Muscarinic Receptors

A Study Notes

• Muscarinic receptors are G protein–coupled receptors (GPCRs) activated by acetylcholine (ACh).

• Found primarily in parasympathetically innervated organs.

• They mediate “rest and digest” effects: slowing the heart, stimulating digestion, bladder emptying, salivation, and pupil constriction.

Two Pharmacological Subtypes

Type	Genes	G-protein coupling	Effect
M1-type	m1, m3, m5	Gq/11	Activates phospholipase C, ↑IP3, ↑DAG, ↑Ca²⁺ → contraction/secretion
M2-type	m2, m4	Gi/o	↓cAMP, opens K⁺ channels → inhibition, hyperpolarization

Key Locations and Physiologic Effects

Organ/System	Receptor Type	Effect
Eye	M3	Miosis (pupil constriction), ciliary muscle contraction → ↑aqueous humor outflow
Heart	M2	↓SA/AV node rate, ↓contractility (bradycardia)
Lungs	M3	Bronchoconstriction, ↑bronchial secretions
GI tract	M3	↑Tone and motility, ↑secretions
Bladder	M3	Detrusor contraction → voiding
Glands	M3	↑Salivation, ↑sweating, ↑lacrimation
Blood vessels	M3 (endothelium)	Vasodilation via NO release, may cause flushing/hypotension

Therapeutic Indications (Muscarinic Agonists)

Target	Clinical Use	Example Drugs
Eye	Glaucoma (↑aqueous humor drainage)	Pilocarpine, Carbachol
GI tract	Post-op GI atony, distention	Bethanechol
Bladder	Atony, urinary retention	Bethanechol (Urecholine)
Glands	Sjögren’s syndrome, dry mouth	Pilocarpine, Cevimeline
Stomach	Reflux (↑LES tone)	Bethanechol

Problems & Contraindications

EYE

• Excess miosis → blurred vision, poor night vision, watery eyes

HEART

• Bradycardia, heart block → contraindicated in heart failure or AV node disease

LUNGS

• Bronchoconstriction, excess mucus → contraindicated in asthma and COPD

GI TRACT

• Diarrhea, cramping, belching → avoid in peptic ulcer disease

STOMACH

• Increased acid secretion → may aggravate ulcers

GLANDS

• Excess sweating, salivation, tearing

BLOOD VESSELS

• Hypotension, flushing (NO-mediated vasodilation)

BLADDER

• Normal Action: Contracts detrusor muscle, relaxes sphincter → promotes urination.

• Therapeutic Use: To relieve urinary retention from bladder atony.

• Problems:

  • Incontinence if bladder tone > sphincter control

  • Pain and swelling if obstruction exists (risk of urinary rupture or reflux)

• Contraindications:

  • Mechanical obstruction (e.g., stones, prostate hypertrophy)

  • Post-surgical bladder wall weakness

  • Severe bradycardia or hypotension (systemic muscarinic effect)

Clinical Note: Giving a muscarinic agonist like Bethanechol to a patient with a blocked bladder outlet can cause agonizing suprapubic pain, swelling, and urinary retention with high intravesical pressure, risking renal reflux.

Key Muscarinic Drugs

Drug	Mechanism / Features	Clinical Notes
Acetylcholine (Miochol)	Non-selective agonist; activates nicotinic + muscarinic; rapid hydrolysis by AChE	Used intraocularly for miosis during surgery
Methacholine	Diagnostic bronchial challenge (tests airway hyperreactivity)	Contraindicated in asthma outside testing
Carbachol (Miostat)	Resistant to AChE; nicotinic + muscarinic	Used topically for glaucoma
Bethanechol (Urecholine)	Muscarinic selective, long-acting, no nicotinic action	For urinary retention and post-op ileus
Pilocarpine	Plant alkaloid, muscarinic-selective	For glaucoma, xerostomia (dry mouth)
Cevimeline (Evoxac)	M1-selective, synthetic	Used in Sjogren’s syndrome
Muscarine	From mushrooms; prototype toxin	Causes sweating, salivation, bradycardia, diarrhea (toxic)

Acetylcholine Synthesis & Release Pathway

1. Choline uptake via CHT (Choline transporter)

2. ACh synthesis by Choline acetyltransferase (ChAT)

3. Vesicular storage via VAT (vesicular ACh transporter)

4. Release triggered by Ca²⁺-dependent exocytosis, involving VAMP and SNAPs proteins

5. Inactivation: Rapid breakdown by acetylcholinesterase (AChE) → choline recycled

6. Inhibition: Presynaptic M2 autoreceptors reduce ACh release when overactive

Nicotinic vs Muscarinic Comparison

Feature	Nicotinic	Muscarinic
Type	Ligand-gated ion channel	G-protein–coupled receptor
Sites	Skeletal muscle (Nm), ganglia/adrenal medulla (Nn)	Smooth muscle, glands, heart
Response	Fast depolarization (Na⁺/K⁺)	Slow, modulatory, enzyme-linked
Agonist Example	Nicotine	Muscarine, Bethanechol
Antagonist Example	Curare	Atropine

Clinical Integration (ICU/Anesthesia Context)

• Bradycardia during anesthesia: Muscarinic agonists worsen it; Atropine (antagonist) is given to reverse.

• Bladder management post-surgery: Bethanechol may be used for atony but must rule out obstruction first.

• Secretions in intubated patients: Excess cholinergic activity increases salivation and bronchial secretions, risking aspiration.

• Pupil effects: Miosis from muscarinic agonists may complicate neurological exams in sedated ICU patients.