Cholinergic Agonists – Study Notes

Cholinergic agonists mimic the action of acetylcholine (ACh).

They act on muscarinic or nicotinic receptors and are classified as:

1. Direct-acting agonists – directly activate cholinergic receptors.

2. Indirect-acting agonists (anticholinesterases) – inhibit acetylcholinesterase (AChE), increasing the availability of ACh at receptor sites.

Autonomic Nervous System Review

System	Origin	Major Neurotransmitter	Receptors
Parasympathetic	Cranial & sacral spinal cord	Acetylcholine	Nicotinic (ganglia) & Muscarinic (organs)
Sympathetic	Thoracic & lumbar spinal cord	Norepinephrine (NE)	Adrenergic (organs), Muscarinic (sweat glands)

Adrenal medulla: Sympathetic innervation → secretes epinephrine (Epi) and norepinephrine (NE) directly into circulation.
Renal vascular smooth muscle: Dopamine is the neurotransmitter.

Dominant tone at rest:

• Sympathetic: Arterioles, veins, sweat glands

• Parasympathetic: Most other organs

Clinical principle:

Blocking the dominant system produces a noticeable physiological effect.

Neurotransmission of Acetylcholine (ACh)

Synthesis

• Choline is transported into the neuron by a Na⁺-dependent choline symporter.

• Choline acetyltransferase catalyzes formation of ACh from choline + acetyl-CoA.

Storage & Release

• ACh is stored in vesicles via an ACh-H⁺ antiporter.

• Depolarization → voltage-gated Ca²⁺ channels open → vesicles fuse with the membrane → ACh released into synaptic cleft.

Fate of Released ACh

1. Binds to postsynaptic receptors (nicotinic or muscarinic).

2. Autoreceptors can reuptake ACh for feedback control.

3. AChE rapidly breaks down ACh → acetate + choline.

Cholinergic Receptors

Receptor Type	Location	Mechanism	Effect
M1	CNS, gastric parietal cells	Gq → ↑ IP₃/DAG, ↑ Ca²⁺	Cognitive, gastric acid secretion
M2	Heart	Gi → ↓ cAMP, opens K⁺ channels	↓ HR, ↓ conduction
M3	Smooth muscle, glands, endothelium	Gq → ↑ IP₃/DAG, ↑ Ca²⁺	Contraction, secretion, NO release
Nm	Neuromuscular junction	Na⁺/K⁺ depolarization channel	Skeletal muscle contraction
Nn	Autonomic ganglia, CNS	Na⁺/K⁺ depolarization channel	Transmission in ganglia

Effects of Cholinergic Stimulation

Organ/System	Receptor	Effect
Eye (M3)	Sphincter contraction → miosis; Ciliary contraction → accommodation for near vision
Heart (M2)	↓ SA node firing, ↓ AV conduction, mild ↓ contractility
Vessels (M3)	Vasodilation via NO (though few cholinergic nerves)
Lungs (M3)	Bronchoconstriction, ↑ glandular secretions
GI tract (M3)	↑ motility, relaxation of sphincters, ↑ secretion
Bladder (M3)	Detrusor contraction, trigone/sphincter relaxation → urination
Glands (M3)	↑ salivation, lacrimation, sweating, nasal secretions

Key Terms

Term	Definition
Cholinomimetic	Drug that mimics ACh action (directly or indirectly)
Anticholinesterase	Inhibits AChE → ↑ ACh availability
Anticholinergic	Blocks ACh action at receptors
Antimuscarinic	Blocks muscarinic receptors
Antinicotinic	Blocks nicotinic receptors
Bradycardia	↓ SA node firing (slow HR)
Tachycardia	↑ SA node firing (fast HR)

Choline Esters (Direct-Acting Agonists)

Drug	Structure / Modification	Cholinesterase Susceptibility	Muscarinic Activity	Nicotinic Activity	Notes
Acetylcholine	Acetic acid + choline	Very high	Yes	Yes	Rapidly degraded; used topically in eye surgery
Methacholine	β-methyl group	Slight	Strong	None	Used in asthma diagnosis
Carbachol	Carbamic acid	Resistant	Yes	Yes	Used for glaucoma (topical)
Bethanechol	Carbamic acid + β-methyl group	Resistant	Yes	None	Oral drug for urinary retention & neurogenic bladder

Note:

• β-methyl group prevents nicotinic binding (→ purely muscarinic).

• Carbachol has mixed actions and is not used systemically (due to nicotinic stimulation and BP changes).

• Bethanechol is the only oral choline ester available.

Alkaloid Cholinergic Agonists

Drug	Receptor Type	Key Use
Pilocarpine	Muscarinic	Glaucoma, xerostomia
Nicotine	Nicotinic	Smoking cessation
Lobeline	Nicotinic	Experimental, rarely used

Indirect-Acting Cholinergic Agonists (AChE Inhibitors)

Mechanism: Inhibit AChE → prolong ACh action at receptors.

Major Agents

Drug	Type	CNS Penetration	Clinical Use
Donepezil	Reversible	Crosses BBB	Alzheimer’s disease
Rivastigmine	Pseudo-irreversible	Crosses BBB	Alzheimer’s, dementia
Galantamine	Reversible	Crosses BBB	Alzheimer’s; also stimulates nicotinic receptors
Neostigmine	Reversible	No	Myasthenia gravis, urinary retention
Pyridostigmine	Reversible	No	Long-acting MG management
Physostigmine	Reversible	Yes	Anticholinergic poisoning
Edrophonium	Short-acting	No	Diagnosis of MG
Echothiophate	Irreversible (organophosphate)	Minimal	Chronic glaucoma (topical)

Clinical Correlations

1. Glaucoma

• M3 agonists (e.g., pilocarpine) contract ciliary muscle → opens canal of Schlemm → ↓ intraocular pressure.

2. GI Disorders

• M3 agonists increase motility → helpful in atony or paralytic ileus.

• M3 blockers used for diarrhea or excessive motility.

3. Urinary Retention

• Bethanechol stimulates detrusor contraction and sphincter relaxation.

4. Alzheimer’s Disease

• Donepezil, Rivastigmine, Galantamine ↑ ACh in CNS → mild cognitive improvement.

5. Myasthenia Gravis

• Neostigmine, Pyridostigmine increase neuromuscular transmission.

• Edrophonium used for diagnostic testing.

Clinical Precautions

Condition	Concern with Cholinergic Agonists
Asthma/COPD	Bronchoconstriction (avoid M3 agonists)
Bradycardia or AV block	Exacerbates conduction slowing
Peptic ulcer	Increases gastric acid secretion
Hyperthyroidism	May trigger arrhythmias

Disorders Related to ACh Transmission

• Lambert-Eaton Myasthenic Syndrome: Autoantibodies against presynaptic Ca²⁺ channels → ↓ ACh release → muscle weakness.

• AV Nodal Block: Excessive M2 stimulation → slow conduction between atria and ventricles.

Key Takeaways

• Direct agonists = bind to and activate receptors.

• Indirect agonists = inhibit ACh breakdown (↑ ACh availability).

• Bethanechol → urinary retention.

• Pilocarpine → glaucoma, dry mouth.

• Donepezil / Rivastigmine / Galantamine → Alzheimer’s.

• Neostigmine / Pyridostigmine → myasthenia gravis.