Donepezil (Aricept)

written by Matthew Brady, pharmacy class of 2010, Dalhousie University

 

 

Acetylcholine esterase inhibitor.

 

Uses

Used primarily in early, mid, and late Alzheimer's Disease (Birks et al, 1998).


Also used in Lewy Body dementia
Evidence for use in vascular dementia (Malouf et al, 2004).

 

 

Mechanism

Donepezil is a non-competitive, reversible acetylcholine esterase (AchE) inhibitor. Inhibition of this enzyme therefore increases the amount of acetylcholine available for neurotransmission. It is more selective for the CNS and thus results in less peripheral side effects (i.e., decreased HR, bronchial constriction).

 

Acetylcholine is a naturally occurring chemical in the brain and the periphery and is said to be deficient in many types of dementia. The peripheral response to acetylcholine include: decrease heart rate, vasodilatation of vascular beds, increase in secretions from exocrine glands, and contraction of smooth muscles in the GI tract, respiratory tract, ciliary body and iris sphincter. In the CNS, acetylcholine has a role in: learning, memory, REM sleep, psychotic states, thermoregulation and reward behaviors.

 

Dose and Half Life

 

Onset: Peak concentration 3 – 4 hrs
Half-life: 104 hrs

 

5 mg p.o. once daily (preferably a.m. although monograph recommends p.m. dosing) for 4 – 6 weeks. If tolerated and/or

suboptimal response increase to maintenance dose of 10 mg p.o. once daily.

If 5 mg p.o. is not tolerated you may have to go slow.

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Adverse Drug Reactions

 

As donepezil increases cholinergic signals, parasympathetic effects could decrease heart rate and respiratory rate, increased urinary frequency, diarrhea, seizures.


The most common (1-10%) side effects are those of the GI tract: Nausea, vomiting, diarrhea, abdominal pain and salivation.


Nightmares have been reported and is associated with the timing of the dose.


Muscle cramps.

 

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Contra-indications and Drug Interactions

 

Precautions

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Pharmacokinetics, Metabolism and Excretion

Onset: Some response approximately 3 weeks, but give a good 4-6 weeks.
Half-Life: 70-104 hrs
Absorption: bioavailability of 100%, regardless of food.
Distribution: Vd ~ 12 L/kg, binds to albumin (major) and alpha-1 acid glycoprotein (minor)
Metabolism: Via glucuronidation, cyp 2D6 and 3A4 with active metabolites with equal potency as donepezil.
Excretion: Renal clearance (major) and fecal (minor). Total body clearance is approximately 0.13 L/hr/kg

 

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Advice for Clinical Practice

 

To avoid nightmares and/or sleeping problems make sure it’s dosed in the a.m.
Gastrointestinal side effects are usually transient and give a 4 – 6 week trial period before considering switching. (Unless there is a failure to thrive)
There is evidence for switching (generally only switch once):
Donepezil to Rivastigmine
Donepezile to Galantamine
(Emre, M.Switching cholinesterase inhibitors in patients with Alzheimer's disease. Int J Clin Pract Suppl. 2002 Jun;(127):64-72.)
If switch is due to side effects, wash out period based on 4 – 5 half lives, and use fast titration of the second drug.
Pharmacodynamic interactions with beta-blockers (BB) should be monitored and/or dose decrease or discontinue (depending on the indication for BB). Respiratory diseases such as asthma/COPD should be monitored very closely for hypoxia, tachypnea, and increased bronchial secretions as these patient groups are at much higher risk of these cholinergic side effects.
If decline in cognition/functioning occurs after nursing home placement wait at least 6 weeks for adjustment before deciding if medication is of no benefit.

 

Resources and References

Birks J, Harvey RJ. Donepezil for dementia due to Alzheimer's disease. Cochrane Database of Systematic Reviews. 1998).

Malouf R, Birks J. 2004. Donepezil for vascular cognitive impairment. Cochrane Database of Systematic Reviews.