Autonomic Nervous System & Pharmacology – Comprehensive Bullet Notes
Introduction
Autonomic Nervous System (ANS) works with endocrine system to regulate & integrate bodily functions.
Endocrine → slow, blood-borne hormones.
Nervous → rapid, electrical impulses → release neuromediators at effector cells.
Clinical relevance: Many drugs exploit differences between endocrine (diffuse, long-lasting) vs. nervous (fast, targeted) signaling to fine-tune therapy.
General Anatomy
Efferent (Motor) Pathway
Two-neuron chain.
Preganglionic neuron
Cell body inside CNS.
Origin: Brain stem or spinal cord; myelinated axon exits to peripheral ganglion.
Postganglionic neuron
Cell body in peripheral ganglion; non-myelinated axon → effector (smooth muscle, cardiac muscle, glands).
Afferent (Sensory) Pathway
Visceral sensory fibres monitor internal environment (e.g., carotid sinus, aortic arch pressure) → reflex arcs adjusting efferent outflow.
Divisions
Sympathetic (thoraco-lumbar).
Parasympathetic (cranio-sacral).
Enteric (independent GI “brain”).
Sympathetic Division
Preganglionic origin: T1 \text{–} L2 intermediolateral horn.
Preganglionic fibres short → paravertebral or prevertebral ganglia.
Postganglionic fibres long → diffuse targets.
Functional profile
↑ HR, BP, contractility.
Mobilise glucose & fatty acids.
Redirect blood to skeletal m. & heart; shunts skin/GI.
Dilate pupil (mydriasis) & bronchioles.
“Fight-or-Flight.”
Table (pathophysiology examples)
Dilated pupils → autonomic dysreflexia.
↓ salivation (viscous).
↑ HR variability abnormalities, etc.
Parasympathetic Division
Preganglionic origin:
Cranial nerves III,\;VII,\;IX,\;X (vagus ≈ 90\% of fibres).
Sacral S2 \text{–} S4.
Preganglionic fibres long; ganglia on/near organ → postganglionic fibres short.
Functions
Homeostasis, digestion, waste elimination.
“Rest-and-Digest.” Opposes sympathetic but not simply antagonistic (e.g., male sexual function requires both).
Table (clinical correlations): pupil constriction, watery saliva, slowed HR, bronchoconstriction with ↑ mucus, stimulated peristalsis & bladder detrusor.
Enteric Division
Plexuses (Auerbach & Meissner) innervate GI tract, pancreas, gallbladder.
Largely autonomous but modulated by S & PS systems.
Controls motility, secretion, local blood flow; disorders → irritable bowel, diabetic gastroparesis.
Chemical Inter-cellular Signaling
Hormones: bloodstream; e.g., cortisol.
Local mediators: paracrine/autocrine; e.g., histamine, prostaglandins.
Neurotransmitters: synaptic; >50 identified; therapeutically key: ACh, NE, Epi, dopamine, serotonin, histamine, glutamate, \gamma-aminobutyric acid (GABA).
Neurotransmitter Categories in ANS
Cholinergic (ACh)
All preganglionic (S & PS).
Postganglionic PS; post-ganglionic sympathetic to sweat glands; adrenal medulla; NMJ; many CNS neurons.
Adrenergic (NE/Epi)
Most post-ganglionic sympathetic.
Cholinergic Neurotransmission Cycle
Synthesis: Choline uptake (blocked by hemicholinium) + AcCoA → ACh (via choline acetyl-transferase).
Storage: ACh packaged in vesicles.
Release: Ca^{2+}-dependent exocytosis (blocked by botulinum toxin; stimulated by black widow spider venom).
Receptor binding: muscarinic or nicotinic sites.
Degradation: AChE cleaves to acetate + choline.
Recycling: choline re-uptake.
Cholinergic Receptors
Muscarinic (M) – GPCR; subtypes M1,\;M2,\;M3 well characterised (M{4,5} CNS).
Locations: eye, heart, glands, bronchus, GI, bladder.
Nicotinic (N) – ligand-gated Na^+/K^+ channel; pentameric.
N_N (ganglia, CNS, adrenal medulla).
N_M (NMJ of skeletal muscle).
Cholinergic Pharmacology
Direct-acting agonists (bind receptor)
ACh: non-selective; limited use (rapid hydrolysis).
Bethanechol: M selective; post-op/partum atonic bladder, ileus.
Carbachol: glaucoma miotic.
Pilocarpine: emergency ↓IOP in acute angle glaucoma; xerostomia; S.E. profuse sweating, salivation.
Indirect-acting (AChE inhibitors)
Reversible
Edrophonium: ultrashort 10\text{–}20 min; dx myasthenia gravis.
Physostigmine: crosses BBB; antidote for antimuscarinic toxicity.
Neostigmine: MG tx; post-op ileus.
Pyridostigmine / Ambenonium: chronic MG (longer t_{1/2}).
Tacrine, donepezil, rivastigmine, galantamine: Alzheimer’s (central cholinergic deficiency).
Irreversible
Echothiophate: chronic glaucoma (rare due toxicity).
Organophosphates (parathion, malathion, sarin): insecticides/nerve gas.
Toxicity → cholinergic crisis (DUMBBELSS): diarrhea, urination, miosis, bronchospasm, bradycardia, excitation, lacrimation, sweating, salivation.
Antidotes: Pralidoxime (re-activates AChE peripherally), Atropine (blocks muscarinic CNS & peripheral).
Common side-effects of cholinergic excess
Diarrhea,\;Diaphoresis,\;Mi!osis,\;Nausea,\;U_rinary\; urgency.
Anticholinergic (Cholinergic Antagonist) Drugs
Antimuscarinics
Atropine (prototype)
Eye: mydriasis & cycloplegia for refraction; danger: angle-closure glaucoma.
GI antispasmodic; pre-op antisecretory; tx bradycardia; antidote for organophosphate poisoning.
Adverse: dry mouth, blurred vision, photophobia, tachycardia, constipation, urinary retention, CNS delirium → collapse.
Scopolamine: strong CNS; prophylaxis motion sickness; post-op nausea.
Ipratropium / Tiotropium: inhaled bronchodilator for COPD & acute asthma; quaternary (minimal CNS).
Benztropine, trihexyphenidyl: adjunct in Parkinson’s (balances dopamine deficiency).
Oxybutynin, solifenacin, trospium: overactive bladder / urge incontinence.
Ganglionic blockers
Nicotine (high dose) or synthetic compounds; obsolete clinically due to widespread effects.
Neuromuscular Blockers
Non-depolarizing (competitive) – tubocurarine, cisatracurium, pancuronium, rocuronium, vecuronium; reversed with AChE inhibitors + muscarinic blockade.
Depolarizing – Succinylcholine; rapid intubation; risks: malignant hyperthermia (treat with dantrolene), apnea (pseudocholinesterase deficiency), hyperkalemia.
Adrenergic Receptors & Physiologic Actions
Alpha (α)
\alpha_1: vascular smooth m. constriction → ↑PR & BP; mydriasis; urinary sphincter contraction.
\alpha_2: presynaptic ↓NE release; ↓ACh & insulin release.
Beta (β)
β_1: heart ↑HR, contractility; ↑lipolysis; ↑renin.
β_2: vasodilation (skeletal m.), bronchodilation, uterine relaxation, ↑glucagon, glycogenolysis.
Dopamine (D1): renal/splanchnic vasodilation.
Adrenergic Agonists
Direct-acting
Non-selective: Epinephrine (α₁α₂β₁β₂) – low dose β predominates → vasodilation; high dose α → vasoconstriction.
Uses: anaphylaxis, cardiac arrest, status asthmaticus, prolong local anesthetic.
NE (α₁α₂β₁): septic/vasodilatory shock.
Isoproterenol (β₁β₂): emergency bradycardia, AV block; potent bronchodilation.
Dopamine: dose-dependent; low (D1 renal vasodilation), moderate (β₁ heart), high (α₁ vasoconstriction). Shock with renal compromise.
Phenylephrine (α₁): hypotension, nasal decongestant, mydriasis.
Clonidine (α₂ central): resistant hypertension, opioid withdrawal.
β₂ Selective inhaled: Albuterol, Terbutaline (acute), Salmeterol/Formoterol (long-acting) – asthma/COPD.
Indirect-acting
Amphetamine: ↑NE release + CNS stimulant → ADHD, narcolepsy.
Tyramine (red wine, cheese): MAO inhibitor ↔ hypertensive crisis.
Cocaine: block NET & DAT re-uptake.
Mixed
Ephedrine/Pseudoephedrine: direct α & β + indirect NE release; oral decongestant; raises BP; banned as sports enhancer.
Adrenergic Antagonists
Alpha Blockers
Non-selective irreversible: Phenoxybenzamine – pre-op pheochromocytoma.
Non-selective competitive: Phentolamine – pheochromocytoma crises, cocaine-induced vasospasm; caution CAD (arrhythmia, angina).
Selective α₁: Prazosin, Terazosin, Doxazosin – HTN; Tamsulosin, Alfuzosin – BPH (uroselective). First-dose syncope.
Selective α₂: Yohimbine – historically erectile dysfunction; ↑sympathetic outflow; unsafe in CV disease.
Beta Blockers
Non-selective: Propranolol, Nadolol (long t_{1/2}), Timolol (glaucoma ↓aqueous humor).
β₁-selective (cardio-selective): Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol (ultrashort IV), Metoprolol, Nebivolol (NO release).
Uses: HTN (esp. w/ pulmonary disease), chronic stable angina, post-MI, CHF (metoprolol, bisoprolol), migraine prophylaxis.
Partial agonists (ISA): Acebutolol (β₁), Pindolol (non-selective) – less bradycardia.
Combined α + β: Labetalol (HTN emergencies, pregnancy HTN), Carvedilol (CHF); SE: orthostatic hypotension.
Key adverse effects of β-blockers
Bronchoconstriction (non-selective) contraindicated in asthma/COPD.
Mask hypoglycemia; caution diabetics.
CNS: fatigue, nightmares, depression.
Sexual dysfunction.
Sudden withdrawal → rebound HTN/angina (up-regulation).
Clinical & Ethical Connections
Organophosphate poisoning frequent in agriculture & warfare (sarin). Rapid recognition & atropine availability are public-health imperatives.
β-blocker use in athletic doping control: propranolol banned in precision sports (archery, shooting) due to tremor reduction.
Over-the-counter sympathomimetics (pseudoephedrine) → precursor for illicit methamphetamine; restricted sales illustrate legislative pharmacology.
Enteric nervous system: Example – opioid-induced constipation via µ-receptor inhibition of enteric neurons; peripherally acting µ-antagonists (e.g., naloxegol) spare CNS analgesia.
Integrative Review Pointers
Always map receptor type → second messenger → organ response → drug effect/side-effect.
Differential ganglionic fibre length helps anticipate side-effects: e.g., sympathetic drugs often diffuse (long post-ganglionic); parasympathetic more organ-specific (short post-ganglionic).
In pharmacologic crises (e.g., cholinergic or adrenergic storm) think ABC (Airway, Breathing, Circulation) + antidote (Atropine/Pralidoxime vs. β-blocker/NTG).