Donepezil Cholinergics

Adverse reactions with donepezil include nausea, vomiting, and diarrhea. These are typical cholinergic side effects to expect with all of the cholinesterase inhibitors. Table 32-6 compares the major side effects for all of the approved agents for Alzheimer s disease.34-38... 

CYP3A4 and 2D6 are the major enzymes involved in the metabolism of galantamine. Pharmacokinetic studies with inhibitors of this system have resulted in increased galantamine concentrations or reductions in clearance. Similarly to donepezil, if inhibitors are given concurrently with galantamine, monitoring for increased cholinergic side effects should be done. Studies with inducers of these enzymes have not been completed.37... 

Haugh, K.H., Bogen, I.L., Osmundsen, H., Walaas, 1., Fonnum, F. (2005) Effects of cholinergic markers in rat brain and blood after short and prolonged administration of donepezil. Neurochem. Res., 30, 1511-1520. 

Like other cholinesterase inhibitors, donepezil carries the risk of cholinergic side effects. In fact, if the dose of a cholinesterase inhibitor is increased too rapidly, it may even worsen behavior. The principal side effects of donepezil include upset stomach, diarrhea, headache, and dizziness. It is usually started at 5 mg taken once daily in the evening. After 1 month, the dose of donepezil can be increased to lOmg/day. 

Pharmacology Donepezil enhances cholinergic function by increasing the concentration of acetylcholine through reversible inhibition of its hydrolysis by acetylcholinesterase (AChE). Donepezil s effect may lessen as the disease process advances and fewer cholinergic neurons remain functionally intact. Pharmacokinetics ... 

Figure 5. Cartoon of a cholinergic synapse showing major steps in the synthesis of acetylcholine. The two major receptor types, the ionotropic nicotinic receptor and the metabotropic muscarinic receptor, are shown (see also Chapter 1). Presynaptic muscarinic (M2) and nicotinic receptors are also depicted. Drugs which have been widely used to manipulate the cholinergic systems, and which are mentioned in the text, include the muscarinic receptor antagonists scopolamine and atropine and the nicotinic receptor agonist nicotine. Anticholinesterases (discussed elsewhere in this volume) include drugs such as physostigmine, rivastigmine, donepezil, and galanthamine.

Nathan, P.J., Baker, A., Carr, E., et ah Cholinergic modulation of cognitive function in healthy subjects acute effects of donepezil, a cholinesterase inhibitor. Hum. Ptychopharmacol. 16, 481-483, 2001. 

The beneficial effect of precursors (e.g., lecithin), cholinesterase inhibitors (e.g., physostigmine, donepezil), or drugs with cholinomimetic effects (e.g., bethanechol) for actue mania was discovered in part from the work of Janowsky et al. ( 29), leading to their cholinergic—noradrenergic balance hypothesis. Interestingly, lithium is also able to raise RBC choline concentrations and CNS cholinergic activity ( 274). 

Donepezil HC1, a piperidine, is a highly selective inhibitor of the enzyme AChE [3,4] that is chemically unique from other AChE inhibitors [5, 6]. In vitro and preclinical studies have demonstrated that donepezil is approximately 1200 times more selective for AChE in the brain than for butyrylcholinesterase (BuChE) in the periphery [3, 4, 7]. Phase II and III studies conducted in the United States have shown that donepezil (5 or 10 mg once daily) produces statistically significant improvements in cognition and global function in patients with AD [8-10]. Its clinical efficacy and minimal side-effect profile are thought to be related to its specific inhibition of AChE in the areas of the brain affected by the cholinergic deficit that typifies this disease [3, 4, 7],... 

It has been demonstrated that AD is associated with a relative decrease in the activity of the cholinergic system in the cerebral cortex and other areas of the brain. Studies suggest that donepezil hydrochloride exerts its... 

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. 

Cholinesterase inhibitors, such as donepezil, are the first line of drug treatment as they can decrease the rate of cognitive decline in some patients. But there are side effects with these agents that are related to excessive cholinergic stimulation, for example abdominal cramps, bronchoconstriction, salivation and so on. 

A 79-year-old nursing home patient was given donepezil 50 mg in error. She developed nausea, vomiting, and persistent bradycardia—typical cholinergic adverse effects. She was treated with atropine, 0.2 mg as needed, for bradycardia (total dose 3 mg over 18 hours) and was discharged on the second day. 

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