IVMS Autonomic and Cardiovascular Pharmacology PowerPoint Book

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IVMS Autonomic and Cardiovascular Pharmacology PowerPoint Book

  1. 1. INSTITUTE FOR MINORITY PHYSICIANS OF THE FUTURE PRESENTS Autonomic and Cardiovascular Basic Medical Science Medical Pharmacology Course Interactive Power Points Book Marc Imhotep Cray, M.D. © August, 2011 Intended Audience: Medical Students and IMG Physicians USMLE Step 1 Preparation. Including 12 presentations: 600 plus richly illustrated Web Interactive high yield plates. Approach: Horizontal (across BMS subjects) and Vertical (BMS to Clinical Science) Integration of Biochemistry the 4 Ps (physiology, pathophysiology, pathology and pharmacology). Download of e-Book has bookmarked Table of Contents for quick access. Uniqueness: IVMS Autonomic and Cardiovascular Medical Pharmacology Course is based on the integration of basic and clinical sciences. “This means that the learning of basic science is placed in the context of clinical and professional practice and is thus made more meaningful and relevant to students. IVMS curriculum integration involves both horizontal and vertical integration and is the pattern of undergraduate medical education that is presently becoming most widespread throughout the world.” Video and Audio Podcast of all lectures presented by Dr. Cray are available. drcray@imhotepvirtualmedsch.com Last updated/10-03-12
  2. 2. IVMS Autonomic and Cardiovascular Medical Pharmacology Course Interactive PowerPoints Book Marc Imhotep Cray, M.D. Professor Basic Medical Sciences http://www.imhotepvirtualmedsch.com/ Last updated/10-03-12
  3. 3. IVMS Online Autonomic and CV Pharmacology Course Syllabus IVMS Autonomic and Cardiovascular Pharmacology Course (Collection) is a part of IVMS Basic Medical Sciences Studies-- It is an upper-level undergraduate course designed for Pre-Med, Medical Students, Nursing students and biomedical science majors. IVMS ACVBMS examines the basic medical science behind the uses of drugs, covering a variety of common prescription medications. There clinical use, mechanism of action, and important side effects of each class of drugs are explored within the context of the body's organ systems. Also, this course is part of a sequential Learning-track from Advance High School leading to medical students sitting successfully for their USMLE Step 1. Directly to Interactive Course of Study Including 12 presentations. 600 plus richly illustrated Web Interactive high yield plates. Approach, Horizontal (across BMS subjects ) and Last updated/10-03-12 Vertical (BMS to Clinical Science) Integration of Biochemistry the 4 Ps. Download of e-Book has bookmarked Table of Contents for quick access. Intended Audience: Medical Students and IMG Physicians USMLE Step 1 Preparation
  4. 4. Hypertext (direct links) to Online Sequence:           Intro to ANS ANS Cholinergic Agents ANS Adrenergic Agents Autonomics Formative Exam I Autonomic Nervous System Summary Notes Autonomics Formative Exam II ANS Review II Ans. and Explain. Heart and Circulation BMS Cardiovascular Notes CV Pathology-Gross and Micro            CAD and Anti-Anginal Agents Anti Hypertensive Agents Anti-Hyperlipidemia Agents Diuretic Agents CV Formative Exam I Anti-Arrhythmic Agents Pathophysiology and Tx of CHF Pathophysiology & Tx of Shock Valvular Heart Disease BMS CV Formative Exam II CV Formative Exam II Ans. Last updated/10-03-12
  5. 5. Autonomic and Cardiovascular Medical Pharmacology Course Interactive PowerPoints Book Contents:(download has hypertext bookmarks) 1. Intro to ANS 2. ANS-Cholinergic Agents 3. ANS-Adrenergic Agents 4. Heart and Circulation BMS 5. CV-Pathology-Gross and Micro 6. CAD and Anti-Anginal Agents 7. Anti Hypertensive Agents 8. Anti-Hyperlipidemia Agents 9. Diuretic Agents 10.Anti-Arrhythmic Agents 11.Pathophysiology and Tx of CHF 12.Pathophysiology & Tx of Shock Last updated/10-03-12
  6. 6. ANS Pharmacology Introduction to the Autonomic Nervous System Recommended Reading: Autonomic Introduction Prepared and Presented by: Marc Imhotep Cray, M.D. Professor Pharmacology and Basic Medical Sciences See: IVMS Autonomic Nervous System Summary Formative Assessment Practice Question Set #1 Clinical: E-Medicine Article Epilepsy and the Autonomic Nervous System
  7. 7. Online Reference Resource IVMS Online Textbook Series PRINCIPLES of PHARMACOLOGY THE PATHOPHYSIOLOGIC BASIS OF DRUG THERAPY ThirdEdition David E. Golan, MD, PhD Editor in Chief Armen H. Tashjian, Jr., MD Deputy Editor Ehrin J. Armstrong, MD, MSc April W. Armstrong, MD, MPH Associate Editors Enrolled learners click to download 2
  8. 8. 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 3
  9. 9. Organization of the Nervous System Schematic From : http://users.rcn.com/jkimball.ma.ultranet/BiologyPages/P/PNS.html structural unit of nervous system >>> neuron & functional unit of nervous system >>> reflex arc 4
  10. 10. Neuron Anatomy Source: http://www.dentalarticles.com/visual/d/neuron-cell-diagram.php 5
  11. 11. Autonomic Reflexes   Afferent fibers from periphery to CNS CNS integration       Cortex Thalamus Hypothalamus Medulla Spinal cord Efferent fibers from CNS to periphery 6
  12. 12. 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 >>>> lateral horn cell of spinal cord >>>> motor (efferent) neuron ( two neurons: pre & post ganglionic ) >>>> effector organ ( smooth, cardiac muscle or 7 gland )
  13. 13. 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 8
  14. 14. 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 Post Effector organ 9
  15. 15. 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 10
  16. 16. Schematized Anatomic Comparison Parasympathetic Cranial or sacral cord Post Pre Ganglion Effector organ Sympathetic Thoracic or lumbar cord Pre Ganglion Post Effector organs11
  17. 17. Somatic Nervous System    Efferent innervation of skeletal muscle No peripheral ganglia Rapid transmission, discrete control of motor units Striated muscle Any spinal segment Motor neuron 12
  18. 18. 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 13
  19. 19. Cholinergic Neurotransmission Denotes ACh Parasympathetic Cranial or sacral cord Post Pre Ganglion Sympathetic Thoracic or lumbar cord Pre Ganglion Effector organ Denotes ACh Post Effector organs14
  20. 20. Neurochemical Transmission in the PNS  Adrenergic nerves   Norepinephrine is the neurotransmitter Locations  Postganglionic, sympathetic axons Sympathetic Thoracic or lumbar cord Pre Ganglion Denotes ACh Denotes Norepinephrine Post Effector organs 15
  21. 21. 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 16
  22. 22. Adrenal Medulla(2) Adrenal medulla Cholinergic neuron Epi and NE released into systemic circulation Denotes ACh 17
  23. 23. 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) 18
  24. 24. ACh Synthesis, Release, and Fate (2) Synthesis and fate of synaptically released acetylcholine at cholinergic synapse. Source: http://www.neurophysiology.ws/autonomicns.htm 19
  25. 25. 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) 20
  26. 26. NE Synthesis, Release, and Fate (2) Synthesis and fate of synaptically released norepinephrine at adrenergic synapse. Source: http://www.neurophysiology.ws/autonomicns.htm 21
  27. 27. Autonomic Ganglia http://www.cvpharmacology.com/autonomic_ganglia.htm 22
  28. 28. 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 See:http://ki.se/content/1/c6/04/97/40/BASIC%20RECEPTORPHARMACOLOGY%20VT 2008%20FoU1967.pdf 23
  29. 29. Mechanism of cAMP dependent signaling 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 amd 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 http://en.wikipedia.org/wiki/Signal_transduction 24
  30. 30. 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 25
  31. 31. Cholinergic Receptors   Activated by ACh and cholinergic drugs Anatomic distribution    Postganglionic, parasympathetic neuroeffector junctions All autonomic ganglia, whethe parasympathetic or sympathetic Somatic neuromuscular junctions 26
  32. 32. Cholinergic Receptor Locations Denotes ACh receptors Parasympathetic Cranial or sacral cord Post Pre Ganglion Sympathetic Thoracic or lumbar cord Pre Ganglion Effector organ Denotes ACh receptors Post Effector organs 27
  33. 33. Cholinergic Receptor Subtypes 28
  34. 34. Cholinergic Receptor Subtype Locations Parasympathetic Cranial or sacral cord M N1 Pre Post Ganglion Effector organ Sympathetic Thoracic or lumbar cord Pre N1 Ganglion Post Effector organs29
  35. 35. Adrenergic Receptors   Activated by NE, Epi, and adrenergic drugs Anatomic distribution   Postganglionic, sympathetic, neuroeffector junctions Subtypes  Alpha-1, 2; Beta-1, 2, 3 30
  36. 36. Adrenergic Receptor Locations Alpha or Beta adrenergic receptors Sympathetic Thoracic or lumbar cord Pre Ganglion Post Effector organs 31
  37. 37. 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 32
  38. 38. Functional Significance of the Autonomic Nervous System (2)  Dual innervaton    Organ responses moderated by both parasympathetic and sympathetic influences Parasympathetic dominant at rest Balance of opposing neurologic influences determines physiologic responses 33
  39. 39. Autonomic Innervation of the Heart and Vasculature (1) The medulla, located in the brainstem, receives sensory input from different systemic and central receptors (e.g., baroreceptors and chemoreceptors) as well as signals from other brain regions (e.g., cerebral cortex and hypothalamus) Autonomic outflow from the brainstem is divided principally into sympathetic and parasympathetic (vagal) branches 34
  40. 40. Autonomic Innervation of the Heart and Vasculature (2) Efferent fibers of these autonomic nerves travel to the heart and blood vessels where they modulate activity of these target organs S-A node is innervated by vagal (parasympathetic) and sympathetic fibers Sympathetic efferent nerves are present throughout the atria (especially in the S-A node) and ventricles, and in the conduction system of the heart Sympathetic nerves also travel to most arteries & veins Parasympathetic fibers innervate blood vessels in certain organs such as salivary glands, gastrointestinal glands, and in genital erectile tissue 35
  41. 41. Autonomic and Somatic Pharmacology Terminology  Some drugs evoke effects by interacting with receptors    Agonists    Affinity Efficacy or (synonym) Intrinsic activity 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 36
  42. 42. Alpha-1 Adrenergic Receptor  Vascular smooth muscle contraction  Arterioles, veins    Agonists support systemic blood pressure     Increased arterial resistance Decreased venous capacitance Increased resistance Redistribution of blood toward heart, increased cardiac output Antagonists decrease blood pressure Iris  Pupillary dilation (mydriasis) 37
  43. 43. Alpha-2 Adrenergic Receptor   Vasoconstriction Modulation of NE release   Spinal alpha-2 receptors mediate analgesia   Presynaptic receptors on axon terminous Agonists used clinically as epidural and spinal analgesics Sedation 38
  44. 44. 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 39
  45. 45. 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 40
  46. 46. Muscarinic Cholinergic Receptor  Myocardium    Iris sphincter muscle    Agoinists evoke pupillary constriction (miosis) Antagoinists evoke mydriasis Gastrointestinal tract   Agonists decrease HR and AV conduction velocity Antagonists used clinically to increase HR and facilitate AV conduction in heart block Agonists increase peristalsis and relax sphincters Urinary bladder  Agonists evoke urination   Detrusor muscle (bladder) contraction Trigone (sphincter) relaxation 41
  47. 47. Modified from: http://www.neurophysiology.ws/autonomicns.htm 42
  48. 48. THE END, THANK YOU FOR YOUR ATTENTION Recommended Reading: Autonomic Introduction Formative Assessment Practice Question Set #1 Clinical: E-Medicine Article Epilepsy and the Autonomic Nervous System
  49. 49. Autonomic Pharmacology: Cholinergic Drugs Recommended Reading: Cholinergic Drugs Tutorial Worth Visiting: Cholinergic ANS Clinical: E-Medicine Articles Myasthenia Gravis Presenter: Marc Imhotep Cray, M.D. Professor Pharmacology
  50. 50. Online Reference Resource IVMS Online Textbook Series PRINCIPLES of PHARMACOLOGY THE PATHOPHYSIOLOGIC BASIS OF DRUG THERAPY ThirdEdition David E. Golan, MD, PhD Editor in Chief Armen H. Tashjian, Jr., MD Deputy Editor Ehrin J. Armstrong, MD, MSc April W. Armstrong, MD, MPH Associate Editors Enrolled learners click to download 2
  51. 51. From IVMS Online Textbook Series Pharm. Book Figure 2-1 Organization of the autonomic nervous system. 3
  52. 52. Cholinergic Biosynthesis Acetylcoline is formed from two precursors:  choline: which is derived from dietary and intraneuronal sources  acetyl coenzyme: which is made from glucose in the mitochondria of neurons   Acetylcholine is synthesized from choline and acetyl-CoA by the enzyme choline acetyl transferase (ChAT) to form acetylcholine, which is immediately stored in small vesicular compartments closely attached to the cytoplasmic side of presynaptic membranes. ChAT is a selective marker for cholinergic neurons 4
  53. 53. Cholinergic Biosynthesis 1) Synthesis of acetylcholine (ACh) from acetyl CoA and choline 2) Storage of ACh in synaptic vesicles 3) Release of ACh ( fusion of synaptic vesicle with presysnaptic membrane and release of ACh into the synapse) 4) Action of ACh by binding to and activating receptors (nicotinic in autonomic ganglia and neuromuscular junction and, muscarinic in many sites) 5) Inactivation by enzymatic breakdown of ACh by acetylcholinesterase (AChE) located in the synapse. ACh is degraded in the synaptic cleft by acetylcholinesterase to choline and acetate 5
  54. 54. Cholinergic Agents-Direct Acting and Indirect Acting Agents-Direct Acting   Choline Esters  Acetylcholine  Bethanechol (Urecholine)  Carbachol  Methacholine (Provocholine) Alkaloids  Muscarine  Pilocarpine (Pilocar) Indirect Acting  There are three main types of cholinesterase:  Short-acting:  medium-acting:  edrophonium neostigmine (2-4h), pyridostigmine (3-6h) physostigmine irreversible: organophosphates, dyflos, ecothiopate 6
  55. 55. Spectrum of Action of Choline Esters Location of cholinergic synapses mainly determine the spectrum of action of acetycholine and choline esters     Cholinergic Synaptic Sites autonomic effector sites: innervated by post-ganglionic parasympathetic fibers some CNS synapses autonomic ganglia and the adrenal medulla skeletal muscle motor endplates (motor nerves) 7
  56. 56. Spectrum of Action of Choline Esters(2) Cholinergic influences are prominent in many organ systems: Choline Ester Sensitivity to ACHE Cardiovasc ular Gastrointe stinal Urinary Bladder Eye (Topical) Atropine Sensitive Activity at Nicotinic Sites Acetylcholine Methacholine Carbachol No Bethanechol No ? ? No 8
  57. 57. Spectrum of Action of Choline Esters(3) Cholinergic Receptors:  Cholinergic refers to responses in various systems to the natural transmitter molecule Acetycholine (ACh)    If one looks at a set of responses where ACh is the normal transmitter, observation has shown that those same responses are differently sensitive to the extrinisic molecules Nicotine and Muscarine Nicotine comes from tobacco, Muscarine comes from certain mushrooms See: NS The Reception and Transmission of Extracellular Information Receptors-A Brief Note 9
  58. 58. Spectrum of Action of Choline Esters(4) Based on the different sensitivities shown above, Cholinergic receptors are subclassified into two categories, Nicotinic and Muscarinic, named for the extrinsic compounds that stimulate only that category. 10
  59. 59. Spectrum of Action of Choline Esters(5) Nicotinic Receptors  Stimulated by ACh and nicotine, not stimulated by muscarine.  Found at all ganglionic synapses.  Also found at neuromuscular junctions  Blocked by hexamethonium. 11
  60. 60. Spectrum of Action of Choline Esters(6) Nicotinic Receptors   The physiological responses to stimulation and block are complex since both sympathetic and parasympathetic systems are affected The final response of any one organ system depends on which system has a stronger tonic influence   EXAMPLE: Under normal circumstances, the heart receives more parasympathetic influence than sympathetic Ganglionic blockade would lower parasympathetic influence more than sympathetic, and thus heart rate would increase 12
  61. 61. Spectrum of Action of Choline Esters(6) Muscarinic Receptors     Stimulated by ACh and muscarine, not stimulated by nicotine Found at target organs when ACh is released by post-ganglionic neurons (all of parasympathetic, and some sympathetic) Stimulated selectively by Muscarine and Bethanechol etc. Blocked by Atropine 13
  62. 62. Spectrum of Action of Choline Esters(7) Muscarinic Receptors Stimulation causes:          Increased sweating Decreased heart rate Decreased blood pressure due to decreased cardiac output Bronchoconstriction and increased bronchosecretion. Contraction of the pupils, and contraction of ciliary body for near vision Tearing and salivation Increased motility and secretions of the GI system. Urination and defecation Engorgement of genitalia 14
  63. 63. Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms Muscarinic Receptor Coupling Mechanisms  Five types of cholinergic receptors have been identified by molecular cloning methods.  The five muscarinic receptor subtypes, M1 - M5, are associated with specific anatomical sites  For example:    M1 -ganglia; secretory glands M2 - myocardium, smooth muscle M3 , M4 :smooth muscle, secretory glands 15
  64. 64. Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms Nicotinic Muscle Receptor Antagonists Tubocurarine alpha-bungarotoxin Tissue Responses Molecular Aspects Neuromuscular Junction Membrane Depolarization leading to muscle contraction Nicotinic (muscle) receptor's cation ion channel opening 16
  65. 65. Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms(2) Nicotinic Neuronal Receptor Antagonists Tissue Responses Molecular Aspects Autonomic Ganglia Mecamylamine (Inversine) Depolarization: Nicotinic postsynaptic cell (muscle) activation receptor's cation ion channel Catecholamine Adrenal Medulla opening secretion CNS unknown 17
  66. 66. Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms(3) Muscarinic Type M1 Antagonist Responses Autonomic Ganglia Atropine Pirenzepine (more selective) Tissue Depolarization (late EPSP) CNS Unknown Molecular Aspects Stimulation of Phospholipase C (PLC): activation of inositol-1,4,5 triphosphate (IP3 ) and diacylglycerol (DAG) leading to increased cytosolic Ca2+ 18
  67. 67. Cholinergic Receptors: Subtypes, Tissues, Responses and Molecular Mechanisms(4) Muscarinic Type M2 Tissue (Heart) SA node Atrium Responses decreased phase 4 depolarization; hyperpolarization decreased contractility; decreased AP duration AV node decreased conduction velocity Ventricle decreased contractility Molecular Aspects K+ channel activation through ß-gamma Gi subunits; Gi -mediated inhibition of adenylyl cyclase which decreases intracellular Ca2+ levels. (Gi can inhibit directly Ca2+ channel opening) 19
  68. 68. Signal Transduction: Comparison of Muscarinic and Nicotinc Receptors Nicotinic Receptors  Ligand-gated ion channels  Agonist effects blocked by tubocurarine  Receptor activation results in:     rapid increases of Na+ and Ca2+ conductance deplorization excitation Subtypes based on differing subunit composition: Muscle and Neuronal Classification Discussed Above 20
  69. 69. Signal Transduction: Comparison of Muscarinic and Nicotinc Receptors Muscarinic Receptors  G-protein coupled receptor system  Slower responses  Agonist effects blocked by atropine  At least five receptor subtypes have been described by molecular cloning 21
  70. 70. Muscarinic Receptors: Second Messenger Systems  Activation of IP3, DAG cascade      DAG may activate smooth muscle Ca2+ channels IP3 releases Ca2+ from endoplasmic and sarcoplasmic reticulum Increase in cGMP Increase in intracellular K+ by cGMP-K+ channel binding inhibition of adenylyl cyclase activity (heart) 22
  71. 71. Muscarinic Receptors: Second Messenger Systems(2) 23
  72. 72. Direct vs. Indirect-Acting Cholinomimetics   A direct-acting cholinomimetic drug produces its pharmacological effect by receptor activation An indirect-acting drug inhibits acetylcholinesterase, thereby increasing endogenous acetylcholine levels, resulting in increased cholinergic response. 24
  73. 73. Pharmacological Effects of Cholinomimetics 1)Vasodilation  This effect is mediated by muscarinic receptor activation and is especially prominent in the salivary gland and intestines 25
  74. 74. Pharmacological Effects of Cholinomimetics(2) Vasodilation cont.  The vascular response is due to endothelial cell nitric oxide (NO) release following agonist interactions with endothelial muscarinic receptor  Increased NO activates guanylate cyclase which increases cyclic GMP concentrations 26
  75. 75. Pharmacological Effects of Cholinomimetics(3) Vasodilation cont.  Subsequent activation of a Ca2+ ion pump reduces intracellular Ca2+  Reduction in intracellular Ca2+ causes vascular smooth muscle relaxation  Ca2+ complexes with calmodulin activating lightchain myosin kinase   Increased cGMP promotes dephosphorylation of myosin light-chains. Smooth-muscle myosin must be phosphorylated in order to interact with actin and cause muscle contraction. 27
  76. 76. Nitric Oxide (NO) and Vasodilitation Schematic below from: http://www.nature.com/nature/journal/v396/n6708/fig_tab/396213a0_F1.html 28
  77. 77. Pharmacological Effects of Cholinomimetics(4) 2)Negative chronotropic effect (Decrease in heart rate)  Decreases phase 4 (diastolic depolarization)   As a result, it takes longer for the membrane potential to reach threshold. Mediated by M2 muscarinic receptors 29
  78. 78. Pharmacological Effects of Cholinomimetics(5) 3) Decreased SA nodal and AV nodal conduction velocity  Excessive vagal tone may induce bradyarrhythmias including partial or total heart block (impulses cannot pass through the AV node to drive the ventricular rate; in this case, the idioventricular or intrinsic ventricular rate must maintain adequate cardiac output)  Transmission through the AV node is especially dependent on Ca2+ currents.  ACh decreases calcium currents in the atrioventricular node 30
  79. 79. Pharmacological Effects of Cholinomimetics(6) 4) Negative inotropism (decreased myocardial contractility)  more prominent in atrial than ventricular tissue.  due to a decrease in Ca2+ inward current  in the ventricle, adrenergic tone dominates;  at higher levels of sympathetic tone, a reduction in contractility due to muscarinic stimulation is noted.  Muscarinic stimulation reduces the response to norepinephrine by opposing increases in cAMP in addition to reducing norepinephrine release from adrenergic terminals 31
  80. 80. Clinical Uses Gastrointestinal & Genitourinary  Bethanechol (Urecholine)  GI smooth muscle stimulant    postoperative abdominal distention paralytic ileus esophageal reflux; promotes increased esophageal motility (other drugs are more effective, e.g. dopamine antagonist (metoclopramide) or serotonin agonists (cisapride) 32
  81. 81. Clinical Uses(2) Urinary bladder stimulant     post-operative; post-partum urinary retention alternative to pilocarpine to treat diminished salivation secondary e.g. to radiation Carbachol not used due to more prominent nicotinic receptor activation Methacholine used for diagnostic purposes.  testing for bronchial hyperreactivity and asthma 33
  82. 82. Clinical Uses(3) Opthalmological Uses  Acetylcholine and Carbachol may be used for intraocular use as a miotic in surgery  Carbachol may be used also in treatment of glaucoma.  Pilocarpine is used in management of glaucoma and has become the standard initial drug for treating the open-angle form.  Sequential adminstration of atropine (mydriatic) and pilocarpine (miotic) is used to break iris-lens adhesions. 34
  83. 83. Adverse Effects: Muscarinic Agonists Adverse Effects: Muscarinic Agonists  salivation  diaphoresis  colic  GI hyperactivity  headache  loss of accommodation 35
  84. 84. Major contraindication to the use of muscarinic agonists     Asthma: Choline esters (muscarinic agonists) can produce bronchoconstriction. In the predisposed patient, an asthmatic attack may be induced. Hyperthyroidism: Choline esters (muscarinic agonists) can induce atrial fibrillation in hyperthyroid patients. Peptic ulcer: Choline esters (muscarinic agonists), by increasing gastric acid secretion, may exacerbate ulcer symptoms. Coronary vascular disease: Choline esters (muscarinic agonists), as a result of their hypotensive effects, can further compromise coronary blood flow. 36
  85. 85. Indirect-acting Cholinomimetic Drugs   1. 2. 3. Acetylcholinesterase Inhibitors There are three classes of anticholinesterase agents Reversible, Short-Acting Anticholinesterases Carbamylating Agents: IntermediateDuration Acetylcholinesterase Inhibitors Phosphorylating Agents: Long-Duration Acetylcholinesterase Inhibitors 37
  86. 86. Reversible, Short-Acting Anticholinesterases 1) edrophonium (Tensilon) and 2) tacrine (Cognex) , associate with the choline binding domain   The short duration of edrophonium (Tensilon) action is due to its binding reversibility and rapid renal clearance. Tacrine (Cognex), being more lipophillic, has a longer duration. 38
  87. 87. Carbamylating Agents: IntermediateDuration Acetylcholinesterase Inhibitors    Physostigmine Neostigmine are acetylcholinesterase inhibitors that form a moderately stable carbamyl-enzyme derivative The carbamyl-ester linkage is hydrolyzed by the esterase, but much more slowly compared to acetylcholine.    As a result, enzyme inhibition by these drugs last about 3 - 4 h (t ½ = 15 - 30 min). Neostigmine possesses a quaternary nitrogen and thus has a permanent positive charge By contrast, physostigmine is a tertiary amine 39
  88. 88. Phosphorylating Agents: LongDuration Acetylcholinesterase Inhibitors   Organophosphate acetylcholinesterase inhibitors, such as diisopropyl fluorophosphate (DFP) form stable phosphorylated serine derivatives. For DFP the enzyme effectively does not regenerate following inhibition. 40
  89. 89. Phosphorylating Agents: LongDuration Acetylcholinesterase Inhibitors(2)   Furthermore, in the case of DFP, the loss, termed "aging", of an isopropyl group, further stabilizes the phosphylated enzyme The application of the terms "reversible" and "irreversible" depends on the duration of enzyme inhibition rather than strictly based on mechanism 41
  90. 90. Organophosphate poisoning Parathion  Parathion, a low volatility and aqueous-stable, organophosphate is used as an agriculural insecticide.  Parathion is converted to paraoxon by mixed function oxidases. Both the parent compound and its metabolite are effective acetylcholinesterase inhibitors (P=S to P=O).   Parathion probably is the most common cause of accidental organophosphate poisoning and death The phosphothioate structure is present in other common insecticides: dimpylate, fenthion, and chlorpyrifos. 42
  91. 91. Tx of Organophosphate poisoning-Pralidoxine    Pralidoxine is a cholinesterase activator It is used as an antidote to organophosphates poisoning Unfortunately, pralidoxine does not cross the blood brain barrier to treat the central effects of organophosphate poisoning.  It has to be given very early after poisoning as within a few hours the phosphorylated enzyme undergoes a change (aging) that renders it no longer susceptible to reactivation 43
  92. 92. Clinical applications of anticholinesterases  organophosphates poisoning They are also used in cases of overdose with either the muscarinic antagonist, atropine, or muscle relaxants (nicotinic antagonists)  Pralidoxine is a cholinesterase activator. 44
  93. 93. Opthalmological Uses of Anticholinesterase Drugs  When applied to the conjunctiva, acetylcholinesterase inhibitors produce:      constriction of the pupillary sphincter muscle (miosis) contraction of the ciliary muscle (paralysis of accommodation or loss of far vision). Loss of accommodation disappears first, while the miotic effect is longer lasting. During miosis, elevated intraocular pressure (glaucoma) declines due to enhanced flow of aqueous humor. In glaucoma, elevation of intraocular pressure can cause damage to the optic disc and blindness. 45
  94. 94. Gastrointestinal and Urinary Bladder   Neostigmine is the anticholinesterase agent of choice for treatment of paralytic ileus or urinary bladder atony. Direct acting cholinomimetic drugs are also useful. 46
  95. 95. Myasthenia Gravis See Clinical: E-Medicine Article Myasthenia Gravis   Myasthenia Gravis appears to be caused by the binding of anti-nicotinic receptor antibodies to the nicotinic cholinergic receptor. Binding studies using snake alphaneurotoxins determined a 70% to 90% reduction of nicotinic receptors per motor endplate in myasthenic patients 47
  96. 96. Myasthenia Gravis(2) Receptor number is reduced by:  increased receptor turnover (rapid endocytosis)  blockade of the receptor binding domain  antibody damage of postsynaptic muscle membrane 48
  97. 97. Myasthenia Gravis(3)   Anticholinesterase, edrophonium (Tensilon), is useful in differential diagnosis for myasthenia gravis. In this use, edrophonium (Tensilon) with its rapid onset (30 s) and short duration (5 min) may cause an increase in muscle strength. 49
  98. 98. Myasthenia Gravis(4)    This change is due to the transient increase in acetylcholine concentration at the end plate. Edrophonium (Tensilon) may also be used to differentiate between muscle weakness due to excessive acetylcholine (cholinergic crisis) and inadequate drug dosing. Anticholinesterase drugs provide 50
  99. 99. Antimuscarinic Effects on Organ Systems Central Nervous System Effects of Antimuscarinic Agents  In normal doses, atropine produces little CNS effect.    In toxic doses, CNS excitation results in restlessness, hallucinations, and disorientation. At very high doses, atropine can lead to CNS depression which causes circulatory and respiratory collapse. By contrast, scopolamine at normal therapeutic doses causes CNS depression, including drowsiness, fatigue and amnesia. 51
  100. 100. Antimuscarinic Effects on Organ Systems Central Nervous System Effects of Antimuscarinic Agents cont.    Scopolamine also may produce euphoria, a basis for some abuse potential. Scopolamine may exhibit more CNS activity than atropine because scopolamine crosses the blood brain barrier more readily. Scopolamine (transdermal) is effective in preventing motion sickness.    Antimuscarinics are used clinically as preanesthetic medication to reduce vagal effects secondary to visceral manipulation during surgery. Antimuscarinics with L-DOPA are used in Parkinson's disease. Extrapyramidal effects induced by some antipsychotic drugs may be treated with antimuscarinic agents. 52
  101. 101. Antimuscarinic Effects on Organ Systems Autonomic Ganglia and Autonomic Nerve Terminals  The primary cholinergic receptor class at autonomic ganglia is nicotinic; however, muscarinic M1-cholinergic receptors are also present.  Muscarinic M1-ganglionic cholinergic receptor activation produce a slow EPSP that may have a modulatory role.  Muscarinic receptors are also located at adrenergic and cholinergic presynaptic sites where their activation reduces transmitter release.  Blockade of these presynaptic receptors increase transmitter release. 53
  102. 102. Antimuscarinic Effects on Organ Systems Opthalmological  Muscarinic receptor antagonists block parasympathetic responses of the ciliary muscle and iris sphincter muscle, resulting in paralysis of accommodation (cycloplegia) and mydriasis (pupillary dilation).  Mydriasis results in photophobia, whereas cycloplegia fixes the lens for far vision only (near objects appear blurred). 54
  103. 103. Antimuscarinic Effects on Organ Systems Opthalmological cont.  Systemic atropine at usual doses does not produce significant ophthalmic effect.  By contrast, systemic scopolamine results in both mydriasis and cycloplegia.  Note that sympathomimetic-induced mydriasis occurs without loss of accommodation.  Atropine-like drugs can increase intraocular pressure, sometimes dangerously, in patients with narrow-angle glaucoma.  Increases in intraocular pressure is not typical in wideangle glaucoma. 55
  104. 104. Antimuscarinic Effects on Organ Systems Muscarinic Type M2 Cardiovascular System The dominant effect of atropine or other antimuscarinic drug administration is an increase in heart rate. This effect is mediated by M2receptor blockade thereby blunting cardiac vagal tone. Antagonist Tissue (Heart) SA node Atrium atropine Responses decreased phase 4 depolarization; hyperpolarization decreased contractility; decreased AP duration AV node decreased conduction velocity Ventricle decreased contractility Molecular Aspects K+ channel activation (hyperpolarizing) through ß-gamma Gi subunits*; Gi -mediated inhibition of adenylyl cyclase* (negative inotropism) (Gi can inhibit directly Ca2+ channel opening) 56
  105. 105. Autonomic Pharmacology Adrenergic Drugs Recommended Reading: Adrenergic Drugs Tutorial Worth Visiting: Adrenergic ANS Formative Assessment Practice Question Set #1 Prepared and Presented by: Marc Imhotep Cray, M.D. Professor Basic Medical Sciences
  106. 106. Online Reference Resource IVMS Online Textbook Series PRINCIPLES of PHARMACOLOGY THE PATHOPHYSIOLOGIC BASIS OF DRUG THERAPY ThirdEdition David E. Golan, MD, PhD Editor in Chief Armen H. Tashjian, Jr., MD Deputy Editor Ehrin J. Armstrong, MD, MSc April W. Armstrong, MD, MPH Associate Editors Password Protected, for Enrolled Students Only 2
  107. 107. Introduction   Distribution of adrenergic receptor subtypes and adrenergic receptor number are important factors in organ or cellular responses to adrenergic input. Adrenergic receptor type in bronchiolar smooth muscle is principally ß2: epinephrine and isoproterenol might be expected to be effective bronchodilators because of their activity at ß2 receptors.  Norepinphrine is unlikely to have this same effect due to its relative lack of activity at ß2 sites. 3
  108. 108. Introduction cont.  Alpha receptor dominate in the cutaneous vascular beds.    Norepinephrine and epinephrine cause constriction. Isoproterenol with limited activity at alpha receptors has little effect. Both alpha and beta adrenergic receptor are present in skeletal muscle vascular beds.    Alpha receptor activation causes vasoconstriction. Beta receptor activation promotes vasodilatation. Since ß2 receptors are activated at lower, physiological concentrations, vasodilation results. 4
  109. 109. Introduction (2) Physiological effects caused by sympathomimetcs are due not only to direct effects, but also to indirect or reflex effects.  Alpha receptor agonist causes an increase in blood pressure.  Carotid/aortic baroreceptors activations initiates a compensatory reflex.  Sympathetic tone is reduced (decreases heart rate)  Parasympathetic tone is increased (decreases heart rate) RESULTS: Blood pressure tends to return to lower levels  5
  110. 110. Categories of Action Adrenergics   Smooth Muscle Effects  Smooth muscle activation, including activation of blood vessel vasculature (skin, kidney).  Activation of glands (salivary and sweat).  Smooth muscle inhibition, including inhibition of smooth muscle of the gut, bronchioles, and skeletal muscle vascular smooth muscle. Cardiac Effects  increased heart rate (positive chronotropic effect)  increased contractility (positive inotropic effect)    Metabolic Effects  increase in rate of muscle and liver glycogenolysis  increase in free-fatty acid release from fat Endocrine  Regulation/modulation of insulin, pituitary, and renin secretion Central Nervous System Effects  Respiratory stimulation  CNS stimulation Appetite attenuation Presynaptic Effects Presynaptic effects: modulation of release of norepinephrine or acetylcholine   6
  111. 111. Epinephrine  Epinephrine is a potent activator of alpha and ß adrenergic receptors  Prominent Cardiovascular Effects 7
  112. 112. Epinephrine and Blood Pressure   Potent vasopressor Systolic pressure increases to a greater extent than diastolic (diastolic pressure may decrease)   pulse pressure widens Epinephrine increases blood pressure by:    enhancing cardiac contractility (positive inotropic effect): ß1receptor effects increasing heart rate (positive chronotropic effect): ß1receptor effects. vasoconstriction a1 receptor effects   precapillary resistance vessels of the skin, kidney, and mucosa veins 8
  113. 113. Epinephrine and Blood Pressure (2)  If epinphrine is administered relatively rapidly, the elevation of systolic pressure is likely to activate the baroreceptor system resulting in a reflex-mediated decrease in heart rate. 9
  114. 114. Epinephrine and Blood Pressure (3)    A principal mechanism for arterial blood pressure control is the baroreceptor reflex. The reflex is initiated by activation of stretch receptors located in the wall of most large arteries of the chest and neck. A high density of baroreceptors is found in the wall of each internal carotid artery (just above the carotid bifurcation i.e. carotid sinus) and in the wall of the aortic arch. 10
  115. 115. Epinephrine and Blood Pressure (4)     As pressure rises and especially for rapid increases in pressure: baroreceptor input to the tractus solitarius of the medulla results in inhibition of the vasoconstrictor center and excitation of the vagal (cholinergic) centers resulting in a vasodilatation of the veins and arterioles in the peripheral vascular beds. negative chronotropic and inotropic effects on the heart. (slower heart rate with reduced force of contraction) 11
  116. 116. Epinephrine and Blood Pressure (5) Adrenergic Sino-atrial (SA) Node Cholinergic beta1; beta2 increased rate decreased rate (vagal) Atrial muscle beta1; beta 2 increased: contractility, conduction velocity decreased: contractility, action potential duration Atrio-ventricular (AV) node beta1; beta 2 increased: automaticity, conduction velocity decreased conduction velocity; AV block His-Purkinje System beta1; beta 2 increased: automaticity, conduction velocity ------ beta1; beta 2 increased: contractility, conduction velocity, automaticity, ectopic pacemaker small decrease in contractility Ventricles 12
  117. 117. Epinephrine and Blood Pressure (6) Summary Blood Pressure Blood Pressure Effects Epinephrine Norepinephrine Systolic Mean Pressure Diastolic variable Mean Pulmonary 0.1-0.4 ug/kg/min infusion rate At lower epinephrine doses: a lessened effect on systolic pressure occurs diastolic pressures may decrease as peripheral resistance is reduced. Peripheral resistance decreased due to ß2-receptor effects 13
  118. 118. Epinephrine-Vascular Effects  Epinephrine has significant effects on smaller arteriolar and precapilliary smooth muscle.  Acting through alpha1 receptors, vasocontrictor effects decrease blood flow through skin and kidney.   Even at doses of epinephrine that do not affect mean blood pressure, substantially increases renal vascular resistance and reduces blood flow (40%). Renin release increases due to epinephrine effects mediated by ß2-receptors associated with juxtaglomerular cells. 14
  119. 119. EpinephrineVascular Effects cont.   Acting through ß2-receptors, epinephrine causes significant vasodilatation which increases blood flow through skeletal muscle and splanchnic vascular beds. If an a receptor blocker is administered, epinephrine ß2-receptor effects dominate and total peripheral resistance falls as does mean blood pressure--this phenomenon is termed "epinephrine reversal". 15
  120. 120. Epinephrine- Cardiac Effects      Epinephrine exerts most of its effects on the heart through activation of ß1adrenergic receptors. ß2- and α-receptors are also present. Heart rate increases Cardiac output increases Oxygen consumption increases Direct Responses to Epinephrine  increased contractility  increased rate of isometric tension development  increased rate of relaxation  increased slope of phase-4 depolarization  increased automaticity (predisposes to ectopic foci 16
  121. 121. Epinephrine- Smooth Muscle Effects Smooth Muscle  Epinephrine has variable effects on smooth muscle depending on the adrenergic subtype present.   GI smooth muscle is relaxed through activation of both alpha and ß -receptor effects. In some cases the preexisting smooth muscle tone will influence whether contraction or relaxation results following epinephrine. 17
  122. 122. Epinephrine- Smooth Muscle Effects (2) During the last month of pregnancy, epinephrine reduces uterine tone and contractions by means of ß2-receptor activation. •This effect provides the rationale for the clinical use of ß2-selective receptor agonists: ritodrine and terbutaline to delay premature labor Uterus alpha1; beta2 Pregnant: contraction (alpha1); relaxation (beta2); Nonpregnant: relaxation (beta2) variable 18
  123. 123. Epinephrine- Pulmonary Effects Epinephrine is a significant respiratory tract bronchodilator. Bronchodilation is caused by ß2-receptor activation mediated smooth muscle relaxation. • This action can antagonize other agents that promote bronchoconstriction. • ß2-receptor activation also decreases mast cell secretion. This decrease may be beneficial is management of asthma also. Pulmonary Adrenergic Effects Cholinergic Tracheal and bronchial muscle beta 2 Relaxation contraction Bronchial glands alpha1, beta2 decrease secretion; increased secretion stimulation 19
  124. 124. Epinephrine- Metabolic Effects Insulin secretion: inhibited by a2 adrenergic receptor activation (dominant) Insulin secretion: enhanced by ß2 adrenergic receptor activation Pancreas Adrenergic Effects Cholinergic Acini alpha decreased secretion secretion Islets (beta cells) alpha2 decreased secretion --------- Islets (beta cells) beta2 increased secretion --------- Glucagon secretion: enhanced by ß adrenergic receptor activation of pancreatic islet alpha cells. •Glycolysis- stimulated: by ß adrenergic receptor activation 20
  125. 125. Epinephrine- Metabolic Effects (2) Liver Adrenergic Liver alpha1; beta2 Effects Cholinergic glycogenolysis and gluconeogenesis ----------- Free fatty acids, increased: by ß adrenergic receptor activation on adipocytes--activation of triglyceride lipase 21
  126. 126. Epinephrine- Metabolic Effects (3) Adipose Tissue Adrenergic Fat Cells alpha2; beta3 lipolysis (thermogenesis) Cholinergic --------- Calorigenic effect (20% - 30% increase in O2 consumption): caused by triglyceride breakdown in brown adipose tissue. 22
  127. 127. Epinephrine- Metabolic Effects (4) Electrolytes  Epinephrine may activate Na+-K+ skeletal muscle pumps leading to K+ transport into cells  Stress-induced epinephrine release may be responsible for relatively lower serum K+ levels preoperatively compared postoperatively.   Mechanistic basis: "Preoperative hypokalemia" can be prevented by nonselective beta-adrenergic receptor antagonists {but not by cardioselective beta1 antagonists} Possible "preoperative hypokalemia" may be associated with preoperative anxiety which promotes epinephrine release-therapeutic decisions based on preinduction serum potassium levels to take into account this possible explanation 23
  128. 128. Norepinephrine   Norepinephrine is the primary neurotransmitter released by postganglionic neurons of the autonomic sympathetic system Norepinephrine (Levophed) is a potent activator of a and ß1 adrenergic receptors 24
  129. 129. NE- Blood Pressure Effects  Potent vasopressor  Systolic and diastolic pressure increase   pulse pressure widens Norepinephrine (Levophed) increases blood pressure by:  vasoconstriction alpha1 receptor effects    precapillary resistance vessels of the skin, kidney, and mucosa veins Elevation of systolic pressure following norepinephrine is likely to activate the baroreceptor system resulting in a reflex-mediated decrease in heart rate. 25
  130. 130. NE- Blood Pressure Effects Blood Pressure Blood Pressure Effects Epinephrine Norepinephrine Systolic Mean Pressure Diastolic variable Mean Pulmonary Adaptation of Table 10-2 from: Hoffman, B.B and Lefkowitz, R.J, Catecholamines, Sympathomimetic Drugs, and Adrenergic Receptor Antagonists, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,(Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) The McGraw-Hill Companies, Inc.,1996, pp.199-242 26
  131. 131. NE-Arterioles Effects Arterioles Adrenergic Cholinergic Coronary alpha1,2; beta 2 constriction;dilatation constriction Skin/Mucosa alpha1,2 constriction dilatation Skeletal Muscle alpha; beta2 constriction,dilatation dilatation Cerebral alpha1 slight constriction dilatation Pulmonary alpha1 , beta2 constriction; dilatation dilatation Abdominal viscera alpha1, beta2 constriction; dilatation ------- Salivary glands alpha1,2 constriction dilatation Renal alpha1,2;beta1,2 constriction;dilatation --------- Based on Table 6-1: Lefkowitz, R.J, Hoffman, B.B and Taylor, P. Neurotransmission: The Autonomic and Somatic Motor Nervous Systems, In, Goodman and Gillman's The Pharmacologial Basis of Therapeutics,( Hardman, J.G, Limbird, L.E, Molinoff, P.B., Ruddon, R.W, and Gilman, A.G.,eds) TheMcGraw-Hill Companies, Inc.,1996, pp.110-111. 27
  132. 132. NE-Vascular Effects       Norepinephrine significantly increases total peripheral resistance, often inducing reflex cardiac slowing. Norepinephrine (Levophed) causes vasoconstriction in most vascular beds. Blood flow is reduced to the kidney, liver and skeletal muscle. Glomerular filtration rates are usually maintained. Norepinephrine may increase coronary blood flow (secondary to increased blood pressure and reflex activity) Norepinephrine (Levophed) may induce variant (Prinzmetal's) angina Pressor effects of norepinephrine (Levophed) are blocked by alpha-receptor blockers. ECG changes following norepinephrine (Levophed) are variable, depending on the extent of reflex vagal effects. 28
  133. 133. NE- Peripheral Circulation Effects Peripheral Circulation Perip