Study Notes: Cholinergic Agonists

Cholinergic Agonists:

Overview:

• Cholinergic neurons: Primarily found in the parasympathetic system but also involved in sympathetic innervation of sweat glands and blood vessels in skeletal muscle.

• Cholinergic neurotransmission involves six major steps.

Steps of Cholinergic Neurotransmission

1. Choline Uptake

   • Choline is transported into the neuron by an energy- and sodium-dependent transport system.

2. Acetylcholine (ACh) Synthesis

   • Choline reacts with acetyl coenzyme A (Acetyl-CoA) to form acetylcholine.

   • Enzyme: Choline acetyltransferase (ChAT).

3. Storage

   • Acetylcholine is transported into presynaptic vesicles, where it is protected from degradation.

4. Release

   • An action potential opens voltage-sensitive calcium channels → calcium influx → vesicle fusion with membrane → ACh release.

5. Receptor Binding

   • ACh binds to:

     • Postsynaptic receptors → cholinergic response.

     • Presynaptic receptors → inhibits further ACh release (negative feedback).

6. Degradation & Recycling

   • Enzyme: Acetylcholinesterase (AChE) breaks ACh into acetate and choline.

   • Free choline is taken up again by the presynaptic neuron → cycle repeats.

Cholinergic Receptors

Two main types:

1. Muscarinic receptors (M)

2. Nicotinic receptors (N)

Muscarinic Receptors

• Have high affinity for muscarine.

• Five subtypes: M₁–M₅ (functionally defined: M₁, M₂, M₃).

Receptor	Location	G-Protein Type	Effect
M₁	Neurons, gastric glands	Gq	↑ intracellular Ca²⁺ → secretion, neurotransmission
M₂	Cardiac cells	Gi	Opens K⁺ channels → hyperpolarization → ↓ HR
M₃	Smooth muscle (eye, lungs, GI), exocrine glands	Gq	↑ Ca²⁺ → contraction, secretion

Summary:

• M₁/M₃ (Gq) → ↑ Ca²⁺ → contraction/secretion.

• M₂ (Gi) → ↑ K⁺ conductance → ↓ HR.

Nicotinic Receptors

• High affinity for nicotine.

• Ligand-gated ion channels.

• ACh binding → conformational change → Na⁺ influx → depolarization.

Type	Location	Function
Nm	Neuromuscular junction	Muscle contraction
Nn	CNS & autonomic ganglia	Transmission of cholinergic signals

Cholinergic Agonist Drugs

Divided into three groups:

1. Direct-acting

2. Indirect-acting (Reversible)

3. Indirect-acting (Irreversible)

1. Direct-Acting Agonists

• Mimic ACh by binding directly to muscarinic or nicotinic receptors.

Drug	Notes	Uses
Acetylcholine	Nonspecific, rapidly inactivated by cholinesterase → limited use.	Ophthalmic: produce miosis during eye surgery.
Carbachol	Resistant to AChE → longer duration.	Locally in eye surgery → miosis, ↓ intraocular pressure.
Pilocarpine	Acts on eye smooth muscle; ↑ aqueous outflow → ↓ IOP.	Acute glaucoma attacks.
Bethanechol	Selective for urinary & GI tracts.	Urinary retention, GI atony (oral or SC).

2. Indirect-Acting (Reversible) Agonists

• Bind to acetylcholinesterase, preventing ACh breakdown → accumulation of ACh in synapse.

Drug	Duration	Notes	Uses
Edrophonium	Very short (10–20 min)	Reversibly binds AChE	Diagnosis of myasthenia gravis (↑ muscle strength after admin).
Physostigmine	Intermediate (30 min–2 hr)	Stimulates both N & M receptors; crosses BBB.	Antidote for anticholinergic overdose (e.g., Atropine).
Neostigmine	Intermediate; more polar → no CNS entry.	Poor GI absorption.	Myasthenia gravis, stimulate bladder/GI, reverse NM blockade.
Pyridostigmine	Similar to Neostigmine; longer acting.	—	Maintenance therapy for myasthenia gravis.
Donepezil, Rivastigmine, Galantamine	Central-acting agents.	Enhance cholinergic function in CNS.	Alzheimer’s disease (symptomatic relief only).

3. Indirect Acting (Irreversible) Agonists

• Form covalent bonds with AChE → long-lasting enzyme inhibition.

• Many are toxic nerve agents (e.g., Sarin gas).

Drug	Notes	Use
Echothiophate	Long acting; causes strong cholinergic stimulation.	Rarely used; open-angle glaucoma only (due to side effects).

Adverse Effects of Cholinergic Agonists

Caused by overstimulation of cholinergic receptors.

Mnemonic: DUMBBELLS

Effect	Description
D	Diarrhea
U	Urination
M	Miosis, Muscle weakness
B	Bronchorrhea
B	Bradycardia
E	Emesis
L	Lacrimation
L	Lethargy (sometimes listed as salivation/secretions)
S	Salivation

Major Takeaways:

• AChE inhibitors ↑ ACh at synapse → enhanced parasympathetic tone.

• M₁, M₂, M₃ receptors mediate most clinically relevant effects.

• Direct agonists act on receptors; indirect inhibit breakdown of ACh.

• Reversible inhibitors used therapeutically; irreversible often toxic.

• DUMBBELLS mnemonic helps recall major side effects.