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ANS Pharmacology -Intro to the Autonomic Nervous System

Individualized Webcam facilitated and e-Classroom USMLE Step 1 Tutorials with Dr. Cray. For questions or more information..

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ANS Pharmacology -Intro to the Autonomic Nervous System

  1. 1. ANS Physiology and Pharmacology Overview | Review of Autonomic Nervous System Marc Imhotep Cray, M.D. Widmaier, EP. Vander’s human physiology 14th Ed. New York: McGraw-Hill, 2016.
  2. 2. Marc Imhotep Cray, M.D. Overall Goal “ Deconstruction, Reconstruction, Integration and Relationships” 2 The nineteenth-century physiologist Claude Bernard put it this way: “After carrying out an analysis of phenomena, we must . . . always reconstruct our physiological synthesis, so as to see the joint action of all the parts we have isolated. . .”
  3. 3. Marc Imhotep Cray, M.D. Topics Outline 3  Homeostasis  Basic Neuroanatomy and Neurophysiology of ANS  Neurotransmitters  Receptors  Receptor-Ligand Interactions & Signal Transduction  Autonomic and Somatic Pharmacology Terminology
  4. 4. Marc Imhotep Cray, M.D. Learning Objectives 4 After this presentation the learner should be able: To describe the two divisions of the ANS and the main functions and effects of each division. To explain how sympathetic and parasympathetic nerves interact with each other to regulate organ function (maintain homeostasis) To describe the fight or flight reaction and explain how sympathetic activation affects the activities of the different organs To list the main organ effects caused by parasympathetic stimulation To describe the different autonomic receptors that are stimulated by acetylcholine, norepinephrine, and epinephrine To describe signaling mechanisms and pharmacology of ANS receptor subtypes
  5. 5. Marc Imhotep Cray, M.D. Autonomic Nervous System (ANS) 5  Autonomic nervous system (ANS) is part of nervous system responsible for homeostasis  Except for skeletal muscle, which gets its innervation from somatomotor nervous system, innervation to all other organs is supplied by ANS
  6. 6. Marc Imhotep Cray, M.D. ANS vs. Endocrine System in Homeostasis 6 Autonomic nervous system (ANS) is moment-to-moment regulator of internal environment regulating specific functions that occur without conscious control:  respiration  circulation  digestion  body temperature  metabolism  sweating, secretions of certain endocrine glands Endocrine system, in contrast, provides slower, more generalized regulation by secreting hormones into the systemic circulation to act at distant, widespread sites over periods of minutes to hours to days
  7. 7. Marc Imhotep Cray, M.D. ANS and Endocrine System [common properties] 7  high-level integration in the brain  ability to influence processes in distant regions of body  extensive use of negative feedback  maintaining homeostasis  both systems use chemicals for transmission of information
  8. 8. Marc Imhotep Cray, M.D. 8  Referring to animal systems, 20th century physiologist Walter Cannon coined the word homeostasis in 1926  “Coordinated physiological reactions which maintain most of the steady states in the body are so complex, and are so peculiar to the living organism, that it was suggested (Cannon, 1929) that a specific designation for these states be employed – homeostasis” Courtesy National Library of Medicine Walter Cannon coined word homeostasis Cannon, WB, Organization for Physiological Homeostasis.pdf Physiological Rev July 1, 1929 9:399-431 Also see: Cray MI. Walter Cannon, Homeostasis and the Physiological Response to Stress, A Web Interactive PowerPoint Presentation
  9. 9. Marc Imhotep Cray, M.D. 9 Homeostasis (1)  The physiologic process of maintaining an internal environment (ECF environment) compatible w normal health  Autonomic reflexes maintain set points and modulate organ system functions via negative feedback in pursuit of homeostasis
  10. 10. Marc Imhotep Cray, M.D. Homeostasis (2) 10 A dynamic steady state of constituents in internal environment (ECF) that surrounds and exchanges materials with cells Factors homeostaticly maintained include: (Controlled Variables)  Concentration of nutrient molecules  Concentration of O2 and CO2  Concentration of waste products  pH  Concentration of water, salts, and other electrolytes  Temperature  Volume and pressure  GFR  …and others
  11. 11. Marc Imhotep Cray, M.D. 11 Nervous Endocrine WirelessWired Hormones Short Distance Long Distance Closeness Receptor Specificity Rapid Onset Delayed Onset Short Duration Prolonged Duration Rapid Response Regulation versus Neurotransmitters Hormones Short Distance Long Distance Homeostasis (3)
  12. 12. Marc Imhotep Cray, M.D. 12 ERROR SIGNAL COMPARATOR SET POINT + - CONTROLLED VARIABLE (SEE NEXT SLIDE) SENSOR EFFECTOR -NEGATIVE FEEDBACK Components of a negative feedback control system Negative feedback: Initiation of responses that counter deviations of controlled variables from their normal range Measures control variable Recognizes deviation of normal set point value Redrawn after: Kibble JD, Halsey CR, Homeostasis. In: Medical Physiology -The Big Picture; McGraw-Hill , 2009; 2. Attempt to restore set point value Important variable maintained within a normal range Effector opposes stimulus stretch receptors, chemo-, baro-, osmo-, and thermo- receptors etc.
  13. 13. Marc Imhotep Cray, M.D. 13 Controlled Variable Typical Set Point Value (Arterial Blood Sample) Arterial O2 partial pressure Arterial CO2 partial pressure Arterial blood pH Glucose Core body temperature Serum Na+ Serum K+ Serum Ca2+ Mean arterial blood pressure Glomerular filtration rate 100 mm Hg 40 mm Hg pH 7.4 90 mg/dL (5 mM) 98.4°F (37°C) 140 mEq/L 4.0 mEq/L 4.5 mEq/L 90 mm Hg 120 mL /min Examples of Physiologic Controlled Variables & Set Points Adopted from: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology :The Big Picture. New York, NY: McGraw-Hill , 2009; 3.
  14. 14. Marc Imhotep Cray, M.D. Important Negative Feedback Control Systems 14 Modified from Carroll RG. Elsevier’s Integrated Physiology. Mosby, Inc. 2007; Table 1-3, Pg. 5.
  15. 15. Marc Imhotep Cray, M.D. 15 ERROR SIGNAL COMPARATOR SET POINT + Mean Arterial Blood Pressure (MAP) SENSOR EFFECTOR -NEGATIVE FEEDBACK Example: Baroreceptor Reflex control of blood pressure stretch receptors in Aortic arch and Carotid sinus N 95 mm Hg CNS| Medulla Oblongata cardiac contractility, vascular tone, urinary fluid excretion Receptors: • Aortic arch transmits via vagus nerve to solitary nucleus of medulla (responds only to BP) • Carotid sinus transmits via glossopharyngeal nerve to solitary nucleus of medulla (responds to and in BP) See Baroreflex pdf
  16. 16. Marc Imhotep Cray, M.D. Baroreceptors & Chemoreceptors 16 • Hypotension- arterial pressure stretch afferent baroreceptor firing efferent sympathetic firing and efferent parasympathetic stimulation vasoconstriction, HR, contractility BP important in response to severe hemorrhage • Carotid massage - pressure on carotid artery stretch afferent baroreceptor firing HR Can by tried for Tachycardia (SVT) • Contributes to Cushing reaction (triad of hypertension, bradycardia, and respiratory depression) intracranial pressure constricts arterioles cerebral ischemia and reflex sympathetic increase in perfusion pressure ( hypertension) stretch reflex baroreceptor induced-bradycardia Chemoreceptors: • Peripheral—carotid and aortic bodies are stimulated by PO2 (< 60 mm Hg), PCO2, and pH of blood • Central—are stimulated by changes in pH and PCO2 of brain interstitial fluid, which in turn are influenced by arterial CO2 Do not directly respond to PO2 Baroreceptors:
  17. 17. Marc Imhotep Cray, M.D. 17 Baroreceptors & Chemoreceptors Mechanism Illustrated Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017.
  18. 18. Marc Imhotep Cray, M.D. 18 Mean Arterial Pressure Control and Autonomic & Hormonal Feedback Loops Katzung & Trevor. Pharmacology Examination & Board Review 10th Ed. New York: ; McGraw-Hill , 2014.
  20. 20. Marc Imhotep Cray, M.D. 20 Peripheral Nervous System (PNS) Peripheral nerves contain both motor and sensory neurons Motor neurons: somatic innervate skeletal muscles autonomic innervate smooth muscle, cardiac muscle, and glands (autonomic motor neurons) Sensory neurons are not subdivided into somatic and autonomic b/c there is overlap in function (input can be from either somatic or ANS) e.g., pain receptors can stimulate both somatic (withdrawal reflex) and autonomic reflexes (increased heart rate)
  21. 21. Marc Imhotep Cray, M.D. 21 Generic Neuron Anatomy Basic structural unit of nervous system >>> neuron
  22. 22. Marc Imhotep Cray, M.D. 22 Autonomic (Visceral) Reflex “Functional unit of the ANS”  Afferent fibers from periphery to CNS  CNS integration  Cortex  Thalamus  Hypothalamus  Medulla  Spinal cord  Efferent fibers from CNS to periphery
  23. 23. Marc Imhotep Cray, M.D. Sympathetic Nervous System Wiring 23 Gray ramus Sympathetic trunk White ramus Intermediolateral cell column (IML) Dorsal root ganglion See: ANS Summary Notes
  24. 24. Marc Imhotep Cray, M.D. 24 Organ receptors ( in viscus ) >>>> sensory (afferent ) neuron >>>>CNS lateral horn cell of spinal cord >>>> motor (efferent) neuron ( two neurons: pre & post ganglionic ) >>>> effector organ (smooth, cardiac muscle or gland) Functional Unit of ANS >> Visceral Reflex Arc Afferent fibers from periphery to CNS CNS integration Spinal cord Medulla Hypothalamus Thalamus Cortex Efferent fibers from CNS to periphery Effector response
  25. 25. Marc Imhotep Cray, M.D. 25 Neurotransmitters  Chemicals synthesized and stored in neurons  Liberated from axon terminus in response to action potentials  Interact with specialized receptors  Evoke responses in innervated tissues See: IVMS Neurotransmitters Notes
  26. 26. Marc Imhotep Cray, M.D. ANS Neurotransmitters 26 Class Small molecule Transmitters Catecholamines Chemical Acetylcholine Dopamine Norepinephrine Synthesis Choline + acetyl CoA, via enzyme Choline Acetyltransferase From the amino acid tyrosine via the enzyme Tyrosine hydroxylase in the catecholamine pathway From dopamine in the catecholamine pathway Postsynaptic Receptors Nicotinic (cation channel) Muscarinic (G-protein– coupled) D1 (stimulatory G- protein– coupled) D2 (inhibitory G-protein– coupled) α & β Adrenergic receptors Signal Termination Extracellular hydrolysis by Acetylcholinestrase Reuptake Reuptake or breakdown via the enzymes monoamine oxidase and catechol–O- methyltransferase Functions ANS Movement control Cognition ANS Movement control General affect ANS Alertness General affect NB: Epinephrine is a catecholamine released upon stimulation of SANS, produced in adrenal medulla. It is a neurohormone, not an ANS neurotransmitter
  27. 27. Marc Imhotep Cray, M.D. 27 Efferent autonomic nerves general arrangement  Innervation of smooth muscle, cardiac muscle, and glands  Preganglionic neuron  Peripheral ganglion - axodendritic synapse  Postganglionic neuron(s)  Effector organ(s) Pre Ganglion Post Effector organ
  28. 28. Marc Imhotep Cray, M.D. 28 Anatomic Divisions of ANS  Parasympathetic (PANS) (CN3,7,9,10) & (S2-S4)  Preganglionic axons originate in brain, and sacral spinal cord  Peripheral ganglia are near, often within* the effector organs  Ratio of postganglionic-to-preganglionic axons is small, resulting in discrete responses  Sympathetic (SANS) T1-L2/L3  Preganglionic axons originate in the thoracic and lumbar cord  Peripheral ganglia are distant from the effector organs  Ratio of post-to-preganglionic axons is large, resulting in widely distributed responses  Enteric Nervous System (ENS) (Discussed in GI) Has been described as a "second brain" for several reasons:  operate autonomous of SANS & PANS  Vertebrate studies show when the vagus nerve is severed, ENS continues to function * Exceptions are the four paired parasympathetic ganglia of head and neck
  29. 29. Marc Imhotep Cray, M.D. 29 Schematized Anatomic Comparison of PANS & SANS (1) (click to expand)
  30. 30. Marc Imhotep Cray, M.D. 30 Schematized Anatomic Comparison of PANS & SANS (2) Pre Ganglion Effector organ PostThoracic or lumbar cord Pre Ganglion Effector organ Post Cranial or sacral cord Parasympathetic Sympathetic Effectors: cardiac muscle, smooth mm, vascular endothelium, exocrine glands, and presynaptic nerve terminals ANS functions:  circulation  digestion  respiration  temperature  sweating  metabolism  some endocrine gland secretions
  31. 31. Marc Imhotep Cray, M.D. 31 Cranial Nerve Parasympathetic Innervations
  32. 32. Marc Imhotep Cray, M.D. 32 Somatic Nervous System (included for comparison)  Efferent innervation of skeletal muscle  No peripheral ganglia  Rapid transmission, discrete control of motor units  Voluntary Any spinal segment Motor neuron Striated muscle Myelinated wi a high conduction velocity In contrast Postganglionic neurons of ANS are unmyelinated w a low conduction velocity
  33. 33. Marc Imhotep Cray, M.D. 33 Neurochemical Transmission in Peripheral Nervous System (PNS)  Cholinergic nerves  Acetylcholine is neurotransmitter  Locations of Ach  Preganglionic neurons to all ganglia  Postganglionic, parasympathetic neurons  “Preganglionic” fibers to adrenal medulla  Postganglionic, sympathetic neurons to sweat glands in most species  Somatic motor neurons
  34. 34. Marc Imhotep Cray, M.D. 34 Cholinergic Neurotransmission Pre Ganglion Effector organs PostThoracic or lumbar cord Pre Ganglion Effector organ Post Cranial or sacral cord Parasympathetic Sympathetic Denotes ACh Denotes ACh
  35. 35. Marc Imhotep Cray, M.D. 35 Adrenergic Neurotransmission  Adrenergic nerves  Norepinephrine is the neurotransmitter  Locations  Postganglionic, sympathetic axons Pre Ganglion Effector organs PostThoracic or lumbar cord Sympathetic Denotes Norepinephrine Denotes ACh
  36. 36. Marc Imhotep Cray, M.D. 36 Adrenal Medulla  Presynaptic nerves are cholinergic  Medullary cells (*Chromaffin cells) synthesize and release two, related catecholamines into systemic circulation  Epinephrine (adrenaline)  Norepinephrine  Epi and NE stimulate adrenergic sites *They release catecholamines: ~80% Epinephrine and ~20% Norepinephrine into systemic circulation for systemic effects on multiple organs (similarly to secretory neurons of the hypothalamus), can also send paracrine signals, hence they are called neuroendocrine cells
  37. 37. Marc Imhotep Cray, M.D. 37 Adrenal Medulla (2) Cholinergic neuron Adrenal medulla Epi and NE released into systemic circulation Denotes ACh  Chromaffin cells are neuroendocrine cells found in the medulla of the adrenal glands  They are in close proximity to pre-synaptic sympathetic ganglia of sympathetic nervous system, with which they communicate  structurally similar to post-synaptic sympathetic neurons
  38. 38. Marc Imhotep Cray, M.D. 38 Summary of Actions of SANS & PANS (1) SYMATHETIC Fright-Fight-or-Flight widely distributed responses PARASYMPATHETIC Rest-Relax-Restoration discrete responses  increase in heart rate  decrease in heart rate  decrease in gastric motility  increase in gastric motility  decrease secretion of salivary and digestive glands  increase in secretion of salivary and digestive glands  dilation of pupils  constriction of pupils  ejaculation  penile erection  vasoconstriction  contraction of smooth muscle in walls of bladder  dilation of bronchioles  increased secretion of sweat glands Of note: Cannon’s emergency reaction: An immediate sympathetic response to life- threatening situations with both SANS and PANS overactivity. The PANS phenomenon includes vagal cardiac arrest with involuntary defecation and urination
  39. 39. Marc Imhotep Cray, M.D. 39 Summary of Actions of SANS and PANS (2) Toy E, Rosenfeld G, Loose D, Briscoe D. CASE 1, Autonomic Sympathetic Nervous System, In Case Files: Pharmacology 2 ed. McGraw-Hill 2008; 16. (click to expand) Sympathetic Responses  heart rate increases  blood pressure increases  blood is shunted from skin & viscera to skeletal muscles  blood glucose increase  bronchioles dilate  pupils dilate Parasympathetic Responses  slows heart rate  protects retina from excessive light (near  lowers blood pressure  empties the bowel and bladder  increases gastrointestinal motility  promotes absorption of nutrients
  40. 40. Marc Imhotep Cray, M.D. 40 ACh Synthesis, Release, and Fate (1)  Synthesized from choline and acetyl-CoA  Released in response to neuronal depolarization (action potential)  Calcium enters the nerve cell  Transmitter vesicles fuse with cell membrane  ACh released by exocytosis  Inactivated by acetylcholinesterase (AChE)
  41. 41. Marc Imhotep Cray, M.D. ACh Synthesis, Release, and Fate (2) 41  CHT - Choline transporter  ChAT - Choline acetyl transferase  VAT - Vesicle-associated transporter  VAMPs - Vesicle-associated membrance proteins  SNAP’s - Synaptosome- associated proteins
  42. 42. Marc Imhotep Cray, M.D. Cholinergic Neuron Pharmacology 42From Le T., Bhushan V. First Aid 2017. New York, NY: M-H. 2017.
  43. 43. Marc Imhotep Cray, M.D. 43 NE Synthesis, Release, and Fate (1)  Catecholamine - synthesized in a multistep pathway starting with tyrosine as the rate limiting step  Released by exocytosis in response to axonal depolarization  Duration of activity primarily limited by neuronal reuptake  Minor metabolism by synaptic monoamine oxidase (MAO) and catechol-O-methyl transferase (COMT)
  44. 44. Marc Imhotep Cray, M.D. NE Synthesis, Release, and Fate (2) 44 VMAT-Vesicular Monoamine transporter
  45. 45. Marc Imhotep Cray, M.D. Adrenergic Neuron Pharmacology 45 From Le T., Bhushan V. First Aid 2017. New York, NY: M-H. 2017.
  46. 46. Marc Imhotep Cray, M.D. 46 Receptors*  Specialized proteins that are binding sites for neurotransmitters and hormones  Postsynaptic cell membranes (neurotransmitters)  Cell nucleus (steroid hormones)  Linked to one of many signal transduction mechanisms “Receptor” (According to Rang & Dale Pharmacology): A target or binding protein for a small molecule (ligand), which acts as an agonist or antagonist. Rang HP, Maureen M. Dale MM, Ritter JM , Flower J Henderson G . Rang & Dale's Pharmacology, 7th ed. Churchill Livingstone; 2011. *“not to be confuse with other drug targets such as enzymes etc.”
  47. 47. Marc Imhotep Cray, M.D. 47 Ligand-Receptor Interactions  Complementary conformations in 3 dimensions  Similar to enzyme-substrate interactions  Physiologic interactions are weak attractions  H-bonding, van der Waal’s forces  Drug mechanisms  Agonists - bind and activate receptors  Antagonists - bind but DO NOT activate receptors "Receptor" according to IUPHAR: (International Union of Basic and Clinical Pharmacology) “A cellular macromolecule, or an assembly of macromolecules, that is concerned directly and specifically in chemical signaling between and within cells. Combination of a hormone, neurotransmitter, drug, or intracellular messenger with its receptor(s) initiates a change in cell function.” See: Basic Receptor Pharmacology/ PDF
  48. 48. Marc Imhotep Cray, M.D. Steps in Signal Transduction Process See: G-protein Signal Transduction (video animations) 48  There are four general classes of signal transducing receptors:  G-proteins are one and are referred to as serpentine receptors Binding of the neurotransmitter, hormone or drug to receptor> signaling of G-protein> enzyme activation> production of a second-messenger> protein kinase activation > phosphorylation of specific proteins (effect)> termination
  49. 49. Marc Imhotep Cray, M.D. 49 Neurohormone epinephrine and its receptor (pink) is used in tis example: Activated receptor releases the Gs alpha protein (tan) from the beta and gamma subunits (blue and green) in the heterotrimeric G-protein complex. The activated Gs alpha protein in turn activates adenylyl cyclase (purple) that converts ATP into the second messenger cAMP Mechanism of cAMP dependent signaling GPCR structure & function (simplified) G-Protein Coupled Receptor Binding of NT, hormone or drug to receptor> signaling of G- protein> enzyme activation> production of a second- messenger> protein kinase activation >phosphorylation of specific proteins (effect) >termination
  50. 50. Marc Imhotep Cray, M.D. 50 3 major G-Protein class subtypes: Compose the largest class of *receptors: 1) Gq Messenger Pathway: (used by H1, Alpha 1, V1, M1, M3 Receptors) (HAVM1&3) Receptor → Gq → Phospholipase C that turns Lipid into PIP2 that is split into IP3 (Increases IC Calcium) and DAG (Activates Protein Kinase C - PKC) 2) Gαs Messenger Pathway: (used by Beta 1, Beta 2, D1, H2, V2 Receptors) (1D2BHV) Receptor → Gαs → Adenylyl Cyclase (AC) that turns ATP into cAMP that activates Protein Kinase A - PKA 3) Gαi Messenger Pathway: (used by M2, Alpha 2, and D2 Receptors) (2MAD) Receptor → Gαi that inhibits Adenylyl Cyclase that in turn decreases cAMP , thus making less active Protein Kinase A G Protein Messenger Pathways * Remember there are four major classes of ligand–receptor interactions (more in Pharm.)
  51. 51. Marc Imhotep Cray, M.D. 51 Sympathetic (Adrenergic-Noradrenergic-R) Alpha 1 Receptor - q - Vasoconstriction and Pupillary Dilator Muscle contraction (Mydriasis), and increased Intestinal Sphincters and Bladder Sphincter contraction  Via PLC-IP3-DAG Alpha 2 Receptor - i - Decreased Sympathetic Outflow, and decreased Insulin release  Via Inhib. AC-cAMP Beta 1 Receptor - s - Increase Heart Rate, Increase Contractility, Increase Renin release, and increase Lipolysis  Via Stim. AC-cAMP Beta 2 Receptor - s - Vasodilation, Bronchodilation, Increase Heart Rate, Increase Contractility, Increase Lipolysis, Increase Insulin release, Decrease Uterine Muscle tone Receptor G-Protein Class Major Function G-protein-linked 2nd messenger mechanisms (1)
  52. 52. Marc Imhotep Cray, M.D. 52 G-protein-linked 2nd messenger mechanisms (2) Parasympathetic (Ach-Cholinergic-R) M1 Receptor - q - found in CNS and Enteric Nervous System M2 Receptor - i - Decrease Heart Rate and Contractility of Atria M3 Receptor - q - Increase Exocrine Gland secretions (Sweat Gland, Parietal Cells), Increase Gut Peristalsis, Increase Bladder Contraction, Bronchoconstriction, Increase Pupillary Sphincter Muscle Contraction (Miosis), Ciliary Muscle Contraction (Accommodation) Receptor G-Protein Class Major Function N.B. Nicotinic ACh receptors are ligand-gated Na+/K+ channels
  53. 53. Marc Imhotep Cray, M.D. 53 G-protein-linked 2nd messenger mechanisms (3)  Dopamine: D1 Receptor - s - Relax Renal Vascular Smooth Muscle D2 Receptor - i - Modulate Neurotransmitter release (especially in Brain) (For sake of completeness)  Histamine: H1 Receptor - q - Increase Mucus production in Nose and Bronchi, Bronchiole Constriction, Pruritis, Pain H2 Receptor - s - Increase Gastric Acid secretion (Parietal Cells)  Vasopressin: V1 Receptor - q - Increase Vasoconstriction V2 Receptor - s - Increase Water Permeability and Water Reabsorption in Collecting Tubule (V2 in 2 Kidneys) Receptor G-Protein Class Major Function
  54. 54. Marc Imhotep Cray, M.D. 54 Cholinergic Receptors  Activated by ACh and cholinergic drugs  Anatomic distribution  Postganglionic, parasympathetic neuroeffector junctions  All autonomic ganglia, whether parasympathetic or sympathetic  Somatic neuromuscular junctions
  55. 55. Marc Imhotep Cray, M.D. 55 Schematic of Cholinergic Receptor Locations Pre Ganglion Effector organs PostThoracic or lumbar cord Pre Ganglion Effector organ Post Cranial or sacral cord Parasympathetic Sympathetic Denotes ACh receptors Denotes ACh receptors
  56. 56. Marc Imhotep Cray, M.D. 56 Cholinergic Receptor Subtypes  Muscarinic  Postganglionic, parasympathetic, neuroeffector junctions (M1-M5)  Nicotinic  Distinction of two different subtypes  Ganglia - type II or type NG  Neuromuscular junctions - type I or type NM  N.B.-Nicotinic ACh receptors are ligand-gated Na+/K+ channels
  57. 57. Marc Imhotep Cray, M.D. 57 Schematic representation of Cholinergic Receptor Subtype Locations Pre Ganglion Effector organ PostThoracic or lumbar cord Pre Ganglion Effector organ Post Cranial or sacral cord Parasympathetic Sympathetic N1 M N1
  58. 58. Marc Imhotep Cray, M.D. 58 Adrenergic Receptors  Activated by NE, Epi, and adrenergic drugs  Anatomic distribution  Postganglionic, sympathetic, neuroeffector junctions  Subtypes  Alpha-1, 2; Beta-1, 2, 3
  59. 59. Marc Imhotep Cray, M.D. 59 Schematic representation of Adrenergic Receptor Locations Sympathetic Pre Ganglion paravertebral , prevertebral or lateral Effector organs PostThoracic or lumbar cord Alpha or Beta adrenergic receptors
  60. 60. Marc Imhotep Cray, M.D. 60 Organ system integration  Parasympathetic  Discrete innervation  Energy conservation  Sympathetic  Highly distributed innervation, global responses  Energy expenditure  Fight or flight responses Functional Significance of ANS (1) “Organ system integration & Dual innervation”
  61. 61. Marc Imhotep Cray, M.D. 61 Functional Significance of ANS (2) Dual innervation  Organ responses moderated by both parasympathetic and sympathetic influences  Parasympathetic dominant at rest  Predominate tone  Balance of opposing neurologic influences determines physiologic responses
  62. 62. Marc Imhotep Cray, M.D. 62 Alpha-1 Adrenergic Receptor  Vascular smooth muscle contraction  Arterioles, veins  Increased arterial resistance  Decreased venous capacitance  Agonists support systemic blood pressure  Increased resistance  Redistribution of blood toward heart, increased cardiac output  Antagonists decrease blood pressure  Iris  Pupillary dilation (mydriasis)
  63. 63. Marc Imhotep Cray, M.D. 63 Alpha-2 Adrenergic Receptor  postsynaptic α2-adrenoceptors (located in bld vessels) cause constriction  Modulation of NE release  Presynaptic receptors on axon terminus  Spinal alpha-2 receptors mediate analgesia  Agonists used clinically as epidural and spinal analgesics  Sedation
  64. 64. Marc Imhotep Cray, M.D. 64 Beta-1 Adrenergic Receptor  To myocardium (renal-renin and fat cell also)  Agonists  Increase HR, contractility, and impulse conduction speed  May be arrhythmogenic  Antagonists  Decrease HR, contractility, and impulse conduction speed  Used clinically as antiarrhythmics
  65. 65. Marc Imhotep Cray, M.D. 65 Beta-2 Adrenergic Receptor  Vascular smooth muscle in skeletal muscle  Agonists evoke active vasodilation, increased blood flow  Bronchial smooth muscle  Agonists evoke bronchodilation, decreased airway resistance
  66. 66. Marc Imhotep Cray, M.D. 66 Muscarinic Cholinergic Receptor (mAChR)  Myocardium  Agonists decrease HR, contractility and AV conduction velocity  Antagonists used clinically to increase HR & facilitate AV conduction such as in heart block  Iris sphincter muscle  Agonists evoke pupillary constriction (miosis)  Antagonists evoke mydriasis  Gastrointestinal tract  Agonists increase peristalsis and relax sphincter  Urinary bladder  Agonists evoke urination  Detrusor muscle (bladder) contraction  Trigone (sphincter) relaxation
  67. 67. Marc Imhotep Cray, M.D. 67 Receptor Function Distribution α1 Constriction of smooth muscles Blood vessels and piloerectors in skin (vasoconstriction and goose bumps) Sphincters (bladder, gastrointestinal [GI]) Uterus and prostate (contraction) Eye (contraction of the radial muscle = pupillary dilation/mydriasis) α2 Inhibition of sympathetic autonomic ganglia (decreases SANS) Presynaptic ganglionic neurons GI tract (less important pharmacologically) Effect of ANS on Organ Systems (1) Sympathetic (NE)
  68. 68. Marc Imhotep Cray, M.D. 68 Effect of ANS on Organ Systems (2) Sympathetic (NE) Receptor Function Distribution|Organ β1 Increase cardiac performance and liberation of energy Heart-most important (increased chronotropy, inotropy, dromotropy) Fat cells (release fat for energy via lipolysis) Kidney (release renin to conserve water) β2 Relaxation of smooth muscles and liberation of energy Lungs (bronchodilation) Blood vessels in muscles (vasodilation) Uterus (uterine relaxation) GI (intestinal relaxation) Bladder (bladder relaxation) Liver (to liberate glucose via glycogenolysis)
  69. 69. Marc Imhotep Cray, M.D. Effect of ANS on Organ Systems (3) Parasympathetic (Ach) Receptor Function Distribution|Organ N (Nicotinic) "Nerve to nerve" & "nerve to muscle" communication SANS & PANS ganglia Neuromuscular junction (NMJ) M (Muscarinic) To oppose most sympathetic actions at the level of the organs Lung (bronchoconstriction) Heart (slower rate, decreased conduction, decreased contractility) Sphincters of GI and bladder (relax) Bladder (constriction) GI (intestinal contraction) Eye (contraction of the circular muscle = pupillary constriction or miosis) Eye (contraction of the ciliary muscle = focus for near vision)
  70. 70. Marc Imhotep Cray, M.D. 70 Nicotinic ACh receptors are ligand-gated Na+/K+channels Two subtypes: NN (found in autonomic ganglia, adrenal medulla) and NM (found in NMJ of skeletal muscle) Muscarinic ACh receptors are G-protein–coupled receptors that usually act through 2nd messengers Five subtypes: M1–5 found in heart, smooth muscle, brain, exocrine glands, and on sweat glands (cholinergic sympathetic) Acetylcholine receptors
  71. 71. Marc Imhotep Cray, M.D. 71 Exception Sympathetic innervation of adrenal medulla is direct from spinal cord and uses ACh as neurotransmitter Adrenal gland functions as a special form of ganglion that secretes Epi & NE in a 4 to 1 ratio directly into the bloodstream Sympathetic postganglionic neurons that innervate renal vascular smooth muscle release dopamine rather than norepinephrine Important note: There is no parasympathetic fiber innervation of blood vessels, but bld vessels do have muscarinic receptors For example, in coronary arteries stimulation M3 receptors cause release of NO which result in vasodilation Sweat glands are innervated by sympathetic nerves, but paradoxically use mAChR Sexual arousal is parasympathetic, but orgasm is sympathetic
  72. 72. Marc Imhotep Cray, M.D. 72 Autonomic and Somatic NS Pharmacology Terminology  Many drugs evoke effects by interacting with receptors  Affinity  Efficacy or (synonym) Intrinsic activity  Agonists  Mimic physiologic activation  Have both high affinity and efficacy  Antagonists  Block actions of neurotransmitters or agonists  Have high affinity, but no efficacy  Often used as pharmacologic reversal agents
  73. 73. Marc Imhotep Cray, M.D. 73 Adrenergic- Receptor Type Physiologic Agonist Signaling Mechanism Pharmacologic Agonist Pharmacologic Antagonist α1 Norepi ≥ Epi IP3/DAG/Ca2+ Phenylephrine Prazosin α2 Norepi ≥ Epi ↓ [cAMP] Clonidine, methyldopa Yohimbine β1 Epi > Norepi ↑ [cAMP] Dobutamine (β1 > β2), isoproterenol (β1 = β2) Metoprolol β2 Epi > Norepi ↑ [cAMP] Albuterol, isoproterenol (β1 = β2) Propranolol (nonselective β1 and β2) Signaling Mechanisms and Pharmacology of ANS Receptor Subtypes- SANS
  74. 74. Marc Imhotep Cray, M.D. 74 Cholinergic- Receptor Type Physiologic Agonist Signaling Mechanism Pharmacologic Agonist Pharmacologic Antagonist N1=NM Acetylcholine Ionotropic receptor Nicotine D-Tubocurarine N2=NG Acetylcholine Ionotropic receptor Nicotine Hexamethonium, mecamylamine M1–5 Acetylcholine Various Bethanechol, methacholine, pilocarpine Atropine, benztropine, ipratropium Signaling Mechanisms and Pharmacology of ANS Receptor Subtypes- PANS
  75. 75. Marc Imhotep Cray, M.D. 75 PNS summary schematic Le T., Bhushan V. First Aid for the USMLE Step 1 2017. New York, NY: M-H. 2017.
  76. 76. Marc Imhotep Cray, M.D. 76 Summary: Take Home Points (1)  ANS functions involve a variety of effector tissues, including: cardiac muscle, smooth mm, vascular endothelium, exocrine glands, and presynaptic nerve terminals  To understand ANS function , and by extension how to pharmacologically manipulate ANS, you will need understand how two divisions of ANS coexist and function, how each subdivision exerts its effects, and finally what physiologic and pharmacologic mechanisms exist to increase or decrease each subdivision’s activity
  77. 77. Marc Imhotep Cray, M.D. 77  By using drugs that mimic or block actions of chemical transmitters and / or their receptor mechanisms, we can selectively modify autonomic functions  Autonomic drugs are useful in many clinical conditions, however a large number of drugs used for other clinical purposes have unwanted effects on autonomic function; and because of ubiquitous nature of ANS, autonomic drugs are frequently non-selective and thus can be assoc. w side effects Bottom line| memorization of receptors, their distribution, signal transduction mechanisms and their effects is mandatory and will enable you to accurately predict effects, side effects, potential toxicities and interactions of ANS drugs Summary: Take Home Points (2)
  78. 78. Marc Imhotep Cray, M.D. 78 THE END See next slide for further study tools.
  79. 79. Marc Imhotep Cray, M.D. Further study: 79 Companion notes ANS Summary Notes Articles Laurie Kelly McCorry. Physiology of the Autonomic Nervous System Am J Pharm Educ. 2007 August 15; 71(4): 78. Goldstein DS, Robertson D, Straus SE, et al. Dysautonomias: clinical disorders of the autonomic nervous system. Ann Intern Med 2002;137(9):753–63. Cannon, WB, Organization for Physiological Homeostasis. PDF Physiological Rev July 1, 1929 9:399-431 PowerPoint Presentation: Cray MI. Walter Cannon, Homeostasis and the Physiological Response to Stress. A Web Interactive PowerPoint Presentation , 2014