Current Treatment 608251 Cholinesterase inhibitors

The cholinergic hypothesis of AD has led to the development of NCEs that increase ACh, which is lost when neurons of the basal forebrain degenerate. ACh is degraded by cholinesterase activity. Two major forms of cholinesterase exist, acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), with differential localization. Both enzymes are found in the brain, although AChE predominates (~ 10-fold greater) and is in synaptic clefts. BuChE is also found in brain, mainly in glia, but is preferentially localized to the periphery (intestine, liver, heart, lungs). AChE is selective for ACh hydrolysis, thus for terminating cholinergic neurotransmission, while BuChE hydrolyzes multiple choline esters. Its function in normal physiology is unknown. Two isoforms of AChE exist in the brain, a tetrameric form (G4) and a monomeric form (G1).28 AChE levels decline with AD progression with preferential loss of the G4 isoform, while BuChE levels increase in the plasma and CSF of AD patients. This enzyme associates with neuritic plaques and tangles. With disease progression, there is an apparent shift in the enzyme dependence of ACh metabolism. Compounds that reversibly inhibit ACh hydrolysis would conceptually facilitate cholinergic neurotransmission by maintaining ACh in the synaptic cleft and maintaining cholinergic tone at muscarinic (mAChR) or nicotinic (nAChR) receptors (Figure 2).

Cholinesterase inhibitors approved for the treatment of mild to moderate AD include: donepezil 2, rivastigmine 3, and galantamine 4. Each drug is structurally dissimilar and all are improvements over the first cholinesterase inhibitor, the aminoacridine tacrine 5, which is no longer used due to its hepatotoxicity and the need for q.i.d. administration.

Dopamine Receptor Picture

Figure 2 The cholinergic synapse: acetylcholine (ACh) is synthesized, packaged into synaptic vesicles, and released into the synaptic cleft. Termination of cholinergic transmission is accomplished by acethylcholinesterase (AChE) which degrades ACh. Blockade of AChE thus will sustain ACh in the synaptic cleft and facilitate cholinergic transmission through interaction with both muscarinic and nicotinic receptors. (Reprinted with permission from Wilkinson, D. G.; Francis, P. T.; Schwam, E.; Payne-Parrish, J. Drugs Aging 2004, 27 453-478.)

Figure 2 The cholinergic synapse: acetylcholine (ACh) is synthesized, packaged into synaptic vesicles, and released into the synaptic cleft. Termination of cholinergic transmission is accomplished by acethylcholinesterase (AChE) which degrades ACh. Blockade of AChE thus will sustain ACh in the synaptic cleft and facilitate cholinergic transmission through interaction with both muscarinic and nicotinic receptors. (Reprinted with permission from Wilkinson, D. G.; Francis, P. T.; Schwam, E.; Payne-Parrish, J. Drugs Aging 2004, 27 453-478.)

6.08.2.5.1.1 Donepezil

Donepezil 2 was approved for the treatment of AD in 1996, and is an indanone derivative of tacrine and physostigmine selectivity for AChE relative to BuChE (1:405). It has a very long elimination half-life, ranging from approximately 60 h in young adults to approximately 100 h in the elderly,29 consistent with q.d. use. Donepezil showed significant improvement versus placebo in ADAS-cog measures (1.5-2.5 units at 5 mg; 2.88-3.1 at 10 mg dose). For the CIBIC, a higher percentage of patients were rated as improved, that is, 26-52% (5mg) and 25-38% (10mg) versus 11-22% (placebo).

6.08.2.5.1.2 Rivastigmine

Rivastigmine 3 targets AChE and BuChE, and exhibits prolonged inhibition of both enzymes, being termed a 'pseudoirreversible' as well as 'brain region'-selective cholinesterase inhibitor.28 The pharmacodynamic effect of rivastigmine (10 h) exceeds its short plasma elimination half-life (1h) because of the nature of its pseudo-irreversible interaction with AChE. Rivastigmine displays greater potency (~4-6 times) for the G1 versus the G4 isoform of AChE, that is reduced in AD, and may thus afford a more prolonged treatment window opportunity relative to other cholinesterase inhibitors without this isoform selectivity profile.

6.08.2.5.1.3 Galantamine

Galantamine 4, a naturally occurring plant tertiary alkaloid, is a reversible AChE inhibitor that is a weak positive allosteric modular of nAChRs.30 Thus galantamine has been proposed both to increase ACh levels and to potentiate the interaction of ACh presynaptically to enhance further ACh release and postsynaptically to facilitate downstream signaling. The proposed presynaptic actions of galantamine may also lead to the modulation of glutamate, serotonin, and norepinephrine release, all of which are affected in AD. Galantamine is approximately 50-fold selective for AChE over BuChE; however, selectivity for erythrocyte AChE versus brain AChE only differs by 10-fold.

Unlike rivastigmine, galantamine is metabolized by cytochrome P450 enzymes, CYP2D6 and CYP3A4, with doses of this drug being lowered if it is co-administered with other drugs that inhibit these enzymes.30 Phase III trials of 3-6 months' duration, with one study extending to 12 months, showed improvements in the ADAS-cog, the disability assessment for dementia (DAD), and the AD cooperative study/activities of daily living (ADCS/ADL) inventory following galantamine treatment.30,31

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