking tacrine, they reverse when the medication is discontinued. Nevertheless, all patients shonld routinely undergo blood tests of liver function before starting tacrine and periodically dnring tacrine therapy. 

Gl disease/dysfunction Tacrine is an inhibitor of cholinesterase and may be expected to increase gastric acid secretion caused by increased cholinergic activity. Therefore, closely monitor patients at increased risk for developing ulcers for symptoms of active or occult Gl bleeding. 

Tacrine has been found to be somewhat effective in patients with mild-to-moderate symptoms of this disease for improvement of cognitive functions. The drug is primarily a reversible cholinesterase inhibitor that increases the concentration of functional ACh in the brain. However, the pharmacology of tacrine is complex the drug also acts as a muscarinic receptor modulator in that it has partial agonistic activity, as well as weak antagonistic activity on muscarinic receptors in the CNS. In addition, tacrine appears to enhance the release of ACh from cholinergic nerves, and it may alter the concentrations of other neurotransmitters such as dopamine and NE. 

The only clinically available cholinergic therapy to date is an anticholinesterase (tacrine). Studies have shown short-term improvement in some aspects of memory and a delay in decline in some patients. It has been generally assumed that these effects are solely the result of enhancement of muscarinic mechanisms however, this assumption may be unwarranted. Direct muscarinic augmentation produces little measurable cognitive improvement and does not generally reproduce the memory-enhancing effects of anticholinesterases (Bruno et al. 1986 Tariot et al. 1988). 

Davies P, Maloney AJF Selective loss of central cholinergic neurons in Alzheimer s disease. Lancet 2 1403, 1976 Davis KL, Powchik P Tacrine. Lancet 345 625-630, 1995... 

K. Sherman, Pharmacodynamics of oral E2020 and tacrine in humans novel approaches, in R. Becker, E. Giacobini (Eds.), Cholinergic Basis for Alzheimer Therapy, Birkhauser, Boston, 1991, pp. 321-328. 

Donepezil is primarily a reversible inhibitor of acetylcholinesterase with a long elimination half-life. It lacks the hepatotoxicity of tacrine but frequently causes nausea, vomiting and diarrhoea. These side effects, together with occasional bradycardia, sycope and changes in the sleep architecture, are directly associated with a central and peripheral enhancement of cholinergic function. At the present time, donepezil is the most widely prescribed anticholinesterase in the United States and Europe. 

Scopolamine-induced impairment of learning and retention in the water maze was fully prevented by ondansetron when given in combination with a cholinesterase inhibitor, tacrine. Combined treatment with ondansetron and flumazenil was able to significantly increase ACh release in situations of cholinergic hypoactivity. 73, 110... 

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