← Back to Part 5

5.2 Cholinergic Drugs (Parasympathomimetics)

Cholinergic drugs enhance parasympathetic activity either by directly activating muscarinic/nicotinic receptors (direct-acting) or by inhibiting acetylcholinesterase to increase ACh availability (indirect-acting). They are used for glaucoma, myasthenia gravis, Alzheimer's disease, and postoperative conditions.

Direct-Acting Cholinergic Agonists

Choline Esters

Quaternary ammonium compounds - poor CNS penetration, hydrolyzed by cholinesterases (except carbachol, bethanechol)

Acetylcholine (ACh)

Receptors: All muscarinic and nicotinic (non-selective)

Use: Rarely used clinically (rapid hydrolysis by AChE). Ophthalmic surgery (miosis)

Effects: ↓ HR, vasodilation, bronchoconstriction, ↑ GI/bladder motility, miosis, salivation

Bethanechol

Receptors: Muscarinic (M3) selective, resistant to cholinesterases

Uses: Postoperative urinary retention, neurogenic bladder, GERD (↑ LES tone)

Adverse: Diarrhea, salivation, sweating, bradycardia (rare at therapeutic doses)

Carbachol

Receptors: Muscarinic + nicotinic, resistant to cholinesterases

Use: Glaucoma (miosis, ↑ aqueous humor outflow), intraocular surgery

Naturally Occurring Alkaloids

Tertiary amines - good CNS penetration, resistant to cholinesterases

Pilocarpine

Receptors: M3>M2, M1 (muscarinic partial agonist)

Uses: Glaucoma (topical, miosis + ↑ outflow), xerostomia (SjΓΆgren's syndrome, radiation-induced dry mouth)

Effects: Profuse sweating, salivation, lacrimation, miosis

Muscarine

Source: Mushrooms (Amanita muscaria, Inocybe)

Note: Not used clinically; prototype for muscarinic receptors. Mushroom poisoning: SLUDGE symptoms

Indirect-Acting: Acetylcholinesterase Inhibitors

Reversible AChE Inhibitors

Edrophonium

Mechanism: Short-acting (5-15 min), electrostatic binding to AChE

Use: Diagnosis of myasthenia gravis (Tensilon test - transient ↑ muscle strength), reversal of neuromuscular blockade

Route: IV only

Neostigmine

Mechanism: Carbamylates AChE (duration 2-4 hours)

Uses: Myasthenia gravis, reversal of non-depolarizing neuromuscular block (with atropine/glycopyrrolate), postoperative ileus, urinary retention

Route: Oral, IV, IM

Adverse: SLUDGE symptoms (controlled with atropine co-administration)

Pyridostigmine

Similar to neostigmine but longer-acting (3-6 hours)

Use: Myasthenia gravis (first-line oral therapy)

Advantage: Fewer muscarinic side effects than neostigmine

Physostigmine

Key feature: Tertiary amine - crosses blood-brain barrier

Uses: Glaucoma (historic), anticholinergic toxicity/overdose (atropine, antihistamines, TCAs)

Adverse: Seizures (CNS cholinergic excess)

AChE Inhibitors for Alzheimer's Disease

↑ CNS cholinergic transmission (cholinergic hypothesis of dementia)

Donepezil

Reversible, long half-life (70 hours), once-daily dosing. Most commonly prescribed for mild-moderate AD.

Rivastigmine

Pseudo-irreversible (carbamylates AChE + butyrylcholinesterase). Oral or transdermal patch. AD and Parkinson's dementia.

Galantamine

Reversible AChE inhibitor + allosteric modulator of nicotinic receptors. Mild-moderate AD.

Common adverse effects: Nausea, diarrhea, bradycardia, insomnia, muscle cramps. Usually mild and transient.

Irreversible AChE Inhibitors (Organophosphates)

Mechanism: Covalent phosphorylation of AChE serine residue β†’ "aging" after hours β†’ permanent inactivation

Examples: Echothiophate (glaucoma, rarely used), insecticides (malathion, parathion), nerve agents (sarin, VX)

Toxicity: SLUDGE + muscle fasciculations, paralysis, CNS (confusion, seizures, coma, respiratory failure)

Treatment: Atropine (muscarinic antagonist), pralidoxime (2-PAM - AChE reactivator, must give before "aging"), supportive care

Clinical Applications

Glaucoma

Goal: ↓ intraocular pressure

Mechanism: M3 activation β†’ ciliary muscle contraction β†’ trabecular meshwork opening β†’ ↑ aqueous humor outflow

Drugs: Pilocarpine (topical), carbachol. Note: Largely replaced by prostaglandin analogs, Ξ²-blockers

Myasthenia Gravis

Pathophysiology: Autoantibodies against nicotinic ACh receptors at NMJ β†’ muscle weakness

Treatment: Pyridostigmine (symptomatic), immunosuppression (corticosteroids, azathioprine)

Myasthenic crisis vs cholinergic crisis: Both present with weakness. Edrophonium test: improves in myasthenic, worsens in cholinergic

Postoperative Conditions

Urinary retention: Bethanechol (↑ detrusor contraction)

Ileus: Neostigmine (↑ GI motility). Alternative: Alvimopan (peripheral ΞΌ-opioid antagonist)

Xerostomia

Causes: SjΓΆgren's syndrome, radiation therapy

Treatment: Pilocarpine or cevimeline (M3 agonists, ↑ salivation)

Adverse Effects and Contraindications

SLUDGE Mnemonic

Classic muscarinic overstimulation syndrome:

  • β€’ Salivation
  • β€’ Lacrimation
  • β€’ Urination
  • β€’ Defecation/Diarrhea
  • β€’ GI upset
  • β€’ Emesis

Additional: Bradycardia, bronchoconstriction, miosis, sweating

Contraindications

  • β€’ Asthma/COPD (bronchoconstriction)
  • β€’ Peptic ulcer disease (↑ acid secretion, ↑ motility)
  • β€’ Mechanical GI/urinary obstruction (↑ pressure proximal to blockage)
  • β€’ Hyperthyroidism (potentiates arrhythmias)
  • β€’ Coronary artery disease (can precipitate ischemia via bradycardia/hypotension)

Treatment of Overdose

Muscarinic effects: Atropine (competitive muscarinic antagonist)

Nicotinic effects: Supportive care (no specific antagonist for nicotinic receptors)

Organophosphate poisoning: Atropine + pralidoxime (2-PAM, reactivates AChE if given early) + supportive care

← 5.1 ANS Overview5.3 Anticholinergics β†’