PHID1502 Integrated Sequence 2 Intro Autonomic Nervous System Winter 2024-2025 Lecture PDF

Winter quarter 2024-2025 [email protected] 1 Integrated Sequence 2 – PHID1502 – Winter 2024/2025 Introduction to the Autonomic Nervous System Required reading: Foye’s, Sixth Edition – Chapter 13, pages 392 – 416; Foye’s, Fifth Editi...

Winter quarter 2024-2025 [email protected] 1 Integrated Sequence 2 – PHID1502 – Winter 2024/2025 Introduction to the Autonomic Nervous System Required reading: Foye’s, Sixth Edition – Chapter 13, pages 392 – 416; Foye’s, Fifth Edition Online – Chapter 10 Recommended: Katzung, Eleventh Edition - Chapter 6, pages 77 – 94. Oliver Grundmann, Ph.D. Adjunct Assistant Professor (MWU) Clinical Professor (UF) Phone: 352-246-4994 [email protected] Winter quarter 2024-2025 [email protected] 3 Outline Review of the Nervous System Review of Sympathetic Autonomous Nervous System (ANS) Introduction Basic Pharmacology of Sympathomimetic Drugs (Agonists & Antagonists) Clinical Pharmacology & Specific Drugs Toxicity Winter quarter 2024-2025 [email protected] 4 The Nervous System Central Nervous System (CNS) Brain & Spinal Cord, and the Peripheral Nervous System (PNS) neuronal tissues outside the CNS Winter quarter 2024-2025 [email protected] 5 The Nervous System The Motor (efferent) portion of the nervous system has two major subdivisions: Autonomic Nervous System (ANS) whose activities are not under conscious control; automatic or reflex- like! Visceral functions like digestion, cardiac output, blood flow to organs, temperature regulation Somatic Nervous System with consciously controlled functions like movement, respiration rate, and posture Winter quarter 2024-2025 [email protected] 6 The Autonomic Nervous System The Autonomic Nervous System (ANS) can be divided (anatomical basis) into two major divisions: Sympathetic Nervous System (SNS) division: thoracolumbar; preganglionic fibers are short, leave CNS through thoracic & lumbar spinal nerves, & terminate in ganglia located close to the spinal cord. Parasympathetic Nervous System (PNS) division: craniosacral; preganglionic fibers are longer, leave the CNS through the cranial nerves & sacral spinal roots & run to ganglia located near the tissues innervated. Winter quarter 2024-2025 [email protected] 7 Nervous System Neurotransmission Winter quarter 2024-2025 [email protected] 8 The Nervous System - neurotransmission The Sensory (afferent) portion of both portions of the nervous system: Provide important information (feedback) regarding the internal and external environments, and modify motor output through reflex arcs of varying size and complexity. It is very important that this information is transmitted using chemicals for transmission of information between nerve cells and their effector cells across synaptic clefts onto specialized receptor molecules  Winter quarter 2024-2025 [email protected] 9 Chemical vs. electrical neurotransmission Chemical neurotransmission allows for a more distinguished and fine- tuned response. In contrast, electrical neurotransmission follows an all-or-nothing principle. Winter quarter 2024-2025 [email protected] 10 Summary of the Autonomous Nervous System Winter quarter 2024-2025 [email protected] 11 Cells of the Nervous System The nervous system is made up primarily of two cell types: nerves or neurons, and glial cells Neurons serve to transmit information Glial cells support and protect neurons Winter quarter 2024-2025 [email protected] 12 Glial cells – functions and location Glial cells make up 90% of cells of the CNS; 50% of the volume Mostly non-excitable; provide structural support & insulation; neuromodulators in some neurotransmitter systems (glutamate) Neuroglia support the functioning of the neuron In the PNS the Schwann cells wrap around the axon leaving small gaps called Nodes of Ranvier between successive cells. They are made of a significant amount of lipoprotein material called myelin, and the series of these cells produces the myelin sheath Winter quarter 2024-2025 [email protected] 13 Schwann cells, myelin and action potentials Winter quarter 2024-2025 [email protected] 14 Types of Glial cells in the CNS In the CNS other types of neuroglia, called oligodendrocytes, produce myelinated fibers. In contrast to Schwann cells, oligodendrocytes often wrap around several neurons (white matter of the spinal cord & brain) Astrocytes are branched glial cells that provide a barrier between nervous tissue & blood (together with capillary endothelial cells these make up the Blood-Brain Barrier). They protect CNS from blood-borne infections & also inhibit some meds from reaching the brain Microglia are small glial cells that are phagocytic (immune system related). They digest the foreign particles that invade the nervous tissue of the brain. Ependymal cells line the ventricles of the brain and serve as a barrier between the fluid in the area (the cerebrospinal fluid) and the nervous tissue Winter quarter 2024-2025 [email protected] 15 Astrocytes and microglia Winter quarter 2024-2025 [email protected] 16 Neurons – structure and function Neurons are excitable; generate action potentials when ion concentrations change enough to do so; they receive, process, initiate, and transmit information to other neurons or organs by chemical or electrical means; neurotransmitters are usually used to transmit information by way of release across a synapse and binding to a receptor on the other neuron or organ. Four main parts of a neuron: cell body, axon, dendrites and terminal (synapse). Allows for extensive information sharing through convergence and divergence.  Winter quarter 2024-2025 [email protected] 17 Neurons – signal transmission pathways Three main classes of neuronal actions: Afferent: transmitting information from receptors and organs to the CNS Efferent: trans- mitting information from the CNS to other neurons or organs Interneurons: trans- mitting information directly between neurons https://www.chegg.com/learn/biology/anatomy-physiology-in-biology/afferent-neurons-in-anatomy-and-physiology  Winter quarter 2024-2025 [email protected] 18 Convergence and divergence of information Convergence of input allows for neuronal cells to be influenced by multiple pathways. Divergence of output allows for controlled release of information via multiple pathways. Winter quarter 2024-2025 [email protected] 19 Neurotransmitters for the efferent nervous system Concerning the Efferent (Motor) Nervous System For both the Autonomic (involuntary) and Somatic (voluntary) Nervous Systems, the efferent systems allow CNS control of function Two neurotransmitters produce almost all effector responses in both systems: - Norepinephrine (adrenergic) - Acetylcholine (cholinergic) Winter quarter 2024-2025 [email protected] 20 Role of acetylcholine and norepinephrine in neurotransmission Winter quarter 2024-2025 [email protected] 21 Nervous System neurotransmission Winter quarter 2024-2025 [email protected] 22 Nervous System neurotransmission All preganglionic neurons → release of acetylcholine (nicotinic receptors) All postganglionic parasympathetic neurons → release of acetylcholine (muscarinic receptors) Most postganglionic sympathetic neurons (exception: sweat glands) → release of norepinephrine (α and β receptors) Winter quarter 2024-2025 [email protected] 23 Summary of autonomous nervous system neurotransmission Each effector neuronal pathway starts in the CNS & ends at an effector organ Each effector neuronal pathway is a two neuron path First neuron has its cell body in the CNS, its axon (pre-ganglionic) synapses with a cell body of the second neuron in a ganglion Second neuron (post-ganglionic) axons terminate in the effector organ https://www.chegg.com/learn/biology/anatomy-physiology-in-biology/afferent-neurons-in-anatomy-and-physiology Winter quarter 2024-2025 [email protected] 28 Differences between sympathetic and parasympathetic neurotransmission Sympathetic Nervous Parasympathetic Nervous System (SNS): System (PNS): originates in thoracic & originates in cranial & lumbar spinal cord sacral spinal cord has short preganglionic has long preganglionic fibers fibers ganglia are near the ganglia are near the spinal effector organs cord (paravertebral) or slightly further away (prevertebral) the postganglionic fibers the postganglionic fibers that innervate the effector that innervate the effector organs are short organs are longer Winter quarter 2024-2025 [email protected] 29 Sympathetic and parasympathetic pathways Winter quarter 2024-2025 [email protected] 30 Sympathetic vs. parasympathetic nervous system – functions Parasympathetic Nervous System (PNS) Activation: Digestion Anabolic processes “Rest and digest” Sympathetic Nervous System (SNS) Activation: utilization of fat/glucose stores catabolic processes “Fight or flight” response  Winter quarter 2024-2025 [email protected] 31 Sympathetic Nervous System – general functions Adrenal cortex (glucocorticoids, aldosterone, androgens) Adrenal medulla (release of catecholamines: norepinephrine (NE) & epinephrine (EPI)) Metabolic effects: Increases glycogenolysis (liver) activates glycogen phosphorylase Decreases glycogenesis (liver) inhibits glycogen synthase Increases glycolysis (muscle) Increases lipolysis (adipose tissue) activates triglyceride lipase Winter quarter 2024-2025 [email protected] 32 Sympathetic Nervous System – physiological effects on organs Winter quarter 2024-2025 [email protected] 33 Dual innervation of effector organs by sympathetic and parasympathetic nervous system Most visceral organs are innervated by both the parasympathetic and sympathetic nervous system Usually both are partially active at all times Usually their actions are antagonistic (opposing) Usually when the activity of one increases the activity of the other decreases (concept of homeostasis) In general dual innervation allows for more rapid changes to occur Winter quarter 2024-2025 [email protected] 34 Dual innervation – types of interactions Winter quarter 2024-2025 [email protected] 35 Neurotransmission pathways for the sympathetic nervous system Winter quarter 2024-2025 [email protected] 36 Neurotransmitter synthesis pathways for the sympathetic nervous system Neurotransmission in the CNS: Catecholaminergic synthesis Tyrosine is an essential amino acid Rate limiting step is the enzyme Tyrosine hydroxylase (which is normally saturated) L-dihydroxyphenylacetic acid (L-DOPA) is rapidly decarboxylated by L-AAD to dopamine In norepinephrine & epinephrine neurons Dopamine Beta-hydroxylase (DBH) changes dopamine into norepinephrine In epinephrine neurons phenylethanolamine- methyltransferase (PNMT) changes norepinephrine into epinephrine Winter quarter 2024-2025 [email protected] 37 Neurotransmitter synthesis pathways for the sympathetic nervous system Winter quarter 2024-2025 [email protected] 38 Neurotransmitter metabolism pathways for the sympathetic nervous system MAO: monoamine oxidase COMT: Catechol-O-methyl transferase Winter quarter 2024-2025 [email protected] 39 Sympathetic nervous system synapse neurotransmission  Winter quarter 2024-2025 [email protected] 40 Autonomic Nervous System receptor types 3 muscarinic acetylcholine receptors Neuronal & muscular nicotinic 2 adrenergic receptors alpha receptors 3 adrenergic beta receptors 5 dopamine receptors  Winter quarter 2024-2025 [email protected] 41 Adrenergic receptors (including dopamine) Alpha–adrenergic subtypes: α1 & α2 Beta-adrenergic subtypes: β1, β2, and β3 Dopaminergic: D1, D2, D3, D4, and D5 General rule of thumb for adrenergic receptor organ response: If it increases or constricts → α1 If it decreases or relaxes → β2 Winter quarter 2024-2025 [email protected] 50 Presynaptic regulation and negative feedback loop Negative feedback Most evidence for noradrenergic fibers Autoreceptors – presynaptic and respond to transmitters released by nerve endings 2 activation decreases further release of norepinephrine 2 activation facilitates release of norepinephrine Heteroreceptors – activated by substances other than neurotransmitters released from the presynaptic neuron Winter quarter 2024-2025 [email protected] 51 Presynaptic negative feedback regulation  Winter quarter 2024-2025 [email protected] 52 Postsynaptic regulation Modulation by prior history of activity at receptor Receptor down-regulation (less receptors will be present on the cell surface, often through phagocytosis followed by DNA and protein changes) Sustained use of agonists Receptor up-regulation (more receptors will be present on the cell surface, initiated by DNA and protein changes) Sustained use of antagonists Denervation hypersensitivity as an extreme form of up-regulation Cut neuron Pharmacological denervation by Reserpine – NE depleter – causes increased sensitivity Winter quarter 2024-2025 [email protected] 53 Receptor regulation Autoreceptors – 2 Heteroreceptors (e.g. norepinephrine decreases GI activity by inhibiting the release of acetylcholine from parasympathetic neurons) Winter quarter 2024-2025 [email protected] 54 Interference with sympathetic neurotransmission Winter quarter 2024-2025 [email protected] 55 Targets for therapeutic interference with sympathetic neurotransmission Winter quarter 2024-2025 [email protected] 56 Effects of Drugs on Nerve Transmission Winter quarter 2024-2025 [email protected] 57 α Adrenoreceptors - selectivity  receptor selectivity defined by the potency series: epinephrine  norepinephrine >> isoproterenol Subtypes of  are determined by selective antagonists 1 blocked by prazosin (Minipress) 2 blocked by yohimbine (Yocon) Further subtypes now known but not yet targeted in therapy Winter quarter 2024-2025 [email protected] 58 β Adrenoreceptors - selectivity  receptor selectivity defined by the potency series: isoproterenol > epinephrine  norepinephrine 1 and 2 subtypes of  determined by affinity 1 affinity - epinephrine = norepinephrine 2 affinity - epinephrine >> norepinephrine 3 have now been categorized and there are experimental drugs that target this receptor for the potential treatment of obesity Winter quarter 2024-2025 [email protected] 59 Dopamine Adrenoreceptors Dopamine (Intropin) - especially important: Splanchnic Renal vasculature Brain Not many drugs target a specific dopamine receptor subtype (although 5 different subtypes exist) Winter quarter 2024-2025 [email protected] 60 Model drugs and adrenoreceptor selectivity – Table 10-1  Winter quarter 2024-2025 [email protected] 61 Receptor selectivity Drug binds preferentially to one subgroup of receptors at concentrations too low to interact with another Pure  = methoxamine (Vasoxyl) Pure  = isoproterenol (Isuprel) Each tissue may express one or more different subtypes of a receptor Ability to synthesize drugs selective for certain tissues and receptors is preferred to limit side effects 1 subtype in prostate – research for benign prostate hyperplasia (BPH) Specificity = nearly absolute selectivity Winter quarter 2024-2025 [email protected] 62 Epinephrine – concentration-dependent selectivity  Winter quarter 2024-2025 [email protected] 63 Molecular mechanisms of adrenoreceptor activation and intracellular signaling cascade 1-receptor activation (G-protein coupled receptor, GPCR) Stimulate polyphosphoinositide hydrolysis → Inositoltriphosphate (IP3) and diacylglycerol (DAG) as intracellular second messengers Activates peptide growth factors such as protein kinase C (PKC)  Winter quarter 2024-2025 [email protected] 64 Molecular mechanisms of adrenoreceptor activation and intracellular signaling cascade 2-receptor activation (GPCR) Inhibits adenylyl cyclase activity (Gi) → decreases cAMP Centrally, inhibit sympathetic tone & BP: peripheral vasoconstriction is masked by the central effect 1, β2, and β3-receptor activation (GPCRs) Activates adenylyl cyclase (Gs) → increases cAMP Liver → activation of glycogen phosphorylase Heart → influx of calcium Smooth muscle → phosphorylation of myosin light chain kinase to inactive form cAMP independent – activate VOC calcium Winter quarter 2024-2025 [email protected] 65 Molecular mechanisms of adrenoreceptor activation and intracellular signaling cascade Winter quarter 2024-2025 [email protected] 66 Molecular mechanisms of adrenoreceptor activation and intracellular signaling cascade Dopamine D1 receptor activation (GPCR) Stimulates adenylyl cyclase → smooth muscle relaxation Vasodilation of splanchnic, renal, coronary, & cerebral resistance vessels D2 receptor activation (GPCR) Inhibits adenylyl cyclase Opens potassium channels Decreases calcium influx Presynaptically decrease norepinephrine release; at higher doses also stimulates β1 and then α1 receptors Winter quarter 2024-2025 [email protected] 68 Summary Nervous System divided into two branches: autonomic and somatic nervous system Autonomic nervous system divided into two branches: sympathetic (fight or flight) and parasympathetic (rest and digest) nervous system Glial cells provide support and structure while neurons are the functional information transmitters for the nervous system All preganglionic neurons are innervated by acetylcholine as the neurotransmitter Sympathetic nervous system effector organ neurotransmitters are epinephrine and norepinephrine Parasympathetic nervous system effector organ neurotransmitter is acetylcholine Winter quarter 2024-2025 [email protected] 69 Summary The rate-limiting step in the synthesis of catecholamines is tyrosine hydroxylase Monoamine oxidase and catechol-O-methyl transferase are important enzymes that metabolize catecholamines All adrenergic receptors are G-protein coupled receptors (GPCRs) with intracellular second messenger pathways Receptor selectivity and organ response: α1: Smooth vasculature, contraction; stimulates IP3 and DAG α2: Presynaptic, CNS, negative feedback loop; inhibits cAMP β1: Heart, increases contraction and rate; activates cAMP β2: Lungs, smooth vasculature, kidney, relaxation; activates cAMP β3: Adipose tissue, increases lipolysis; activates cAMP Winter quarter 2024-2025 [email protected] 70 Kahoot! Several Kahoot games will be played across the whole ANS lectures There are PRIZES to be won at the conclusion of the ANS lectures: 1st prize: $20 Amazon gift card 2nd prize: $15 Amazon gift card 3rd prize: $10 Amazon gift card IMPORTANT: you need to always use the same name for each of the Kahoot! Games since the results need to be saved to calculate the total! Otherwise you will be excluded and cannot compete. Suggestion: use your firstname.lastname (please – use a SFC name)