5.3 Anticholinergic Drugs (Muscarinic Antagonists)
Anticholinergic drugs competitively block muscarinic acetylcholine receptors, reducing parasympathetic activity. They are used for bradycardia, COPD, overactive bladder, motion sickness, Parkinson's disease, and as antidotes for cholinergic toxicity.
Prototypical Agents: Belladonna Alkaloids
Atropine
Source: Atropa belladonna (deadly nightshade)
Mechanism: Competitive antagonist at all muscarinic receptors (M1-M5), no selectivity
Pharmacokinetics: Tertiary amine, crosses BBB, tยฝ ~4 hours
Clinical uses:
- โข Bradycardia: Sinus bradycardia, AV block (blocks M2 receptors on heart)
- โข Organophosphate/cholinergic poisoning: Antidote (reverses muscarinic effects)
- โข Preanesthetic medication: โ secretions (salivation, bronchial)
- โข Ophthalmology: Mydriasis and cycloplegia for eye exams
- โข GI spasm: Rarely used (better alternatives available)
Scopolamine (Hyoscine)
Source: Hyoscyamus niger (henbane)
Key difference from atropine: Greater CNS effects (sedation, amnesia, antiemetic)
Clinical uses:
- โข Motion sickness: Transdermal patch (most effective prophylaxis)
- โข Postoperative nausea/vomiting: Transdermal patch applied before surgery
- โข Preanesthetic: Sedation + antisialagogue
Adverse: Drowsiness, dry mouth, blurred vision, confusion (especially elderly)
Organ System-Selective Anticholinergics
Respiratory: Bronchodilators
Block M3 receptors on bronchial smooth muscle โ bronchodilation
Ipratropium
Route: Inhaled (MDI, nebulizer)
Uses: COPD (first-line), asthma (adjunct to ฮฒ2-agonists)
Advantage: Quaternary amine (poorly absorbed, minimal systemic effects)
Tiotropium
Route: Inhaled (dry powder inhaler)
Uses: COPD maintenance (once-daily dosing)
Kinetics: Long-acting (24 hours), kinetic selectivity for M3>M2
Aclidinium, Umeclidinium, Glycopyrrolate (inhaled)
Long-acting muscarinic antagonists (LAMAs) for COPD. Often combined with LABAs (ฮฒ2-agonists)
Urological: Overactive Bladder
Block M3 receptors on detrusor muscle โ โ bladder contractions, โ capacity
Oxybutynin
Route: Oral, transdermal patch
Also has: Direct smooth muscle relaxant effects, local anesthetic properties
Adverse: Dry mouth, constipation, cognitive impairment (crosses BBB)
Tolterodine
Selectivity: Relatively bladder-selective (less dry mouth than oxybutynin)
Forms: Immediate-release (BID), extended-release (once daily)
Solifenacin, Darifenacin, Fesoterodine
Newer agents with once-daily dosing, variable M3 selectivity. Darifenacin is most M3-selective.
Trospium
Key feature: Quaternary amine (doesn't cross BBB โ no CNS effects). Preferred in elderly.
Ophthalmology: Mydriatics and Cycloplegics
Block M3 โ pupil dilation (mydriasis) + ciliary muscle paralysis (cycloplegia)
Tropicamide
Use: Short-acting (4-6 hours) mydriatic for fundoscopic exam. Rapid onset.
Cyclopentolate
Use: Medium duration (6-24 hours) for refraction in children
Atropine (ophthalmic)
Use: Long-acting (7-14 days) for uveitis, amblyopia treatment. Caution: Risk of angle-closure glaucoma
GI: Antispasmodics
Dicyclomine
Use: IBS (โ intestinal smooth muscle spasm). Anticholinergic + direct muscle relaxant.
Hyoscyamine
Use: GI spasm, peptic ulcer (adjunct). L-isomer of atropine.
Glycopyrrolate (oral)
Use: Peptic ulcer disease (rarely used now; PPIs preferred). Quaternary amine.
CNS Indications
Parkinson's Disease
Rationale: PD has relative cholinergic excess (due to dopamine deficiency). Anticholinergics restore balance.
Benztropine, Trihexyphenidyl
Uses: Tremor in PD (especially in younger patients), drug-induced parkinsonism/dystonia (antipsychotics)
Limitations: Less effective for bradykinesia/rigidity. Cognitive side effects limit use in elderly.
Motion Sickness and Vertigo
Scopolamine: Most effective for motion sickness (transdermal patch)
Meclizine, Dimenhydrinate: H1 antihistamines with anticholinergic properties (less effective than scopolamine)
Adverse Effects
Peripheral Anticholinergic Effects
- โข Dry mouth (xerostomia): Most common, โ salivation
- โข Blurred vision: Cycloplegia (loss of accommodation), mydriasis
- โข Constipation: โ GI motility
- โข Urinary retention: โ detrusor tone (especially in men with BPH)
- โข Tachycardia: M2 blockade in heart (less pronounced with peripheral agents)
- โข Decreased sweating: Anhidrosis โ hyperthermia risk
Central Anticholinergic Effects
Mild: Drowsiness, memory impairment, confusion
Severe (toxicity): Delirium, hallucinations, agitation, seizures, coma
High-risk population: Elderly (โ BBB permeability, โ cholinergic reserve)
Mnemonic: "Hot as a hare, dry as a bone, red as a beet, mad as a hatter, blind as a bat"
Special Considerations
Angle-closure glaucoma: Absolute contraindication (mydriasis can precipitate acute attack)
Dementia/cognitive impairment: Avoid if possible (worsens cognition)
Heat exposure: Impaired sweating โ hyperthermia risk
Anticholinergic Toxicity
Clinical Presentation
Peripheral: Mydriasis, dry mucous membranes, flushed skin, tachycardia, hyperthermia, urinary retention, โ bowel sounds
CNS: Confusion, agitation, hallucinations, picking at bedclothes, seizures
Sources: Intentional overdose (atropine, scopolamine), plant ingestion (jimsonweed, deadly nightshade), drug interactions
Treatment
Supportive care: IV fluids, cooling (hyperthermia), benzodiazepines (agitation/seizures)
Physostigmine: Tertiary amine AChE inhibitor (crosses BBB). Reverses both peripheral and central effects.
Physostigmine indications: Severe CNS toxicity (hallucinations, seizures, coma), hemodynamic instability
Contraindications to physostigmine: Cardiac conduction abnormalities, asthma, GI/GU obstruction
Dose: 0.5-2 mg IV slowly (risk of cholinergic crisis, seizures if given too fast)
Drug Interactions
Additive Anticholinergic Effects
Many drugs have anticholinergic properties: TCAs, first-generation antihistamines, antipsychotics, muscle relaxants. Combination โ โ toxicity risk.
Pharmacokinetic Interactions
โ GI motility โ altered absorption of other drugs. Can โ bioavailability of slowly dissolved drugs or โ absorption of drugs requiring rapid dissolution.