ANS Physiology and Receptors in brief.pptx

Ans physiology and receptors

1. AUTONOMIC NERVOUS SYSTEM Moderator – Dr. Radha Sundari Assistant Professor, dept. of anesthesiology

2. Nervous system CENTRAL PERIPHERAL SOMATIC AUTONOMIC SYMPATHETIC ENTERIC PARASYMPATHETIC

3. AUTONOMIC NERVOUS SYSTEM Autonomy means Self Governing Controls Involuntary activities of the body outside consciousness. Essential – oversees responses to immediate life threatening challenges and body’s vital maintenance needs Primary defense against challenges to homeostasis

4. Sympathetic nervous system Redistribution of blood flow Increases Cardiac Function Sweating Pupillary Dilatation Produces Amplification Response Para-Sympathetic nervous system More closely governs digestive and genitourinary functions Produces more discrete and narrowly targeted response

5. history Claude Bernard – Role of ANS in Homeostasis Sherrington – Study of Reflex functions J.J.Abel – First synthesized Epinephrine Langley – Proposed DENERVATION SENSITIVITY Sir Henry Dale – Isolated Choline Jacob Winslow – Coined the term Sympathetic

6. Central organization of ans Cerebral cortex is the highest level of ANS integration. The principal ANS organization is the Hypothalamus. SNS functions are controlled by nuclei in the postero -lateral hypothalamus. PNS functions are governed by nuclei in the midline and some anterior nuclei of the hypothalamus.

7. Somatic vs autonomic

8. Cholinergic nerves Motor nerves that innervate Skeletal Muscle (Somatic NS) Post Ganglionic Para Sympathetic Pre Ganglionic Sympathetic and Para Sympathetic Central Cholinergic Neurons Some Post Ganglionic Sympathetic – Sweat Gland Pre Ganglionic Neurons from Greater Splanchnic Nerve that innervate Adrenal Medulla

9. Adrenergic neurons Post Ganglionic Sympathetic Neurons Some Interneurons Certain Central Neurons Adrenergic Neurons release only Nor-Epinephrine at Neuro Effector Junction whereas Adrenal Medulla release both Epinephrine and Nor-Epinephrine

10. Sympathetic nervous system Thoraco Lumbar Outflow – T 1-12 & L 1-3 Cell bodies lie in the Inermediolateral Columns of Spinal Cord Grey Matter Nerve fibers extend to three types of Ganglia Paired Sympathetic Chains Unpaired Distal Plexus Terminal/Collateral Ganglia near the Target organs

11. Paired sympathetic chains Pre Ganglionic Cell bodies lie in the Intermediolateral Columns of Spinal Grey Matter Fibers leave via the Anterior Nerve Roots to join the spinal nerve trunks Enter the ganglia at the respective level through White Myelinated Ramus Post Ganglionic fibers leave the ganglion and re-enter spinal nerves through Grey Unmyelinated Ramus and innervate pilomotor and sweat glands and blood vessels of skeletal muscles and skin Sympathetic innervation to Head and neck (vasomotor and pupillodilator ) originate in the upper thoracic segments

12. Unpaired pre-vertebral ganglia They reside in the abdomen and pelvis anterior to Vertebral Column Celiac Ganglia – T 5 -T 12 – Innervates Spleen, Liver, Kidney, Pancreas, Small Bowel and Proximal Colon Superior Mesenteric – Innervates Distal Colon Inferior Mesenteric - Innervates Bladder, Rectum and Genitals Terminal/collateral ganglia Small and few near Target organs Eg – Adrenal Medulla

13. Parasympathetic nervous system Cranio Sacral Ouflow CN – 3,7,9,10 Sacral – S 2 -S 4 Ganglia are more close to the effector organs Pre Ganglionic fibers originate from – Midbrain, Medulla and Sacral part of spinal cord

14. Cn - iii Fibers originating from Edinger-Westphal Nucleus course in Mid Brain to synapse in Ciliary Ganglion They Innervate Smooth Muscles of iris and Ciliary Muscle

15. Cn - vii From the Medulla it gives of para sympathetic fibers to Chorda tympani which synapses in ganglia of Sub-Maxillary and Sub-Lingual Glands Fibers to Greater Superficial Petrosal Nerves synapses in the Sphenopalatine Ganglia

16. Cn - ix It synapses in the Otic Ganglion Post Ganglionic fibers innervate Mucous, Salivary and Lacrimatory Glands They also carry Vasodilatory fibers

17. Cn - x This is most important as it carries our 75% of Para Sympathetic Nervous system Supplies – Hear, Tracheobronchail tree, Liver, Spleen, Kidney, Entire GIT except distal colon Most fibers synapse with Nerve to Effector cell in 1:1 ratio Vagal innervation of Auerbach plexus connect 1 nerve fiber to 8000 cells

18. Sacral outflow Called Nervi Erigentes /Pelvic Splanchnic Nerves Synapse in Terminal Ganglia associated with Rectum and Genitourinary functions

19. Enteric nervous system Within the walls of GIT including Pancreas and Gall Bladder Extra-ordinary degree of Local Autonomy Digestion and peristalsis, occurs after spinal cord transection or during spinal anesthesia, although sphincter function may be impaired. Although functionally discrete, gut if influenced by SNS & PNS Sympathetic pre ganglionic from T 8 -L 3 inhibit gut action through celiac, superior and inferior mesenteric ganglia Nor–Epinephrine is Post Ganglionic Transmitter When viscera are handled during abdominal surgeries, reflex firing of Adrenergic Nerves inhibit the Motor activity of Intestine for extended period This is the basis of Post-Op ILEUS

20. It contains two plexus Myenteric/ Aeurbach Plexus Between External longitudinal and Circular Muscle Layers Nerve strands and small Ganglia are present Sub Mucous/Meissner’s Plexus Nerve Cell bodies, Glial cells and Neuronal Processess Ach is the principal Excitatory trigger of non specific portion of ENS which cause muscle contractions Cholinergic Neurons have several roles in ENS, including excitation of External Muscle, Activation of Motor Neurons and Augmenting Secretion of Water and Electrolytes and Stimulation of Gastric Cells

21. Enteric Motor Neurons are evoked by local reflexes. Eg - Distention evokes polarized reflexes like proximal contraction and distal relaxation which synchronously constitute peristalisis Nicotinic antagonists abolish enteric reflexes, thus suggesting that sensory neurons or interneurons in pathway are cholinergic In case of Cholinergic overload, like insecticide poisoning or excess Neostigmine when reversing a NDMR, the gut has tendency to become hyperactive NANC Neurotransmitters like NO, Substance – P, Opiate Peptides, VIP are also present in the gut

22. ANTAGONISTIC CONTROL Most organs have dual innervation of Sympathetic and Para sympathetic Eg - Heart – Sympathetic – Increases HR Parasymp . - Decreases HR One system usually predominates giving a resting Tone Exception to this dual innervation rule is SWEAT GLANDS AND BV SMOOTH MUSCLE having only sympathetic Exception to antagonism rule Sometimes SNS and PNS work co-operatively Eg - Parasymp – Erection Sympathe – Ejaculation in sexual function

23. Sympathetic nervous system Predominant Neurotransmitter is Epinephrine CATECHOLAMINES A catecholamine is any compound having a catechol nucleus (a benzene ring with 2 adjacent OH group) and an amine containing side. Endogenous catecholamines in humans are dopamine, NE and EPI. Dopamine is a neurotransmitter in CNS and primarily involved in co-ordinating motor activity in the brain. It is a precursor of NE. NE is synthesized and stored in the nerve endings of postganglionic SNS neurons. Catecholamines are often referred to as adrenergic drugs because their effector action is mediated through receptors specific for the SNS.

24. STORAGE OF NOR-EPINEPHRINE In dense core vesicles along with binding proteins Vesicles contain calcium, ATP and peptide Depending on the nature and freq. of physiologic stimuli ATP is released sometimes although predominant NT is Nor-Epi. Release of nor-epinephrine Membrane depolarization causes Ca +2 influx which leads to Vesicular docking and fusion and finally release of contents Ag-II, Histamine, Prostacycline Potentiate release Ach, PG-E Inhibit release

25. Inactivation Most of the Nor-Epinephrine is transported into storage vesicles for reuse This is driven by Electrochemical proton gradient across synaptic cleft This Vacuolar proton pump is a large hetero oligomeric complex containing 8-9 subunits No reuptake in peripheral BV and so rapid rates of Nor-Epi. Synth is required for vascular tone modulation metabolism By MAO/COMT/both in Blood, Liver, Kidney End product – VMA Due to rapid clearance, half life of Nor-Epi in plasma is short <1min and so infusion is required

26. TYRAMINE Synthesized from Tyrosine Present in Aged Cheese Enters symp . Nerve terminal, displaces Nor-Epi from vesicles into cytoplasm, from which it leaks out of nerve terminal and causes hypertension

27. α -Adrenergic Members of 7 Transmembrane segment gene superfamily which uses signal Transduction Core of 175 AA β -Adrenergic 7 Helices passing through cell membrane – M1-M7 Antagonists have specific binding sites whereas agonists are more diffusely attached to hydrophobic membrane

28. Dopamine Receptors DA-1 Post Synaptic Renal, Mesenteric, Splenic, Coronary Vascular SM Vasodilation Act via Adenylate Cyclase stimulation and Increase cAMP Vasodilator effect maximal in Renal Arteries In renal tubules modulate natriuresis through Na + -K + ATPase DA-2 Pre Synaptic Inhibit Nor-Epi and Ach release Central DA2 receptors mediate Nausea and Vomiting

29. Gtp binding regulatory proteins G-Proteins are heteromeric compounds composed of three subunits α , β , γ β , γ form a stable complex and α -subunit associates with them in reversible fashion α has 20 subtypes which determines the function of G-Protein Four classes of α subunits are α s , α i , α q , α 12 Correspondingly G s , G i , G q , G α 1 --- G q ---activates Phospholipase-C α 2 - -- Gi---Inhibits Adenyl Cyclase β ---- G s ---activates Adenyl Cyclase-----causes cAMP formation

30. Para sympathetic nervous system Predominant NT is Acetyl Choline Synthesis Choline + Acetyl Co-A Ach which is transported into vesicles Ach is stored in Vesicle pools VP-1 – Reserve Pool VP-2 – Readily releasable pool VP-2 – Smaller, ordinarily released transmitter VP-1 – Tethered to cytoskeleton in filamentous network made up of primarily Actin, Synapsin (Actin Binding Protein), Spectrin and Synaptogramin Choline Acetyl Transferase

31. Vesicles are coated by Membrane Proteins Synaptophysin – Glycoprotein component of Vesicular Membrane Synaptogramin – Vesicle Ca +2 sensor Synapsin – Phosphorylation of which cause Vesicular trafficking to release site Synaptobrevin – SNARE protein which forms a ternary complex with syntaxin (SNAP-25) nerve terminal membrane protein (SNARE – Soluble N- ethylmeleinide Sensitive attachment protein receptor) The amount of Ach release by each impulse is large - at least 200 quanta One Quanta = 500 Ach Molecules With each impulse number of Ach receptors activated = 5,00,000

32. metabolism By Ach Esterase or reuptake Ach Esterase is a Type-B Carboxyl esterase enzyme One molecule of Ach reacts with only one receptor before it is hydrolyzed Due to its rapid Metabolism, Ach is destroyed in <1 millisecond after its relase

33. Nicotinic receptors Pentamers of 5 sub units – Ligand gated ion channels Three isoforms exist Junctional or Mature Extra-Junctional or Immature or Fetal Neuronal Mature – 2 α , 1 β , 1 δ , 1ε subunits Immature - 2 α , 1 β , 1 δ , 1 γ subunits Neuronal - 5 α 7 subunits Each subunit = 400-500 AA Ach, agonists and antagonists attach over α subunits

34. muscarinic receptors Uses G- Protein coupled receptors with 7 helical structure M1-M7 with structural variability between 6 th and 7 th No selective drugs on these receptors M2 predominates in Visceral Organs M2,3 on airway smooth muscles More M2 receptors than β -Adrenergic and so β agonists cannot reverse cholinergic broncho constriction M1,3,5- Hydrolysis of Phospho inositide M2,4 – Adenylate Cyclase Due to this complex coupling mechanism, response of Muscarinic receptors is sluggish and slow Although Ach is short-lived, the events that it initiates causes the response to continue for many minutes

35. M 1,3,5 M 4,5

36. Adrenergic function Endogenous Catechol amines - Epinephrine and Nor-Epinephrine has α and β activity Nor Epi.- Minimal β 2 receptor activity α - mediated is responsible for most of the sympathetically induced SM contraction throughout the body, including ciliary muscle of eye α 2 - decreases Pancreatic insulin release Although Acute changes in Arterial BP and HR are caused by Nor-epi and epinephrine, chronic HTN do not appear to be related to circulating levels of these hormones 85% of Resting Arterial BP is determined by the level of Renin activity

37. GI and GU sphincter mechanisms are stimulated by α adrenergic receptors α 1 causes Arterial constriction α 2 causes Venous Constriction β 1 – Cardiac effects, Release of FA and renin β 2 – SM relaxation and Hyperglycemia Public Speaking stimulates adrenal gland and leads to disproportionate rise in Serum Epinephrine Physical Exercise increases Serum Nor-Epinephrine

38. Blood glucose β 3 stimulates lipolysis from Adipose Tissue and glycogenesis in Liver which causes blood glucose levels to rise In Neonates, Epinephrine plays a role in the exothermic breakdown of brown fat to maintain body temperature – Non shivering Thermogenesis Pancreatic α 2 activation suppress Insulin secretion. If these receptors are blocked, Increases Insulin and Lowers Blood Glucose Stimulation of β 2 receptors increase glucagon and insulin secretion and also decrease peripheral sensitivity to Insulin

39. Potassium shift Epinephrine controls serum Potassium levels β 2 adrenergic stimulation Glucose Efflux K + shifts out of Hepatic Cells Initial Transient Hyperkalemia Drives K + into RBC & Muscle Cells Prolonged Hypokalemia later Cardiac Arrhythmias with MI

40. Cholinergic function More localized Massive Parasympathetic response causes – Salivation, weeping, wheezing, vomiting, urinating, defecating and sneezing – in short all secretions increase CVS SA-NODE – Causes Membrane Hyperpolarization and so ability to reach threshold potential is delayed and HR is decreased AV-NODE – Decreases Conduction velocity and Increases Effective Refractory Period. This can be seen as a complete heart block when large amounts of Ach are given In Ventricles decreases Automaticity in Purkinje System and thus increases fibrillation Threshold Inhibits adrenal stimulation of heart pre synaptically by inhibiting Nor-Epi. release from sympathetic Nerve endings and post synaptically by opposing effects of catecholamines on heart

41. In Heart, Nor Epi Ach M2 G i /G o Inhibit Adenyalte Cyclase Decrease HR β 1 Gs Stimulate Adenyalte Cyclase Increase HR But the current caused by G o >>> G s Therefore in Heart, Vagal Control of HR predominates

42. Others SM Contraction GIT, GUT - SM in walls constricts but sphincter relaxes causing incontinence Topically constricts SM of iris - Miosis Local Vascular Tone Control Blood borne Ach dilates all the Blood Vessels due to EDRF production Endothelial cells also have receptors for Histamine, Serotonin, Adenosine, Catecholamines When Endothelium is damaged, EDRF production decreases causing vasoconstriction Endothelial cells also metabolize many vaso active amines, convert Ag-I to Ag-II, secrete Prostacyclins and Vasoconstrictive peptide Endothelin - I

43. AUTONOMIC REFLEXES

44. NON-ADRENERGIC NON-CHOLINERGIC NT’S IN ANS Mono-Amines, Purines, AA’s, Polypeptides NT’s in perivascular nerves include ATP, Adenosine, VIP, Substance-P, 5-HT, Neuropeptide-Y, Calcitonin Gene Related Peptide (CGRP) MC in Sympathetic – Nor-Epi, ATP, NPY Parasympathetic – Ach, VIP Sensorimotor Nerves – Substance-P, CGRP, ATP

45. Perivascular sympathetic nerves release ATP and Nor-Epi from same nerve endings ATP acts via P 2 purinoceptors by Voltage dependent Ca +2 channels causing fast component of Vessel Contraction Nor-Epinephrine via α 1 causes sustained vaso constriction ATP released in HTN---binds to MgCl 2 -----vasodilator-----Decrease BP ATP and NO stimulus in GIT inhibit Peristalsis NPY is a Neuromodulator Prejunctionally inhibit Nor-Epi release Postjunctionally enhance Nor-Epi Action It also acts as a direct vasoconstrictor in spleen, skeletal muscle, cerebral vasculature, coronary vasculature In Heart and Brain it is the principal NT in local intrinsic non sympathetic neurons

46. In Para symp – Ach and VIP are stored in separate vesicles Depending on the intensity and frequency of the stimulus they are release Ach is released at low frequencies of stimulation VIP is released at high frequencies of stimulation In Salivary Glands, they act independently on Acinar Cells and Glandular BV

47. References Miller’s Anesthesia – 8 th Edition Ganong’s Physiology – 24 th Edition K.D.Tripathi Medical Pharmacology – 7 th Edition

48. Thank you