Anticholinesterases

Anticholinesterases inhibit the enzymes acting upon acetylcholine.

They are the inhibitors of Cholinesterases:-

• Acetyl cholinesterase (AchE)
• Butyryl cholinesterase (BChE)

Classification

1. Centrally Acting (Used for the treatment of Alzheimer’s Disease)

Tacrine
Donepezil
Rivastigmine
Galanthamine

2. Peripherally Acting

I.    Reversible 

1.  Carbamates:

a) Tertiary Amines

Physostigmine

b) Quaternary Ammonium Compounds(poor lipid soluble, cannot cross BBB)

Neostigmine

Pyridostigmine

Ambenonium

Distigmine

Demecarium

2.  Alcohols:

Edrophonium (short duration of action, limited Vd)

II.   Irreversible (organophosphate compounds)

1.   Insecticides:

Dyflos
Diisopropyl fluorophosphates (DFP)
Tetra  methyl pyrophosphate (TMPP)
Octa methyl pyrophosphotetraamide (OMPA)
Parathion (highly dangerous for human race, not converted into non-toxic metabolites)
Malathion (toxic in insects, with vertebrates form non-toxic metabolites but have toxic effects in fish)

2.         War gases(banned by Geneva accord)

Sarin
Tabun
Soman

3.   Therapeutically useful drugs:

Echothiophate (topical application for glaucoma, chronic use not recommended as after 6 months may cause cataracts, it does not cross BBB)

Mechanism of Action

Acetylcholine is acted upon esterase enzyme. When the ligand binds, only specific region is involved. Acetylcholine esterase has two binding sites:

1. Esteretic site-acetylcholine binds
2. Peripheral anionic site

Once acetylcholine binds, it is acetylated. By addition of water, choline and acetic acid are produced. Hence the active site is available once again.

When alcohols bind the active site, bond produced is weak hydrogen and electrostatic. They are readily washed away. The hydration of bond becomes easy. Thus the duration of action is hardly 2-6 minutes.

Carbamates-like neostigmine and physostigmine have carbamyl group. The carbamyl group is transferred to the active site of the enzyme, thus stronger bond is produced. Their duration of action is 30 minutes to 6 hours. They cannot be rapidly hydrolyzed.

Organophosphates phosphorylate the active site. The bond produced is strong covalent. Thus the duration of action is several days to weeks.

Aging

The binding of organophosphate compounds with enzyme is tighter, so aging might occur due to:

1. loss of alkyl group from this complex
2. loss of oxygen phosphorus may take place

which might lead to stronger bond, producing highly irreversible bonds.

Enzymes known as oximes are used to revert aging in these cases, but within specific time.

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Neostigmine

Physostigmine

Pyridostigmine, Edrophonium and Echothiophate

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