Page 6 - Drug Class Review

Final Report Update 1 Drug Effectiveness Review Project

Initial pharmacologic strategies for AD focused on increasing cholinergic transmission in the brain based
on the “cholinergic hypothesis” of memory dysfunction. Among different strategies employed to increase

synaptic levels of acetylcholine (ACh), blocking the breakdown of ACh by inhibiting acetylcholinesterase
(AChE) has proven most successful to date. Inhibiting the enzyme butyrylcholinesterase (BuChE), which
is a minor constituent in normal brains but in the brains of AD patients is increased in association with

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plaques and tangles, may also improve cholinergic transmission.

Centrally active ChEIs, which differ in targeting AChE alone or affecting both AChE and BuChE, were
the first class of drugs approved by the US Food and Drug Administration (FDA) for the treatment of AD.
Currently available ChEIs include donepezil hydrochloride (donepezil), galantamine hydrochloride

(galantamine), rivastigmine tartrate (rivastigmine), and tacrine hydrochloride (tacrine). Among these
agents galantamine also acts as an allosteric nicotinic receptor modulator, which has been shown to
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stimulate the presynaptic release of acetylcholine and other neurotransmitters in laboratory preparations.
Because of their more favorable therapeutic profiles, greater convenience, and absence of liver toxicity,
the second-generation ChEI agents (i.e., donepezil, galantamine, and rivastigmine) largely have

supplanted the first approved drug in this class, tacrine. Neuropharmacologic and pharmacokinetic
properties of the currently available ChEIs are summarized in Table 1.

More recent evidence implicates the excitatory neurotransmitter glutamate as playing a role in the
pathophysiology of AD. 9-11 Currently, the only available drug targeting cognitive symptoms via a putative
glutamatergic mechanism is memantine hydrochloride (memantine). Memantine has been widely used in

Germany for more than two decades to treat a variety of conditions, including dementia, PD, neurogenic
bladder, and neuropathic pain. 12, 13 Memantine has been promoted as a treatment for dementia in

Germany since 1989; in 2002 the European Union approved its use in AD. Memantine is a low-affinity
noncompetitive NMDA receptor antagonist that blocks pathologic neural toxicity associated with
prolonged glutamate release without interfering with the normal physiologic actions of glutamate required

for learning and memory functions. 14, 15 Neuropharmacologic and pharmacokinetic properties of
memantine are summarized in Table 1.

Other more poorly documented pharmacologic approaches include drugs like nicotine, selegiline, vitamin
E, ginkgo biloba, piracetam, hormone replacement therapy, anti-inflammatory drugs, statins, and folic

acid; 14, 16 these will not be considered in this review.

Alzheimer's Drugs Page 6 of 205