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IVMS ANS Pharmacology -Intro to the Autonomic Nervous System

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

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

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  • Here is what we have learned from this Introduction to the Nervous System:The nervous system is the major controlling, regulatory, and communicating system in the body. It is the center of all mental activity including thought, learning, and memory.The various activities of the nervous system can be grouped together as three general, overlapping functions: sensory, integrative, and motor.Neurons are the nerve cells that transmit impulses. Supporting cells are neuroglia.The three components of a neuron are a cell body or soma, one or more afferent processes called dendrites, and a single efferent process called an axon.The central nervous system consists of the brain and spinal cord. Cranial nerves, spinal nerves, and ganglia make up the peripheral nervous system.The afferent division of the peripheral nervous system carries impulses to the CNS; the efferent division carries impulses away from the CNS.There are three layers of meninges around the brain and spinal cord. The outer layer is dura mater, the middle layer is arachnoid, and the innermost layer is pia mater.The spinal cord functions as a conduction pathway and as a reflex center. Sensory impulses travel to the brain on ascending tracts in the cord. Motor impulses travel on descending tracts.
  • organ receptors ( in the 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 )
  • In this figure, the neurotransmitter epinephrine (adrenaline) and its receptor (pink) is used as an example.  The 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
  • cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; Epi, epinephrine; IP3, inositol 1,4,5-triphosphate; M1-5, muscarinic receptors (five subtypes);N1, nicotinic receptor at the neuromuscular junction; N2, nicotinic receptor at autonomic ganglia; Norepi, norepinephrine.
  • cAMP, cyclic adenosine monophosphate; DAG, diacylglycerol; Epi, epinephrine; IP3, inositol 1,4,5-triphosphate; M1-5, muscarinic receptors (five subtypes);N1, nicotinic receptor at the neuromuscular junction; N2, nicotinic receptor at autonomic ganglia; Norepi, norepinephrine.
  • (

IVMS ANS  Pharmacology -Intro to the Autonomic Nervous System IVMS ANS Pharmacology -Intro to the Autonomic Nervous System Presentation Transcript

  • ANS Physiology and Pharmacology Introduction|Review of the Autonomic Nervous System (Abridged) Prepared and presented by: Marc Imhotep Cray, M.D. Basic Medical Sciences Teacher http://www.imhotepvirtualmedsch.com/ From Henry Gray (1821–1865) Anatomy of the Human Body 1918
  • *Suggested Review Books & Resources Companion Notes: ANS Summary Notes Formative Assessment  Review Test for Autonomic Nervous System  Review Test for Autonomic Nervous System answers and explanations *e-Books & learning tools available to enrolled learners at thePOINT Clinical Correlate: e-Medicine Article Epilepsy and the Autonomic Nervous System If you are using a different review book, the chapters may be organized differently, but the material covered is approximately the same. Simply find the corresponding material in your book for each lecture. Marc Imhotep Cray, M.D. 2
  • Overall Goal of Reviews “ Deconstruction, Reconstruction, Integration and Relationships” 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. . . .” http://en.wikipedia.org/wiki/Claude_Bernard Marc Imhotep Cray, M.D. 3
  • Topics Outline  Homeostasis  Basic Neuroanatomy and Neurophysiology of ANS  Neurotransmitters  Receptors  Receptor-Ligand Interactions & Signal Transduction  Autonomic and Somatic Pharmacology Terminology Marc Imhotep Cray, M.D. 4
  • Review Objectives After presentation you should be able to:  Describe the two divisions of the ANS and the main functions and effects of each division.  Explain how sympathetic and parasympathetic nerves interact with each other to regulate organ function (maintain homeostasis)  Describe the fight or flight reaction and explain how sympathetic activation affects the activities of the different organs  List the main organ effects caused by parasympathetic stimulation  Describe the different autonomic receptors that are stimulated by acetylcholine, norepinephrine, and epinephrine  Describe signaling mechanisms and pharmacology of ANS receptor subtypes Marc Imhotep Cray, M.D. 5
  • Autonomic Nervous System (ANS) The autonomic nervous system (ANS) is the part of the nervous system that is responsible for homeostasis Except for skeletal muscle, which gets its innervation from the somatomotor nervous system, innervation to all other organs is supplied by the ANS Marc Imhotep Cray, M.D. 6
  • Autonomic nervous system vs. Endocrine system in Homeostasis Autonomic nervous system (ANS) is the moment-tomoment regulator of the 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 Marc Imhotep Cray, M.D. 7
  • ANS and Endocrine System common properties  high-level integration in the brain  ability to influence processes in distant regions of body  extensive use of negative feedback  maintain homeostasis  both systems use chemicals for transmission of information Marc Imhotep Cray, M.D. 8
  • Walter Cannon coined the word homeostasis  Referring to animal systems, pioneering 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 Courtesy National Library of Medicine (NLM) http://en.citizendium.org/wiki/File:William_cannon.jpg so complex, and are so peculiar #Licensing to the living organism, that it was suggested (Cannon, 1929) that a specific designation for these Cannon, WB, Organization for Physiological Homeostasis/PDF states be employed Physiological Rev July 1, 1929 9:399-431 Cray MI. Walter Cannon, Homeostasis and the homeostasis Physiological Response to Stress, A Web Interactive PowerPoint Presentation Marc Imhotep Cray, M.D. 9
  • Homeostasis (1)   The physiologic process of maintaining an internal environment (ECF environment) compatible with normal health Autonomic reflexes maintain set points and modulate organ system functions via negative feedback in pursuit of homeostasis See: Walter Cannon, Homeostasis and the Physiological Response to Stress Web Interactive Ppt. Marc Imhotep Cray, M.D. 10
  • Homeostasis (2) A dynamic steady state of the constituents in the internal environment (ECF) that surrounds and exchanges materials with the cells Factors homeostatically maintained: (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 Marc Imhotep Cray, M.D. 11
  • Homeostasis (3) Nervous versus Endocrine Wired Wireless Neurotransmitters Hormones Hormones Short Distance Short Distance Long Distance Long Distance Closeness Receptor Specificity Rapid Onset Delayed Onset Short Duration Prolonged Duration Rapid Response Regulation Marc Imhotep Cray, M.D. 12
  • Components of a negative feedback control system Recognizes deviation of normal set point value Attempt to restore set point value Measures control variable COMPARATOR SENSOR stretch receptors, chemo-, baro-, osmo-, and thermoreceptors etc. SET POINT ERROR SIGNAL EFFECTOR CONTROLLED VARIBLE (SEE NEXT SLIDE) Redrawn after: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology -The Big Picture; McGraw-Hill ,2009:2 Important variable maintained within a normal range Marc Imhotep Cray, M.D. + - Negative feedback: Initiation of responses that counter deviations of controlled variables from their normal range NEGATIVE FEEDBACK Effector opposes stimulus 13
  • Examples of Physiologic Controlled Variables Controlled Variable (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 Typical Set Point Value 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 Adopted from: Kibble JD, Halsey CR, Homeostasis: In Medical Physiology The Big Picture; McGraw-Hill ,2009:3 Marc Imhotep Cray, M.D. 14
  • Example: Baroreceptor Reflex control of blood pressure + EFFECTOR ERROR SIGNAL cardiac contractility, vascular tone, urinary fluid excretion COMPARATOR SENSOR stretch receptors in Aortic arch and Carotid sinus SET POINT N 95 mm Hg CNS| Medulla Oblongata Mean Arterial Blood Pressure (MAP) - NEGATIVE FEEDBACK 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) Marc Imhotep Cray, M.D. 15
  • Baroreceptors(2) Hypotension - arterial pressure stretch afferent baroreceptor firing efferent sympathetic firing and efferent parasympathetic stimulation vasoconstriction, HR, contractility, B P Important in the response to severe hemorrhage • Carotid massage - pressure on carotid artery baroreceptor firing HR stretch afferent 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. Marc Imhotep Cray, M.D. 16
  • Examples of Physiologic Controlled Variables Controlled Variable (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 Marc Imhotep Cray, M.D. Typical Set Point Values 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 17
  • Organization of the Nervous System CENTRAL NERVOUS SYSTEM (CNS) BRAIN & SPINAL CORD AFFERENT EFFERENT (Sensory) (Motor) NERVES NERVES EXTEROCEPTORS INTEROCEPTORS EFFECTOR ORGANS SKELETAL MUSCLES VOLUNTARY Monosynaptic Marc Imhotep Cray, M.D. PERIPHERAL NERVOUS SYSTEM (PNS) SOMATIC AUTONOMIC SMOOTH MUSCLE, CARDIAC MUSCLES AND GLANDS INVOLUNTARY Pre & Post Ganglionic Fiber
  • 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) Marc Imhotep Cray, M.D. 19
  • Generic Neuron Anatomy Basic structural unit of nervous system >>> neuron From: http://en.wikipedia.org/wiki/Neuron Marc Imhotep Cray, M.D. 20
  • 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 See Baroreflex pdf Marc Imhotep Cray, M.D. 21
  • Sympathetic Nervous System Wiring Dorsal root ganglion Intermediolateral cell column (IML) Sympathetic trunk Gray ramus White ramus Marc Imhotep Cray, M.D. 22
  • Functional Unit of ANS >>> Reflex Arc Illustration Afferent fibers from periphery to CNS CNS integration Spinal cord Medulla Hypothalamus Thalamus Cortex Efferent fibers from CNS to periphery Effector response Source: http://www.alexmed.edu.eg/forums/showthread.php?2116-Today-s-lecture-gt-gt-gt-BY-M..S organ receptors ( in the 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 ) Marc Imhotep Cray, M.D. 23
  • Neurotransmitters     Chemicals synthesized and stored in neurons Liberated from axon terminus in response to action potentials Interact with specialized receptors Evoke responses in the innervated tissues See: IVMS Neurotransmitters Notes Marc Imhotep Cray, M.D. 24
  • ANS Neurotransmitters Class Chemical Synthesis Small molecule Transmitters Acetylcholine Catecholamines Dopamine Norepinephrine Choline + acetyl CoA, via the 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 Signal Termination Functions ANS Nicotinic (cation channel) Muscarinic (G-protein– coupled) D1 (stimulatory G- protein– coupled) D2 (inhibitory G-protein– coupled) Extracellular hydrolysis by Acetylcholinestrase Movement control Cognition Reuptake ANS Movement control General affect α & β Adrenergic receptors Reuptake or breakdown via the enzymes monoamine oxidase and catechol–Omethyltransferase ANS Alertness General affect N.B Epinephrine is a catecholamine released upon stimulation of SANS, produced in the adrenal medulla. It is a neurohormone, not an ANS neurotransmitter Marc Imhotep Cray, M.D. 25
  • 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) Post Pre Effector organ Ganglion Marc Imhotep Cray, M.D. 26
  • Anatomic Divisions of the ANS  Parasympathetic (PANS) (CN3,7,9,10) & (S2-S4)     Sympathetic (SANS) T1-L2/L3     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 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 the head and neck Marc Imhotep Cray, M.D. 27
  • Schematized Anatomic Comparison of PANS & SANS (1) (click to expand) Marc Imhotep Cray, M.D. 28
  • Schematized Anatomic Comparison of PANS & SANS (2) Effectors: cardiac muscle, smooth mm, vascular endothelium, exocrine glands, and presynaptic nerve terminals Cranial or sacral cord ANS functions:  circulation  digestion  respiration  temperature  sweating  metabolism  some endocrine gland secretions Thoracic or lumbar cord Marc Imhotep Cray, M.D. Parasympathetic Post Pre Ganglion Effector organ Sympathetic Pre Ganglion Post Effector organ 29
  • Cranial Nerve Parasympathetic Innervations Marc Imhotep Cray, M.D. 30
  • Somatic Nervous System (included for comparison)     Efferent innervation of skeletal muscle No peripheral ganglia Rapid transmission, discrete control of motor units Voluntary Striated muscle Any spinal segment Motor neuron Myelinated with a high conduction velocity In contrast Postganglionic neurons of ANS are unmyelinated with a low conduction velocity Marc Imhotep Cray, M.D. 31
  • Neurochemical Transmission in Peripheral Nervous System (PNS)  Cholinergic nerves   Acetylcholine is the neurotransmitter Locations  Preganglionic neurons to all ganglia  Postganglionic, parasympathetic neurons  “Preganglionic” fibers to adrenal medulla   Marc Imhotep Cray, M.D. Postganglionic, sympathetic neurons to sweat glands in most species Somatic motor neurons 32
  • Cholinergic Neurotransmission Denotes ACh Parasympathetic Cranial or sacral cord Post Pre Ganglion Sympathetic Thoracic or lumbar cord Marc Imhotep Cray, M.D. Pre Ganglion Effector organ Denotes ACh Post Effector organs 33
  • Adrenergic Neurotransmission  Adrenergic nerves   Norepinephrine is the neurotransmitter Locations  Postganglionic, sympathetic axons Sympathetic Thoracic or lumbar cord Pre Ganglion Denotes ACh Marc Imhotep Cray, M.D. Denotes Norepinephrine Post Effector organs 34
  • Adrenal Medulla   Presynaptic nerves are cholinergic Medullary cells (*Chromaffin cells) synthesize and release two, related catecholamines into the 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 Marc Imhotep Cray, M.D. 35
  • Adrenal Medulla(2) Adrenal medulla Cholinergic neuron 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 the sympathetic nervous system, with which they communicate  structurally they are similar to post-synaptic sympathetic neurons Marc Imhotep Cray, M.D. 36
  • Summary of Actions of SANS and PANS (1) SYMATHETIC PARASYMPATHETIC widely distributed responses discrete responses Fright-Fight-or-Flight Rest-Relax-Restoration  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 Marc Imhotep Cray, M.D. Of note: Cannon’s emergency reaction: An immediate sympathetic response to lifethreatening situations with both SANS and PANS overactivity. The PANS phenomenon includes vagal cardiac arrest with involuntary defecation and urination 37
  • Summary of Actions of SANS and PANS (2) (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 Illustration from: Toy E, Rosenfeld G, Loose D, Briscoe D. CASE 1, Autonomic Sympathetic Nervous System, In Case Files: Pharmacology; McGraw-Hill 2 ed. 2008:16 Marc Imhotep Cray, M.D. 38
  • 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) Marc Imhotep Cray, M.D. 39
  • ACh Synthesis, Release, and Fate (2) Schematic source: http://www.neurophysiology.ws/autonomicns.htm Marc Imhotep Cray, M.D. 40
  • 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) Marc Imhotep Cray, M.D. 41
  • NE Synthesis, Release, and Fate (2) Tyrosine Schematic source: http://www.neurophysiology.ws/autonomicns.htm Marc Imhotep Cray, M.D. 42
  • 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, Churchill Livingstone; 7th edition 2011 “not to be confuse with other drug targets as enzymes etc.” Marc Imhotep Cray, M.D. 43
  • Ligand-Receptor Interactions  Complementary conformations in 3 dimensions   Physiologic interactions are weak attractions   Similar to enzyme-substrate interactions 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 Marc Imhotep Cray, M.D. 44
  • Steps in Signal Transduction Process See: G-protein Signal Transduction (video animations)  There are three 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 Also see: http://themedicalbiochemistrypage.org/sign al-transduction.html Marc Imhotep Cray, M.D. 45
  • GPCR structure & function (simplified) G-Protein Coupled Receptor Mechanism of cAMP dependent signaling Binding of the neurotransmitter, hormone or drug to receptor> signaling of G-protein> enzyme activation> production of a secondmessenger> protein kinase activation >phosphorylation of specific proteins (effect)>termination The neurohormone epinephrine and its receptor (pink) is used in tis example: The 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 Source: http://en.wikipedia.org/wiki/Signal_transduction Marc Imhotep Cray, M.D. 46
  • G Protein Messenger Pathways 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 * Remember there are four major classes of ligand–receptor interactions (more on this in Pharm.) Marc Imhotep Cray, M.D. 47
  • G-protein-linked 2nd messenger mechanisms (1) Sympathetic (Adrenergic-Noradrenergic-R) Receptor G-Protein Class Major Function 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 Marc Imhotep Cray, M.D. 48
  • G-protein-linked 2nd messenger mechanisms (2) Parasympathetic (Ach-Cholinergic-R) Receptor G-Protein Class Major Function 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) N.B. Nicotinic ACh receptors are ligand-gated Na+/K+ channels Marc Imhotep Cray, M.D. 49
  • G-protein-linked 2nd messenger mechanisms (3) Receptor G-Protein Class Major Function  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) Marc Imhotep Cray, M.D. 50
  • Cholinergic Receptors   Activated by ACh and cholinergic drugs Anatomic distribution    Postganglionic, parasympathetic neuroeffector junctions All autonomic ganglia, whether parasympathetic or sympathetic Somatic neuromuscular junctions Marc Imhotep Cray, M.D. 51
  • Schematic of Cholinergic Receptor Locations Denotes ACh receptors Parasympathetic Cranial or sacral cord Post Pre Ganglion Sympathetic Thoracic or lumbar cord Marc Imhotep Cray, M.D. Pre Ganglion Effector organ Denotes ACh receptors Post Effector organs 52
  • 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 Marc Imhotep Cray, M.D. 53
  • Schematic representation of Cholinergic Receptor Subtype Locations Parasympathetic M N1 Cranial or sacral cord Post Pre Ganglion Effector organ Sympathetic Thoracic or lumbar cord Marc Imhotep Cray, M.D. Pre N1 Ganglion Post Effector organ 54
  • Adrenergic Receptors   Activated by NE, Epi, and adrenergic drugs Anatomic distribution   Postganglionic, sympathetic, neuroeffector junctions Subtypes  Alpha-1, 2; Beta-1, 2, 3 Marc Imhotep Cray, M.D. 55
  • Schematic representation of Adrenergic Receptor Locations Alpha or Beta adrenergic receptors Sympathetic Thoracic or lumbar cord Pre Ganglion paravertebral , prevertebral or lateral Marc Imhotep Cray, M.D. Post Effector organs 56
  • Functional Significance of the Autonomic Nervous System (1) “Organ system integration & Dual innervation” Organ system integration  Parasympathetic    Discrete innervation Energy conservation Sympathetic    Marc Imhotep Cray, M.D. Highly distributed innervation, global responses Energy expenditure Fight or flight responses 57
  • Functional Significance of the Autonomic Nervous System (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 Marc Imhotep Cray, M.D. 58
  • 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) Marc Imhotep Cray, M.D. 59
  • 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 Marc Imhotep Cray, M.D. 60
  • 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 Marc Imhotep Cray, M.D. 61
  • Beta-2 Adrenergic Receptor  Vascular smooth muscle in skeletal muscle   Agonists evoke active vasodilation, increased blood flow Bronchial smooth muscle  Marc Imhotep Cray, M.D. Agonists evoke bronchodilation, decreased airway resistance 62
  • 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 Marc Imhotep Cray, M.D. 63
  • Effect of ANS on Organ Systems (1) Sympathetic (NE) Receptor Function α1 Constriction of smooth muscles α2 Inhibition of sympathetic autonomic ganglia (decreases SANS) Marc Imhotep Cray, M.D. Distribution 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) Presynaptic ganglionic neurons GI tract (less important pharmacologically) 64
  • Effect of ANS on Organ Systems (2) Sympathetic (NE) Receptor β1 β2 Marc Imhotep Cray, M.D. Function Increase cardiac performance and liberation of energy Relaxation of smooth muscles and liberation of energy Distribution|Organ Heart-most important (increased chronotropy, inotropy, dromotropy) Fat cells (release fat for energy via lipolysis) Kidney (release renin to conserve water) Lungs (bronchodilation) Blood vessels in muscles (vasodilation) Uterus (uterine relaxation) GI (intestinal relaxation) Bladder (bladder relaxation) Liver (to liberate glucose via glycogenolysis) 65
  • 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 Lung (bronchoconstriction) actions at the level of the organs Heart (slower rate, decreased conduction, decreased contractility) Sphincters of GI and bladder (relax) Bladder (constriction) GI (intestinal contraction) Marc Imhotep Cray, M.D. Eye (contraction of the circular muscle = pupillary constriction or miosis) Eye (contraction of the ciliary muscle = focus for near vision)
  • Exceptions 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 N.B. Notes There is no parasympathetic fiber innervation of blood vessels, but bld vessels do have muscarinic receptors For example, in the coronary arteries stimulation M3 receptors cause the 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 Marc Imhotep Cray, M.D. 67
  • 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 Marc Imhotep Cray, M.D. 68
  • Signaling Mechanisms and Pharmacology of ANS Receptor Subtypes- SANS AdrenergicReceptor 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) Marc Imhotep Cray, M.D. 69
  • Signaling Mechanisms and Pharmacology of ANS Receptor Subtypes- PANS CholinergicReceptor 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 Marc Imhotep Cray, M.D. Bethanechol, methacholine, pilocarpine Atropine, benztropine, ipratropium 70
  • 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 the ANS, you will need understand how the two divisions of the 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 Marc Imhotep Cray, M.D. 71
  • Summary: Take Home Points (2)  By using drugs that mimic or block the 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 the ubiquitous nature of the ANS, autonomic drugs are frequently non-selective and thus can be associated with 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 Marc Imhotep Cray, M.D. 72
  • THE END, THANK YOU FOR YOUR ATTENTION References and Further Study: Articles Laurie Kelly McCorry. Physiology of the Autonomic Nervous System Am J Pharm Educ. 2007 August 15; 71(4): 78. PMCID: PMC1959222 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 Cray MI. Walter Cannon, Homeostasis and the Physiological Response to Stress, A Web Interactive PowerPoint Presentation Review Books  Kibble JD, Halsey CR, Homeostasis: In Medical Physiology -The Big Picture; McGraw-Hill ,2009  Costanzo L., Neurophysiology: In BRS Physiology , LLW 5thEd , 2011  Toy E, Rosenfeld G, Loose D, Briscoe D. CASE 1, In Case Files: Pharmacology; McGraw-Hill 2 ed. 2008  Rosenfeld GC, Loose DS. BRS Pharmacology (Board Review Series); LLW 6thEd, 2013 73 Marc Imhotep Cray, M.D.
  • Next Lecture: ANS Pharmacology-Cholinergic Agents (Agonist & Antagonist) Website: http://www.imhotepvirtualmedsch.com/ Learn about our individualized webcam facilitated USMLE Step 1 preparation tutorials with Dr. Cray Online portfolio of Interactive Notes and PowerPoint Presentations |Slide Packets Join our Socio-educational Network Marc Imhotep Cray, M.D.