PharmacologyTier 1Medical Sciences concept

Comparative anticholinergic potency of drugs (solifenacin, TCAs, antihistamines)

Core concept

Antimuscarinic effect is a property, not a class - dozens of drugs given for other reasons block M receptors
Two determinants of clinical harm
- Intrinsic potency at the muscarinic receptor
- CNS penetration - lipophilicity, low molecular weight, uncharged, not a P-gp substrate
Anticholinergic burden is cumulative and additive - three "mild" agents equal one strong one
Older people are more vulnerable: dec central cholinergic reserve, inc BBB permeability, dec renal clearance

Burden	Agents
High	Tertiary amine TCAs - amitriptyline, dosulepin, imipramine, doxepin; first-generation antihistamines - promethazine, diphenhydramine, chlorphenamine; oxybutynin (immediate release); benztropine, hyoscine, clozapine, olanzapine, chlorpromazine
Moderate	Paroxetine, quetiapine, solifenacin, tolterodine, darifenacin, cyclizine, prochlorperazine, carbamazepine, loperamide
Low but additive	Furosemide, digoxin, prednisolone, warfarin, ranitidine, codeine, theophylline
Negligible	Nortriptyline < amitriptyline; second-generation antihistamines (loratadine, fexofenadine, cetirizine - P-gp substrates excluded from CNS); mirabegron; trospium (quaternary, does not cross the BBB)

Bladder antimuscarinics are relatively but not absolutely selective for M3 - solifenacin and darifenacin are more selective than oxybutynin, but all still cause central effects in the elderly
- Oxybutynin immediate-release has the worst cognitive profile; extended-release and transdermal are better; trospium and mirabegron (beta-3 agonist) avoid the problem
Peripheral toxidrome: dry as a bone, blind as a bat, red as a beet, hot as a hare, mad as a hatter - plus urinary retention, tachycardia, ileus
Central: delirium, confusion, cognitive decline, falls
Anticholinergic Cognitive Burden (ACB) and Drug Burden Index quantify it; score >=3 associates with dementia risk, delirium, falls and mortality
A ChEI prescribed for dementia alongside oxybutynin for bladder is pharmacological cancellation - look for it in every polypharmacy question

Delirium, constipation, urinary retention or a fall in an older inpatient -> total the anticholinergic burden before adding anything
Substitutions worth knowing
- Amitriptyline for neuropathic pain -> nortriptyline (or duloxetine, gabapentinoid)
- Oxybutynin for overactive bladder -> mirabegron or trospium
- Promethazine for nausea/sleep -> ondansetron, or nothing
- First-generation antihistamine -> cetirizine, loratadine, fexofenadine
Anticholinergic delirium - benzodiazepines for agitation, supportive care; physostigmine only in specialist hands (asystole and seizure risk, contraindicated with TCA co-ingestion)
Antimuscarinics precipitate acute angle-closure glaucoma and urinary retention in BPH
Benztropine for drug-induced parkinsonism worsens the cognitive picture in an older patient - reduce the antipsychotic instead

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