Anticholinesterases inhibit the enzymes acting upon acetylcholine.
They are the inhibitors of Cholinesterases:-
- Acetyl cholinesterase (AchE)
- Butyryl cholinesterase (BChE)
1. Centrally Acting (Used for the treatment of Alzheimer’s Disease)
2. Peripherally Acting
a) Tertiary Amines
b) Quaternary Ammonium Compounds(poor lipid soluble, cannot cross BBB)
Edrophonium (short duration of action, limited Vd)
II. Irreversible (organophosphate compounds)
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)
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:
- Esteretic site-acetylcholine binds
- 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.
The binding of organophosphate compounds with enzyme is tighter, so aging might occur due to:
- loss of alkyl group from this complex
- 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.