5.1 Autonomic Nervous System Overview
The autonomic nervous system (ANS) controls involuntary physiological functions including heart rate, blood pressure, digestion, and glandular secretion. Understanding ANS pharmacology is essential for treating cardiovascular, respiratory, GI, and urinary disorders.
Organization of the ANS
Sympathetic Division
Origin: Thoracolumbar (T1-L2 spinal segments)
Ganglia: Paravertebral (sympathetic chain) and prevertebral (celiac, superior/inferior mesenteric)
Anatomy: Short preganglionic, long postganglionic fibers
Function: "Fight or flight" - ↑ cardiac output, bronchodilation, pupil dilation, ↓ GI motility, glucose mobilization
Parasympathetic Division
Origin: Craniosacral (cranial nerves III, VII, IX, X + S2-S4)
Ganglia: Near or within target organs
Anatomy: Long preganglionic, short postganglionic fibers
Function: "Rest and digest" - ↓ heart rate, bronchoconstriction, pupil constriction, ↑ GI motility/secretion, bladder contraction
Neurotransmission in the ANS
Cholinergic Transmission
Neurotransmitter: Acetylcholine (ACh)
Synthesis: Choline + Acetyl-CoA → ACh (via choline acetyltransferase, ChAT)
Storage: Vesicular ACh transporter (VAChT) packages ACh into vesicles
Release: Ca²⁺-dependent exocytosis
Termination: Acetylcholinesterase (AChE) rapidly hydrolyzes ACh → choline + acetate
Sites: All preganglionic neurons, parasympathetic postganglionic neurons, sympathetic postganglionic to sweat glands
Adrenergic Transmission
Neurotransmitters: Norepinephrine (NE), epinephrine (adrenal medulla)
Synthesis: Tyrosine → DOPA (tyrosine hydroxylase) → Dopamine (DOPA decarboxylase) → NE (dopamine β-hydroxylase) → Epinephrine (PNMT, adrenal medulla)
Storage: Vesicular monoamine transporter (VMAT)
Release: Ca²⁺-dependent exocytosis
Termination: Reuptake (NET, norepinephrine transporter) > metabolism (MAO, COMT)
Site: Most sympathetic postganglionic neurons
Receptor Types
Cholinergic Receptors
Nicotinic (nAChR): Ligand-gated ion channels
- • N_N (neuronal): All autonomic ganglia, CNS
- • N_M (muscle): Neuromuscular junction (somatic, not ANS)
- • Agonists: ACh, nicotine, succinylcholine
- • Antagonists: Ganglionic blockers (hexamethonium, mecamylamine), NMJ blockers (separate class)
Muscarinic (mAChR): GPCRs (M1-M5)
- • M1: CNS, gastric parietal cells (Gq, ↑ acid secretion)
- • M2: Heart (Gi, ↓ HR, ↓ conduction), presynaptic autoreceptors
- • M3: Smooth muscle (Gq, contraction), glands (secretion), vascular endothelium (NO release)
- • M4, M5: Primarily CNS
Adrenergic Receptors
α-Adrenergic (GPCRs):
- • α1 (A, B, D subtypes): Gq → vasoconstriction, mydriasis, urethral/prostate contraction
- • α2 (A, B, C subtypes): Gi → presynaptic inhibition (↓ NE release), CNS (↓ sympathetic outflow), platelet aggregation
β-Adrenergic (GPCRs):
- • β1: Gs → heart (↑ HR, ↑ contractility), kidney (renin release)
- • β2: Gs → bronchodilation, vasodilation, uterine relaxation, tremor, glycogenolysis
- • β3: Gs → lipolysis (adipose), bladder relaxation
Organ System Responses
| Organ | Sympathetic Effect | Receptor | Parasympathetic Effect | Receptor |
|---|---|---|---|---|
| Heart | ↑ Rate, ↑ contractility | β1 | ↓ Rate, ↓ conduction (AV) | M2 |
| Blood vessels | Constriction (most) | α1 | Dilation (via NO, M3 endothelium) | M3 |
| Bronchi | Dilation | β2 | Constriction, ↑ secretions | M3 |
| GI tract | ↓ Motility, ↓ secretion | α2, β2 | ↑ Motility, ↑ secretion | M3 |
| Eye (pupil) | Dilation (mydriasis) | α1 | Constriction (miosis) | M3 |
| Bladder | Relaxation (detrusor), contraction (sphincter) | β3, α1 | Contraction (detrusor), relaxation (sphincter) | M3 |
| Sweat glands | Secretion (cholinergic sympathetic) | M3 | — | — |
| Metabolism | Glycogenolysis, lipolysis | β2, β3 | Insulin release (indirect) | M3 |
Pharmacological Principles
Direct vs Indirect Agonists
Direct: Activate receptors directly (phenylephrine at α1, albuterol at β2). Indirect: Enhance endogenous neurotransmitter (amphetamine releases NE, neostigmine inhibits AChE)
Selectivity and Specificity
Selective drugs target specific receptor subtypes (e.g., β1-selective metoprolol). Non-selective drugs affect multiple subtypes (e.g., propranolol blocks β1 and β2)
Reflex Responses
α1 agonists ↑ BP → baroreceptor reflex → ↓ HR. Pure β1 agonists ↑ HR directly but also ↓ diastolic BP → reflex ↑↑ HR. Consider total effect.
Denervation Supersensitivity
Loss of innervation → ↑ receptor expression and sensitivity. Exaggerated response to direct agonists. Diminished response to indirect agonists (no neurotransmitter to release)
Clinical Overview
ANS drugs are among the most widely prescribed medications:
- • Cardiovascular: β-blockers (hypertension, heart failure, angina), α-blockers (hypertension, BPH)
- • Respiratory: β2-agonists (asthma, COPD), anticholinergics (COPD)
- • Urological: α-blockers (BPH), antimuscarinics (overactive bladder)
- • Ophthalmology: β-blockers, α-agonists (glaucoma), muscarinic agonists (glaucoma)
- • Anesthesia: Neuromuscular blockers, anticholinesterases (reversal)
- • GI: Antimuscarinics (IBS), cholinergic agonists (postoperative ileus)