Introduction to Medical Pharmacology  ·  Chapter 6  ·  Module 4
Muscarinic Antagonists
Belladonna alkaloids  ·  Organ-selective agents  ·  Anticholinergic toxidrome  ·  Autonomic dysfunction
Section 1 — Belladonna Alkaloids: Structural Basis of Central Nervous System Penetration
Drug Structure CNS Penetration Key Clinical Uses Key Adverse Effects
Atropine Tertiary amine — lipid-soluble, un-ionized at physiological pH Yes — crosses blood-brain barrier Symptomatic bradycardia; organophosphate antidote; cycloplegia; preoperative antisialagogue Dry mouth, tachycardia, urinary retention, confusion at higher doses
Scopolamine Tertiary amine — greater central penetration than atropine Yes — greater than atropine Motion sickness (transdermal patch); preoperative amnesia Sedation, confusion, hallucinations; worse in elderly
Ipratropium Quaternary ammonium — permanent positive charge No — barrier impermeable; <1% lung absorption COPD bronchodilation (first-line); adjunct in acute severe asthma Minimal systemic effects; avoid in narrow-angle glaucoma
Section 2 — Organ-Selective Muscarinic Antagonists
Bladder — Overactive Bladder
Overactive Bladder Antimuscarinics
  • Oxybutynin — non-selective, mixed mechanism; extended-release and patch formulations reduce adverse effects
  • Tolterodine — lower central nervous system penetration; fewer cognitive adverse effects
  • Solifenacin, Darifenacin — muscarinic subtype 3 preference; once-daily dosing; darifenacin has highest subtype 3 selectivity
  • Trospium — quaternary ammonium; no blood-brain barrier penetration; safest for cognitively vulnerable patients
  • Mirabegron — beta-3 agonist, not a muscarinic antagonist; zero anticholinergic burden; first-line alternative
Airway — Bronchodilation
Inhaled Antimuscarinics
  • Ipratropium — short-acting (4–6 hours); combined with albuterol in acute severe asthma
  • Tiotropium — once-daily; slow dissociation from muscarinic subtype 3 receptors; first-line COPD maintenance; reduces exacerbations
  • Aclidinium — twice-daily; rapid plasma hydrolysis limits systemic effects
  • Umeclidinium — once-daily; often combined with a long-acting beta-2 agonist for dual bronchodilator therapy
  • Long-acting agents not recommended as asthma monotherapy without inhaled corticosteroids
Anticholinergic Burden
Cumulative Muscarinic Burden
  • Many drug classes carry anticholinergic activity: first-generation antihistamines, tricyclic antidepressants, antipsychotics, disopyramide
  • Cumulative burden in older adults: cognitive impairment, falls, urinary retention, increased mortality
  • Alzheimer disease patients on acetylcholinesterase inhibitors: any anticholinergic drug directly opposes treatment — deprescribe
  • Prefer trospium or mirabegron in cognitively vulnerable patients requiring bladder treatment
Key rule: assess the total anticholinergic burden, not just the individual drug being prescribed.
Section 4 — The Anticholinergic Toxidrome
Hot as a hare Hyperthermia — sweat glands blocked; no sweating; heat cannot be dissipated
Dry as a bone All exocrine secretions blocked — dry mouth, dry skin, dry eyes
Red as a beet Cutaneous flushing — vasodilation as the only remaining heat dissipation mechanism
Blind as a bat Mydriasis (dilated fixed pupils) and cycloplegia (loss of accommodation)
Mad as a hatter Agitation, confusion, hallucinations; seizures and coma in severe toxicity
Anticholinergic Toxidrome
Skin: hot, dry, flushed
Pupils: mydriasis (dilated)
Heart rate: tachycardia
Secretions: absent
Bladder: urinary retention
Bowel: ileus, absent sounds
Mental status: agitation, hallucinations
Treatment: physostigmine (after ECG screening)
vs
Cholinergic Toxidrome (Organophosphate)
Skin: wet, diaphoretic, pale
Pupils: miosis (constricted)
Heart rate: bradycardia
Secretions: excessive — bronchorrhea, hypersalivation
Bladder: urinary incontinence
Bowel: diarrhea, cramps
Neuromuscular: fasciculations, weakness
Treatment: atropine + pralidoxime + benzodiazepines
Physostigmine Absolute Contraindication

Physostigmine is the antidote for central anticholinergic toxicity. It is absolutely contraindicated in tricyclic antidepressant overdose because it has caused fatal bradyarrhythmias and asystole in that setting. Always check an electrocardiogram before administering. QRS complex prolongation = do not give physostigmine.

Section 5 — Autonomic Dysfunction Drug Summary
Neurogenic Orthostatic Hypotension
Fludrocortisone
  • Class: Synthetic mineralocorticoid
  • Mechanism: Renal sodium and water retention → expands plasma volume → raises standing blood pressure
  • Adverse effects: Supine hypertension, edema, hypokalemia
Neurogenic Orthostatic Hypotension
Midodrine
  • Class: Alpha-1 adrenoceptor agonist prodrug
  • Mechanism: Converted peripherally to alpha-1 agonist → constricts arterioles and veins → raises standing blood pressure
  • Key property: Does not cross blood-brain barrier — no central nervous system effects
  • Caution: Do not take within 4–6 hours of bedtime — causes supine hypertension
Neurogenic Orthostatic Hypotension
Droxidopa
  • Class: Norepinephrine precursor (synthetic amino acid)
  • Mechanism: Converted directly to norepinephrine in sympathetic nerve terminals by aromatic amino acid decarboxylase
  • Niche: When sympathetic terminals are intact but norepinephrine synthesis is deficient
  • Adverse effects: Supine hypertension, headache
Postural Orthostatic Tachycardia Syndrome
Management Approach
  • Definition: Heart rate rise of 30 bpm or more on standing without orthostatic hypotension
  • Non-pharmacological first: Increased salt and fluid, compression garments, graded exercise
  • Propranolol (low dose): Beta-1 blockade reduces exaggerated tachycardia; caution in hyperadrenergic subtype
  • Ivabradine: Slows sinoatrial node without affecting blood pressure; alternative when propranolol not tolerated
Diabetic Autonomic Neuropathy
High-Yield Manifestations
  • Cardiovascular: Resting tachycardia (loss of vagal tone); orthostatic hypotension; silent myocardial ischemia (no chest pain)
  • Gastrointestinal: Gastroparesis (delayed gastric emptying) → early satiety, nausea, erratic glycemia
  • Genitourinary: Neurogenic bladder with large residual urine volumes
  • Management: Glycemic control to slow progression; symptom-specific pharmacotherapy