Cholinesterase (ChE) inhibitor

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--Km39 13:55, 22 March 2007 (PDT)


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Description

Alzheimer’s disease causes a progressive dementia leading to a steady decline in cognitive function which adversely affects functional abilities required for activities of daily living. Alzheimer’s disease impacts 15 million people worldwide and there is no cure. Treatment is the only means to slow this devastating disease.[1] Approximately 5% of the population over the age of 65 is affected by Alzheimer’s and the prevalence doubles every 5 years after the age of 65. [2] It appears that synaptic loss is the primary factor in the creation of dementia symptoms. The synaptic neurotransmitters include acetylcholine, glutamate and serotonin. Donepezil is a cholinesterase inhibitor which inhibits the breakdown of acetylcholine.[3]


The first cholinesterase inhibitor was tacrine, which was associated with hepatic toxicity.[3] Tacrine has a half-life of 2-3 hours and must be administered four times a day[4]Donepezil is the first piperidine-type reversible cholinesterase inhibitor.[4] Donepezil is given once a day because of its long half life of 70 hours. It is well tolerated when titrated over four to six weeks. [5] Donepezil's major side effects reported in clinical trails include 21% nausea, 12% vomiting, and 16% diarrhea.[6] Rivastigmine is a long-acting reversible carbamate Cholinesterase Inhibitor. It also inhibits butyrylcholinesterase, which makes up 10% of the cholinesterase activity.[2] Butyrylcholinesterase may be a vestigial enzyme, serving as a backup for acetylcholinesterase.[6] It is administered two-three times daily.[4] Rivastigmine has a large adverse effect profile in which 47% of patients in clinical trials developed nausea, 31% developed vomiting and 19% complained of diarrhea.[6] Galantamine phenanthrene alkaloid, which is a reversible inhibitor of acetylcholinesterase, is also a nicotinic agonist. It may increase the number of nicotinic receptors, presynaptic neuronal levels of calcium, and the sensitivity of nicotinic receptors. This may lead to an increased response to acetylcholine. The major side effects in clinical trials include 24% nausea, 13% vomiting, and 9% diarrhea.[6]

The Cholinesterase Inhibiotrs are thought to prolong a patient’s ability to perform activities of daily living by facilitating improvement in cognition, memory, behavior and mood; they are not a cure for Alzheimer’s disease.[3] Although some studies suggest that donepezil may have neuroproective effects, further studies are needed to confirm this belief.[7] Rivistigmine, galantamine and donepezil all show comparable efficacy in Alzheimer's disease, with different adverse effect profiles. [8][9]


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Mechanism of action

Donepezil is the first piperidine-type reversible cholinesterase inhibitor. Cholinesterase inhibition is aimed at increasing the acetylcholine in the synaptic terminals. It reversibly obstructs the hydrolysis of acetylcholine in the synapse, allowing for more acetylcholine at the muscarinic and nicotinic receptors.[3][5] Muscarinic and nicotinic receptors make up the cholinergic receptors. It is the synaptic dysfunction that seems to be responsible for the dementia symptoms of donepezil.[3] Donepezil doesn’t affect the production of acetylcholine.[6]


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Cholinesterase Inhibitors

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References

  1. ↑ Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer's disease. N Engl J Med 2003;348(14):1333-41.
  2. ↑ 2.0 2.1 Klafki HW, Staufenbiel M, Kornhuber J, Wiltfang J. Therapeutic approaches to Alzheimer's disease. Brain 2006;129(Pt 11):2840-55.
  3. ↑ 3.0 3.1 3.2 3.3 3.4 Grutzendler J, Morris JC. Cholinesterase inhibitors for Alzheimer’s disease. Drugs 2001;61(1):41-52.
  4. ↑ 4.0 4.1 4.2 Grutzendler J, Morris JC. Cholinesterase inhibitors for Alzheimer's disease. Drugs. 2001;61(1):41-52.
  5. ↑ 5.0 5.1 Aricept (Donepezil hydrochloride) package insert, New York, NY; Pfizer:2006 October http:/ www.pfizer.com/pfizer/download/uspi_aricept.pdf.
  6. ↑ 6.0 6.1 6.2 6.3 6.4 Wilkinson DG, Francis PT, Schwam E, Payne-Parrish J. Cholinesterase inhibitors used in the treatment of Alzheimer’s disease: the relationship between pharmacological effects and clinical efficacy. Drugs Aging 2004;21(7):453-78.
  7. ↑ Mori E, Hashimoto M, Krishnan KR, Doraiswamy PM, Mori E, Hashimoto M, et al. What constitutes clinical evidence for neuroprotection in Alzheimer disease: support for the cholinesterase inhibitors? Alzheimer Disease & Associated Disorders. 2006 Apr-Jun;20(2 Suppl 1):S19-26.
  8. ↑ Wilkinson DG, Passmore AP, Bullock R, Hopker SW, Smith R, Potocnik FC, et al. A multinational, randomised, 12-week, comparative study of donepezil and rivastigmine in patients with mild to moderate Alzheimer's disease. International journal of clinical practice. 2002 Jul-Aug;56(6):441-6.
  9. ↑ Wilcock G, Howe I, Coles H, Lilienfeld S, Truyen L, Zhu Y, et al. A long-term comparison of galantamine and donepezil in the treatment of Alzheimer's disease. Drugs Aging. 2003;20(10):777-89
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