Autonomic Nervous System (ANS) — Cholinergics and Anticholinergics
🟢 Lite — Quick Review (1h–1d)
Cholinergic Receptors:
| Receptor | Location | Mechanism | G-protein |
|---|---|---|---|
| Nicotinic (Nm) | NMJ, autonomic ganglia | Ligand-gated Na⁺/K⁺ channel | — |
| Nicotinic (Nn) | Postganglionic sympathetics (adrenal medulla) | Ligand-gated Na⁺/K⁺ channel | — |
| Muscarinic M1 | CNS, gastric parietal cells, autonomic ganglia | ↑ PLC → IP3/DAG | Gq |
| Muscarinic M2 | Heart (SA/AV node, atria) | ↓ cAMP (↓ K⁺ conductance) | Gi |
| Muscarinic M3 | Smooth muscle, exocrine glands, vascular endothelium | ↑ PLC → IP3/DAG | Gq |
| Muscarinic M4 | CNS, nerve terminals | ↓ cAMP | Gi |
| Muscarinic M5 | CNS | ↓ cAMP | Gi |
Parasympathetic Effects on Heart:
- M2 activation → ↓ HR (negative chronotropy), ↓ AV conduction velocity (negative dromotropy), ↓ contractility (negative inotropy)
- Atropine — competitive antagonist at M receptors; dose-dependent: low dose (0.5mg) may cause initial bradycardia (central effect), mid dose (1-2mg) → tachycardia, high dose → mydriasis, dry mouth
Acetylcholine Synthesis and Breakdown:
Choline + Acetyl-CoA → Acetylcholine (via Choline Acetyltransferase - ChAT) ACh → Acetate + Choline (via Acetylcholinesterase - AChE) AChE = True/cholinesterase (in synaptic cleft); Butyrylcholinesterase = Pseudocholinesterase (in plasma, liver)
🟡 Standard — Regular Study (2d–2mo)
Cholinergic Drugs — Direct Agonists:
| Drug | Mechanism | Clinical Use | Notes |
|---|---|---|---|
| Acetylcholine | M + N agonist | Cataract surgery (eye) | Very short acting; NOT given systemically |
| Bethanechol | M3 agonist (selective) | Urinary retention, postoperative ileus | Does NOT activate N receptors |
| Carbachol | M + N agonist | Glaucoma (eye), cataract surgery | Also activates N receptors; longer acting than ACh |
| Pilocarpine | M agonist | Glaucoma (open-angle), xerostomia (Sjögren’s) | Crosses BBB → can cause sweating, salivation |
| Methacholine | M agonist (synthetic) | Bronchial challenge test (asthma diagnosis) | Less N activity than ACh |
Indirect Cholinomimetics (AChE Inhibitors):
| Drug | Reversibility | Clinical Use | Notes |
|---|---|---|---|
| Edrophonium | Rapid/reversible | Myasthenia gravis (diagnosis), Torsades | Very short acting; N作用短 |
| Neostigmine | Reversible (competitive) | Myasthenia gravis, reversal of NMJ block, ileus | Quaternary amine (doesn’t cross BBB) |
| Pyridostigmine | Reversible (competitive) | Myasthenia gravis (longer acting than neostigmine) | Also used in orthostatic hypotension |
| Physostigmine | Reversible (competitive) | Anticholinergic toxicity (crosses BBB) | Tertiary amine (crosses BBB) |
| Donepezil/Rivastigmine/Galantamine | Reversible (competitive) | Alzheimer’s disease | CNS effects |
| Echothiophate | Irreversible | Glaucoma | Organophosphate; causes miosis |
| Malathion | Irreversible (low toxicity in humans) | Pediculosis | Requires metabolic activation |
| Parathion | Irreversible (highly toxic) | Agricultural insecticide | Proconverted to paraoxon |
Organophosphate Poisoning:
- Mechanism: Irreversibly inhibits AChE → excess ACh at all cholinergic synapses
- SLUDGE/DUMBBBELS mnemonic:
| SLUDGE | DUMBBBELS |
|---|---|
| Salivation | Diarrhea |
| Lacrimation | Urination |
| Urination | Miosis |
| Defecation | Bronchospasm/bronchorrhea |
| GI upset | Bradycardia |
| Emesis | Emesis |
| Lacrimation | |
| Salivation |
- Muscarinic effects: Miosis, bradycardia, bronchospasm, bronchorrhea, sweating
- Nicotinic effects: Muscle fasciculations, weakness, paralysis, tachycardia (initially), hypertension
- CNS effects: Confusion, seizures, coma, respiratory depression
- Treatment:
- Atropine — competitive M antagonist (doses of 2-4mg IV q5-10min); titrate to drying secretions
- Pralidoxime (2-PAM) — reactivates AChE (must give within 24-48h before “aging” occurs); dose: 1-2g IV over 10-30min
- Supportive: Oxygen, suction, airway management
Anticholinergic Drugs — Classification:
| Drug | Selectivity | Clinical Use |
|---|---|---|
| Atropine | Non-selective M blocker | Bradycardia, bradyarrhythmias, organophosphate poisoning, cycloplegic for eye |
| Scopolamine | Non-selective M blocker (crosses BBB) | Motion sickness (patch), perioperative antiemetic |
| Homatropine | Non-selective M blocker | Mydriasis, cycloplegia (short-acting) |
| Tropicamide | Non-selective M blocker | Mydriasis for eye exam (short acting ~4h) |
| Ipratropium | Non-selective M blocker (inhaled) | COPD, asthma (bronchodilation) |
| Tiotropium | M3 blocker (long-acting inhaled) | COPD maintenance |
| Glycopyrrolate | Non-selective M blocker | Preanesthetic (↓ secretions), COPD |
| Dicyclomine | Non-selective M blocker | Irritable bowel syndrome (antispasmodic) |
| Propantheline | Non-selective M blocker | Peptic ulcer, GI hypermotility |
| Oxybutynin | M3 > M1/M2 | Urinary incontinence (overactive bladder) |
| Tolterodine | M3 > M1/M2 | Overactive bladder |
| Darifenacin | M3 selective | Overactive bladder |
| Solifenacin | M3 selective | Overactive bladder |
| Cyclopentolate | Non-selective M blocker | Mydriasis for eye exam |
Muscarinic Antagonists — Organ-based Effects:
| Organ | Effect of M-blockade |
|---|---|
| Eye | Mydriasis (↓ pupil constriction), cycloplegia (↓ accommodation), ↑ IOP (angle closure glaucoma contraindicated) |
| Heart | Tachycardia (↑ SA node firing), ↑ AV conduction |
| Bronchi | Bronchodilation (↓ secretions) |
| GI | ↓ motility, constipation, ↓ secretions |
| Bladder | ↓ detrusor contraction → urinary retention (BPH caution) |
| Salivary glands | Dry mouth (xerostomia) |
| Sweat glands | Anhidrosis → hyperthermia (especially children) |
| CNS | Antiemetic (scopolamine), anti-Parkinsonian, anti-motion sickness |
🔴 Extended — Deep Study (3mo+)
Neuromuscular Junction (NMJ) — Detailed:
Anatomy:
- Motor nerve terminal → vesicles release ACh → ACh binds Nm receptors on motor end plate → depolarization → muscle contraction
- AChE in synaptic cleft terminates signal (~1ms)
Nm Receptor Structure:
- Pentameric (2α + 1β + 1δ + 1ε or γ in fetal/neonatal)
- Two ACh binding sites (α-δ and α-ε interfaces)
- Opening of central ion channel (Na⁺ influx)
Depolarizing NMJ Blockers:
- Succinylcholine (SCh) — only depolarizing agent used clinically
- Mechanism: Binds Nm receptor → persistent depolarization → phase I block
- Metabolism: Plasma pseudocholinesterase (butyrylcholinesterase); genetic variations cause prolonged effect
- Scoline apnea — pseudocholinesterase deficiency (autosomal recessive)
- Side effects: ↑ K⁺ (hyperkalemia — contraindicated in burns, trauma, denervation, MS, stroke), ↑ intraocular pressure, ↑ intragastric pressure, muscle pain (myalgia)
- Phase II block — with prolonged administration → non-depolarizing pattern (tolerance)
Non-Depolarizing NMJ Blockers:
- Competitive antagonists at Nm receptor (compete with ACh)
- Reversed by AChE inhibitors (neostigmine, edrophonium)
- Potentiated by: aminoglycosides, vancomycin, Mg²⁺, Li⁺, hypothermia, acidosis, hypokalemia
| Drug | Onset | Duration | Elimination | Notes |
|---|---|---|---|---|
| Rocuronium | Rapid (60-90s) | Medium (30-45min) | Hepatic | Most commonly used; vagolytic (tachycardia) |
| Vecuronium | Intermediate | Medium | Hepatic (+ renal) | Minimal CV effects; metabolism affected by renal failure |
| Atracurium | Intermediate | Medium | Hofmann elimination (non-enzymatic) | Ideal for renal/hepatic failure; causes histamine release |
| Cisatracurium | Intermediate | Medium | Hofmann elimination | Less histamine than atracurium |
| Mivacurium | Rapid | Short | Plasma cholinesterase | Contraindicated in pseudocholinesterase deficiency |
| Pancuronium | Intermediate | Long | Renal | Vagolytic (tachycardia); long duration |
| d-Tubocurarine | Slow | Long | Renal | Historical; causes histamine release |
Reversal of NMJ Block:
- Neostigmine — 0.04-0.07 mg/kg IV; onset 2-4 min; peak 6-10 min; duration 1-2h
- Sugammadex — γ-cyclodextrin; encapsulates rocuronium/vecuronium directly; faster than neostigmine; dose 2-16 mg/kg
- Edrophonium — shorter acting; used for myasthenia gravis diagnosis/treatment
Ganglionic Blockers:
- Mecamylamine, Trimethaphan — block Nn receptors in autonomic ganglia
- Rarely used clinically now
- Side effects: Orthostatic hypotension, constipation, urinary retention
Autonomic Innervation — Summary:
| System | Neurotransmitter | Receptor | Effects |
|---|---|---|---|
| Parasympathetic | ACh | Muscarinic (M2/M3) | Rest and digest |
| Sympathetic (most) | NE | α1, β1, β2 | Fight or flight |
| Sympathetic (sweat glands) | ACh | Muscarinic (M3) | Sympathetic cholinergic (唯一例外) |
| Adrenal medulla | ACh | Nn | Secretion of Epi/NE |
| Sympathetic (vasodilator) | ACh | M | Active vasodilation in skeletal muscle |
Catecholamine Synthesis Pathway:
Tyrosine → DOPA (via tyrosine hydroxylase — rate-limiting step) → Dopamine → NE → Epi (via PNMT) Note: Adrenal medulla converts NE to Epi via phenylethanolamine-N-methyltransferase (PNMT); requires cortisol (from adrenal cortex)
Catecholamine Storage and Release:
- Stored in vesicles (with ATP, chromogranins)
- Release via exocytosis (Ca²⁺-dependent)
- Amphetamines — displace catecholamines from vesicles → ↑ release
- Reserpine — depletes vesicular catecholamine stores (irreversible)
- Guanethidine — inhibits NE release from nerve terminals
Adrenergic Receptors — Detailed:
| Receptor | Location | G-protein | Effect |
|---|---|---|---|
| α1 | Vascular smooth muscle, GU smooth muscle, liver, heart | Gq | Vasoconstriction, mydriasis, ↓ GI motility |
| α2 | Presynaptic nerve terminals, CNS, pancreas | Gi | ↓ NE release (autoreceptor), sedation, ↓ insulin release |
| β1 | Heart, juxtaglomerular cells | Gs | ↑ HR, ↑ contractility, ↑ conduction, ↑ renin |
| β2 | Bronchi, vasculature, uterus, liver | Gs | Bronchodilation, vasodilation, uterine relaxation, glycogenolysis |
| β3 | Fat cells, heart | Gs | Lipolysis, thermogenesis |
Dopamine Receptors:
- D1 (DA1) — Gs → vasodilation (renal, mesenteric, coronary)
- D2 (DA2) — Gi → ↓ sympathetic outflow, antiemetic
Dopamine Doses:
- Low (< 3 μg/kg/min): D1 > β1 > α1 → renal vasodilation, natriuresis
- Medium (3-10 μg/kg/min): β1 effects predominate → ↑ cardiac output
- High (> 10 μg/kg/min): α1 effects predominate → vasoconstriction, ↑ BP
Key NEET-PG Clinical Pearls:
- Atropine eye drops — systemic absorption possible → tachycardia, flushing; contraindicated in narrow-angle glaucoma
- Scopolamine patch — for motion sickness; apply behind ear; change q72h; causes drowsiness, dry mouth
- Neostigmine — glycopyrrolate preferred over atropine for reversal (glycopyrrolate doesn’t cross BBB → no CNS stimulation)
- Succinylcholine — contraindicated in: burns >24h, denervation injuries, muscle dystrophies, hyperkalemia, malignant hyperthermia, ↑ intraocular pressure, history of denervation (spared cord injury after 24h)
- Pseudocholinesterase deficiency — prolonged succinylcholine paralysis (scoline apnea); normal nerve function but abnormal plasma enzyme
- Donepezil — AChE inhibitor for Alzheimer’s; side effects: nausea, diarrhea, bradycardia
- Rivastigmine — AChE inhibitor; used for Alzheimer’s and Parkinson’s disease dementia
- Bethanechol — used for urinary retention (post-operative, neurogenic); contraindicated in obstruction, active asthma, peptic ulcer
- Pilocarpine — side effects: sweating, salivation, bradycardia, bronchospasm; used in glaucoma and xerostomia
- Ipratropium — inhaled; causes minimal systemic effects; blocks M3 in bronchi
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