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Indirectly acting cholinergic agents

These drugs inhibit the metabolism of acetylcholine and thereby increase Ach levels at synaptic cleft enhancing cholinergic transmission. As they are not directly acting on cholinergic receptor instead increase the action of acetylcholine they are called as indirectly acting parasympathomimetics.

Since they inhibit acetylcholinesterase enzyme they also named as cholinesterase inhibitors or anticholinesterases.

Based on the duration of the action and reversibility of their action, these drugs can be classified into three categories

  • Reversible
    • Short acting
    • Medium acting
  • Irreversible
    • Long acting
classification of cholinesterase inhibitors

Short acting

Edrophonium is one of the short acting drug with duration of action around 10 min.

structure of edrophonium

Medium acting

Drugs like physostigmine, neostigmine and pyridostigmine are medium acting cholinesterase inhibitors.

Among these, physostigmine is a natural alkaloid obtained from dried seeds of physostigma veninosum.Chemically it belongs to pyrroloindole alkaloids which you can observe in its structure.

structure of physostigmine

On the other hand, neostigmine and pyridostigmine are synthetic derivatives. Neostigmine has substituted aniline ring with carbamate moiety.

stucture of neostigmine

Similarly, pyidostigmine has pyridine ring with carbamate moiety.

structure of pyridostigmine

One of the common structural feature in all these compounds is carbamate group either with monoalkyl or dialkyl substitution on nitrogen.

You can find these drugs by the suffix stimgine in all these names. As the two synthetic agents are the structural relatives of the natural product physostigmine, they share the same suffix in their names.

Long acting

These drugs produce irreversible inhibition of acetylcholinesterase enzyme hence long acting. Dyflos is one of the drug with inorganic fluorine atom that acts as leaving group in the compound.

structure of dyflos

All other drugs are organophosphates with an organic group attached through sulfur or oxygen. Ecothiopate is such a drug with quaternary ammonium alkyl chain present as organic group.

structure of organophosphates

Why pesticides are neurotoxic?
Chemically pesticides belong to carbamates,organochlorines or organophosphates. All these are toxic substances and particularly organophosphates can produce irreversible block of cholinesterase not only in the periphery but also in the CNS. This leads to loss of neuronal activity, desensitization and profound neurotoxicity.

The duration of action of cholinesterases can be summarised in the following table.

Drug Duration of action
Edrophonium10-20 min
Neostigmine30 min – 2 hr
Physostgmine2-4 hr
Pyridostimgine3-6 hr
Ambenonium4-8 hr
Ecothiopate1 week

In the next section, let's see how the block of cholinesterase activity is related with duration of action of these drugs.

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