Cholinergic Agonists

Cholinergic Agonists: Overview & Receptors - Acetylcholine's Allies

• Acetylcholine (ACh): Primary neurotransmitter in PNS; also CNS.
  • Synthesis: Choline + Acetyl CoA (by ChAT).
  • Degradation: Rapidly by Acetylcholinesterase (AChE).
• Cholinoceptor Types:
  • Muscarinic (M): GPCRs; 5 subtypes (M1-M5).
    • M1 ("Neural"): CNS, enteric nerves; Gq. 📌 "M1 CNS Gq"
    • M2 ("Cardiac"): Heart (↓HR, ↓force); Gi. 📌 "M2 Heart Gi"
    • M3 (Glands/Smooth Muscle): Glands, SM, eye (miosis); Gq. 📌 "M3 Glands/Smooth Gq"
  • Nicotinic (N): Ligand-gated ion channels; rapid Na+/K+ influx.
    • Nn: Autonomic ganglia, adrenal medulla, CNS.
    • Nm (Muscle): Skeletal neuromuscular junction (NMJ).

⭐ Bethanechol (direct M-agonist) treats urinary retention (post-op, neurogenic) via M3 action on bladder detrusor.

Direct-Acting Cholinergic Agonists - Receptor Rockstars

• Directly activate Muscarinic (M) / Nicotinic (N) receptors.
• Bethanechol: 📌 "Bethanechol for Bowels & Bladder"
  • M3 selective. Uses: Post-op ileus, urinary retention.
  • Resistant to AChE.
• Pilocarpine:
  • M3 agonist. Tertiary amine (CNS entry possible).
  • Uses: Glaucoma (open-angle, acute angle-closure), Sjögren's (xerostomia).

  ⭐ Pilocarpine rapidly induces miosis, opening trabecular meshwork to ↓ Intraocular Pressure (IOP) in acute angle-closure glaucoma.

• Carbachol:
  • M + N agonist.
  • Uses: Glaucoma, surgical miosis. Resistant to AChE.
• Methacholine:
  • M3 agonist. Use: Asthma diagnosis (bronchial challenge test).
• Cevimeline:
  • M3 selective. Use: Sjögren's syndrome (dry mouth/eyes).
• Side Effects (DUMBBELSS): Diarrhea, Urination, Miosis, Bronchoconstriction, Bradycardia, Emesis, Lacrimation, Salivation, Sweating. Treat with Atropine (muscarinic antagonist).

Indirect-Acting Reversible Cholinergic Agonists - Signal Boosters

• Mechanism: Inhibit acetylcholinesterase (AChE) enzyme → ↑acetylcholine (ACh) concentration at cholinergic synapses.
• Key Drugs & Specifics:
  • Physostigmine: Tertiary amine (crosses BBB). Uses: Atropine overdose, glaucoma.
  • Neostigmine: Quaternary amine (no CNS). Uses: Myasthenia Gravis (MG), postoperative ileus/urinary retention, reversal of non-depolarizing muscle relaxants.
  • Pyridostigmine: Quaternary amine. Longer duration. Use: MG (chronic management).
  • Edrophonium (Tensilon): Quaternary amine. Short-acting (diagnostic). Use: MG diagnosis (Tensilon test).
  • Alzheimer's Disease Drugs: Donepezil, Rivastigmine, Galantamine (CNS active, improve cognitive function).
• Adverse Effects: Cholinergic crisis (DUMBELS: Diarrhea, Urination, Miosis, Bronchospasm/Bradycardia, Emesis, Lacrimation, Salivation/Sweating). Antidote: Atropine.
• 📌 Mnemonic (Neostigmine uses): No Mystery Please - Neostigmine for Myasthenia, Post-op ileus/urinary retention.

⭐ Physostigmine is the drug of choice for treating poisoning with atropine or other antimuscarinic drugs due to its ability to cross the blood-brain barrier and antagonize central anticholinergic effects.

Indirect-Acting Irreversible Cholinergic Agonists & Toxicity - Deadly Duty

• Examples: Organophosphates (Malathion, Parathion, Diazinon), Nerve gases (Sarin, Soman). Echothiophate (rarely for glaucoma).

• Mechanism: Irreversibly phosphorylate acetylcholinesterase (AChE) → ↑Acetylcholine (ACh) at all sites.

  • "Aging": Enzyme-inhibitor complex strengthens over time, rendering oximes (e.g., Pralidoxime) ineffective.

• Toxicity (Cholinergic Crisis):

  • Muscarinic: 📌 DUMBBELSS: Diarrhea, Urination, Miosis (pinpoint pupils), Bronchospasm/Bronchorrhea, Bradycardia, Emesis, Lacrimation, Salivation/Sweating.
  • Nicotinic: Muscle fasciculations, weakness, paralysis (can lead to respiratory failure).
  • CNS: Agitation, confusion, seizures, coma.

• Management:

  • Atropine: Muscarinic antagonist. Titrate to dry secretions, HR > 80/min. Does not reverse paralysis.
  • Pralidoxime (PAM): AChE reactivator. Crucial before "aging" of enzyme complex. Primarily for nicotinic effects.
  • Diazepam: For seizures. Supportive ventilation often vital.

• ⭐ > Atropine reverses muscarinic and CNS effects of organophosphate poisoning but NOT nicotinic effects like muscle paralysis. Respiratory support is critical.

High‑Yield Points - ⚡ Biggest Takeaways

• Direct agonists (e.g., Pilocarpine, Bethanechol) stimulate muscarinic/nicotinic receptors.
• Indirect agonists (AChE inhibitors) like Neostigmine ↑ACh by blocking its breakdown.
• Pilocarpine: treats glaucoma (↑outflow) and xerostomia (Sjögren's).
• Bethanechol: for postoperative ileus and urinary retention (atonic bladder).
• Myasthenia gravis: treat with Neostigmine/Pyridostigmine; diagnose with Edrophonium.
• Organophosphate poisoning (irreversible AChE block): SLUDGEM; treat with Atropine + Pralidoxime.
• Physostigmine (crosses BBB): antidote for central anticholinergic toxicity (atropine overdose).