INDIRECTLY ACTING CHOLINERGIC STIMULANTS(AGONISTS)
These are the drugs enhancing cholinergic activities indirectly by inhibiting the enzyme acetylcholinesterase (which is responsible for hydrolyzing and inactivating acetylcholine) and thereby enhancing the acetylcholine activities.
There are two types of enzyme inhibitors as follows:-
A.IRREVERSIBLE INHIBITORS(PESTICIDE POISONING)
The followings are a few examples:-
1.Isoflurophate
2.Echothiophate
3.Parathion
All the above examples belong to a chemical group of organophosphates the pesticide poisons. Most of the pesticides contain organophosphates and are used for suicidal self-poisoning or careless accidental poisoning. In the olden days, these compounds are used in wars as nerve gases.
Organophosphates are very powerful and cause serious side effects as they irreversibly inactivate the enzyme acetylcholinesterase by forming covalent bonds. This will cause prolonged and overactivity of acetylcholine causes serious cholinergic crisis such as
1.Respiratory depression(Bronchoconstriction and increased secretions)
2.Bradycardia(depressed heart rate)
3.Diarrhea
4.Enuresis(Involuntary urination)
5.Over sweating
6.Blurred vision(Miosis)
and all the already elucidated DUMBELS cholinergic crisis leads to death.
These covalent bonds are mostly irreversible yet if a cholinesterase reactivator such as pralidoxime is given immediately along with a muscarinic antagonist like atropine in order to avoid phosphorylation of the enzyme irreversibly. Pralidoxime act immediately at bonding reaction between the active site of the enzyme and the phosphate radical of the drug. This action prevents the aging of the bond to become irreversible and the phosphate radical would easily be removed from the enzyme which becomes active again.
Treatments of organophosphates pesticide poisoning need immediate hospitalization with blood samples for assays to estimate the level of inactivation of the enzyme. The loss of fluids and electrolytes due to diarrhea should be compensated. Respiration should be monitored and corrected by giving appropriate respiratory stimulants.
Atropine should be given according to the doctor's advice along with the enzyme reactivators.
Uses
Very rarely these compounds are used in glaucoma, accommodative esotropia (Crossed Eye)
B.REVERSIBLE INHIBITORS
1.Edrophonium (short-acting)
2.Physostigmine
3.Neostigmine
4.Pyridostigmine
All the above are natural and synthetic alkaloids. Physostigmine occurs naturally in Calabar beans(Physostigma venenosum)
Unlike organophosphates, these compounds have not inactivated the enzyme irreversibly. They do not form covalent bonds with the enzyme. Hence they have some therapeutic values.
A.Physostigmine
1.Second choice of drug in glaucoma after pilocarpine
2.Used to counteract an overdose of atropine, phenothiazines, and tricyclic antidepressants.
3.Used in intestinal atony.
Side effects:-
Physostigmine can cross CNS as it is a tertiary amine(unionized), can cause convulsions. Other effects are similar to DUMBELS
B.Neostigmine
Neostigmine is a synthetic alkaloid similar to physostigmine but it will not enter into CNS by crossing the blood-brain barrier as it is a quaternary carbamate compound forms highly polarized hydrophilic positive quaternary ammonium ion.
Use
1. This is the drug of choice in the treatment of myasthenia gravis the neuromuscular disease in which muscle weakness and fatigue manifest.
2.Treating urinary retention
3.Treating paralysis of the small intestine(paralytic ileus)
4.The antidote for tubocurarine poisoning.
Neostigmine is acting a short course of action when compared with physostigmine usually of 2 to 4 hours
Side effects:-
DUMBELS
C.Edrophonium
Edrophonium is similar to neostigmine and its a course of action is very shorter than neostigmine such as 5 to 15 minutes.
Because of this edrophonium is not used in maintenance therapy but can be as a diagnostic agent to differentiate myasthenia gravis from the cholinergic crisis. Both conditions can bring muscle weakness but administration of edrophonium may improve myasthenia gravis but worsens the cholinergic crisis.
Side effects:-
DUMBELS
C.Pyridostigmine
Its duration of action is 3 to 6 hours.
Used conveniently in myasthenia gravis
Side effects:-
DUMBELS
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