Indirect Cholinergic Agonists

Indirect Cholinergic Agonists

• Indirect cholinergic agonists are covered, including their classification, mechanism of action, and uses.
• Organophosphorus poisoning is also addressed.

Cholinesterase Types

• True Cholinesterase (ChE):
  • Found in ganglia, neuromuscular junctions (NMJ), and the central nervous system (CNS).
  • Specifically metabolizes acetylcholine (Ach).
  • Deficiency is fatal, regenerates in 2-3 months.
• Pseudo Cholinesterase (ChE):
  • Located in plasma and the liver.
  • Metabolizes Ach and other drugs like succinylcholine.
  • Deficiency is not fatal, regenerates in 2-3 weeks.

Indirect-Acting Parasympathomimetic Drugs

• These drugs are cholinesterase inhibitors.
• Reversible Inhibitors:
  • Physostigmine
  • Neostigmine
  • Pyridostigmine
  • Donepezil
• Irreversible Inhibitors:
  • Organophosphate compounds

Physostigmine

• Derived from a natural plant alkaloid and is a tertiary amine.
• Well-absorbed from the gastrointestinal tract (GIT).
• Capable of crossing into the CNS.
• It is a reversible cholinesterase inhibitor, increasing endogenous Ach, which affects muscarinic (M) and nicotinic (N) receptors.
  • It is used to treat glaucoma (as eye drops) and as an antidote for atropine poisoning.

Neostigmine

• Synthetic and a quaternary ammonium compound.
• Poorly absorbed from the GIT.
• Cannot pass into the CNS.
• It is a reversible cholinesterase inhibitor, increasing endogenous Ach, which affects M and N receptors. -Directly stimulates Nm receptors at the NMJ.
  • It is used to treat myasthenia gravis, post-operative retention of urine, post-operative paralytic ileus, and as an antidote to D-tubocurarine.

Neostigmine Substitutes

• Pyridostigmine:
  • Has a longer duration of action than neostigmine.
  • More selective on the NMJ than neostigmine.
  • Used to treat myasthenia gravis.
• Edrophonium:
  • Very short-acting (5 minutes).
  • More selective on the NMJ than neostigmine.
  • Used for the diagnosis of myasthenia gravis.

Central Cholinesterase Inhibitors

• Donepezil and Rivastigmine:
  • Can cross the blood-brain barrier.
  • Increases acetylcholine levels at central cholinergic synapses.
  • Used to treat Alzheimer's disease and improve cognitive functions.

Organophosphorus Compounds

• Examples:
  • Echothiophate (eye drops for glaucoma)
  • Insecticides like parathion and malathion
  • Nerve gases like sarin and soman
• Highly lipid-soluble and rapidly absorbed through all routes, including the skin.
• Exhibits rapid CNS penetration.
• Irreversibly inhibits cholinesterase, leading to increased endogenous Ach at synapses and severe muscarinic and nicotinic symptoms.
• Aging of the ChE enzyme results in complete enzyme inhibition, with the bond strengthening within 12 hours.

Manifestations of Organophosphate Poisoning (Toxicity)

• Diarrhea
• Urination
• Miosis
• Bradycardia
• Bronchospasm
• Lacrimation, salivation, and sweating
• Emesis, excitation of the CNS (hallucinations, convulsions, and coma)
• Skeletal muscle twitches and paralysis
• Respiratory failure is the main cause of death, due to blocked airway, paralyzed respiratory muscles, and inhibited respiratory center (RC).

Treatment of Organophosphate Toxicity

1. Ensure a patent airway and provide artificial respiration.
2. Perform a stomach wash and skin wash.
3. Administer intravenous normal saline to raise blood pressure (BP).
4. Administer the following drugs:
   • Atropine: Antagonizes peripheral and central muscarinic manifestations, and should be given in high doses.
   • Pralidoxime: A cholinesterase re-activator that dephosphorylates the ChE, effective only before enzyme aging (within 12 hours).
   • Diazepam: Used to control convulsions.