Thursday, April 9, 2015

Study group discussion: Pathological basis of drugs used in the treatment of Alzheimers disease

Discussion on drugs for Alzheimer's.

What is the basic pathology in Alzheimers disease?

Amyloid deposition in the Ach neurons. Hence, decrease acetylcholine in the brain.

Amyloid precusor proteins in the circulation are acted upon by two enzymes -
Alpha secretase: Which forms soluble proteins. These are good.
Beta gamma secretase: Which forms insoluble proteins. These are bad.

These insoluble proteins polymerise to form the plaque. So these insoluble plaque get preferentially deposited in Ach neurons and cause a foreign body reaction.. Leading to inflammation and death of neurons. Hence Alzheimers.

How alpha secretase is good?

Cause it cause soluble products.. These can be washed out by blood. The insoluble ones will precipitate.

There are 5 classes of drugs.. Guess their mechanism based on the pathology discussion!

First class: AchE inhibitors. How do they help?

They will inhibit break down of Ach.. Indirectly, increasing their levels.
Donepezil, Rivastigmine and Galantamine are examples.
They are lipid soluble and cross the blood brain barrier easily. They are also called centrally acting anticholinesterase.

Interesting fact: Nicotine acts both presynaptic and post synaptically to release Ach hence smoking is thought to be protective against AD. However, one of the hypothesis for AD is free radical damage, which can be caused by smoking.

Second class: A drug which will increase activity of alpha secretase.

The name for this drug is deprenyl.

Third class: A drug that inhibits beta secretase.

Beta- gamma secretase has got an inhibitor called tarenflurbil.

Fourth class: These are primary drugs. Inhibit polymerization.

Drug named Tramiprostate

Fifth class: This one removes the pre formed polymers.

Bapineuzumab is the drug.

I love the way you explain things. Starting right from basics!

Extras -

Glutamate antagonists - Memantine. How would antagonism of glutamate help?

Block glutamate excitotoxicity.

Related post: Drugs used in the treatment of Alzheimers disease

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