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 (Sjögren'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 → "aging" after hours → 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 → ciliary muscle contraction → trabecular meshwork opening → ↑ aqueous humor outflow
Drugs: Pilocarpine (topical), carbachol. Note: Largely replaced by prostaglandin analogs, β-blockers
Myasthenia Gravis
Pathophysiology: Autoantibodies against nicotinic ACh receptors at NMJ → 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 μ-opioid antagonist)
Xerostomia
Causes: Sjögren's syndrome, radiation therapy
Treatment: Pilocarpine or cevimeline (M3 agonists, ↑ salivation)
Adverse Effects and Contraindications
SLUDGE Mnemonic
Classic muscarinic overstimulation syndrome:
- • Salivation
- • Lacrimation
- • Urination
- • Defecation/Diarrhea
- • GI upset
- • Emesis
Additional: Bradycardia, bronchoconstriction, miosis, sweating
Contraindications
- • Asthma/COPD (bronchoconstriction)
- • Peptic ulcer disease (↑ acid secretion, ↑ motility)
- • Mechanical GI/urinary obstruction (↑ pressure proximal to blockage)
- • Hyperthyroidism (potentiates arrhythmias)
- • 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