Neurotransmitters in Pharmacology PDF

PAS-506: Foundations of Clinical Medicine Neurotransmitters in Pharmacology Ashley Foster, PharmD October 14, 2024  PANCE BLUEPRINT Task: Managing Patients- Pharmaceutical Therapeutics (15%) Knowledge of:...

PAS-506: Foundations of Clinical Medicine Neurotransmitters in Pharmacology Ashley Foster, PharmD October 14, 2024  PANCE BLUEPRINT Task: Managing Patients- Pharmaceutical Therapeutics (15%) Knowledge of: Skill in: Assessing patient adherence to drug Alternative/complementary therapies and their side regimens eff ects, interactions, and toxicities Drafting a prescription Contraindications Evaluating, treating, and reporting Drug interactions, including presentation and treatment adverse drug reactions and/or adverse Indications for use eff ects Identifying and managing medication Mechanism of action issues Methods to reduce medication errors Maintaining knowledge of relevant Monitoring and follow-up of pharmacologic regimens pharmacologic agents Pharmacokinetics, pharmacogenomics, and Monitoring pharmacologic regimens and adjusting as appropriate pharmacodynamics Prescribing controlled substances Prescribing, monitoring, and regulating controlled appropriately substances Selecting appropriate pharmacologic Presentation and management of adverse eff ects, therapy and dosing allergic reactions, and toxicities Special populations requiring drug/dose modifi cation Substances of abuse  COURSE LEARNING OBJECTIVES CLO CLO Statement(s) Assessment Method(s) Didactic Phase ARC-PA Code Learning Standard(s) Outcome(s) CLO1 Explain the cellular, genetic, and molecular principles that are foundational in Multiple-Choice Examination MK1 and MK2 B2.02 e medical physiology. CLO2 Discuss the principles of pharmacokinetics and pharmacodynamics that are Written Assignments MK1 B2.02 d important in prescribing and administering drug therapy. B2.12 a Multiple-Choice Examination CLO3 Explain the physiologic processes that contribute to and regulate each organ Multiple-Choice Examination MK1 and MK2 B2.02 b system within the human body. CLO4 Discuss the physiologic targets, mechanisms of action, adverse effects, and Multiple-Choice Examination MK1 B2.02 d contraindications of specific medications used in the treatment of common B2.07 d disorders. CLO5 Explain the physiologic changes that occur during surgery. Multiple-Choice Examination MK1 B2.08 c CLO6 Discuss the characteristics of pathogens that cause infections in humans. Multiple-Choice Examination MK1 and MK2 B2.02 c CLO7 Discuss the characteristics of various classes of antimicrobial agents. Multiple-Choice Examination MK1 and MK2 B2.02 d CLO8 Determine the most appropriate antimicrobial therapy based on Multiple-Choice Examination MK1 and MK2 B2.02 d suspected/confirmed pathogen(s). CRPSA6 B2.07 d  INSTRUCTIONAL LEARNING OBJECTIVES Classify the peripheral nervous system and its divisions (efferent, afferent). Distinguish the autonomic and somatic nervous systems. Identify neurotransmitters and their role in the body. Outline signal transduction. Recall possible targets for and predicted effects of pharmacologic therapies. Compare and contrast cholinergic and adrenergic neurons. Differentiate types of cholinergic receptors (muscarinic, nicotinic). Recognize adrenergic receptors, the neurotransmitters that bind them, and the resulting effects.  APPLYING FOUNDATIONAL SCIENTIFIC CONCEPTS Organization of nervous system Anatomy of nervous system Signal transduction  TOPIC LIST Organization of nervous system Peripheral nervous system divisions Anatomy Function Neurotransmitters Signal transduction Cholinergic neurons and receptors Cholinergic drug actions Adrenergic neurons and receptors Adrenergic drug actions NERVOUS SYSTEM ORGANIZATION & DIVISIONS FLOW CHART OF NERVOUS SYSTEM ORGANIZATI ON https://www.pinterest.com/pin/49138500933767884  ORGANIZATION OF NERVOUS SYSTEM Central Nervous System Brain and spinal cord  ORGANIZATION OF NERVOUS SYSTEM Peripheral Nervous System Afferent division- sensory signals sent TO CNS Efferent division- signal FROM CNS to effector organs  ORGANIZATION OF NERVOUS SYSTEM Peripheral Nervous System Afferent- sensory signals sent TO CNS Visceral stimuli Internal organs and mucosal surfaces Sensory stimuli External sources Ex: touch a hot object heat sensory signal to CNS  ANATOMY OF AFFERENT NEURONS Afferent neurons Sensory receptors Fibers Important for reflex regulation and in signaling CNS of need for efferent neurons to respond https://www.biologyonline.com/dictionary/afferent- nerve  ORGANIZATION OF NERVOUS SYSTEM Peripheral Nervous System Efferent- signal FROM CNS to effector organs Somatic nervous system Ex: response signal from spinal cord through efferent neurons to skeletal muscles to move away from or let go of hot object Autonomic nervous system FUNCTIONAL DIVISION OF EFFERENT PNS Somatic Nervous System (SNS) Conscious, voluntary, controlled function Autonomic Nervous System (ANS) Unconscious, involuntary, regulatory function  ANATOMY OF EFFERENT NEURONS Efferent neurons (somatic and autonomic) Preganglionic neurons Cell body originated in CNS Emerge from brainstem or spinal cord and form synaptic connection in ganglia Myelinated Postganglionic neurons Cell body begins in ganglia End on effector organ Nonmyelinated Ganglia Synaptic relay stations between neurons Neural clusters that act as gatekeepers of signal Can transmit signal or redirect/diffuse SOMATIC NERVOUS SYSTEM (SNS) Somatic Nervous System Conscious, voluntary, controlled function Cholinergic motor neurons innervate skeletal muscle  ANATOMY OF SOMATIC NEURONS Somatic Direct connection from CNS to skeletal muscle No ganglia Myelinated (fast transmission) AUTONOMIC NERVOUS SYSTEM (ANS) Autonomic Nervous System (ANS) Unconscious, involuntary, regulatory function Cholinergic and adrenergic neurons innervate various target organs Rapid transmission of electrical impulses that end at effector organs  AUTONOMIC NERVOUS SYSTEM (ANS) Sympathetic Fight or flight Releases energy Parasympathetic Rest and digest Conserves energy Enteric Digestive organs Covered in more detail in GI lectures  ANATOMY OF SYMPATHETIC & PARASYMPATHETIC NEURONS Sympathetic Most arise from thoracic and lumbar region of spinal cord Preganglionic neurons shorter than postganglionic neurons Ganglia closer to CNS Parasympathetic Arise from cranial nerves III, VII, IX, X and sacral region of spinal cord (S2-S4) Preganglionic neurons are longer than postganglionic neurons Ganglia closer to effector organs FUNCTION OF SYMPATHETIC NERVOUS SYSTEM (SANS) Fight or flight response Triggered by direct sympathetic activation and stimulation of adrenal medulla Adrenal medulla releases epinephrine Functions as a unit Discharges as a complete system ILLUSTRATED EFFECTS OF SYMPATHETIC NERVOUS SYSTEM  FUNCTION OF PARASYMPATHETIC NERVOUS SYSTEM (PANS) Maintains homeostasis Maintains essential bodily functions Opposes or balances actions of sympathetic div. Never discharges as a complete system Innervates specific organs, activates targets separately ILLUSTRATED EFFECTS OF PARASYMPATHETIC NERVOUS SYSTEM  REVIEW Compare and contrast the somatic and autonomic nervous systems. Describe the pathway of the somatic neuron. What are some effects of the sympathetic nervous system? What are some effects of the parasympathetic nervous system? Which is longer, a preganglionic sympathetic neuron or a preganglionic parasympathetic neuron? Which has ganglia closer to the central nervous system? NEUROTRANSMITTER S AND SIGNAL TRANSDUCTION  CONSIDER How are signals sent from CNS to effector organs? What stimulates the propagation of a signal? How might signals be good drug targets?  SEVERAL TYPES OF CHEMICAL CELLULAR SIGNALING Neurotransmitters (NTMs) Released from nerve terminals Communication from neuron to neuron Communication from neuron to effector organs Hormones Specialized endocrine cells release hormones into bloodstream Local mediators Chemicals act locally on cells in immediate environment Mediators are rapidly destroyed and removed Ex: prostaglandins  NEUROTRANSMITTERS (NTMs) Action potential (AP) leads to release of neurotransmitter (NTM) AP arrives at axon terminal depolarization opens voltage gated Ca2+ channels Ca2+ enters cell, signals vesicles to move to membrane Vesicles merge with membrane, release NTM into synapse NTM diffuses across synapse, binds to receptors on postsynaptic neuron triggers response if response is great http://loretocollegebiology.weebly.com/ enough, will trigger another action synapses.html potential  COMMON NEUROTRANSMITTERS Adrenergi Adrenergi Dopaminer Serotoner Neurotransmitte c c gic gic r functions Neurotransmitte r/ neuron classification pairings Autonomic nerve fibers Cholinergic (ACh) Adrenergic GABAergic Cholinergi Glutamatergi Opioid (NE) c c  MAJOR NEUROTRANSMITTERS Adrenergi Adrenergi Dopaminer Serotoner Glutamate c c gic gic Major excitatory NTM GABA Major inhibitory NTM Each balances the other Imbalance disease GABAergic Cholinergi Glutamatergi Opioid c c SOME NEUROTRANSMITTER/RECEPTOR PAIRS Neurotransmitters Receptors Epinephrine, Norepinephrine α & β adrenergic receptors (NE) Dopamine (DA) D receptors Serotonin (5-HT) 5-HT receptors GABA GABA receptor (NMDA, AMPA) Acetylcholine (ACh) Nicotinic & muscarinic cholinergic receptors Glutamate (Glu) NMDA, AMPA, mGluR receptors (GABA-R) Endorphins Opioid receptors  NEUROTRANSMITTER SYNTHESIS Notice all the enzymes involved When you see enzymes, think good drug targets  CHOLINERGIC NERVE FIBERS Neurons that release acetylcholine (ACh) All somatic motor neurons Release ACh, which binds to nicotinic R on skeletal muscle cell All preganglionic autonomic neurons Sympathetic and parasympathetic Release ACh, which binds to nicotinic R Parasympathetic postganglionic neurons Release ACh, which binds to muscarinic R Directly to adrenal medulla Release ACh, which binds to nicotinic R on adrenal medulla  ADRENERGIC NERVE FIBERS Release norepinephrine (NE) From sympathetic postganglionic neurons To adrenergic receptors on effector organ cells *Adrenal medulla releases epinephrine into blood Epinephrine acts as chemical messenger in effector organs Sometimes acts as nt, mostly acts as hormone SUMMARY ILLUSTRATION OF AUTONOMIC INNERVATION https://aneskey.com/central-and-autonomic-nervous-systems/ CHOLINERGIC & ADRENERGIC RECEPTORS  CHOLINERGIC RECEPTORS Cholinergic receptors Nicotinic receptors Located? Ligand-gated ion channels Ionotropic NTM binds to ion channel affects ion permeability Muscarinic receptors Located? G protein-coupled receptors Metabotropic Activate second messenger systems Which is faster?  ADRENERGIC RECEPTORS Adrenergic receptors Located? G protein-coupled receptors Metabotropic Activate second messenger system  ONE MORE THING ABOUT NEUROTRANSMITTERS Most autonomic nerves also release co-transmitters Enhance effects of primary NTM Possible targets for pharmacologic therapies Synthesis Storage Release Termination of action Receptor effects  REVIEW What is the function of a NTM? What is the relationship of a receptor to a NTM? What NTM binds to cholinergic receptors? Name 2 types of cholinergic receptors. How are they different? What NTMs binds to adrenergic receptors?  SUMMARY REVIEW TABLE- EFFERENT PERIPHERAL NEURONS Characteristic Somatic Neurons Sympathetic Neurons Parasympathetic Neurons Site of origin Certain cranial nerves __________________________ Certain cranial nerves and spinal nerves __________________________ and sacral area of spinal cord Length of fibers Long, direct from __________________________ Long preganglionic origin to skeletal __________________________ Short postganglionic muscle Location of ________________ Close to spinal cord Within or near effector ganglia organs Preganglionic N/A Extensive ____________________ fiber branching Types of neurons Cholinergic (ACh) Cholinergic (ACh, _____________________ (NTM) preganglionic) Adrenergic (NE, postganglionic) Type of response Direct muscle __________________________ Discrete (d/t specific CHOLINERGIC NEURONS AND RECEPTORS CHOLINERGIC NEURONS  CHOLINERGIC NEURONS Release ACh 1. Preganglionic fibers ending in the adrenal medulla 2. Autonomic preganglionic fibers (parasympathetic and sympathetic) 3. Postganglionic fibers of parasympathetic division 4. Somatic fibers 5. Postganglionic sympathetic division of sweat glands (exception to adrenergic neurons of sympathetic division- ILLUSTRATED OVERVIEW OF CHOLINERGI C NEURON ACTIVITY  SYNTHESIS OF ACETYLCHOLINE (ACh) Choline transported into cytoplasm of cholinergic neuron via choline transporter (CHT) Rate limiting step of ACh synthesis Inhibited by hemicholinium Energy-dependent carrier system (ChT) also cotransports Na+ Choline acetyltransferase (ChAT) enzymes responsible for reaction of choline with acetyl coenzyme A to form acetylcholine  STORAGE OF ACETYLCHOLINE (ACh) Vesicular active transport (VAT) system packages and stores ACh in presynaptic vesicles Transport (VAT) system inhibited by vesamicol ACh doesn’t get into vesicle Mature vesicle contains ACh, ATP, proteoglycan, peptides  RELEASE OF ACETYLCHOLINE (ACh) AP arrives Ca++ channels open Ca++ influx synaptic vesicles fuse with cell membrane and causes release of contents into synaptic space Release of contents can be blocked by botulinum toxin https://www.researchgate.net/figure/Schematic-representation-of-the- acetylcholine-release-course-and-cholinergic-hypothesis_fig1_338191887  ACh BINDING TO RECEPTORS ACh crosses synaptic space to bind to: Receptor on postsynaptic cell Nicotinic (ionotropic), muscarinic (metabotropic), depending on location/function Which is pictured here? Presynaptic receptors on cholinergic neuron Negative feedback mechanism Other targeted presynaptic receptors ACTIONS OF ACETYLCHOLINE (PARASYMPATHETIC ACTIONS) Decreases heart rate, cardiac output, blood pressure Stimulates salivary secretion Increases gastric acid secretion Stimulates intestinal secretions and motility Increases bronchiolar secretions Causes bronchoconstriction Increases detrusor muscle tone causes urination Stimulates ciliary muscle contraction for near vision Constriction of pupillae sphincter muscle miosis  ACTIONS OF ACETYLCHOLINE Memory trick for effects of acetylcholine SLUDG E  DEGRADATION OF ACETYLCHOLINE (ACH) Signal at postjunctional effector site is rapidly terminated Acetylcholinesterase (AChE) breaks down acetylcholine (ACh) to choline and acetate in https://sites.psu.edu/rbo5016neurostudyblog/2014/02/26/ acetylcholine-ach/ the synaptic cleft norepinephrine > > isoproterenol Very low affinity for isoproterenol Two subtypes based on affinities for α agonists and antagonists α1 α2  ALPHA-1 RECEPTORS Primarily present on postsynaptic membrane of effector organs Mediate many of classic effects involving smooth muscle constriction Activation starts series of reactions through G-protein activation of phospholipase C generation of second messengers DAG and IP3 IP3 triggers release of calcium from ER into cytosol DAG turns on other proteins in the cell  ALPHA-2 RECEPTORS Found primarily on sympathetic presynaptic nerve endings Control release of NE Most of NE that is released activates the sympathetic adrenergic postsynaptic neuron but some of the released NE circles back and reacts with alpha-2 receptors on presynaptic membrane Presynaptic receptor stimulation leads to feedback inhibition and blocks further release of NE from the adrenergic neuron that was stimulated Blocking action acts as a local mechanism for regulating NE output during high sympathetic activity  BETA-ADRENORECEPTORS Strong response to isoproterenol Isoproterenol>epinephrine>norepinephrine Divided into 3 subgroups based on affinities for adrenergic agonists and antagonists Β1-heart Β2- lungs Β3- adipose tissue β1 equal affinity for epinephrine and NE Β2 higher affinity of epinephrine than NE Binding causes activation of adenylyl cyclase and increased cAMP concentrations inside the cell LOCATIONS OF ALPHA AND BETA RECEPTORS https://www.pharmaguideline.com/2022/03/drugs- acting-on-autonomic-nervous-system-sdrenergic- neurotransmitters.html CHARACTERISTIC RESPONSES MEDIATED BY ADRENORECEPTORS α1 receptor stimulation- vasoconstriction and increase in total peripheral resistance and blood pressure Stimulation of β1receptors - cardiac stimulation Stimulation of β2 receptors - vasodilation and smooth muscle relaxation A B C D 1 2 SUMMARY TABLE OF ADRENORECEPTORS IN ANS SUMMARY OF ADRENORECEPTORS ADRENERGIC DRUG ACTIONS  QUICK REVIEW Where are adrenergic neurons located? What is the significance of 5-6 steps of adrenergic neuron activity (see pic)? Describe the actions of NE at effector organs.  ADRENERGIC DRUG ACTIONS Affect receptors stimulated by NE or epinephrine Sympathomimetics- activate adrenergic receptors Direct acting agonists- directly activate adrenergic receptors Indirect-acting agonists- enhance release or stop reuptake of NE Sympatholytics- block activation of adrenergic receptors SUMMARY REVIEW TABLE- ADRENERGIC RECEPTORS AND DRUG ACTIONS (fill in the blanks) Adrenergic Effect when stimulated Actions of Actions of Receptor receptor receptor agonist antagonist alpha-1 Vasoconstriction ____________________ Contraction of urine ____________________ sphincter (urine retention) alpha-2 Presynaptic: Decreases NE ____________________ release ____________________ Postsynaptic: Decreases sympathetic outflow Beta-1 Increase HR, contractility ____________________ Increase renin ____________________ Beat-2 Bronchodilation ____________________ Arteriole dilation (except ____________________ skin and brain)  REFERENCES DiPiro JT, Yee GC, Haines ST, Nolin TD, Ellingrod VL, Posey LM. eds. DiPiro’s Pharmacotherapy: A Pathophysiologic Approach. 12th ed. New York, NY: McGraw Hill; 2023. Barrett KE, Barman SM, Brooks HL, Yuan JJ. eds. “Neurotransmitters & Neuromodulators.” Ganong’s Review of Medical Physiology. 26th ed. New York, NY: McGraw Hill; 2020. Katzung BG, Vanderah TW. eds. “Introduction to Autonomic Pharmacology.” Basic & Clinical Pharmacology. 16th ed. New York, NY: McGraw Hill; 2023. Katzung BG, Vanderah TW. eds. “Cholinoceptor-Activating & Cholinesterase-Inhibiting Drugs.” Basic & Clinical Pharmacology. 16th ed. New York, NY: McGraw Hill; 2023. Katzung BG, Vanderah TW. eds. “Cholinoceptor Blocking Drugs.” Basic & Clinical Pharmacology. 16th ed. New York, NY: McGraw Hill; 2023. Katzung BG, Vanderah TW. eds. “Introduction to Autonomic Pharmacology.” Basic & Clinical Pharmacology. 16th ed. New York, NY: McGraw Hill; 2023. Whalen KL, Lerchenfeldt SM, Giordano CR. eds. Lippincott Illustrated Reviews: Pharmacology. 8th ed. Philadelphia, PA: Wolters Kluwer Health; 2023.