(2) 26: Direct and Indirect Acting Cholinergic Agonists

What is acetylcholine (ACh)?

• ACh = a neurotransmitter (chemical messenger) that sends signals between nerves or from nerves to target cells.

• ACh produces its effects by binding to cholinergic receptors

Where are the 3 main cholinergic receptor types located?

• Nn → Autonomic ganglia (nerve → nerve) and adrenal medulla.

• Nm → Skeletal muscle at NMJ (nerve → muscle).

• Muscarinic → Parasympathetic target organs.

What are the signaling pathways for muscarinic vs. nicotinic receptors?

• M1, M3, M5 → Gq → ↑ Ca²⁺

• M2, M4 → Gi → ↓ cAMP

• Nn, Nm → Ligand-gated Na⁺/K⁺ ion channels- Depolarization (turning cell on)

• Muscarinic → GPCR (slower)

• Nicotinic → Ion channel (faster)

WHAT ACh DOES TO THE BODY? (OVERALL!)

rest and digest

define Cholinergic agonists

• drugs that produce ACh-like effects.

What are the 2 types of agonists?

• Direct → Binds and activates cholinergic receptors.

  • DIRECT-ACTING MUSCARINIC AGONISTS

• Indirect → Inhibits AChE → ↑ ACh → stimulates muscarinic and nicotinic receptors.

Physiological effects of ACh

Give me the organ with its major receptor and effect.

Organ	Receptor	Effect
Brain (CNS)	M1, M4, M5	Learning memory sleep
Glands	M3 (M1 contributes to saliva)	↑ Saliva, tears, sweat,
Eye	M3	Miosis (Iris sphincter contraction) accommodation (Ciliary muscle contraction) ↓ IOP (Ciliary muscle contraction → ↑ aqueous humor drainage → ↓ IOP)
Heart	M2	↓ heart rate (negative chronotropy), ↓ AV conduction (negative dromotropy), ↓ contractility (negative inotropy).
Blood vessels	M3	Vasodilation through NO
Lungs	M3	Bronchoconstriction ↑ secretions
Urinary bladder	M3	Detrusor contracts + sphincter relaxes → urination
GI tract	M3	Smooth muscle contracts + sphincter relaxes → ↑ digestion and defecation.

Excessive muscarinic activity

Letter	Symptom
D	Diarrhea/defecation
U	Urination
M	Miosis
B	Bradycardia
B	Bronchoconstriction
E	Emesis (vomiting)
L	Lacrimation (tears)
S	Salivation/sweating

DIRECT-ACTING MUSCARINIC AGONISTS

1. Broken into 2 categories

1. Choline esters: Have chemical structures similar to ACh.

   • Acetylcholine, methacholine, carbachol, bethanechol

2. Alkaloids/analogs: Have different chemical structures from ACh.

   • Pilocarpine, cevimeline.

We talk about:

1. Bethanechol 🚽

2. Cevimeline 👄💧

DIRECT-ACTING MUSCARINIC AGONISTS

Bethanechol

• Mainly muscarinic.

• M3 Bladder→ Detrusor contracts + sphincter relaxes → urination.

• Use → Nonobstructive urinary retention, including postoperative/postpartum retention.

  
  

DIRECT-ACTING MUSCARINIC AGONISTS

Cevimeline

• M1/M3 agonist (high M3 affinity) → ↑ saliva

• treats xerostomia (dry mouth) from Sjögren's syndrome.

DIRECT-ACTING MUSCARINIC AGONISTS

Which direct muscarinic drugs resist cholinesterase breakdown, and why?

• bethanechol → Carbamoyl group → resistant to cholinesterase degradation → longer action.

How do you predict muscarinic agonist adverse effects?

Remember DUMBBELS.

• M3 glands → Sweating/salivation.

• M2 heart → Bradycardia.

• M3 lungs → Bronchoconstriction.

• M3 GI → Cramping/diarrhea.

Indirect Cholinergic Agonists

What is the MOA of acetylcholinesterase inhibitors?

Inhibit AChE → ↑ ACh at synapse → prolonged muscarinic AND nicotinic stimulation.

Indirect Cholinergic Agonists

How do direct muscarinic agonists differ from indirect AChE inhibitors in cardiac effects?

• Direct muscarinic → M2 → ↓ HR.

• Indirect moderate dose → Bradycardia.

• Indirect high dose → Paradoxical tachycardia + hypertension from sympathetic/adrenal effects.

Indirect Cholinergic Agonists

What happens at the NMJ with moderate vs. high doses of AChE inhibitors?

• Moderate dose → Fasciculations/tremors.

• High dose → Persistent depolarization → desensitization → flaccid paralysis and possible respiratory collapse.

Indirect Cholinergic Agonists

What are the main classes of AChE inhibitors and example drugs?

• Reversible, very short → Edrophonium.

• Reversible, intermediate → Neostigmine, pyridostigmine, ambenonium.

• Reversible, CNS → Donepezil.

• Irreversible, long → Echothiophate/organophosphates.

Indirect Cholinergic Agonists

Neostigmine

• Inhibits AChE → ↑ ACh at Nm

• reverses nondepolarizing neuromuscular blockade after surgery.

Indirect Cholinergic Agonists

Pyridostigmine

• Inhibits AChE → ↑ ACh at Nm

• improves muscle signaling and strength → myasthenia gravis.

Indirect Cholinergic Agonists

What is myasthenia gravis, and why does pyridostigmine work?

• myasthenia gravis- Autoantibodies interfere with ACh receptors at NMJ → muscle weakness.

• Pyridostigmine → ↑ ACh → stimulates remaining functional receptors → improves strength.

How can you distinguish muscarinic vs. nicotinic adverse effects of AChE inhibitors?

• Muscarinic → Sweating, salivation, bronchial secretions.

• Nicotinic (Nm) → fasciculations, muscle weakness/Cramps,

Organophosphate Poisoning

What is the mechanism of organophosphate poisoning?

Inhibits AChE → ↑ ACh → excessive muscarinic, nicotinic, and CNS stimulation.

Organophosphate Poisoning

What are the symptoms and major cause of death in organophosphate poisoning?

• Muscarinic → DUMBBELS, bronchial secretions.

• Nicotinic → Fasciculations, muscle weakness, paralysis.

• CNS → Confusion, convulsions, coma.

• Major cause of death → Respiratory failure.

Organophosphate Poisoning

Treatment

atropine and pralidoxime

Organophosphate Poisoning

How do atropine and pralidoxime differ?

• Atropine → Muscarinic antagonist → blocks muscarinic symptoms; does NOT reverse Nm paralysis.

• Pralidoxime (2-PAM) → Reactivates AChE before aging → can help reverse nicotinic muscle weakness.

How does direct muscarinic poisoning differ from indirect AChE inhibitor poisoning?

• Direct muscarinic poisoning

  • Mainly muscarinic symptoms (DUMBBELS).

• Indirect AChE inhibitor poisoning

  • Muscarinic + nicotinic symptoms (e.g., weakness/fasciculations); high doses can also cause tachycardia and hypertension.