Abhirama B Sarepaka

N 0241092
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What is Alzheimers Disease

Is the most common form of Dementia.

Is incurable, terminal ailment affecting the

brain mainly the Memory and Language

centres (Areas 44-45 for language and the
temporal lobe.)

Areas Affected and A Patient of Alzheimers

Pathophysiology of Alzheimers
Disease

Treatment of Alzheimers
Disease
No permanent cure for Alzheimers disease.
The class of drugs used in the treatment of Alzheimers Disease are

called Acetylcholinesterase (AChEs) Inhibitors.

These agents occur naturally in the form of venom and poisons e.g.

Scorpion and Snake Venom; Belladonna.

Synthetically, they comprise of agents such as Organophosphates,

Carbamates such as Rivastigmine, Phenantherene derivatives

such as Galantamine and Piperidine derivatives such as
Donepezil.

Donepezil: 2-[(1-benzyl-4piperidyl)methyl]-5,6-dimethoxy-2,3
dihydroinden-1-one
Galantamine: (4aS, 6R, 8aS)-5, 6, 9, 10, 11, 12hexahydro-3-methoxy-11-methyl-4aH-[1]
benzofuro[3a, 3, 2-ef] [2] benzapin-6-ol

Rivastigmine: (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino)
ethyl]-phenyl carbamate

Mechanism of interaction of Donepezil with Acetylcholinesterase

Minor groove

Major groove
The active site gorge has two binding sites, a catalytic site (consisting of the catalytic triad together with Trp84 &
Phe330) and a peripheral site (including Trp 279 & Tyr 121), which helps prebind the substrate and direct it toward the
active site.
Bioavailability: 100%
Half-life elimination: 70 hours; time to steady-state: 15 days
Time to peak, plasma: 3-4 hours
The X-ray structure of the Donepezil-TcAChE complex shows that Donepezil has unique orientation with active-site
gorge.
Donepezil does not, however, interact directly with either the catalytic triad or the 'oxyanion hole' but only indirectly 7
via solvent molecules

Studies carried out on Donepezil

Cholinesterase inhibitors for patients with Alzheimers Disease: Systematic review of randomised clinical trials BMJ 2005;331;321-327

Side effects of Donepezil Vs Placebo

Cholinesterase inhibitors for patients with Alzheimers Disease: Systematic review of randomised clinical trials BMJ 2005;331;321-327

Mechanism of interaction of Galantamine with Acetylcholinesterase

Absorption of galantamine is rapid and complete and shows linear pharmacokinetics.

It is well absorbed with absolute oral bioavailability between 80 and 100%. It has a half-life of 7 hours.
Galantamine is a competitive and reversible cholinesterase inhibitor.
It is believed it works by enhancing cholinergic function by increasing the concentration of acetylcholine
in the brain.
The structure of the complex of GAL and TcAChE shows that GAL binds at the base of the gorge
interacting with both the acyl-binding pocket and the principal quaternary ammonium-binding site,
the indole ring of Trp-84.

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Studies on Rivastigmine and galantamine

Cholinesterase inhibitors for patients with Alzheimers Disease: Systematic review of randomised clinical trials BMJ 2005;331;321-327

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Side effects of Rivastigmine and Galantamine

Cholinesterase inhibitors for patients with Alzheimers Disease: Systematic review of randomised clinical trials BMJ 2005;331;321-327

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Comparitive Analysis of Donepezil and Galantamine

From the clinical trials, it is evident that Donepezil has a better effect as a
Acetylcholinesterase Inhibitor as compared to Galantamine or Rivastigmine.

However, further research is still on to determine the extent of the beneficial nature of
Donepezil as compared to Galantamine and Rivastigmine.
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