ANS Pharmacology Intro to the Autonomic Nervous System

ANS PharmacologyIntro to the Autonomic Nervous System : ANS PharmacologyIntro to the Autonomic Nervous System Presenter: Marc Imhotep Cray, M.D. Associate Professor Pharmacology Recommended Reading:  Autonomic Introduction Formative Assessment Practice Question Set #1 Clinical: E-Medicine Article Epilepsy and the Autonomic Nervous System

Homeostasis : 9/28/2009 2 Homeostasis The physiologic process of maintaining an internal environment compatible with normal health Autonomic reflexes maintain setpoints and modulate organ system functions in pursuit of homeostasis See: Human homeostasis http://en.wikipedia.org/wiki/Human_homeostasis

Slide 3 : 9/28/2009 3 Schematic From: Organization of the Nervous System http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/PNS.html

Autonomic Reflexes : 9/28/2009 4 Autonomic Reflexes Afferent fibers from periphery to CNS CNS integration Cortex Thalamus Hypothalamus Medulla Spinal cord Efferent fibers from CNS to periphery

Neurotransmitters : 9/28/2009 5 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: http://en.wikipedia.org/wiki/Neurotransmitter

Efferent Autonomic Nerves : 9/28/2009 6 Efferent Autonomic Nerves Innervation of smooth muscle, cardiac muscle, and glands Preganglionic neuron Peripheral ganglion - axodendritic synapse Postganglionic neuron(s) Effector organ(s) Pre Ganglion Effector organ

Anatomic Divisions of the ANS : 9/28/2009 7 Anatomic Divisions of the ANS Parasympathetic Preganglionic axons originate in the 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 Preganglionic axons originate in the thoracolumbar cord Peripheral ganglia are distant from the effector organs Ratio of post-to-preganglionic axons is large, resulting in widely distributed responses

Schematized Anatomic Comparison : 9/28/2009 8 Schematized Anatomic Comparison Pre Ganglion Effector organs Post Thoracic or lumbar cord Sympathetic

Somatic Nervous System : 9/28/2009 9 Somatic Nervous System Efferent innervation of skeletal muscle No peripheral ganglia Rapid transmission, discrete control of motor units Any spinal segment Motor neuron Striated muscle

Neurochemical Transmission in the Peripheral Nervous System : 9/28/2009 10 Neurochemical Transmission in the Peripheral Nervous System Cholinergic nerves Acetylcholine is the neurotransmitter Locations 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

Cholinergic Neurotransmission : 9/28/2009 11 Cholinergic Neurotransmission Sympathetic

Neurochemical Transmission in the PNS : 9/28/2009 12 Neurochemical Transmission in the PNS Adrenergic nerves Norepinephrine is the neurotransmitter Locations Postganglionic, sympathetic axons

Adrenal Medulla : 9/28/2009 13 Adrenal Medulla Presynaptic nerves are cholinergic Medullary cells synthesize and release two, related catecholamines into the systemic circulation Epinephrine (adrenaline) Norepinephrine Epi and NE stimulate adrenergic sites

Adrenal Medulla(2) : 9/28/2009 14 Adrenal Medulla(2) Cholinergic neuron Adrenal medulla Epi and NE released into systemic circulation Denotes ACh

ACh Synthesis, Release, and Fate : 9/28/2009 15 ACh Synthesis, Release, and Fate 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)

NE Synthesis, Release, and Fate : 9/28/2009 16 NE Synthesis, Release, and Fate Catecholamine - synthesized in a multistep pathway starting with tyrosine 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)

Receptors : 9/28/2009 17 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

Ligand-Receptor Interactions : 9/28/2009 18 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

Cholinergic Receptors : 9/28/2009 19 Cholinergic Receptors Activated by ACh and cholinergic drugs Anatomic distribution Postganglionic, parasympathetic neuroeffector junctions All autonomic ganglia, whethe parasympathetic or sympathetic Somatic neuromuscular junctions

Cholinergic Receptor Locations : 9/28/2009 20 Cholinergic Receptor Locations Sympathetic

Cholinergic Receptor Subtypes : 9/28/2009 21 Cholinergic Receptor Subtypes Muscarinic Postganglionic, parasympathetic, neuroeffector junctions Nicotinic Distinction of two different subtypes Ganglia - type I or type G Neuromuscular junctions - type II or type M

Cholinergic Receptor Subtype Locations : 9/28/2009 22 Cholinergic Receptor Subtype Locations Sympathetic N1 M N1

Adrenergic Receptors : 9/28/2009 23 Adrenergic Receptors Activated by NE, Epi, and adrenergic drugs Anatomic distribution Postganglionic, sympathetic, neuroeffector junctions Subtypes Alpha-1, 2; Beta-1, 2, 3

Adrenergic Receptor Locations : 9/28/2009 24 Adrenergic Receptor Locations Sympathetic

Functional Significance of the Autonomic Nervous System : 9/28/2009 25 Functional Significance of the Autonomic Nervous System Organ system integration Parasympathetic Discrete innervation Energy conservation Sympathetic Highly distributed innervation, global responses Energy expenditure Fight or flight responses

Functional Significance of the Autonomic Nervous System : 9/28/2009 26 Functional Significance of the Autonomic Nervous System Dual innervaton Organ responses moderated by both parasympathetic and sympathetic influences Parasympathetic dominant at rest Balance of opposing neurologic influences determines physiologic responses

Introduction to Autonomic and Somatic Pharmacology : 9/28/2009 27 Introduction to Autonomic and Somatic Pharmacology Some 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

Alpha-1 Adrenergic Receptor : 9/28/2009 28 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)

Alpha-2 Adrenergic Receptor : 9/28/2009 29 Alpha-2 Adrenergic Receptor Vasoconstriction Modulation of NE release Presynaptic receptors on axon terminous Spinal alpha-2 receptors mediate analgesia Agonists used clinically as epidural and spinal analgesics Sedation

Beta-1 Adrenergic Receptor : 9/28/2009 30 Beta-1 Adrenergic Receptor Exclusive to myocardium Agonists Increase HR, contractility, and impulse conduction speed May be arrhythmogenic Antagonists Decrease HR, contractility, and impulse conduction speed Used clinically as antiarrhythmics

Beta-2 Adrenergic Receptor : 9/28/2009 31 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

Muscarinic Cholinergic Receptor : 9/28/2009 32 Muscarinic Cholinergic Receptor Myocardium Agonists decrease HR and AV conduction velocity Antagonists used clinically to increase HR and facilitate AV conduction in heart block Iris sphincter muscle Agoinists evoke pupillary constriction (miosis) Antagoinists evoke mydriasis Gastrointestinal tract Agonists increase peristalsis and relax sphincters Urinary bladder Agonists evoke urination Detrusor muscle (bladder) contraction Trigone (sphincter) relaxation