Autonomic Nervous System PDF

Autonomic Nervous System BMS 100 Autonomic Nervous System Anatomy overview Sympathetic Nervous System Intermediolateral horn, gray and white rami communicantes Paravertebral ganglia, Prevertebral Ganglia, and Splanchnic Nerves Parasympathetic Nervous System Nerves and terminal ganglia Messenger...

Autonomic Nervous System BMS 100 Autonomic Nervous System Anatomy overview Sympathetic Nervous System Intermediolateral horn, gray and white rami communicantes Paravertebral ganglia, Prevertebral Ganglia, and Splanchnic Nerves Parasympathetic Nervous System Nerves and terminal ganglia Messengers of the ANS Epinephrine, Norephinephrine, Acetylcholine, and their Receptors Actions of the ANS Basic Pharmacology of the ANS General Organization – Nervous System Brain Somatic Motor, cranial: Cranial skeletal muscles Cranial Nerves Spinal Cord Special Sensory: Hearing, equilibrium, sight, smell, taste Cranial Somatic Sensory Cranial Nerves Visceral Sensory: stretch, pain, temperature, chemical stimuli Cranial & Spinal Nerves Somatic Sensory, non-cranial: Touch, pain, pressure, vibration, temperature Spinal Nerves Visceral motor: Parasympathetic nervous system Cranial Nerves Somatic Motor, non-cranial: non-cranial skeletal muscles Spinal Nerves Visceral motor: autonomic nervous system – all SNS and sacral PaNS Spinal Nerves Focus on the Autonomic Nervous System Brain Somatic Motor, cranial: Cranial skeletal muscles Cranial Nerves Spinal Cord Special Sensory: Hearing, equilibrium, sight, smell, taste Cranial Somatic Sensory Cranial Nerves Visceral Sensory: stretch, pain, temperature, chemical stimuli Cranial & Spinal Nerves Somatic Sensory, non-cranial: Touch, pain, pressure, vibration, temperature Spinal Nerves Visceral motor: Parasympathetic nervous system Cranial Nerves Somatic Motor, non-cranial: non-cranial skeletal muscles Spinal Nerves Visceral motor: autonomic nervous system – all SNS and sacral PaNS Spinal Nerves Sympathetic Nervous System General model of the SNS: 1. Motor output to the sympathetic nervous system descends from the brain OR input from afferents (from the body) synapses on neurons in the intermediolateral cell column (gray matter) ▪ Located from T1 – L3 2. SNS neurons send efferent axons through the white rami communicantes to a paravertebral ganglion 3. Within the paravertebral ganglion, the axon can: ▪ Synapse within the paravertebral ganglion at that spinal level ▪ Continue to another paravertebral ganglion at a different spinal level and synapse there ▪ Pass through the paravertebral ganglion and continue to a prevertebral ganglion (through a splanchnic nerve) and synapse there Basic SNS Anatomy - Overview • Solid lines = efferents from spinal cord to 1st ganglion ▪ pre-gangionic fibre • Dotted lines = efferents from gangion to target organ ▪ post-ganglionic fibre Anatomy and Physiology, 2nd ed. p. 594, fig. 15.2 Intermediolateral horn/column • Found in lamina VII of the thoracic and upper lumbar spinal cord ▪ The descending pathways that influence neurons in this column are diffuse and hard to distinguish • Reflex pathways from afferents also impact the activity of neurons in this column Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 5-11 Basic SNS Anatomy – “Option 1” • Neuron in the intermediolateral horn (pre-ganglionic neuron) → synapses on a neuron in the paravertebral ganglion at that same spinal level ▪ Axon travels through the white rami communicantes, synapses on the post-ganglionic neuron ▪ White rami communicantes are myelinated • The postganglionic neuron sends efferents out to visceral organs ▪ Gray rami communicantes (unmyelinated fibres) join the spinal nerve Small error – the post-ganglionic fibre should enter the gray ramus → spinal nerve Anatomy and Physiology, 2nd ed. p. 594, fig. 15.3 Basic SNS Anatomy – “Option 1” • Model is typical of sympathetic inputs to skin, blood vessels at that spinal level • Also some of the inputs to the heart and lungs Anatomy and Physiology, 2nd ed. p. 594, fig. 15.2 Basic SNS Anatomy – “Option 2” • Neuron in the intermediolateral horn (pre-ganglionic neuron) → synapses on a neuron in a paravertebral ganglion at a different spinal level • Cervical ganglia – receive fibres from the upper thoracic intermediolateral horn: ▪ Superior cervical ganglion – around the level of C1 – C4 ▪ Middle cervical ganglion C5-C6 ▪ Inferior cervical ganglion C7-C8 • The inferior cervical ganglion fuses with fibres from the first thoracic ganglion to form the stellate ganglion Anatomy and Physiology, 2nd ed. p. 594, fig. 15.3 Basic SNS Anatomy – “Option 2” • Superior cervical ganglion – SNS input to the cranial nerves ▪ nerves travel along blood vessels and often join the parasympathetic fibres of cranial nerves • i.e. CNs III, VII, IX, X • Middle + stellate – SNS input to: ▪ heart ▪ trachea, bronchi, bronchioles • The heart and lungs receive inputs from “Option 1” and “Option 2” gray ramii ▪ forms web-like cardiac and pulmonary plexuses that innervate these structures Anatomy and Physiology, 2nd ed. p. 594, fig. 15.2 Synthesizing from Neuroanatomy • Long ciliary nerves → SNS input to pupil ▪ pupillary dilation ▪ accompany short ciliary nerves (CN III) • SNS input tends to make tears, saliva less “watery”, more “mucus-y” ▪ the SNS inputs tend to accompany the cranial nerves at some point along their course ▪ CN VII, IX Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 5-11 Basic SNS Anatomy – “Option 3” • Neuron in the intermediolateral horn → passes through the paravertebral ganglion (no synapse) → synapses on a prevertebral ganglion • The white ramii form nerves on the way to the prevertebral ganglion ▪ greater splanchnic nerve → celiac ganglion (T5 – T9) ▪ lesser splanchnic nerve → superior mesenteric ganglia, aorticorenal ganglia (T10 – T11) ▪ least splanchnic nerve → renal plexus/ganglia (T12) ▪ lumbar & sacral splanchnic nerves→ inferior mesenteric ganglia, plexuses to pelvic and lower abdominal organs (L1 – L2) Anatomy and Physiology, 2nd ed. p. 594, fig. 15.3 Basic SNS Anatomy – “Option 3” The “pretty diagram version” • It’s easy to see the preganglionic splanchnic nerves and the ganglia • Picture doesn’t show the “sacral” sympathetic trunk – fibres that leave the spinal cord from L1L2, but form sacral paravertebral ganglia Moore’s Clinically-Oriented Anatomy, p. 1241, fig. 5.88 Basic SNS Anatomy A more realistic picture • Splanchnic nerves and prevertebral ganglia look all jumbled together Moore’s Clinically-Oriented Anatomy, p. 1242, fig. 5.89 Comparing the SNS and PaNS • Sympathetic nervous system ▪ short pre-ganglionic fibres, longer post-ganglionic fibres ▪ Neuronal cell bodies in the intermediolateral horn of T1 – L2 ▪ Ganglia can be paravertebral or prevertebral ▪ Pre-ganglionic fibres can be white rami communicantes from the spinal cord or splanchnic nerves • Parasympathetic nervous system ▪ Long pre-ganglionic fibres, short post-ganglionic fibres ▪ Neuronal cell bodies in the brainstem (cranial nerve nuclei) or sacral spinal levels ▪ No prevertebral or postvertebral ganglia Comparing the SNS and PaNS Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 20-1 Basic PaNS Anatomy • Cranial parasympathetic nervous system: ▪ Pupillary constriction (CN III): • Edinger-Westphal nucleus (midbrain) → ciliary ganglion ▪ Lacrimal gland, nasal mucous secretions (CN VII): • Superior salivatory nucleus (pons) → sphenopalatine ganglion ▪ Sublingual, submaxillary salivary glands (CN VII): • Superior salivatory nucleus (pons) → submandibular ganglion ▪ Parotid salivary glands (CN IX): • Inferior salivatory nucleus (medulla) → otic ganglion Synthesizing from Neuroanatomy • Salivary & lacrimal secretion is mainly under parasympathetic nervous system control • PaNS → more saliva, more watery, more digestive enzymes • SNS → less fluid, more “sticky” Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 20-4 Basic PaNS Anatomy – the Vagus • Responsible for most parasympathetic output ▪ nucleus –dorsal motor nucleus of the vagus ▪ Longest course of any cranial nerve – leaves through jugular foramen and descends alongside the carotid arteries ▪ Forms anterior and posterior trunks at the stomach and divides to supply plexuses in the abdominal cavity, all the way to the left (distal) colon Moore’s Clinically-Oriented Anatomy, p. 2410, fig. 10.16 Basic PaNS Anatomy – Sacral Efferents • Bodies found in S2 – S4 levels • Travel with pelvic splanchnic nerves to supply: ▪ the rectum ▪ bladder ▪ male and female reproductive organs Waxman, S.G. Clinical Neuroanatomy, 29th ed. Fig. 20-5 ANS - Neurotransmitters • The sympathetic and parasympathetic nervous systems use particular neurotransmitters (and therefore receptors) at particular sites SNS Preganglionic SNS Postganglionic PaNS Preganglionic PaNS Postganglionic Neuronal Cell Body Intermediolateral column, T1 – L3 Prevertebral and paravertebral Brainstem nuclei & sacral segments Small ganglia in walls of viscera Myelinated? Yes No Yes No Main Neurotransmitter Acetylcholine Norepinephrine (+ Epinephrine in adrenal medulla) Acetylcholine Acetylcholine Main receptors Nicotinic Adrenergic Alpha and Beta Nicotinic Muscarinic Notable exceptions Acetylcholine in skin Adrenal glands don’t have post-ganglionic innervation… they “are” the ganglion Sp. Cd. Sp. Cd. SOMATIC NERVOUS SYSTEM muscle AUTONOMIC NERVOUS SYSTEM Sympathetic ACH N ACH α,β, : NE Heart, Sm. mus. Glands → E, → NE Ad. M. N (M: Most (ACH) Sweat Glands) (ACH) N Brainstem or Sp. Cd. ACH N: Skeletal Parasympathetic ACH N M: Heart, ACH Sm. mus. Glands The Sympathetic Nervous System - Review • “Fight or Flight” ▪ ▪ ▪ ▪ ▪ ▪ ▪ ▪ Increases heart rate and cardiac output Improves ventilation Decreases digestive function Increases glucose availability (gluconeogenesis, glycogenolysis) Increases blood flow to skeletal muscles, heart Decreases blood flow to GI tract, skin, kidneys Reduced contraction of bladder, contraction of urethral sphincter Major neurotransmitters: epinephrine and norepinephrine • Note – the sympathetic nervous system tends to supply visceral AND “non-visceral” organs ▪ Non visceral includes: • Skin (blood vessels, glands) • Skeletal muscles (blood vessels, general metabolism) The Parasympathetic Nervous System - Review • “Rest and digest” ▪ ▪ ▪ ▪ ▪ Decreases heart rate and cardiac output Bronchoconstriction and increased mucous secretion Increases digestive function and GI motility Increases blood flow to digestive tract Increased bladder contraction, relaxation of urethral sphincter ▪ Increased blood flow to external genitalia ▪ Major neurotransmitter: acetylcholine • Note: the parasympathetic nervous system has relatively little impact on blood vessels outside of: ▪ the GI system ▪ the reproductive system Autonomic Nervous System Actions – an Overview Boron & Boulpaep, Medical Physiology: A Cellular and Molecular Approach, 2005: fig. 14-4 Acetylcholine Metabolism • Acetylcholine is synthesized in presynaptic nerve terminals and then stored in vesicles ▪ Reaction: • Acetyl-CoA + Choline ----------------> Acetylcholine • Enzyme: choline acetyltransferase • After it is secreted into the synapse, it’s degraded by acetylcholinesterase ▪ Degraded to acetate and choline (choline is taken back up into the presynaptic terminal) Basic cholinergic synapse • Acetylcholinesterase is widely distributed in connective tissue throughout the body and in the synapse of cholinergic terminals Katzung & Vanderah, Basic and Clinical Pharmacology, 15th ed., fig. 6-3 Catecholamine Synthesis • Norepinephrine synthesis is slightly more complicated: ▪ Outside the vesicle: • Tyrosine ---------------------> Dopa (hydroxylation) • Dopa -------------------------> Dopamine (decarboxylation) ▪ Then, dopamine is transported into the synaptic vesicle: • Dopamine -------------------> Norepinephrine (hydroxylation) ▪ In the adrenal medulla, most norepinephrine is converted into epinephrine through methylation (in the vesicle) • Norepinephrine ------------> Epinephrine (methylation) Catecholamine Synthesis https://commons.wikimedia.org/wiki/File:Catecholamines_biosynthesis.svg Catecholamine degradation • 50 – 80% of secreted norepinephrine is taken up again into the presynaptic terminal ▪ Not an option for epinephrine, which is secreted into the bloodstream by the adrenal medulla (endocrine) • Norepinephrine can be broken down by monoamine oxidase near the synapse ▪ degradation product – dihydromandelic acid (FYI) • It can also be broken down by catechol-O-methyltransferase (COMT) ▪ COMT is widely distributed throughout tissues ▪ degradation product is metanephrine (FYI) Major Types of Receptors Receptor Type Agonist Antagonist Gprotein Signaling pathway Nicotinic Acetylcholine Curare N/A Ionotropic receptor → sodium channel 1 adrenergic NE > Epi Phenylephrine Phentolamine Prazosin Gq PLC → IP3, DAG → increased calcium 2 adrenergic NE > Epi Clonidine Phentolamine Gi Inhibits AC→ decreased cAMP 1 adrenergic Epi > NE isoproterenol Metoprolol Propanolol Gs Excites AC → increased cAMP 2 adrenergic 3 adrenergic Epi > NE albuterol Propanolol Gs Excites AC → increased cAMP M1 muscarinic M3 muscarinic Acetylcholine Atropine Gq PLC → IP3, DAG → increased calcium M2 muscarinic Acetylcholine Atropine Gi Inhibits AC → decreased cAMP Organ Sympathetic Stimulation Parasympathetic Stimulation Heart - Increased rate & contractility (β1) - Mostly decreased rate & (M) Blood vessels - Constriction in skin and most vascular beds (α1) - Dilation in sk. mus., coronary arteries, liver (β2) *- Vasodilation (M) Lung - Relaxation of bronchial muscle (β2) and decreased mucous secretion - Contraction of bronchial muscle & secretions from glands (M) GI tract - Decreased motility (β2) - Sphincter contraction (α1) - Increased motility (M) - Sphincter relaxation (M) Bladder - Relaxation of detrusor muscle (β2) - Contraction of sphincter (α1) - Contraction of detrusor mus. (M) - Relaxation of sphincter (M) Kidney - Renin secretion (β) - Ureter peristalsis (M) Liver - Glycogenolysis (α1, β2) - Glycogenesis (M) Adipose - Lipolysis (β3/1) - Lipogenesis (M) Eye - Dilation of pupil (mydriasis) (α1) - Constriction of pupil (M) - Contraction of ciliary muscle (M) - Lacrimal gland secretion (M) Salivary glands - Minimal, viscous secretions (α1) - Profuse, watery secretions (M) Sweat glands - Increased secretions on hands & feet (α1) - Increased secretions except hands & feet (M) General Considerations • Eye: ▪ Both the parasympathetic (constriction) and sympathetic (dilation) outputs are important for pupillay size ▪ However, focusing the lens is mostly under control of the parasympathetic system • Nasal, lacrimal, salivary, gastrointestinal glands: ▪ strongly stimulated by parasympathetic activity – lots of watery secretions that are rich in enzymes (when enzymes apply) ▪ glandular secretion can also be stimulated by the SNS – less watery, therefore usually lower rate of secretion ▪ The glands of the intestines are less controlled by the ANS, more by the food in the lumen of the gut General Considerations • Sweat glands ▪ stimulated by the sympathetic nervous system – however, the neurotransmitter secreted is acetylcholine • Blood vessels ▪ Sympathetic nervous system – vasoconstriction in most vascular beds – mediated by alpha-1 receptors • Vasodilation in others mediated by beta-2 receptors in skeletal muscles, heart, liver ▪ Parasympathetic nervous system – very limited effect on any blood vessels outside the GI tract and reproductive organs General Considerations • Heart: ▪ Sympathetic nervous system – beta-1 receptors increase contractility (basically, force of contraction) and heart rate → increased cardiac output ▪ Parasympathetic – muscarinic receptors decrease heart rate but have a small (negative) influence on contractility • Glucose metabolism: ▪ No role for the parasympathetic nervous system ▪ Gluconeogenesis, glycogenolysis, hyperglycemia with sympathetic nervous system stimulation General Considerations • The parasympathetic nervous system usually causes specific, localized responses ▪ Many of these are mediated through the reflexes in the next slide • The sympathetic nervous system can participate in specific, localized responses as well – the usual day-to-day function of the SNS • The SNS can also be overwhelmingly activated (mass discharge) to accomplish the “fight or flight” response ▪ Arterial pressure, heart rate, and perfusion to skeletal muscle, heart, brain increase ▪ Decreased blood flow through the GI tract, skin, kidneys ▪ Hyperglycemia, increased general cellular metabolism, and increased coagulation Autonomic Nervous System Reflexes • Major reflexes include: ▪ Baroreceptor reflex • afferent – baroreceptors from CNs IX and X • efferent – parasympathetic and sympathetic → CN X, thoracic plexus ▪ GI reflexes mediated by sensing food (whether sight/taste/smell or presence of food/secretions in the lumen) • afferent – visceral receptors from CN X • efferent – CN X ▪ Micturition (urination) reflex • afferents & efferents at the level of the sacral spinal cord Nucleus tractus solitarius in the medulla receives input from the afferents, sends output to a wide variety of other brain areas Intro to ANS Pharmacology • Adrenergic Agonists ▪ Acting outside receptors ▪ Acting directly at the receptor • Adrenergic Antagonists ▪ Acting outside receptors ▪ Acting directly at the receptor • Brief overview of Cholinergics ▪ Cholinomimetics ▪ Anticholinergics Autonomic Pharmacology Is Complex • How could we increase activation of the catecholamine receptor on the postsynaptic membrane? • How could we decrease it? Indirect Affects on Post-Synaptic Adrenergic Transmission • Prevention of storage in the NT vesicle ▪ Reserpine – blocks VMAT → depletion of catecholamines ▪ Increase or decrease in catecholamine transmission? • Non-vesicle-mediated “leakage” of neurotransmitter from the presynaptic terminal ▪ Amphetamine, tyramine ▪ Increase or decrease in catecholamine transmission? Indirect Affects on Post-Synaptic Adrenergic Transmission • Inhibition of reuptake at the presynaptic terminal ▪ Cocaine, selective norepinephrine reuptake inhibitors (i.e. Effexor) ▪ Increase or decrease in catecholamine transmission? • Inhibition of NT degradation ▪ Mono-amine oxidase inhibitors (tranylcypromine) ▪ Increase or decrease in catecholamine transmission? • Inhibition of NT release due to auto-receptor activation ▪ Clonidine thought to be a major example ▪ Increase or decrease in catecholamine transmission? Agonists and Antagonists • Agonist – a substance that activates a receptor when it binds to it ▪ Variation – a partial agonist is a substance that binds to a receptor but doesn’t activate it fully • Antagonist – a substance that inactivates a receptor or enzyme when it binds to it ▪ Can be reversible – it will eventually “let go” of the receptor or enzyme ▪ Can be irreversible – it stays bound, and the receptor or enzyme (usually enzyme) is rendered useless Receptor Selectivity • Alpha and beta receptors have different affinities for different agonists and antagonists ▪ For example – beta receptors have a high affinity for isoproterenol, but alpha receptors have a negligible affinity • Isoproterenol is therefore a selective beta-agonist ▪ Beta-1 receptors have a high affinity for metoprolol, but beta-2 receptors don’t • Metoprolol is therefore a selective beta-1 antagonist Autonomic Nervous System Actions – an Overview Boron & Boulpaep, Medical Physiology: A Cellular and Molecular Approach, 2005: fig. 14-4 Organ Sympathetic Stimulation Parasympathetic Stimulation Heart - Increased rate & contractility (β1) - Mostly decreased rate & (M) Blood vessels - Constriction in skin and most vascular beds (α1) - Dilation in sk. mus., coronary arteries, liver (β2) *- Vasodilation (M) Lung - Relaxation of bronchial muscle (β2) and decreased mucous secretion - Contraction of bronchial muscle & secretions from glands (M) GI tract - Decreased motility (β2) - Sphincter contraction (α1) - Increased motility (M) - Sphincter relaxation (M) Bladder - Relaxation of detrusor muscle (β2) - Contraction of sphincter (α1) - Contraction of detrusor mus. (M) - Relaxation of sphincter (M) Kidney - Renin secretion (β) - Ureter peristalsis (M) Liver - Glycogenolysis (α1, β2) - Glycogenesis (M) Adipose - Lipolysis (β3/1) - Lipogenesis (M) Eye - Dilation of pupil (mydriasis) (α1) - Constriction of pupil (M) - Contraction of ciliary muscle (M) - Lacrimal gland secretion (M) Salivary glands - Minimal, viscous secretions (α1) - Profuse, watery secretions (M) Sweat glands - Increased secretions on hands & feet (α1) - Increased secretions except hands & feet (M) Notable Alpha-Adrenergic Agonists • Phenylephrine ▪ Selective agonist for alpha-1 receptors ▪ Main indication is as an over-the-counter decongestant • Causes vasoconstriction and decreased secretions from the nasal mucosa ▪ Can also be used IV (emergently) to increase blood pressure • Clonidine ▪ Selective alpha-2 agonist • Acts on presynaptic terminals to reduce adrenergic transmission in the central nervous system ▪ Main indication is as an antihypertensive – reduction of sympathetic nervous system activity Notable Beta-Adrenergic Agonists • Isoproteronol and dobutamine are mostly used in internal medicine/intensive care settings ▪ Isoproteronol – activates beta-1 and beta-2 receptors ▪ Dobutamine – activates beta-1 receptors with less beta2 receptor effect ▪ Both increase cardiac output… but dobutamine will increase blood pressure the most • Why would this be? • Albuterol, salbutamol are inhaled selective beta-2 agonists ▪ Activate beta-2 receptors in the bronchioles