INDIRECT ACTING CHOLINOMIMETICS (CHOLINESTERASE INHIBITORS)

1. Cholinesterase inhibitors are of three groups:
   • Alcohols and quaternary ammonium groups (e.g. erdrophonium)
   • Carbamates (e.g. neostigmine)
   • Organophosphates (e.g. echothiophate)

1. These drugs inhibit acetylcholinesterase and bytyrylcholinesterase, leading to increased acetylcholine at cholinoreceptors.
2. Quaternary alcohols (e.g. erdrophonium) bind electrostatically to ACh-ase. Their action is short-lived (2-10 minutes) due to the lack of covalent bonds.
3. Carbamate esters (e.g. neostigmine) have one covalent bond. The hydrolysis process takes correspondingly longer (30 minutes to 6 hours)
4. The organophosphates will form a covalent bond that is initially already very stable, and can further undergo a second step called “aging” that further stabilizes the bond.
   • Pralidoxime (a nucleophile) may be effective as an antidote against organophosphate poisoning if given before the aging process. It acts as a “cholinesterase regenerator”.
5. Organ system effects
   • CNS
     • Increased excitability, leading to convulsions, then coma and respiratory arrest.
   • CVS
     • Increased parasympathetic transmission – bradycardia (negative inotropy, dromotropy and chronotropy)
     • Effect on sympathetic ganglia may cause initial hypertension, but toxic doses cause marked bradycardia, reduced cardiac output and hypotension.
   • Neuromuscular blockade
     • Fasciculations, fibrillations and a depolarizing blockade (akin to Sux) may occur at toxic doses.

Mnemonic for cholinergic symptoms is SLUDGE-M (salivation, lacrimation, urination, defecation, GI upset, emesis and miosis)

The duration of action of cholinesterase inhibiting drugs is as follows:

1. All organophosphates (except echothiophate) are very lipid soluble and therefore can be absorbed through skin/lung/GIT and conjunctiva. They also easily penetrate the CNS.

1. Quaternary carbamates (e.g. erdrophonium, neostigmine and pyridostigmine) are very ionized and not lipid soluble.
2. Tertiary amines (e.g. physiostigmine) may cross the BBB, and are therefore more toxic.
3. All organophosphates are very lipid soluble and will penetrate the CNS.

1. Eye
   • Treatment of acute close angle glaucoma.
   • ACH-ase inhibitors cause contraction of the ciliary body, therefore allowing increased outflow of aqueous humor. Pilocarpine or physiostigmine may be used to treat ACAG.
2. NM junction
   • Erdrophonium is used in the diagnosis of myasthenia gravis.
   • Pyridostigmine or neostigmine may be used in the long term treatment of MG.
   • Neostigmine may also be used to reverse neuromuscular blockade in anaesthesia.
3. GIT/GUT
   • Post-op ileus/urinary retention
4. Others
   • Alzheimer’s disease (donepezil, rivastigmine)

1. Patient usually present with SLUDGE-M symptoms, then convulsions, and then NM blockade.
2. Treatment is as follows:
   • Good supportive care
   • Decontamination (Shower, remove clothes, etc.)
   • Specific antidotes are atropine and pralidoxime. BZDs for seizure.
   • Intubation and ventilation for NM blockade