IVMS Autonomic and Cardiovascular Pharmacology PowerPoint Book

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IVMS Autonomic and Cardiovascular Pharmacology PowerPoint Book

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  • 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. 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. 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. 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. 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. 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. 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. 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. 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. Neuron Anatomy Source: http://www.dentalarticles.com/visual/d/neuron-cell-diagram.php 5
  • 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. 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. 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. 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. 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. Schematized Anatomic Comparison Parasympathetic Cranial or sacral cord Post Pre Ganglion Effector organ Sympathetic Thoracic or lumbar cord Pre Ganglion Post Effector organs11
  • 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. 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. 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. 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. 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. Adrenal Medulla(2) Adrenal medulla Cholinergic neuron Epi and NE released into systemic circulation Denotes ACh 17
  • 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. 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. 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. 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. Autonomic Ganglia http://www.cvpharmacology.com/autonomic_ganglia.htm 22
  • 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. 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. 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. 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. 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. Cholinergic Receptor Subtypes 28
  • 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. 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. Adrenergic Receptor Locations Alpha or Beta adrenergic receptors Sympathetic Thoracic or lumbar cord Pre Ganglion Post Effector organs 31
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Modified from: http://www.neurophysiology.ws/autonomicns.htm 42
  • 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. 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. 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. From IVMS Online Textbook Series Pharm. Book Figure 2-1 Organization of the autonomic nervous system. 3
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Muscarinic Receptors: Second Messenger Systems(2) 23
  • 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. 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. 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. 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. Nitric Oxide (NO) and Vasodilitation Schematic below from: http://www.nature.com/nature/journal/v396/n6708/fig_tab/396213a0_F1.html 28
  • 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. 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. 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. 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. 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. 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. Adverse Effects: Muscarinic Agonists Adverse Effects: Muscarinic Agonists  salivation  diaphoresis  colic  GI hyperactivity  headache  loss of accommodation 35
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. Epinephrine  Epinephrine is a potent activator of alpha and ß adrenergic receptors  Prominent Cardiovascular Effects 7
  • 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. 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. NE- Peripheral Circulation Effects Peripheral Circulation Peripheral Circulation Epinephrine Norepinephrine Total Peripheral Resistance Cerebral Blood Flow no effect or decrease Muscle Blood Flow no effect or decrease Cutaneous Blood Flow Renal Blood Flow Splanchnic Blood Flow increase, decrease 0.1-0.4 ug/kg/min IV infusion no effect or increase Therapeutic use: Norepinephrine may be used in treatment of shock 29
  • 134. Dopamine Cardiovascular Effects (Dopamine) Vasodilator:  At low doses, dopamine (Intropin) interactions with D1 receptor subtype results in renal, mesenteric and coronary vasodilation.   This effect is mediated by an increase in intracellular cyclic AMP Low doses result in enhancing glomerular filtration rates (GFR), renal blood flow, and sodium excretion. Vasopressor: At high doses dopamine (Intropin) causes vasoconstriction by activating a1 adrenergic receptors Positive inotropism:  At higher doses, dopamine increase myocardial contractility through activation of ß1 adrenergic receptors  Dopamine (Intropin) also promotes release of myocardial norepinephrine.  Dopamine (Intropin) at these higher dosages causes an increase in systolic blood and arterial pulse pressure with little effect on diastolic pressures. 30
  • 135. Therapeutic use (Dopamine) Cardiogenic and hypovolemic Unique among catecholamines in that Dopamine can shock simultaneously increase  by enhancing renal perfusion  myocardial contractility despite low cardiac output  glomerular filtration rate  Oligouria may be an indication of  sodium excretion inadequate renal perfusion  Example: dopamine may be used, in  urine output  renal blood flow postoperative cardiopulmonary bypass patients who exhibit:  low systemic blood-pressure  increased atrial filling pressures  low urinary output 31
  • 136. Therapeutic use (Dopamine) (2)    Increased sodium excretion following dopamine may be due to inhibition of aldosterone secretion. Dopamine may inhibit renal tubular solute reabsorption(suggesting that natriuresis & diuresis may occur by different mechanisms.) Fenoldopam and dopexamine: newer drugs  may be useful in treating heart failure by improving myocardial contractility 32
  • 137. Therapeutic use (Dopamine) (3)    Dopamine (Intropin) at higher doses increases myocardial contractility by ß1 - adrenergic receptor activation. Ventilation effects: -- dopamine IV infusion interferes with ventilatory responses to arterial hypoxemia Dopamine (Intropin) acts as inhibitory neurotransmitter at carotid bodies)  Consequence: Unexpected ventilation depression in patients treated with IV dopamine (Intropin) to enhance myocardial contractility 33
  • 138. Dopexamine     Dopexamine--synthetic catecholamine Activation of dopaminergic and beta 2 receptors Slight positive inotropic effect (beta2adrenergic agonists activity; potentiation those endogenous norepinephrine secondary to reuptake blockade) Dopexamine enhances creatinine clearance 34
  • 139. Isoproterenol (Isuprel)     Activates ß adrenergic receptors (both ß1 and ß2 -receptor subtypes) Has limited action at a adrenergic receptors i.v. influsion of isoproterenol results in a slight decrease in mean blood pressure with a marked drop in diastolic pressure. ß2 - adrenergic receptor-mediated reduction in peripheral resistance (reflected in the diastolic pressure effects) is primarily due to vasodilation of skeletal muscle vasculature. Renal and mesenteric vascular beds are also dilated. 35
  • 140. Isoproterenol (Isuprel) (2)     Activation of cardiac ß1 - adrenergic receptors: increased contractility and heart rate. Activation of ß2 - adrenergic receptors: Bronchial and GI smooth muscle relaxation. Isoproterenol and ß2 -selective adrenergic agonists inhibit antigen-mediated histamine release. Isoproterenol: Limited therapeutic uses:  emergency settings to treat heart block or severe bradycardia  management of torsades de pointes (a ventricular arrhythmia) 36
  • 141. Isoproterenol (Isuprel) (3)   management of torsades de pointes (a ventricular arrhythmia) Isoproterenol (Isuprel) adverse effects:     palpitations tachycardia arrhythmias coronary insufficiency 37
  • 142. Dobutamine (Dobutrex)     Structurally similar to dopamine (Intropin). Pharmacological effects exerted through interaction with a and ß adrenergic receptor interactions no effect on release no action through dopamine receptors     Pharmacological effects are due to complex interactions of (-) and (+) enantiometic forms present in the clinically used racemate with a and ß adrenergic receptors. Dobutamine (Dobutrex) is a positive inotropic agent usually causing limited increase in heart rate. Positive inotropism is mediated through ß adrenergic receptor activation. Some peripheral a1 activity causes modest vasoconstriction, an effect opposed by dobutamines ß2 effects. 38
  • 143. Dobutamine (Dobutrex) (2) Dobutamine (Dobutrex): Adverse Effects  Significant blood pressure and heart rate increases may occur.  Ventricular ectopy  Increased ventricular following rate in patient with atrial fibrillation.  Increased myocardial oxygen demand that may worsen post-infarct myocardial damage Dobutamine (Dobutrex): Therapeutic Use  Short-term management of pump failure following surgery, during acute congestive heart failure, or post-myocardial infarction.  Uncertain long-term efficacy. 39
  • 144. ß2 Selective Adrenergic Agonists  Metaproterenol (Alupent)  Terbutaline (Brethine)  Albuterol (Ventolin,Proventil)  Ritodrine (Yutopar) 40
  • 145. Metaproterenol (Alupent)    ß2 adrenergic receptor-selective: resistant to COMT (catechol-O-methyl transferase) metabolism Less ß2 selective compared to terbutaline (Brethine) and albuterol (Ventolin,Proventil). May be used for long-term and acute treatment of bronchospasm 41
  • 146. Terbutaline [Brethine]     ß2 adrenergic receptor-selective: resistant to COMT Active after oral, subcutaneous, or administration by inhalation Rapid onset of action. Used for management of chronic obstructive lung disease and for treatment of acute bronchospasm (smooth muscle bronchoconstriction), including status asthmaticus 42
  • 147. Albuterol [Ventolin]    ß2 adrenergic receptor-selective Effective following inhalation or oral administration. Commonly used in chronic and acute asthma management. 43
  • 148. Ritodrine (Yutopar) ß2 adrenergic receptor-selective: developed as a uterine relaxant  May be administered by i.v. in certain patients for arresting premature labor; if successful, oral therapy may be started  ß2 adrenergic receptor-selective agonists may not improve perinatal mortality and may increase maternal morbidity  In women being treated for premature labor, ritodrine (Yutopar) or terbutaline (Brethine) may cause pulmonary edema . 44
  • 149. Adverse Effects-B2 Agonists    Excessive cardiovascular stimulation Skeletal muscle tremor (tolerance develops, unknown mechanism) due to ß2 adrenergic receptor activation Overusage may be a factor in morbidity and mortality in asthmatics. 45
  • 150. Alpha1 Selective Adrenergic Agonists  Alpha1 selective adrenergic agonists activate a adrenergic receptors in vascular smooth muscle producing vasoconstriction.    Peripheral vascular resistance is increased. Blood pressure may be increased, causing a reflex reduction heart rate a1 adrenergic agonists are used clinically in management of hypotension and shock. 46
  • 151. Alpha1 Selective Adrenergic Agonists Direct Acting  Phenylephrine (Neo-Synephrine) and methoxamine (Vasoxyl) are directacting vasoconstrictors. Mixed Acting  Mephentermine (Wyamine) and metaraminol (Aramine) act both by direct receptor activation and by promoting epinephrine release. 47
  • 152. Methoxamine (Vasoxyl) specific alpha1 receptor agonist     increases peripheral resistance causes an increase in blood pressure that precipitates sinus bradycardia (decreased heart rate) due to vagal reflex. Reflex bradycardia may be block by atropine (muscarinic antagonist) Clinical use:   hypotensive states termination (by vagal reflex) of paroxysmal atrial tachycardia (adenosine may be preferable) 48
  • 153. Phenylephrine (NeoSynephrine) Specific alpha1 receptor agonist  Increases peripheral resistance  Causes an increase in blood pressure that precipitates sinus bradycardia (decreased heart rate) due to vagal reflex.  Reflex bradycardia may be block by atropine (muscarinic antagonist)  Clinical use:    hypotensive states mydriatic nasal decongestant 49
  • 154. Alpha 2 Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists   alpha2 selective adrenergic agonists are used to treat essential hypertension. Mechanism of action:   activation of central a2 adrenergic receptors at cardiovascular control centers activation decreases sympathetic outflow, reducing sympathetic vascular tone. 50
  • 155. alpha2 Selective Adrenergic Agonists Clonidine (Catapres) is primarily used in treating essential hypertension.  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.  This response is due to a2 selective adrenergic receptor activation 51
  • 156. alpha2 Selective Adrenergic Agonists Clonidine (Catapres)(2)      Adverse Effects: dry mouth sedation sexual dysfuction Clonidine's a2 selective adrenergic receptor activation of vascular smooth muscle may increase blood pressure in patients with severe autonomic dysfunction with profound orthostatic hypotension (in these patients the reduction of central sympathetic outflow in not clinically important) 52
  • 157. alpha2 Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists Alpha-methyl DOPA (methyldopa (Aldomet)), metabolically converted to alphamethyl norepinephrine, is used for treating essential hypertension  A prolonged hypotensive response results from a decrease in CNS sympathetic outflow.  This response is due to a2 selective adrenergic receptor activation.  Adverse Effects:   dry mouth sedation 53
  • 158. alpha2 Selective Adrenergic Agonists and Miscellaneous Adrenergic Agonists Amphetamine  CNS stimulant (releasing biogenic nerve terminal amines):     respiratory center mood elevation decreased perception of fatigue Other effects: headache, palpitations, dysphoria    Appetite suppression Weight loss due to decrease food intake psychological tolerance/dependence 54
  • 159. Amphetamine (2) Indirect acting sympathomimetic Toxicity:  CNS: restlessness, tremor, irritablity, insomnia, aggressiveness, anxiety, panic, suicidal ideation, etc.  Cardiovascular: arrhythmias, hypertension or hypotension, angina  GI: dry mouth, anorexia, vomiting, diarrhea, cramping  Treatment:    urinary acidification by ammonium chloride hypertension: nitroprusside or alpha adrenergic receptor antagonist CNS: sedative-hypnotic drugs 55
  • 160. Amphetamine (3) Therapeutic Use:  Narcolepsy  Obesity  Attention-deficit hyperactivity disorder 56
  • 161. Methylphenidate (Ritalin)     Mild CNS stimulant, chemically related to amphetamine Effects more prevalent on mental than motor activities General pharmacological profile similar to amphetamine Major Therapeutic Use:  Narcolepsy  Attention-deficit hyperactivity disorder 57
  • 162. Ephedrine alpha and ß adrenergic receptor agonist  Indirect sympathomimetic also, promoting norepinephrine release  non-catechol structure, orally active Pharmacological effects:  increases heart rate, cardiac output  usually increases blood pressure  may cause uriniary hesitancy due to stimulation of a smooth muscle receptors in bladder base.  bronchodilation: ß adrenergic receptor response 58
  • 163. Ephedrine(2)   Limited Clinical Use due to better pharmacological alternatives (asthma, heart block, CNS stimulation) Vasoconstrictors for Nasal Mucosal Membranes and for the Eye 59
  • 164. Adrenergic Drug Lists Summary Catecholamines Drug Receptors Epinephrine alpha1, alpha2 ß1, ß2 Norepinephrine (Levophed) alpha1, alpha2, ß1 Isoproterenol (Isuprel) ß1, ß2 Dobutamine (Dobutrex) ß1 (alpha1) Dopamine (Intropin) D-1 (alpha1 and ß1 at high doses) 60
  • 165. Adrenergic Drug Lists Summary Direct adrenoceptor agonists Drug Receptor Selectivity Phenylephrine (Neo-Synephrine) alpha1 Methoxamine (Vasoxyl) alpha1 Oxymetazoline (Afrin) alpha1, alpha2 Clonidine (Catapres) alpha2 Ritodrine (Yutopar) ß2 Terbutaline (Brethine) ß2 Albuterol (Ventolin,Proventil) ß2 Salmeterol (Serevent) ß2 61
  • 166. Adrenergic Drug Lists Summary Indirect sympathomimetics •Ephedrine, Pseudoephedrine •Cocaine •Tyramine •Amphetamine •Release & direct receptor activation •Uptake Inhibitor •Release •see ephedrine, but greater CNS actions 62
  • 167. Adrenergic Drug Lists Summary Alpha-Adrenoceptor antagonists Drug Receptor Selectivity (a1 vs. a2) Prazosin (Minipress) alpha1 Terazosin (Hytrin) alpha1 Trimazosin alpha1 Doxazosin (Cardura) alpha1 Phentolamine (Regitine) non-selective Phenoxybenzamine (Dibenzyline) only slightly selective for alpha1 (non-competitive) Tolazoline (Priscoline) non-selective Labetalol (Trandate, Normodyne) alpha1 (also non-selective betaantagonist) Yohimbine (Yocon) alpha2 63
  • 168. Adrenergic Drug Lists Summary ß-Adrenoceptor antagonists Drug Receptor Selectivity (ß1 vs. ß2) Propranolol (Inderal) non-selective Metoprolol (Lopressor) ß1 Esmolol (Brevibloc) ß1 Atenolol (Tenormin) ß1 Nadolol (Corgard) non-selective Timolol (Blocadren) non-selective Pindolol (Visken) non-selective (partial agonist) Labetalol (Trandate, Normodyne) non-selective (selective a1antagonist) 64
  • 169. Heart Rate Acceleration (ex) Slowing (in) Contractility Increased (ex) Decreased (in) Skin and most others Constriction (ex) — Skeletal muscle Dilation (ex) — Salivary Viscid secretion (ex) Watery secretion (ex) Lacrimal — Secretion (ex) Sweat Secretion (ex) — Relaxation (in) Contraction (ex) Relaxation (in) Contraction (ex) Contraction (ex) Relaxation (in) Fundus Relaxation (in) Contraction (ex) Trigone; sphincter Contraction (ex) Relaxation (in) Penis Ejaculation (ex) Erection (in) Uterus Relaxation (in) — Gluconeogenesis (ex) — Glycogenolysis (ex) — Kidney Renin secretion(ex) — Fat Cells Lipolysis (ex) Arterioles Glands Bronchial muscle GI tract Muscle wall Sphincters Urinary bladder Metabolism Liver 65
  • 170. Adrenergics High Yield Synopsis (1) 66
  • 171. Adrenergics High Yield Synopsis(2) 67
  • 172. Adrenergics High Yield Synopsis(3) 68
  • 173. Adrenergics High Yield Synopsis(4) 69
  • 174. Adrenergics High Yield Synopsis(5) 70
  • 175. Heart and Circulation An Integrated Basic Medical Sciences Perspective and Presentation Prepared and Presented by: Marc Imhotep Cray, M.D. Professor Pharmacology and BMS Animated Image from: http://www.primalpictures.com/news.aspx
  • 176. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Online Reference Resource IVMS Online Textbook Series Download 2
  • 177. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Functions of the Circulatory System (continued)  Regulation:  Hormonal:  Carry hormones to target tissues to produce their effects.  Temperature:  Divert blood to cool or warm the body.  Protection:  Blood clotting.  Immune:  Leukocytes, cytokines and complement act against pathogens. 3
  • 178. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Components of Circulatory System  Cardiovascular System (CV):  Heart:   Blood vessels:   Pumping action creates pressure head needed to push blood through vessels. Permits blood flow from heart to cells and back to the heart.  Arteries, arterioles, capillaries, venules, veins. Lymphatic System:  Lymphatic vessels transport interstitial fluid.  Lymph nodes cleanse lymph prior to return in venous blood. 4
  • 179. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Composition of Blood  Plasma:  Straw-colored liquid.  Consists of H20 and dissolved solutes.   Ions, metabolites, hormones, antibodies. + is the major solute of the plasma.  Na Plasma proteins:  Constitute 7-9% of plasma.  Albumin:   Accounts for 60-80% of plasma proteins. Provides the colloid osmotic pressure needed to draw H20 from interstitial fluid to capillaries.  Maintains blood pressure. 5
  • 180. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Composition of the Blood  Plasma proteins (continued):  Globulins:  a globulin:    Transport lipids and fat soluble vitamins. b globulin:  Transport lipids and fat soluble vitamins. g globulin:   (continued) Antibodies that function in immunity. Fibrinogen:   Constitutes 4% of plasma proteins. Important clotting factor.  Converted into fibrin during the clotting process. 6
  • 181. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Composition of the Blood  Serum:  Fluid from clotted blood.   (continued) Does not contain fibrinogen. Plasma volume:  Number of regulatory mechanisms in the body maintain homeostasis of plasma volume.    Osmoreceptors. ADH. Renin-angiotensin-aldosterone system. 7
  • 182. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Erythrocytes    Flattened biconcave discs. Provide increased surface area through which gas can diffuse. Lack nuclei and mitochondria.    Half-life ~ 120 days. Each RBC contains 280 million hemoglobin with 4 heme chains (contain iron). Removed from circulation by phagocytic cells in liver, spleen, and bone marrow. 8
  • 183. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Leukocytes   Contain nuclei and mitochondria. Move in amoeboid fashion.   Can squeeze through capillary walls (diapedesis). Almost invisible, so named after their staining properties.  Granular leukocytes:  Help detoxify foreign substances.   Release heparin. Agranular leukocytes:  Phagocytic.  Produce antibodies. 9
  • 184. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Platelets (thrombocytes)  Smallest of formed elements.     Capable of amoeboid movement. Important in blood clotting:    Constitute most of the mass of the clot. Release serotonin to vasoconstrict and reduce blood flow to area. Secrete growth factors:   Are fragments of megakaryocytes. Lack nuclei. Maintain the integrity of blood vessel wall. Survive 5-9 days. 10
  • 185. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Cells and Platelets 11
  • 186. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Hematopoiesis    Undifferentiated cells gradually differentiate to become stem cells, that form blood cells. Occurs in myeloid tissue (bone marrow of long bones) and lymphoid tissue. 2 types of hematopoiesis:  Erythropoiesis:   Formation of RBCs. Leukopoiesis:  Formation of WBCs. 12
  • 187. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Erythropoiesis  Active process.   2.5 million RBCs are produced every second. Primary regulator is erythropoietin.     Binds to membrane receptors of cells that will become erythroblasts. Erythroblasts transform into normoblasts. Normoblasts lose their nuclei to become reticulocytes. Reticulocytes change into mature RBCs.   Old RBCs are destroyed in spleen and liver.   Stimulates cell division. Iron recycled back to myeloid tissue to be reused in hemoglobin production. Need iron, vitamin B12 and folic acid for synthesis. 13
  • 188. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Leukopoiesis     Cytokines stimulate different types and stages of WBC production. Multipotent growth factor-1, interleukin-1, and interleukin-3:  Stimulate development of different types of WBC cells. Granulocyte-colony stimulating factor (G-CSF):  Stimulates development of neutrophils. Granulocyte-monocyte colony stimulating factor (GMCSF):  Simulates development of monocytes and eosinophils. 14
  • 189. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. RBC Antigens and Blood Typing   Each person’s blood type determines which antigens are present on their RBC surface. Major group of antigens of RBCs is the ABO system: Type AB: Type A: Both A and B antigens present.  Only A antigens present.   Type B: Only B antigens present.   Type O: Neither A or B antigens present.  15
  • 190. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. RBC Antigens and Blood Typing (continued) Each person inherits 2 genes that control the production of ABO groups.  Type A:  May have inherited A gene from each parent. May have inherited A gene from one parent and O gene from the other.  Type B:  May have inherited B gene from each parent. May have inherited B gene from one parent and O gene from the other parent.  Type AB:  Inherited the A gene from one parent and the B gene from the other parent.  Type O:  Inherited O gene from each parent.  16
  • 191. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Transfusion Reactions   If blood types do not match, the recipient’s antibodies attach to donor’s RBCs and agglutinate. Type O:  Insert fig. 13.6 Universal donor:     Lack A and B antigens. Recipient’s antibodies cannot agglutinate the donor’s RBCs. Type AB:  Universal recipient:   Lack the anti-A and anti-B antibodies. Cannot agglutinate donor’s RBCs. 17
  • 192. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Rh Factor   Another group of antigens found on RBCs. Rh positive:   Rh negative:   Has Rho(D) antigens. Does not have Rho(D) antigens. Significant when Rh- mother gives birth to Rh+ baby.  At birth, mother may become exposed to Rh+ blood of fetus.   Mother at subsequent pregnancies may produce antibodies against the Rh factor. Erythroblastosis fetalis:  Rh- mother produces antibodies, which cross placenta.  Hemolysis of Rh+ RBCs in the fetus. 18
  • 193. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Clotting  Function of platelets:  Platelets normally repelled away from endothelial lining by prostacyclin (prostaglandin).   Do not want to clot normal vessels. Damage to the endothelium wall:  Exposes subendothelial tissue to the blood. 19
  • 194. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Clotting  (continued) Platelet release reaction:   Endothelial cells secrete von Willebrand factor to cause platelets to adhere to collagen. When platelets stick to collagen, they degranulate as platelet secretory granules:  Release ADP, serotonin and thromboxane A2.    Serotonin and thromboxane A2 stimulate vasoconstriction. ADP and thromboxane A2 make other platelets “sticky.”  Platelets adhere to collagen.  Stimulates the platelet release reaction. Produce platelet plug.  Strengthened by activation of plasma clotting factors. 20
  • 195. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Clotting   Platelet plug strengthened by fibrin. Clot reaction:    (continued) Contraction of the platelet mass forms a more compact plug. Conversion of fibrinogen to fibrin occurs. Conversion of fibrinogen to fibrin:  Intrinsic Pathway:  Initiated by exposure of blood to a negatively charged surface (collagen).   This activates factor XII (protease), which activates other clotting factors. Ca2+ and phospholipids convert prothrombin to thrombin.  Thrombin converts fibrinogen to fibrin.  Produces meshwork of insoluble fibrin polymers. 21
  • 196. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Clotting  (continued) Extrinsic pathway:   Thromboplastin is not a part of the blood, so called extrinsic pathway. Damaged tissue releases thromboplastin.  Thromboplastin initiates a short cut to formation of fibrin. 22
  • 197. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Clotting (continued) 23
  • 198. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Dissolution of Clots  Activated factor XII converts an inactive molecule into the active form (kallikrein).   Plasmin is an enzyme that digests the fibrin.   Kallikrein converts plasminogen to plasmin. Clot dissolution occurs. Anticoagulants:  Heparin:   Activates antithrombin III. Coumarin:  Inhibits cellular activation of vitamin K. 24
  • 199. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Acid-Base Balance in the Blood     Blood pH is maintained within a narrow range by lungs and kidneys. Normal pH of blood is 7.35 to 7.45. Some H+ is derived from carbonic acid. H20 + C02 H2C03 H+ + HC03- 25
  • 200. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Acid-Base Balance in the Blood (continued)  Types of acids in the body:  Volatile acids:  Can leave solution and enter the atmosphere as a gas.  Carbonic acid. H20 + C02  H2C03 Nonvolatile acids:  H+ + HC03- Acids that do not leave solution.   Byproducts of aerobic metabolism, during anaerobic metabolism and during starvation. Sulfuric and phosphoric acid. 26
  • 201. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Buffer Systems  Provide or remove H+ and stabilize the pH. Include weak acids that can donate H+ and weak bases that can absorb H+. HC03- is the major buffer in the plasma.  H+ + HC03-    H2C03 Under normal conditions excessive H+ is eliminated in the urine. 27
  • 202. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Acid Base Disorders  Respiratory acidosis:  Hypoventilation.  Hyperventilation.   pH decreases. Respiratory alkalosis:  Metabolic acidosis: Accumulation of CO2.    Excessive loss of CO2.  pH increases. Gain of fixed acid or loss of HCO3-.  Plasma HCO3- decreases.   pH decreases. Metabolic alkalosis:  Loss of fixed acid or gain of HCO3-.  Plasma HCO3- increases.  pH increases. 28
  • 203. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. pH    Normal pH is obtained when the ratio of HCO3- to C02 is 20:1. Henderson-Hasselbalch equation: pH = 6.1 + log = [HCO3-] [0.03PC02] 29
  • 204. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Pulmonary and Systemic Circulations  Pulmonary circulation:   Systemic circulation:   Path of blood from right ventricle through the lungs and back to the heart. Oxygen-rich blood pumped to all organ systems to supply nutrients. Rate of blood flow through systemic circulation = flow rate through pulmonary circulation. 30
  • 205. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Atrioventricular and Semilunar Valves  Atria and ventricles are separated into 2 functional units by a sheet of connective tissue by AV (atrioventricular) valves.    At the origin of the pulmonary artery and aorta are semilunar valves.    One way valves. Allow blood to flow from atria into the ventricles. One way valves. Open during ventricular contraction. Opening and closing of valves occur as a result of pressure differences. 31
  • 206. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Atrioventricular and Semilunar Valves 32
  • 207. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cardiac Cycle See: Hyper heart  Refers to the repeating pattern of contraction and relaxation of the heart.    Systole:  Phase of contraction. Diastole:  Phase of relaxation. End-diastolic volume (EDV):   Stroke volume (SV):   Total volume of blood in the ventricles at the end of diastole. Amount of blood ejected from ventricles during systole. End-systolic volume (ESV):  Amount of blood left in the ventricles at the end of systole. 33
  • 208. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cardiac Cycle  Step 1: Isovolumetric contraction:   QRS just occurred. Contraction of the ventricle causes ventricular pressure to rise above atrial pressure.   AV valves close. Ventricular pressure is less than aortic pressure.  Semilunar valves are closed.   (continued) Volume of blood in ventricle is EDV. Step 2: Ejection:  Contraction of the ventricle causes ventricular pressure to rise above aortic pressure.   Semilunar valves open. Ventricular pressure is greater than atrial pressure.  AV valves are closed.  Volume of blood ejected: SV. 34
  • 209. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cardiac Cycle  Step 3: T wave occurs:   Ventricular pressure drops below aortic pressure. Step 4: Isovolumetric relaxation:  Back pressure causes semilunar valves to close.  AV valves are still closed.   (continued) Volume of blood in the ventricle: ESV. Step 5: Rapid filling of ventricles:  Ventricular pressure decreases below atrial pressure.  AV valves open.  Rapid ventricular filling occurs. 35
  • 210. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cardiac Cycle  Step 6: Atrial systole:   P wave occurs. Atrial contraction.  Push 10-30% more blood into the ventricle. 36
  • 211. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Heart Sounds   Closing of the AV and semilunar valves. Lub (first sound):   Produced by closing of the AV valves during isovolumetric contraction. Dub (second sound):  Produced by closing of the semilunar valves when pressure in the ventricles falls below pressure in the arteries. 37
  • 212. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Heart Murmurs   Abnormal heart sounds produced by abnormal patterns of blood flow in the heart. Defective heart valves:   Valves become damaged by antibodies made in response to an infection, or congenital defects. Mitral stenosis:  Mitral valve becomes thickened and calcified.    Impairs blood flow from left atrium to left ventricle. Accumulation of blood in left ventricle may cause pulmonary HTN. Incompetent valves:  Damage to papillary muscles.  Valves do not close properly.  Murmurs produced as blood regurgitates through valve flaps. 38
  • 213. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Heart Murmurs  Septal defects:  Usually congenital.    Holes in septum between the left and right sides of the heart. May occur either in interatrial or interventricular septum. Blood passes from left to right. 39
  • 214. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Electrical Activity of the Heart  SA node:  Demonstrates automaticity:   Functions as the pacemaker. Spontaneous depolarization (pacemaker potential):  Spontaneous diffusion caused by diffusion of Ca2+ through slow Ca2+ channels.  Cells do not maintain a stable RMP. 40
  • 215. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Pacemaker AP  Depolarization:  VG fast Ca2+ channels open.    Opening of VG Na+ channels may also contribute to the upshoot phase of the AP. Repolarization:  VG K+ channels open.   Ca2+ diffuses inward. K+ diffuses outward. Ectopic pacemaker:  Pacemaker other than SA node:  If APs from SA node are prevented from reaching these areas, these cells will generate pacemaker potentials. 41
  • 216. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Myocardial APs   Majority of myocardial cells have a RMP of –90 mV. SA node spreads APs to myocardial cells.   When myocardial cell reaches threshold, these cells depolarize. Rapid upshoot occurs:  VG Na+ channels open.   Inward diffusion of Na+. Plateau phase:  Rapid reversal in membrane polarity to –15 mV.  VG slow Ca2+ channels open.  Slow inward flow of Ca2+ balances outflow of K+. 42
  • 217. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Myocardial APs  (continued) Rapid repolarization: +  VG K channels open.  Rapid outward diffusion of K+. 43
  • 218. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Conducting Tissues of the Heart    APs spread through myocardial cells through gap junctions. Impulses cannot spread to ventricles directly because of fibrous tissue. Conduction pathway:      SA node. AV node. Bundle of His. Purkinje fibers. Stimulation of Purkinje fibers cause both ventricles to contract simultaneously. 44
  • 219. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Conducting Tissues of the Heart (continued) 45
  • 220. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Conduction of Impulse   APs from SA node spread quickly at rate of 0.8 - 1.0 m/sec. Time delay occurs as impulses pass through AV node.   Slow conduction of 0.03 – 0.05 m/sec. Impulse conduction increases as spread to Purkinje fibers at a velocity of 5.0 m/sec.  Ventricular contraction begins 0.1–0.2 sec. after contraction of the atria. 46
  • 221. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Refractory Periods     Heart contracts as syncytium. Contraction lasts almost 300 msec. Refractory periods last almost as long as contraction. Myocardial muscle cannot be stimulated to contract again until it has relaxed.  Summation cannot occur. 47
  • 222. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Excitation-Contraction Coupling in Heart Muscle  Depolarization of myocardial cell stimulates opening of VG Ca2+ channels in sarcolema.  Ca2+ diffuses down gradient into cell.    Stimulates opening of Ca2+-release channels in SR. Ca2+ binds to troponin and stimulates contraction (same mechanisms as in skeletal muscle). During repolarization Ca2+ actively transported out of the cell via a Na+-Ca2+exchanger. 48
  • 223. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Electrocardiogram (ECG/EKG)  The body is a good conductor of electricity.   Tissue fluids have a high [ions] that move in response to potential differences. Electrocardiogram:  Measure of the electrical activity of the heart per unit time.   Potential differences generated by heart are conducted to body surface where they can be recorded on electrodes on the skin. Does NOT measure the flow of blood through the heart. 49
  • 224. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. ECG Leads  Bipolar leads:    Record voltage between electrodes placed on wrists and legs. Right leg is ground. Unipolar leads:   Voltage is recorded between a single “exploratory electrode” placed on body and an electrode built into the electrocardiograph. Placed on right arm, left arm, left leg, and chest.  Allow to view the changing pattern of electrical activity from different perspectives. 50
  • 225. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. ECG  P wave:   QRS complex:    Atrial depolarization. Ventricular depolarization. Atrial repolarization. T wave:  Ventricular repolarization. 51
  • 226. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Correlation of ECG with Heart Sounds  First heart sound:    Produced immediately after QRS wave. Rise of intraventricular pressure causes AV valves to close. Second heart sound:   Produced after T wave begins. Fall in intraventricular pressure causes semilunar valves to close. 52
  • 227. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Systemic Circulation      Arteries. Arterioles. Capillaries. Venules. Veins.  Role is to direct the flow of blood from the heart to the capillaries, and back to the heart. 53
  • 228. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Vessels  Walls composed of 3 “tunics:”  Tunica externa:   Tunica media:   Outer layer comprised of connective tissue. Middle layer composed of smooth muscle. Tunica interna:    Innermost simple squamous endothelium. Basement membrane. Layer of elastin. 54
  • 229. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Vessels  Elastic arteries:  Numerous layers of elastin fibers between smooth muscle.  Expand when the pressure of the blood rises.   Act as recoil system when ventricles relax. Muscular arteries:    (continued) Are less elastic and have a thicker layer of smooth muscle. Diameter changes slightly as BP raises and falls. Arterioles:  Contain highest % smooth muscle.  Greatest pressure drop.  Greatest resistance to flow. 55
  • 230. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Blood Vessels  Most of the blood volume is contained in the venous system.  Venules:  Formed when capillaries unite.   Very porous. Veins:  Contain little smooth muscle or elastin.    (continued) Capacitance vessels (blood reservoirs). Contain 1-way valves that ensure blood flow to the heart. Skeletal muscle pump and contraction of diaphragm:  Aid in venous blood return of blood to the heart. 56
  • 231. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Types of Capillaries  Capillaries:  Smallest blood vessels.  1 endothelial cell thick.   Continuous:  Adjacent endothelial cells tightly joined together.   Intercellular channels that permit passage of molecules (other than proteins) between capillary blood and tissue fluid.  Muscle, lungs, and adipose tissue. Fenestrated:  Wide intercellular pores.   Provide direct access to cells.  Permits exchange of nutrients and wastes. Provides greater permeability.  Kidneys, endocrine glands, and intestines. Discontinuous (sinusoidal):  Have large, leaky capillaries.  Liver, spleen, and bone marrow. 57
  • 232. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Atherosclerosis   Most common form of arteriosclerosis (hardening of the arteries). Mechanism of plaque production:  Begins as a result of damage to endothelial cell wall.   HTN, smoking, high cholesterol, and diabetes. Cytokines are secreted by endothelium; platelets, macrophages, and lymphocytes.  Attract more monocytes and lymphocytes. 58
  • 233. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Atherosclerosis  Monocytes become macrophages.   (continued) Engulf lipids and transform into foam cells. Smooth muscle cells synthesize connective tissue proteins.  Smooth muscle cells migrate to tunica interna, and proliferate forming fibrous plaques. 59
  • 234. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cholesterol and Plasma Lipoproteins    High blood cholesterol associated with risk of atherosclerosis. Lipids are carried in the blood attached to protein carriers. Cholesterol is carried to the arteries by LDLs (low-density lipoproteins).  LDLs are produced in the liver.  LDLs are small protein-coated droplets of cholesterol, neutral fat, free fatty acids, and phospholipids. 60
  • 235. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cholesterol and Plasma Lipoproteins (continued)  Cells in various organs contain receptors for proteins in LDL.  LDL protein attaches to receptors.   The cell engulfs the LDL and utilizes cholesterol for different purposes. LDL is oxidized and contributes to:     Endothelial cell injury. Migration of monocytes and lymphocytes to tunica interna. Conversion of monocytes to macrophages. Excessive cholesterol is released from the cells.  Travel in the blood as HDLs (high-density lipoproteins), and removed by the liver.  Artery walls do not have receptors for HDL. 61
  • 236. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Ischemic Heart Disease  Ischemia:  Oxygen supply to tissue is deficient.    Increased [lactic acid] produced by anaerobic respiration. Angina pectoris:   Most common cause is atherosclerosis of coronary arteries. Substernal pain. Myocardial infarction (MI):   Changes in T segment of ECG. Increased CPK and LDH. 62
  • 237. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Arrhythmias Detected on ECG  Arrhythmias:   Abnormal heart rhythms. Flutter:  Extremely rapid rates of excitation and contraction of atria or ventricles.   Atrial flutter degenerates into atrial fibrillation. Fibrillation:  Contractions of different groups of myocardial cells at different times.  Coordination of pumping impossible.  Ventricular fibrillation is life-threatening. 63
  • 238. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Arrhythmias Detected on ECG (continued)  Bradycardia:   Tachycardia:   HR slower < 60 beats/min. HR > 100 beats/min. First–degree AV nodal block:  Rate of impulse conduction through AV node exceeds 0.2 sec.   P-R interval. Second-degree AV nodal block:  AV node is damaged so that only 1 out of 2-4 atrial APs can pass to the ventricles.  P wave without QRS. 64
  • 239. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Arrhythmias Detected on ECG (continued)  Third-degree (complete) AV nodal block:   None of the atrial waves can pass through the AV node. Ventricles paced by ectopic pacemaker. 65
  • 240. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Lymphatic System  3 basic functions:    Transports interstitial (tissue) fluid back to the blood. Transports absorbed fat from small intestine to the blood. Helps provide immunological defenses against pathogens. 66
  • 241. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Lymphatic System  Lymphatic capillaries:   (continued) Closed-end tubules that form vast networks in intercellular spaces. Lymph:  Fluid that enters the lymphatic capillaries.   Lymph carried from lymph capillaries, to lymph ducts, and then to lymph nodes. Lymph nodes filter the lymph before returning it to the veins. 67
  • 242. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cardiovascular Animations and Interactive Tutorials           Cardiovascular System Topics by ADAM Basic Heart Circulation Bristol-Myers Squibb Heart Structure by Nucleus Communications Heart functions and Problems Cardiology Associates Electrocardiogram -ECG Technician Nobel eMuseum Hyper heart by Knowlege Weavers The Arrhythma Center HeartCenterOnline Cardiac Cell Death San Diego State University Prenatal Heart HeartCenterOnline Congenital Heart Disease HeartCenterOnline 68
  • 243. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Cardiovascular Animations and Interactive Tutorials(2)          Electro Cardio Gram by Knowlege Weavers The Electrocardiogram Basics McGill University Heart Animations Science Museum of Minnesota Operation Heart Transplant from PBS Interpeting an EKG EKG Tutorial RnCeus Interactive Blaufuss Medical Multimedia Heart Valves Movie by Marcy Thomas at Wellesley Cadaver Dissection of the Human Heart 69
  • 244. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Free Useful Plugins     Adobe Acrobat Reader - Document Distribution Adobe Flash Player - Web Animation -The leading rich client for Internet content and applications across the broadest range of platforms. Adobe Shockwave Player - With Adobe Shockwave Player, you can enjoy multimedia games and learning applications, using exciting new 3D technology. Adobe Authorware Player - With Adobe Authorware Web Player, you can experience online learning applications on the Web . QuickTime Player- Streaming/Multimedia 70
  • 245. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Free Useful Plugins      RealOne Player - Streaming/Multimedia Microsoft Windows Media Player - Streaming/Multimedia Microsoft Word Viewer - Viewing Word documents online (required if Word is not installed on resident computer; PC only) Microsoft PowerPoint Viewer - Viewing PowerPoint presentations online (required if PowerPoint is not installed on computer) Animated PowerPoint Add-in -needed if you do not have Office XP Microsoft Excel Viewer - Viewing Excel documents online (required if Excel is not installed on resident computer; PC only) MDL Chime interactively displays 2D and 3D molecules directly in Web pages. 71
  • 246. Cardiovascular Pathology Gross and Microscopic Source of Images in this Presentation Webpath- University of Utah Prepared and presented by Marc Imhotep Cray, M.D. Basic Medical Sciences Professor 1
  • 247. Normal Heart 2
  • 248. Normal heart, gross • This is the external appearance of a normal heart.The epicardial surface is smooth and glistening. • The amount of epicardial fat is usual.The left anterior descending coronary artery extends down from the aortic root to the apex 3
  • 249. Normal tricuspid valve, gross • This is the tricuspid valve. The leaflets and thin and delicate. • Just like the mitral valve, the leaflets have thin chordae tendineae that attach the leaflet margins to the papillary muscles of the ventricular wall below 4
  • 250. Normal coronary artery, microscopic • This is a normal coronary artery. • The lumen is large, without any narrowing by atheromatous plaque. The muscular arterial wall is of normal proportion 5
  • 251. Normal myocardium, medium power microscopic • This is the normal appearance of myocardial fibers in longitudinal section. • Note the central nuclei and the syncytial arrangement of the fibers, some of which have pale pink intercalated disks 6
  • 252. Atherosclerotic Cardiovascular Disease 7
  • 253. Coronary artery with atherosclerotic narrowing, microscopic • The coronary artery shown here has narrowing of the lumen due to build up of atherosclerotic plaque. • Severe narrowing can lead to angina, ischemia, and infarction 8
  • 254. Coronary artery with recanalized thrombosis, microscopic • This section of coronary artery demonstrates remote thrombosis with recanalization to leave only two small, narrow channels 9
  • 255. Coronary artery with calcific atherosclerosis, microscopic • There is a severe degree of narrowing in this coronary artery. • It is "complex" in that there is a large area of calcification on the lower right, which appears bluish on this H&E stain. • Complex atheroma have calcification, thrombosis, or hemorrhage. Such calcification would make coronary angioplasty difficult 10
  • 256. Aortas demonstrating various degrees of atherosclerosis, gross • These three aortas demonstrate mild, moderate, and severe atherosclerosis from bottom to top. • At the bottom, the mild atherosclerosis shows only scattered lipid plaques. • The aorta in the middle shows many more larger plaques. The severe atherosclerosis in the aorta at the top shows extensive ulceration in the plaques 11
  • 257. Aorta, atherosclerotic aneurysm, gross • Here is an example of an atherosclerotic aneurysm of the aorta in which a large "bulge" appears just above the aortic bifurcation. • Such aneurysms are prone to rupture when they reach about 6 to 7 cm in size. • They may be felt on physical examination as a pulsatile mass in the abdomen.Most such aneurysms are conveniently located below the renal arteries so that surgical resection can be performed with placement of a dacron graft 12
  • 258. CT scan with contrast • This abdominal high speed CT scan with contrast demonstrates an abdominal aortic aneurysm approximately 6 cm in diameter. • At this size, there is increased risk for rupture 13
  • 259. Coronary artery, mild atherosclerosis, gross • A coronary artery has been opened longitudinally. • The coronary extends from left to right across the middle of the picture and is surrounded by epicardial fat. Increased epicardial fat correlates with increasing total body fat. • There is a lot of fat here, suggesting one risk factor for atherosclerosis. • This coronary shows only mild atherosclerosis, with only an occasional yellow-tan lipid plaque and no narrowing 14
  • 260. Coronary artery, severe atherosclerosis, gross • This is the left coronary artery from the aortic root on the left. • Extending across the middle of the picture to the right is the anterior descending branch. • This coronary shows severe atherosclerosis with extensive calcification. At the far right, there is an area of significant narrowing 15
  • 261. Coronary artery, hemorrhage into plaque, gross • This is coronary atherosclerosis with the complication of hemorrhage into atheromatous plaque, seen here in the center of the photograph. • Such hemorrhage acutely may narrow the arterial lumen 16
  • 262. Heart and LAD coronary artery with recent thrombus, gross • The anterior surface of the heart demonstrates an opened left anterior descending coronary artery. • Within the lumen of the coronary can be seen a dark red recent coronary thrombosis. • The dull red color to the myocardium as seen below the glistening epicardium to the lower right of the thrombus is consistent with underlying myocardial infarction 17
  • 263. Myocardial Infarction 18
  • 264. Heart, left ventricle, acute myocardial infarction, gross • This is the left ventricular wall which has been sectioned lengthwise to reveal a large recent myocardial infarction. • The center of the infarct contains necrotic muscle that appears yellow-tan. • Surrounding this is a zone of red hyperemia. Remaining viable myocardium is reddishbrown 19
  • 265. Heart, left ventricle and septum, myocardial infarction, gross • This cross section through the heart demonstrates the left ventricle on the left. • Extending from the anterior portion and into the septum is a large recent myocardial infarction. • The center is tan with surrounding hyperemia. • The infarction is "transmural" in that it extends through the full thickness of the wall 20
  • 266. Heart, transmural myocardial infarction with rupture and hemopericardium, gross • One complication of a transmural myocardial infarction is rupture of the myocardium. • This is most likely to occur in the first week between 3 to 5 days following the initial event, when the myocardium is the softest. • The white arrow marks the point of rupture in this anterior-inferior myocardial infarction of the left ventricular free wall and septum. • Note the dark red blood clot forming the hemopericardium. The hemopericardium can lead to tamponade 21
  • 267. Heart, left ventricular aneurysm, gross • A cross section through the heart reveals a ventricular aneurysm with a very thin wall at the arrow. • Note how the aneurysm bulges out. The stasis in this aneurysm allows mural thrombus, which is present here, to form within the aneurysm 22
  • 268. Arterial Dissection 23
  • 269. Aorta, dissection with tear in arch, gross • There is a tear (arrow) located 7 cm above the aortic valve and proximal to the great vessels in this aorta with marked atherosclerosis. • This is an aortic dissection 24
  • 270. Hemopericardium with cardiac tamponade, gross • An aortic dissection may lead to hemopericardium when blood dissects through the media proximally. • Such a massive amount of hemorrhage can lead to cardiac tamponade 25
  • 271. Aorta, dissection, gross • This aorta has been opened longitudinally to reveal an area of fairly limited dissection that is organizing. • The red-brown thrombus can be seen in on both sides of the section as it extends around the aorta. The intimal tear would have been at the left. • This creates a "double lumen" to the aorta. • This aorta shows severe atherosclerosis which, along with cystic medial necrosis and hypertension, is a risk factor for dissection 26
  • 272. Aorta, dissection, microscopic • Here, the dissection went into the muscular wall. In any case, an aortic dissection is an extreme emergency and can lead to death in a matter of minutes. • The blood can dissect up or down the aorta. • Blood dissecting up around the great vessels can close off the carotids. • Blood can dissect down to the coronaries and shut them off 27
  • 273. Carotid artery, dissection with compression, gross • The right carotid artery is compressed by blood dissecting upward from a tear with aortic dissection. • Blood may also dissect to coronary arteries. • Thus patients with aortic dissection may have symptoms of severe chest pain (for distal dissection) or may present with findings that suggest a stroke (with carotid dissection) or myocardial ischemia (with coronary dissection). 28
  • 274. Infective Endocarditis 29
  • 275. Aortic valve, infective endocarditis, gross • This is infective endocarditis. The aortic valve demonstrates a large, irregular, reddish tan vegetation. • Virulent organisms, such as Staphylococcus aureus, produce an "acute" bacterial endocarditis, while some organisms such as Streptococcus viridans produce a "subacute" bacterial endocarditis 30
  • 276. Infective endocarditis spreading to myocardium, gross • In this case, the infective endocarditis demonstrates how the infection tends to spread from the valve surface. • Here, vegetations can be seen on the endocardial surfaces, and the infection is extending into to underlying myocardium 31
  • 277. Infective endocarditis, microscopic • Microscopically, the valve in infective endocarditis demonstrates friable vegetations of fibrin and platelets (pink) mixed with inflammatory cells and bacterial colonies (blue). • The friability explains how portions of the vegetation can break off and embolize 32
  • 278. Pericarditis 33
  • 279. Fibrinous pericarditis, gross • A window of adherent pericardium has been opened to reveal the surface of the heart. • There are thin strands of fibrinous exudate that extend from the epicardial surface to the pericarial sac. • This is typical for a fibrinous pericarditis 34
  • 280. Hemorrhagic pericarditis, gross • The pericarditis here not only has fibrin, but also hemorrhage. Thus, this is called a "hemorrhagic pericarditis". • It is really just fibrinous pericarditis with hemorrhage. Without inflammation, blood in the pericardial sac would be called "hemopericardium 35
  • 281. Neoplasia 36
  • 282. Heart, rhabdomyoma, gross • This two year old child died suddenly. At autopsy, a large firm, white tumor mass was found filling much of the left ventricle. • This is a cardiac rhabdomyoma. Such primary tumors of the heart are rare 37
  • 283. Heart, atrial myxoma, gross • The left atrium has been opened to reveal the most common primary cardiac neoplasm--an atrial myxoma. • These benign masses are most often attached to the atrial wall, but can arise on a valve or in a ventricle. • They can produce a "ball valve" effect by intermittently occluding the atrioventricular valve orifice. Embolization of fragments of tumor may also occur. Myxomas are easily diagnosed by echocardiography 38
  • 284. Heart, epicardium, metastases, gross • Primary tumors of the heart are uncommon. • Metastases to the heart are more common, but rare overall (only about 5 to 10% of all malignancies have cardiac metastases). • Seen over the surface of the epicardium are pale white-tan nodules of metastatic tumor. Metastases may lead to a hemorrhagic pericarditis. 39
  • 285. Congenital Heart Disease 40
  • 286. Congenital Heart Disease • Type of Defect Mechanism 41
  • 287. Type of Defect Mechanism • Ventricular Septal Defect (VSD) There is a hole within the membranous or muscular portions of the intraventricular septum that produces a left-to-right shunt, more severe with larger defects • Atrial Septal Defect (ASD) A hole from a septum secundum or septum primum defect in the interatrial septum produces a modest left-to-right shunt • • Patent Ductus Arteriosus (PDA) The ductus arteriosus, which normally closes soon after birth, remains open, and a left-to-right shunt develops 42
  • 288. Type of Defect Mechanism • Tetralogy of Fallot Pulmonic stenosis results in right ventricular hypertrophy and a right-to-left shunt across a VSD, which also has an overriding aorta • Transposition of Great Vessels The aorta arises from the right ventricle and the pulmonic trunk from the left ventricle. A VSD, or ASD with PDA, is needed for extrauterine survival. There is right-toleft shunting . Truncus ArteriosusThere is incomplete separation of the aortic and pulmonary outflows, along with VSD, which allows mixing of oxygenated and deoxygenated blood and right-to-left shunting • • 43
  • 289. Type of Defect Mechanism • Hypoplastic Left Heart Syndrome There are varying degrees of hypoplasia or atresia of the aortic and mitral valves, along with a small to absent left ventricular chamber • Coarctation of Aorta Either just proximal (infantile form) or just distal (adult form) to the ductus is a narrowing of the aortic lumen, leading to outflow obstruction • Total Anomalous Pulmonary Venous Return (TAPVR) The pulmonary veins do not directly connect to the left atrium, but drain into left innominate vein, coronary sinus, or some other site, leading to possible mixing of blood and right-sided overload 44
  • 290. Heart, atrial septal defect, gross • In the region of the foramen ovale on the interatrial septum is a small atrial septal defect, as seen in this heart opened on the right side. • Here the defect is not closed by the septum secundum, so a shunt exists across from left to right 45
  • 291. Heart, ventricular septal defect, gross • This is the heart of a premature stillborn with Trisomy 13 in which a ventricular septal defect is visible in the membranous septum. • About 90% of VSD's are in the membranous septum and 10% in the muscular septum. 46
  • 292. Aorta, coarctation, gross • This portion of aorta was resected from a patient with a coarctation. • The aorta narrows postductally here to about a 3 mm opening 47
  • 293. Aorta, coarctation, gross • The aorta is opened longitudinally here to reveal a coarctation. • In the region of the narrowing, there was increased turbulence that led to increased atherosclerosis. 48
  • 294. Heart, tetralogy of Fallot, diagram This diagram depicts the features of Tetralogy of Fallot: 1. Ventricular septal defect; 2. Overriding aorta; 3. Pulmonic stenosis; 4. Right ventricular hypertrophy. The obstruction to right ventricular outflow creates a right-to-left shunt that leads to cyanosis. 49
  • 295. Heart, transposition of great vessels, diagram • In the diagram, transposition of the great vessels is shown • occurs when the trunco-conal septum does not spiral down. Instead, it descends straight down. As a result, outflow of right ventricle is into aorta and outflow from left ventricle is into the pulmonic trunk. • In order for this system to work, there must be a connection between the system and pulmonic circulations. • Sometimes this is through a ventricular septal defect or an atrial septal defect. • In the diagram at the left, this is through a patent ductus arteriosus 50
  • 296. Cardiomyopathies 51
  • 297. Type of CMP Findings • Dilated (Congestive) All four chambers are dilated, and there is also hypertrophy. The most common cause is chronic alcoholism, though some may be the end-stage of remote viral myocarditis. • Hypertrophic The most common form, idiopathic hypertrophic subaortic stenosis (IHSS) results from asymmetric interventricular septal hypertrophy, resulting in left ventricular outflow obstruction. • Restrictive The myocardium is infiltrated with a material that results in impaired ventricular filling. The most common causes are amyloidosis and hemochromatosis. 52
  • 298. Heart, dilated cardiomyopathy, gross • This very large heart has a globoid shape because all of the chambers are dilated. • It felt very flabby, and the myocardium was poorly contractile. • This is an example of a cardiomyopathy. • This term is used to denote conditions in which the myocardium functions poorly and the heart is large and dilated, but there is no specific histologic finding 53
  • 299. Heart, dilated cardiomyopathy, [XRAY] • This chest radiograph demontrates marked cardiomegaly, with the left heart edge appearing far to the left 54
  • 300. Heart, cardiomyopathy, microscopic • Microscopically, the heart in cardiomyopathy • demonstrates hypertrophy of myocardial fibers (which also have prominent dark nuclei) along with interstitial fibrosis 55
  • 301. Heart, hypertrophic cardiomyopathy, explanted heart, gross • • • • There is marked left ventricular hypertrophy, with asymmetric bulging of a very large interventricular septum into the left ventricular chamber. This is hypertrophic cardiomyopathy. About half of these cases are familial, though a variety of different genes may be responsible for this disease. Both children and adults can be affected, and sudden death can occur. Seen here is the explanted heart. Pacemaker wires enter the right ventricle. The atria with venous connections, along with great vessels, remained behind to connect to the transplanted heart (provided by someone who cared enough to make transplantation possible). 56
  • 302. Heart, hypertension with left ventricular hypertrophy, gross • This left ventricle is very thickened (slightly over 2 cm in thickness), but the rest of the heart is not greatly enlarged. • This is typical for hypertensive heart disease. • The hypertension creates a greater pressure load on the heart to induce the hypertrophy 57
  • 303. Heart, hypertrophy with hypertension, gross • The left ventricle is markedly thickened in this patient with severe hypertension that was untreated for many years. • The myocardial fibers have undergone hypertrophy 58
  • 304. Arterial and Venous Diseases 59
  • 305. Renal arteriole, fibrinoid necrosis with malignant hypertension, microscopic • One complication of hyperplastic arteriolosclerosis with malignant hypertension is fibrinoid necrosis, as seen here in a renal arteriole 60
  • 306. Varicose veins, gross • The prominent veins shown here on the lower leg are varicosities. Varicose veins are a common problem with aging. The venous valves become incompetent. • There may be muscular atrophy with less tone to provide a massage effect on the large superficial veins, and skin becomes less elastic with time. • Hydrostatic pressure from standing for long periods exacerbates the problem 61
  • 307. Cardiovascular Pharmacology Global Overview/Review Topics discussed: Antihypertensive Drugs Drugs for Angina ACE Inhibitors Calcium Channel Blockers Adrenergic Blockers Prepared and Presented by: Marc Imhotep Cray, M.D. Cardiac Glycosides 1
  • 308. Online Reference Resource IVMS Online Textbook Series Enrolled Students click to access/download e-books 2
  • 309. High Yield Autonomic Pharmacology Principles First Aid for the Basic Sciences-General Principles.pdf 3
  • 310. Click for source/reading: http://www.zuniv.net/physiology/book/chapter8.html 4
  • 311. Blood Pressure 5
  • 312. Antihypertensive Drugs See Antihypertensive Agents
  • 313. Autonomic Nervous System and Blood Pressure Control • Cardiac Output (Output of Pump) – heart rate x stroke volume • Caliber of Arteries & Arterioles • (Flow Resistance) – Neural • sympathetic & parasympathetic NS – Hormonal • Renin-angiotensin-aldosterone system – Local transmitters • Nitric Oxide (NO) 7
  • 314. Neural Control of the CVS: The Autonomic Nervous System Higher Centers Vasomotor Center Carotid Sinus Brain Stem Parasympathetic (Vagus) -Adrenoceptor Spinal Cord Sympathetic -Adrenoceptor Arteriole 8
  • 315. Baroreceptor Reflexes in BP Control 1  BP Parasympathetic Sympathetic 9
  • 316. Baroreceptor Reflexes in BP Control 2 1  BP Carotid sinus senses  BP Parasympathetic Sympathetic 10
  • 317. Baroreceptor Reflexes 1  BP in BP Control Vasomotor Center responds with  Symp. NS activity 3 and  Parasymp. activity 2 Carotid sinus senses  BP Parasympathetic Sympathetic 11
  • 318. Baroreceptor Reflexes in BP Control 3 Vasomotor Center responds with  Symp. NS activity and  Parasymp. activity 1 2  BP Carotid sinus senses  BP Parasympathetic 4 Sympathetic  Heart rate and contractility 4  PVR 12
  • 319. Baroreceptor Reflexes in BP Control Vasomotor Centre responds with  Symp. NS activity 3 and  Parasymp. activity 2 1  BP Carotid sinus senses  BP Parasympathetic 4 Sympathetic  Heart rate and contractility 4  PVR 5  BP 13
  • 320. Blood Pressure Control: Control of Stroke Volume • Cardiac Output (Output of Pump) – heart rate x stroke volume • Caliber of Arteries & Arterioles (Flow Resistance) – Neural • sympathetic & parasympathetic NS – Hormonal • Renin-angiotensin-aldosterone system – Local transmitters • Nitric Oxide (NO) 14
  • 321. Stroke volume (SV) • Stroke volume (SV) is the volume of blood pumped by the right/left ventricle of the heart in one contraction. • Specifically, it is the volume of blood ejected from ventricles during systole. Calculation Its value is obtained by subtracting endsystolic volume (ESV) from end-diastolic volume (EDV) for a given ventricle: SV = EDV − ESV In a healthy 70-kg man, the left ventricular EDV is 120 ml and the corresponding ESV is 50 ml, giving a stroke volume of 70 ml. • The stroke volume is not all of the blood contained in the left ventricle. • Normally, only about two-thirds of the blood in the ventricle is put out with each beat. What blood is actually pumped from the left ventricle is the stroke volume and it, together with the heart rate, determines the cardiac output. 15
  • 322. Blood Pressure Control: Control of Stroke Volume Factors Determining Stroke Volume • Contractility –  sympathetic activity increases contractility • End-diastolic volume – Determined by venous filling pressure (distensible ventricle) 16
  • 323. Blood Pressure Control: Control of Stroke Volume Venous filling pressure and stroke volume Stroke Volume • The Frank-Starling relationship Output increases with increased filling pressure Overdistended, output falls End diastolic volume (filling pressure) 17
  • 324. Blood Pressure Control: Control of Stroke Volume What determines venous filling pressure? • Blood volume, mostly contained in a distensible venous circulation! 18
  • 325. Blood Pressure Control: Renin-Angiotensin • Cardiac Output (Output of Pump) – heart rate x stroke volume • Caliber of Arteries & Arterioles (Flow Resistance) – Neural • sympathetic & parasympathetic NS – Hormonal • Renin-angiotensin-aldosterone system – Local transmitters • Nitric Oxide (NO) 19
  • 326. The Renin-Angiotensin System Liver SENSOR IN KIDNEY Angiotensin Precursor (Circulating) Renin (Circulating) Angiotensin I OUTCOMES Angiotensin II Vasoconstriction Na+ Retention K+ Excretion Aldosterone from adrenal cortex AT1 Receptor 20
  • 327. Antihypertensive Drug Strategies • Reduce cardiac output – -adrenergic blockers – Ca2+ Channel blockers • Dilate resistance vessels – Ca2+ Channel blockers – Renin-angiotensin system blockers – 1 adrenoceptor blockers – Nitrates** • Reduce vascular volume – diuretics 21
  • 328. Calcium Channel Blocking Drugs Calcium-channel blockers (CCBs) (Also have uses in treating cardiac rhythm disturbances & angina)
  • 329. Membrane Ca2+ Channels • • • • All cells, voltage or ligand-gated, several types [Ca2+]e  2.5mM [Ca2+]i  100nM (maintained by Na+/Ca2+ antiport) [Ca2+]i  Signaling Actin-myosin interaction Myocardial membrane depolarization (Phase 2) 23
  • 330. Effect of Ca2+ Influx: Muscle Contraction Ca2+ Channel Ca2+ Plasma Membrane “Trigger” Sarcoplasmic Reticulum Ca2+ Ca2+  contraction (myocardial or vascular) Actin & Myosin 24
  • 331. Ca2+ Channel Blockers • Cardioselective – verapamil • Non-selective – diltiazem • Vascular selective – dihydropyridines • nifedipine • felodipine • amlodipine 25
  • 332. Ca2+ Channel Blockers • Myocardial selective: – Reduce cardiac contractility – Also reduce heart rate (action on heart rhythm) •  BP,  heart work • Vascular smooth muscle selective – Reduce vascular resistance •  BP,  heart work 26
  • 333. 1 Adrenoceptor Antagonists Beta-adrenoceptor antagonists (beta-blockers)
  • 334. Cardiac 1 Adrenoceptor Stimulation •  Heart rate •  contractility  blood pressure  heart work 28
  • 335. Cardiac 1 Adrenoceptor Blockade •  Heart rate •  contractility   blood pressure   heart work 29
  • 336. Cardiac 1 Adrenoceptor Blockers • Metoprolol • Atenolol 30
  • 337. Cardiac 1 Adrenoceptor Blockers: Clinical Uses • Antiarrhythmic (slows some abnormal fast rhythms) • Antihypertensive • Antiangina: via reduced heart work 31
  • 338. Blockade of Renin-AngiotensinAldosterone System 1. Angiotensin converting enzyme (ACE) inhibitors 2. Angiotensin II receptor (AT1) antagonists 32
  • 339. Renin-angiotensin system Liver Renal Blood Flow Na+ load Angiotensin Precursor Renin Angiotensin I Angiotensin Converting Enzyme Angiotensin II Vasoconstriction Na+ Retention K+ Excretion Aldosterone AT1 Receptor 33
  • 340. Angiotensin Converting Enzyme (ACE) Inhibitors • Captopril • Enalapril • anything else ending in -pril – (lisinopril, trandolapril, fosinopril, perindopril, quinapril, etc) 34
  • 341. AT1 Blockers (ARB’s) • Candesartan, • irbesartan, • others ending in -sartan 35
  • 342. ACE-Inhibitors & AT1 Blockers: Clinical Uses •  reduced vascular resistance •  aldosterone   salt & H2O retention Uses • Antihypertensive • Heart failure 36
  • 343. 1 Adrenoceptor Blockers Alpha-adrenoceptor antagonists (alpha-blockers) 37
  • 344. Neural Control of Circulation: Autonomic NS Higher Centers Vasomotor Center Carotid Sinus Brain Stem Parasympathetic (Vagus) -Adrenoceptor Spinal Cord Sympathetic 1-Adrenoceptor 38
  • 345. 1 Adrenoceptor Blockers • Peripheral vasodilator   vascular resistance • Agents: – Prazosin 39
  • 346. Volume Reduction • See “Diuretics” lecture • Reduces cardiac filling pressure • Thus reduces stroke volume and cardiac output 40
  • 347. Clinical Use of Antihypertensives • Consequences of chronic high blood pressure – heart failure – arterial disease • kidney failure • strokes • myocardial infarction (heart attack) • Aim of treatment – prevent consequences of high BP 41
  • 348. Drug Treatment of Angina Antianginal
  • 349. What is Angina and Why Does it Happen? • Oxygen demand depends on heart work • Coronary artery partial obstruction (due to atherosclerosis) limits blood supply to part of the myocardium • Coronary circulation can meet oxygen demands of myocardium at rest, but not when heart work increased by exercise, etc. • Ischaemia (O2 deficiency) causes pain: “angina” 43
  • 350. Determinants of Heart Work • Heart work determined by: 1. Heart rate 2. Cardiac contractility 3. Peripheral resistance See: Antihypertensive Agents Physiological Factors Influencing Arterial Pressure for full discussion 44
  • 351. Drug Treatment of Angina: Limiting Heart Work • Reduce heart rate and contractility –  adrenoceptor blockers – Ca2+ channel blockers (verapamil and diltiazem) • Dilate resistance vessels – Ca2+ channel blockers (nifedipine, felodipine, amlodipine) – Nitrates 45
  • 352. Nitrates • Glyceryl trinitrate (GTN) • Isosorbide (di)nitrate 46
  • 353. GTN Vascular Smooth Muscle Cell R-SH OrganicNitrate NO2 - R-SH NO Nitrosothiols (R-SNO) Ester Reductase + See : Nitrates, Digoxin and Calcium Channel Blockers Dr. Paul Forrest Royal Prince Alfred Hospital Guanylate Cyclase cGMP RELAXATION GTP Protein Kinase G 47
  • 354. Nitrous Oxide and Vasodilation After receptor stimulation, L-argininedependent metabolic pathway produces nitric oxide (NO) or thiol derivative (RNO). NO causes increase in cyclic guanosine monophosphate (cGMP), which causes relaxation of vascular smooth muscle. EDRF=endotheliumderived relaxing factor. From: Inhaled Nitric Oxide Therapy ROBERT J. LUNN, M.D. From the Department of Anesthesiology, Mayo Clinic Rochester, Rochester, Minnesota. http://www.mayoclinicproceedings.com/inside.asp?ref=70 03sc 48
  • 355. Use of Nitrates • Very fast, short-lived vascular dilatation (Greater in venules than arterioles • lower vascular resistance means less heart work • less heart work means less need for coronary artery blood flow • therefore, nitrates help the chest pain (angina) that happens during exercise when there is coronary artery obstruction. • Not used for managing chronic high blood pressure 49
  • 356. Digitalis purpurea (Foxglove) Cardiostimulatory Medicines from foxgloves are called "Digitalin". The use of Digitalis purpurea extract containing cardiac glycosides for the treatment of heart conditions was first described in the English speaking medical literature by William Withering, in 1785. It is used to increase cardiac contractility (it is a positive inotrop) and as an antiarrhythmic agent to control the heart rate, particularly in the irregular (and often fast) atrial fibrillation. It is therefore often prescribed for patients in atrial fibrillation, especially if they have been diagnosed with heart failure. From: http://en.wikipedia.org/wiki/Digitalis 50
  • 357. Cardiac Glycosides: Digoxin 51
  • 358. Digoxin Mechanism of Action Na+/K+ ATPase Outside Na+ Ca2+ Na+ Na+ Inside K+ Channels K+ Pump Ca2+ Exchanger 52
  • 359. Digoxin blocks Na+/K+ ATP’ase P P Mg2+ ATP’ase K+ Mg2+ ATP’ase Dig  less efficient Na+/K+ exchange  diminished Na+ gradient  diminished K+ gradient 53
  • 360. Digoxin increases intracellular Ca2+ Na+ K+ Pump Na+ Ca2+ Exchanger diminished Na+ gradient   intracellular Ca2+ 54
  • 361. Effect of  [Ca2+]i Na+/Ca2+ antiporter Na+/K+ ATP’ase K+ Na+ + Ca2+ Na K+ Na+ Ca2+ channel Ca2+ “Trigger” Sarcoplasmic Reticulum Ca2+ Ca2+   contractility Actin & Myosin 55
  • 362. Digoxin Effects on Rhythm Therapeutic •  Vagus nerve activity – Slower heart rate – Slower AV conduction Toxic • Various abnormal rhythms 56
  • 363. Uses of Digoxin • Atrial fast arrhythmias: slows rate • Heart Failure: increases contractile strength 57
  • 364. CV Pharmacology Anti-Anginal Agents Recommended Reading: Antianginal Drugs Formative Assessment Practice question Clinical: E-Medicine Article Angina Pectoris Coronary Artery Disease Prepared and Presented: Marc Imhotep Cray, M.D. Professor Pharmacology and BMS
  • 365. Online Reference Resource IVMS Online Textbook Series Enrolled Students click to access/download e-books 2
  • 366. Coronary heart disease (CHD) Defined (Etiologic Dx)    Coronary heart disease (CHD) is a condition in which proper circulation of blood and oxygen are not provided to heart and surrounding tissue. Result is due to a narrowing of small blood vessels, which normally supply heart with blood and oxygen. Coronary heart disease, a type of cardiovascular disease, is the leading cause of death for both men and women in the United States. 3
  • 367. Causes (Anatomic Dx)  The typical cause of coronary heart disease is atherosclerosis, which takes place with plaque and fatty build up on the artery walls, narrowing the vessels. http://en.wikipedia.org/wiki/Atherosclerosis 4
  • 368. 5
  • 369. CAD Risk Factors  1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Certain conditions are considered to put an individual at greater risk for coronary heart disease. The following are some risk factors: Age (particularly 40+) Diabetes Genetics (heredity) High blood pressure High bad cholesterol (LDL) Increased levels of C-reactive protein, fibrinogen, or homocysteine Lack of sufficient physical activity Low good cholesterol (HDL) Menopause Obesity Smoking 6
  • 370. Symptoms  1. 2. 3. Some more frequent symptoms of coronary heart disease include: Angina (ischemic pain) Myocardial Infarction Shortness of breath 7
  • 371. Diagnosis  1. 2. 3. 4. 5. 6. 7. 8. 9. Diagnosis of coronary heart disease may be accomplished by a variety of means: Coronary angiography Coronary arteriography Coronary CT angiography Echocardiogram Electrocardiogram (ECG) Electron-beam CT (EBCT) Exercise stress test Magnetic resonance angiography Nuclear scan 8
  • 372. Treatment  1. 2. 3. 4. 5. 6. Coronary heart disease treatment methods may include: (depends on the presenting Physiologic Dx) Angioplasty with stenting Coronary artery bypass surgery Medication Minimally invasive heart surgery Proper diet and exercise Quitting smoking 9
  • 373. Coronary Artery O2 Supply and Demand 10
  • 374. Angina Pectoris (Chest Pain)   When the supply of oxygen and nutrients in the blood is insufficient to meet the demands of the heart, the heart muscle aches The heart demands a large supply of oxygen to meet the demands placed on it The myocardial supply:demand ratio--a critical review. [Am J Cardiol. 1978] 11
  • 375. R/O MI Algorithm Contemporary Diagnosis and Management of Unstable Angina GUYS. REEDER, MD From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minn. http://www.mayoclinicproceedings.com/insid e.asp?AID=1529&UID= 12
  • 376. Antianginal Pharmacologic Agents    Nitrates Beta blockers Calcium channel blockers 13
  • 377. Types of Angina  Chronic stable angina (also called classic or effort angina)  Unstable angina (also called preinfarction or crescendo angina)  Vasospastic angina (also called Prinzmetal’s or variant angina) 14
  • 378. Antianginal Agents: Therapeutic Objectives   Increase blood flow to ischemic heart muscle and/or Decrease myocardial oxygen demand 15
  • 379. Antianginal Agents: Therapeutic Objectives    Minimize the frequency of attacks and decrease the duration and intensity of anginal pain Improve the patient’s functional capacity with as few side effects as possible Prevent or delay the worst possible outcome, MI 16
  • 380. Antianginal Agents: 1)Nitrates Available forms: Sublingual Buccal Chewable tablets Capsules Ointments Transdermal patches Inhalable sprays Intravenous solutions 17
  • 381. Antianginal Agents: Nitrates(2)    Cause vasodilation due to relaxation of smooth muscles Potent dilating effect on coronary arteries Used for prophylaxis and treatment of angina 18
  • 382. Antianginal Agents: Nitrates(3) Nitroglycerin     Prototypical nitrate Large first-pass effect with PO forms Used for symptomatic treatment of ischemic heart conditions (angina) IV form used for BP control in perioperative hypertension, treatment of CHF, ischemic pain, and pulmonary edema associated with acute MI 19
  • 383. Antianginal Agents: Nitrates(4)   isosorbide dinitrate (Isordil, Sorbitrate, Dilatrate SR) isosorbide mononitrate (Imdur, Monoket, ISMO) Used for:    Acute relief of angina Prophylaxis in situations that may provoke angina Long-term prophylaxis of angina 20
  • 384. Antianginal Agents: Nitrates(5) Side Effects    Headache  Usually diminish in intensity and frequency with continued use Tachycardia, postural hypotension Tolerance may develop 21
  • 385. Antianginal Agents: 2)Beta Blockers     atenolol (Tenormin) metoprolol (Lopressor) propranolol (Inderal) nadolol (Corgard) 22
  • 386. Antianginal Agents: Beta Blockers(2) Mechanism of Action   Decrease the HR, resulting in decreased myocardial oxygen demand and increased oxygen delivery to the heart Decrease myocardial contractility, helping to conserve energy or decrease demand 23
  • 387. Antianginal Agents: Beta Blockers(3) Therapeutic Uses    Antianginal Antihypertensive Cardioprotective effects, especially after MI 24
  • 388. Antianginal Agents: Beta Blockers(4) Side Effects Body System Effects Cardiovascular Metabolic bradycardia, hypotension second- or third-degree heart block heart failure Altered glucose and lipid metabolism 25
  • 389. Antianginal Agents: Beta Blockers(5) Side Effects Body System Effects CNS Other dizziness, fatigue, mental depression, lethargy, drowsiness, unusual dreams impotence wheezing, dyspnea 26
  • 390. Antianginal Agents: 3) Calcium Channel Blockers Medicinal Chemistry Classes Prototypical Agents  verapamil (Calan)  diltiazem (Cardizem)  nifedipine (Procardia) •Dihydropyridines •Amlodipine (Norvasc), Felodipine (Plendil) •Nimodipine •Isradipine •Nicardipine •Nifedipine •Non-Dihydropyridines •Bepridil (Vascor) •Diltiazem (Cardiazem) •Verapamil (Isoptin, Calan) 27
  • 391. Antianginal Agents: Calcium Channel Blockers(2) Mechanism of Action    Cause peripheral arterial vasodilation Reduce myocardial contractility (negative inotropic action) Result: decreased myocardial oxygen demand 28
  • 392. Antianginal Agents: Calcium Channel Blockers(2) Therapeutic Uses    First-line agents for treatment of angina, hypertension, and supraventricular tachycardia Short-term management of atrial fibrillation and flutter Several other uses 29
  • 393. Antianginal Agents: Calcium Channel Blockers(3) Side Effects   Very acceptable side effect and safety profile May cause hypotension, palpitations, tachycardia or bradycardia, constipation, nausea, dyspnea 30
  • 394. CV Pharmacology- Antihypertensive Agents Recommended Reading: Antihypertensive Drugs Formative Assessment Practice question Clinical: E-Medicine Articles Hypertension Prepared and Presented by: Marc Imhotep Cray, M.D. Professor Pharmacology
  • 395. Online Reference Resource IVMS Online Textbook Series Enrolled Students click to access/download e-books 2
  • 396. Normal Control of BP  Normal control of BP: sympathoadrenal axis-- response to a decrease in BP   Sensed by Central baroreceptors {heart & great arteries} Stimulation of ß-adrenergic systems     increased heart rate (positive chronotropic response) increased force of contraction (contractility, positive inotropic response) increased renin secretion {juxtaglomerular renal cells} Stimulation of a-adrenoceptor systems: causes vasoconstriction 3
  • 397. Essential Hypertension With essential hypertension, previous slide mechanisms function inappropriately  Excessive sympathetic activation  Elevated norepinephrine may promote through vascular endothelium injury:       vascular hypertrophy atherogenesis ß-adrenergic receptor down-regulation Reduced endothelium-mediated vascular relaxation Consequence: increased vasoconstrictive tone (chronic vasoconstriction) Excessive sympathetic activation promotes enhanced peripheral vascular resistance in hypertensive patients 4
  • 398. Hypertension Defined Re: Table in the next slide  Based on recommendations of the Seventh Report of the Joint National Committee of Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) New Hypertension Guidelines Quick Reference Card http://www.nhlbi.nih.gov/guideline s/hypertension/phycard.pdf Also see: E-Medicine Article Hypertension 5
  • 399. Classification of Blood Pressure (JNC VII) Category Systemic BP (mm Hg) Diastolic BP (mm Hg) Normal <130 <85 High normal 130-139 85-89 Hypertension Stage 1 Stage 2 Stage 3 Stage 4 140-159 160-169 180-209  210 90-99 100-109 110-119  120 6
  • 400. Classification of HTN Primary Hypertension    Specific cause unknown 90% of the cases Also known as essential or idiopathic hypertension Secondary Hypertension   Cause is known (such as eclampsia of pregnancy, renal artery disease, pheochromocytoma) 10% of the cases 7
  • 401. Physiological Factors Influencing Arterial Pressure Arterial pressure is determined by a number of interacting factors  Preload & Contractility  Heart rate  Peripheral resistance 8
  • 402. Physiological Factors Influencing Arterial Pressure Preload & Contractility   As blood volume returning to heart increases, preload increases and there is enhanced filling with ventricular dilation According to Starling's Law, increased ventricular stretch usually leads to increased contractility 9
  • 403. Physiological Factors Influencing Arterial Pressure Preload & Contractility(2)   Increased preload and increased contractility lead to increased stroke volume and ultimately an increase in arterial pressure, all other factors remaining equal Some antihypertensive drugs decrease preload 10
  • 404. Physiological Factors Influencing Arterial Pressure Preload & Contractility(3) The Nitrates are an example of preload reducing agents See: IAU CV Pharmacology Anti-Anginal Agents 11
  • 405. Physiological Factors Influencing Arterial Pressure Heart Rate Heart rate:  Since the product of heart rate and stroke volume equals cardiac output, an increase in heart rate will increase arterial blood pressure, all other factors remaining equal Some antihypertensive agents decrease heart rate (ß-adrenergic receptor antagonists, e.g.) Heart Rate X Stroke Volume = Cardiac Output  Cardiac Output X Peripheral Resistance = Arterial Pressure 12
  • 406. Physiological Factors Influencing Arterial Pressure Peripheral resistance Peripheral resistance:  For a given cardiac output, blood pressure depends only on peripheral resistance  Some antihypertensive drugs act to reduce peripheral resistance (Also known as afterload reducing agents) 13
  • 407. Physiological Factors Influencing Arterial Pressure Depending on mechanism of action, a given antihypertensive may:       Reduce preload Reduce afterload Decrease heart rate Reduce peripheral resistance Reduce contractility. Many antihypertensive drugs have multiple effects 14
  • 408. Anti-Hypertensive Drug Classes 1. 2. 3. 4. 5. Diuretics Sympatholytics Vasodilators Calcium Channel Blockers Angiotensin Converting Enzyme (ACE) Inhibitor 15
  • 409. Anti-Hypertensive Drug Classes-1) Diuretics Thiazides Potassium Sparing Loop Diuretics •Hydrochlorothiazide (HydroDIURIL) •Chlorthalidone (Hygroton) •Chlorothiazide (Diuril) •Indapamide (Lozol) •Metolazone (Zaroxolyn) •Amiloride (Midamor) •Spironolactone (Aldactone) •Triamterene (Dyrenium) •Furosemide (Lasix), Bumetanide (Bumex), Ethacrynic acid (Edecrin) •Torsemide (Demadex) 16
  • 410. Anti-Hypertensive Drug Classes2) Sympatholytics Centrally Active •Clonidine (Catapres) •Methyldopa (Aldomet) •Guanabenz (Wytensin) •Guanfacine (Tenex) Adrenergic Neuron Blocker Adrenoceptor Antagonists •Guanadrel (Hylorel) •Guanethidine (Ismelin) •Reserpine • Labetalol (Trandate, Normodyne) (alpha & beta) •Prazosin (Minipress) (alpha), Terazosin (Hytrin) (alpha) 17
  • 411. Anti-Hypertensive Drug Classes3) Vasodilators Diazoxide (Hyperstat) Hydralazine (Apresoline) Minoxidil (Loniten) Nitroprusside sodium (Nipride) 18
  • 412. Anti-Hypertensive Drug Classes4) Calcium Channel Blockers •Dihydropyridines •Amlodipine (Norvasc), Felodipine (Plendil) •Nimodipine •Isradipine •Nicardipine •Nifedipine •Non-Dihydropyridines •Bepridil (Vascor) •Diltiazem (Cardiazem) •Verapamil (Isoptin, Calan) 19
  • 413. Anti-Hypertensive Drug Classes5) Angiotensin Converting Enzyme Inhibitors •Benazepril (Lotensin) •Captopril (Capoten) •Enalapril (Vasotec) •Fosinopril (Monopril) •Lisinopril (Prinvivil, Zestril) •Moexipril (Univasc) •Quinapril (Accupril) •Ramipril (Altace) •Losartin (Cozaar), Irbesartin*** *** ***angiotensin receptor blocker 20
  • 414. Antihypertensive Agents: Categories Discussion       Adrenergic agents Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Calcium channel blockers Diuretics Vasodilators 21
  • 415. Antihypertensive Agents: Categories  Adrenergic Agents      Alpha1 blockers Beta blockers (cardioselective and nonselective) Centrally acting alpha blockers Combined alpha-beta blockers Peripheral-acting adrenergic agents 22
  • 416. Antihypertensive Agents: Mechanism of Action Adrenergic Agents Alpha1 Blockers (peripherally acting)   Block the alpha1-adrenergic receptors The SNS is not stimulated Result: DECREASED blood pressure Stimulation of alpha1-adrenergic receptors causes HYPERtension Blocking alpha1-adrenergic receptors causes decreased blood pressure 23
  • 417. Antihypertensive Agents: Adrenergic Agents Alpha1 Blockers    doxazosin (Cardura) prazosin (Minipress) terazosin (Hytrin) 24
  • 418. Antihypertensive Agents: Mechanism of Action Adrenergic Agents Central-Acting Adrenergics   Stimulate alpha2-adrenergic receptors Sympathetic outflow from the CNS is decreased Result: decreased blood pressure 25
  • 419. Antihypertensive Agents: Adrenergic Agents Central-Acting Adrenergics   clonidine (Catapres) methyldopa (Aldomet) (drug of choice for hypertension in pregnancy) 26
  • 420. Antihypertensive Agents: Mechanism of Action Adrenergic Agents Adrenergic Neuronal Blockers (peripherally acting)  Inhibit release of norepinephrine  Also deplete norepinephrine stores  SNS (peripheral adrenergic nerves) is not stimulated Result: decreased blood pressure 27
  • 421. Antihypertensive Agents: Adrenergic Agents Adrenergic Neuronal Blockers (peripherally acting)    reserpine guanadrel (Hylorel) guanethidine (Ismelin) 28
  • 422. Antihypertensive Agents: Adrenergic Agents Therapeutic Uses  Alpha1 blockers (peripherally acting)  Treatment of hypertension  Relief of symptoms of BPH  Management of of severe CHF when used with cardiac glycosides and diuretics 29
  • 423. Antihypertensive Agents: Adrenergic Agents Therapeutic Uses  Central-Acting Adrenergics  Treatment of hypertension, either alone or with other agents  Usually used after other agents have failed due to side effects 30
  • 424. Antihypertensive Agents: Adrenergic Agents Therapeutic Uses  Central-Acting Adrenergics(2)  Also may be used for treatment of severe dysmenorrhea, menopausal flushing, glaucoma  Clonidine is useful in the management of withdrawal symptoms in opioid- or nicotine-dependent persons 31
  • 425. Antihypertensive Agents: Adrenergic Agents Therapeutic Uses  Adrenergic neuronal blockers (peripherally acting)  Treatment of hypertension, either alone or with other agents  Seldom used because of frequent side effects 32
  • 426. Antihypertensive Agents: Adrenergic Agents Side Effects Most common: Other: dry mouth drowsiness sedation constipation headaches sleep disturbances nausea rash cardiac disturbances (palpitations) HIGH INCIDENCE OF ORTHOSTATIC HYPOTENSION 33
  • 427. Antihypertensive Agents: Categories- (ACE Inhibitors) Angiotensin-Converting Enzyme Inhibitors (ACE Inhibitors)    Large group of safe and effective drugs Often used as first-line agents for CHF and hypertension May be combined with a thiazide diuretic or calcium channel blocker 34
  • 428. Antihypertensive Agents: Mechanism of Action ACE Inhibitors RAAS: Renin Angiotensin-Aldosterone System  When the enzyme angiotensin I is converted to angiotensin II, the result is potent vasoconstriction and stimulation of aldosterone 35
  • 429. Antihypertensive Agents: Mechanism of Action(2) ACE Inhibitors   Result of vasoconstriction: increased systemic vascular resistance and increased afterload Therefore, increased BP 36
  • 430. Antihypertensive Agents: Mechanism of Action(3) ACE Inhibitors   Aldosterone stimulates water and sodium resorption. Result: increased blood volume, increased preload, and increased B 37
  • 431. Antihypertensive Agents: Mechanism of Action(4) ACE Inhibitors   ACE Inhibitors block the angiotensin-converting enzyme, thus preventing the formation of angiotensin II. Also prevent the breakdown of the vasodilating substance, bradykinin Result: decreased systemic vascular resistance (afterload), vasodilation, and therefore, decreased blood pressure 38
  • 432. Diagram illustrates the reninangiotensin-aldosterone axis 39
  • 433. 40
  • 434. Antihypertensive Agents ACE Inhibitors captopril (Capoten)  Short half-life, must be dosed more frequently than others enalapril (Vasotec)  The only ACE inhibitor available in oral and parenteral forms 41
  • 435. Antihypertensive AgentsACE Inhibitors(2) lisinopril (Prinivil and Zestril) quinapril (Accupril)   Newer agents, long half-lives, once-aday dosing Several other agents available 42
  • 436. Antihypertensive Agents: Therapeutic Uses ACE Inhibitors     Hypertension CHF (either alone or in combination with diuretics or other agents) Slows progression of left ventricular hypertrophy after an MI Renal protective effects in patients with diabetes Drugs of choice in hypertensive patients with CHF 43
  • 437. Antihypertensive Agents: Side Effects ACE Inhibitors  Fatigue Dizziness  Headache Mood changes  Impaired taste Dry, nonproductive cough, reverses when therapy is stopped NOTE: first-dose hypotensive effect may occur!! 44
  • 438. Antihypertensive Agents: Categories Angiotensin II Receptor Blockers (A II Blockers or ARBs)    Newer class Well-tolerated Do not cause coughing 45
  • 439. Antihypertensive Agents: Mechanism of Action Angiotensin II Receptor Blockers   Allow angiotensin I to be converted to angiotensin II, but block the receptors that receive angiotensin II Block vasoconstriction and release of aldosterone 46
  • 440. Antihypertensive Agents: Angiotensin II Receptor Blockers       losartan (Cozaar) eposartan (Teveten) valsartan (Diovan) irbesartan (Avapro) candesartan (Atacand) telmisartan (Micardis) 47
  • 441. Antihypertensive Agents: Therapeutic Uses Angiotensin II Receptor Blockers    Hypertension Adjunctive agents for the treatment of CHF May be used alone or with other agents such as diuretics 48
  • 442. Antihypertensive Agents: Side Effects Angiotensin II Receptor Blockers    Upper respiratory infections Headache May cause occasional dizziness, inability to sleep, diarrhea, dyspnea, heartburn, nasal congestion, back pain, fatigue 49
  • 443. Antihypertensive Agents: Categories Calcium Channel Blockers    Benzothiazepines Dihydropyridines Phenylalkylamines 50
  • 444. Antihypertensive Agents: Mechanism of Action Calcium Channel Blockers    Cause smooth muscle relaxation by blocking the binding of calcium to its receptors, preventing muscle contraction This causes decreased peripheral smooth muscle tone, decreased systemic vascular resistance Result: decreased blood pressure 51
  • 445. Antihypertensive AgentsCalcium Channel Blockers  Benzothiazepines:   Phenylalkamines:   diltiazem (Cardizem, Dilacor) verapamil (Calan, Isoptin) Dihydropyridines:   amlodipine (Norvasc), bepridil (Vascor), nicardipine (Cardene) nifedipine (Procardia), nimodipine (Nimotop) 52
  • 446. Antihypertensive Agents: Therapeutic Uses Calcium Channel Blockers     Angina Hypertension Dysrhythmias Migraine headaches 53
  • 447. Antihypertensive Agents: Side Effects Calcium Channel Blockers  Cardiovascular   Gastrointestinal   hypotension, palpitations, tachycardia constipation, nausea Other  rash, flushing, peripheral edema, dermatitis 54
  • 448. Antihypertensive Agents: Diuretics Decrease the plasma and extracellular fluid volumes  Results: decreased preload decreased cardiac output decreased total peripheral resistance   Overall effect: decreased workload of the heart, and decreased blood pressure 55
  • 449. Antihypertensive Agents: Mechanism of Action Vasodilators  Directly relaxes arteriolar smooth muscle  Result: decreased systemic vascular response, decreased afterload, and PERIPHERAL VASODILATION 56
  • 450. Nitrous Oxide and Vasodilation After receptor stimulation, L-argininedependent metabolic pathway produces nitric oxide (NO) or thiol derivative (R-NO). NO causes increase in cyclic guanosine monophosphate (cGMP), which causes relaxation of vascular smooth muscle. EDRF=endothelium-derived relaxing factor. From: Inhaled Nitric Oxide Therapy ROBERT J. LUNN, M.D. From the Department of Anesthesiology, Mayo Clinic Rochester, Rochester, Minnesota. http://www.mayoclinicproceedings.com/inside.asp?re f=7003sc 57
  • 451. Antihypertensive Agents Vasodilators     diazoxide (Hyperstat) hydralazine HCl (Apresoline) minoxidil (Loniten, Rogaine) sodium nitroprusside (Nipride, Nitropress) 58
  • 452. Antihypertensive Agents: Therapeutic Uses Vasodilators    Treatment of hypertension May be used in combination with other agents Sodium nitroprusside and diazoxide IV are reserved for the management of hypertensive emergencies 59
  • 453. Antihypertensive Agents: Side Effects Vasodilators  Hydralazine:   dizziness, headache, anxiety, tachycardia, nausea and vomiting, diarrhea, anemia, dyspnea, edema, nasal congestion Sodium nitroprusside:  bradycardia, hypotension, possible cyanide toxicity 60
  • 454. Stepwise Approach to Tx of Antihypertensive Essential HTN Medication Sequence     beginning with a low dosage of either an ACE inhibitor, calcium channel blocker or beta blocker and proceeding, if needed to add a diuretic and ultimately additional more powerful drugs, such as centrally acting sympatholytics, peripheral vasodilators or combination. At each step dosages are reviewed and if the patient's hypertension is controlled then therapy may be continued with review for possible removal of medication. Figure adapted from Harrison's "Principles of Internal Medicine, Thirteenth Edition, p. 1128 61
  • 455. Resources JNC GUIDELINES  The Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7)  On the JNC home page, there are a number of important resources for clinicians as well as patient resources, including:  JNC 7 Complete Report: The Science Behind the New Guidelines (86 pages)  JNC 7 Express Highlights "Must Know" Clinical Practice Updates (34 pages)  JNC 7 Reference Card (2 pages)- A great summary of Evaluation, Treatment, 62
  • 456. CV Pharmacology- Drugs Used in Treating Hyperlipidemia Recommended Reading: Management of Hyperlipidemic States Formative Assessment Practice question Clinical: E-Medicine Articles Hypertriglyceridemia Prepared and presented by: Marc Imhotep Cray, M.D. Professor Pharmacology
  • 457. Definition    Hyperlipidemia, hyperlipoproteinemia or dyslipidemia is the presence of raised or abnormal levels of lipids and/or lipoproteins in the blood Lipids are insoluble in aqueous solution Lipids (fatty molecules) are transported in a protein capsule, and the density of the lipids and type of protein determines the fate of the particle and its influence on metabolism 2
  • 458. Definition(2) see notes and link out for more on cholesterol    Lipid and lipoprotein abnormalities are extremely common in the general population, and are regarded as a highly modifiable risk factor for cardiovascular disease due to the influence of cholesterol, one of the most clinically relevant lipid substances, on atherosclerosis In addition, some forms may predispose to acute pancreatitis Link out: http://themedicalbiochemistrypage.org/cholesterol.html 3
  • 459. Schematic and Notes Below From: http://www.emedicine.com/MED/topic2921.htm#Multimediamedia3 4
  • 460. Links to Cholesterol Metabolism and Lipoprotein on themedicalbiochemistrypage.org            Intestinal Uptake of Lipids Composition of Lipoprotein Complexes Lipid Profile Values Classification of Apoproteins Chylomicrons Very Low Density Lipoproteins, LDLs Intermediate Density Lipoproteins, IDLs Low Density Lipoproteins, LDLs High Density Lipoproteins, HDLs LDL Receptors Clinical Significance of Lipoprotein Metabolism Cholesterol Biosynthesis http://themedicalbiochemistryp age.org/cholesterol.html 5
  • 461. Classification of Hyperlipidemia Fredrickson classification of Hyperlipidemias Hyperlipopr oteinemia Source: http://en.wikipedia.org/wiki/Hyperlipidemia#Classification 6
  • 462. Pathobiology of Atherosclerosis    When excess cholesterol deposits on cells and on the inside walls of blood vessels it forms an atherosclerotic plaque The first step of atherosclerosis is injury to the endothelium which results in atherosclerotic lesion formation When the plaque ruptures, blood clots form which lead to decreased blood flow, resulting in cardiovascular events 7
  • 463. Complications of Hyperlipidemia  Macrovascular complications:      Unstable Angina (chest pain) Myocardial Infarction (heart attack) Ischemic Cerebrovascular Disease (stroke) Coronary Artery Disease (heart disease) Microvascular complications:    Retinopathy (vision loss) Nephropathy (kidney disease) Neuropathy (loss of sensation in the feet and legs) 8
  • 464. 9
  • 465. Risk Factors for Hyperlipidemia         High fat intake Obesity Type 2 diabetes mellitus Advanced age Hypothyroidism Obstructive liver disease Genetics Drug induced: glucocorticoids, thiazide diuretics, beta blockers, protease inhibitors, sirolimus, cyclosporine, progestins, alcohol 10
  • 466. How to Diagnose Patients with Hyperlipidemia   The fasting lipid profile (TC, LDL-C, HDL-C, TG) is analyzed The following individuals are recommended for screening:   All adults 20 years and older should be screened at least once every 5 years Individuals with family history of premature cardiovascular disease should be screened more frequently 11
  • 467. How to Diagnose Patients with Hyperlipidemia (2)  History and physical examination:     Presence of cardiovascular risk factors or cardiovascular disease Family history of premature cardiovascular disease, hyperlipidemia, or diabetes mellitus Diabetes mellitus or glucose intolerance Central obesity     High blood pressure Presence or absence of risk factors Presence or absence of kidney or liver disease, peripheral vascular disease, abdominal aortic aneurysm, cerebral vascular disease An individual with a combination of lipid profile with history and physical exam, will be treated according to the ATP III guideline See: Adult Treatment Panel III (ATP III) Guidelines National Cholesterol Education Program Slide Shows 12
  • 468. Lipoprotein Level Classification  LDL-C < 100 mg/dL-----------------------------Optimal      Total -C     <200 mg/dL------------------------------ Desirable 200-239 mg/dL---------------------------Borderline high > or= 240 mg/dL-------------------------High TG-C:      100-129 mg/dL --------------------------Near or above optimal 130-159 mg/dL---------------------------Borderline high 160-189 mg/dL --------------------------High > or = 190 mg/dL -----------------------Very high <150 mg/dL------------------------------Optimal 150-199 mg/dL --------------------------Borderline high 200-499 mg/dL --------------------------High > or = 500 mg/dL -----------------------Very high HDL cholesterol:   <40 mg/dL -------------------------------Low >60 or = 60 mg/dL --------------------- High 13
  • 469. Treatment Goals 1. Reduce total cholesterol and LDL (bad) cholesterol 2. Prevent the formation of atherosclerotic plaques and stop the progression of established plaques 3. Prevent heart disease 4. Prevent morbidity and mortality 14
  • 470. Non-Pharmacological Treatment Lipid lowering therapy should be started with lifestyle modification for at least 12 weeks 1. Increase physical activity 2. Weight reduction 3.          Diet modification: Total fat 25-35% of total calories Saturated fat <7% of total calories Polyunsaturated fat up to 10% total calories Monounsaturated fat up to 20% total calories Carbohydrates 50-60% total calories Fiber 20-30 g/ day total calories Protein 15% total calories Cholesterol <200 mg/day Total calories Achieve and maintain desirable body weight See: Treatment of Diabetic Dyslipidemia / Medscape WebMD Med Student Section 15
  • 471. Pharmacological Treatment   If non-pharmacological treatment is not successful, a lipid-lowering drug should be started, especially in high risk populations 1st step:     Initiate LDL-lowering drug therapy Start with statins, bile acid sequestrants, or nicotinic acid Evaluate after 6 weeks 2nd step:      3rd step:    If goal is not reached, intensive lipid lowering should be continued or individual should be referred to a lipid specialist If goal was reached, other lipid risk factors should be treated 4th step:  Monitor response and compliance If goal was not reached, intensive lipidlowering treatment should be started Increase dose of statins Bile acid sequestrants or nicotinic acid should be added Evaluate after 6 weeks 16
  • 472. Pharmacological Treatment Statins (HMG CoA Reductase Inhibitors)  Atorvastatin (Lipitor® )  Simvastatin (Zocor®)  Lovastatin (Mevacor®): extended release  Pravastatin (Pravachol®)  Fluvastatin (Lescol®):  Lescol XL: 80 mg tablets  Rosuvastatin (Crestor®): tablets 17
  • 473. Statins (HMG CoA Reductase Inhibitors)(2) Effectiveness of statins:  Reduce LDL cholesterol by 18-55% Decrease TG by 7-30%  Raise HDL cholesterol by 5-15%  Statins are the most effective in lowering LDL cholesterol  Statins are the most effective in patient who has low HDL and high LDL 18
  • 474. Statins (HMG CoA Reductase Inhibitors)(3) Mechanism of action:  Statins inhibit HMG-CoA reductase (enzyme involved in cholesterol synthesis) thus decreasing mevalonic acid production and stimulating LDL breakdown Click and learn more 19
  • 475. Statins (HMG CoA Reductase Inhibitors)(4) Side effects:  Muscle aches  Increased liver enzymes Muscle break down leading to renal failure  Fatigue, mild stomach disturbances, headache, or rash 20
  • 476. Statins (HMG CoA Reductase Inhibitors)(5) Avoid use in:  Active or chronic liver disease and pregnancy Use with caution with:  Concomitant use of cyclosporine, macrolide antibiotics, antifungal agents.  For example: Itraconazole, ketoconazole, erythromycin, clarithromycin, cyclosporine, nefazodone, HIV antiretrovirals  When statins are used with fibric acids and niacin, appropriate caution should be taken because of increasing incidence of muscle breakdown 21
  • 477. Statins (HMG CoA Reductase Inhibitors)(6) Drug- food interaction:  Grapefruit juice increases concentration of statins  Pravastatin, rosuvastatin & fluvastatin concentrations are not affected by grapefruit juice Monitoring:  Muscle soreness, tenderness, or pain  Liver function tests : baseline, 4-6 weeks after starting therapy, and then annually  Muscle enzyme levels when individual has muscle pain 22
  • 478. Bile Acid Sequestrants Mechanism of action:  Bile acid sequestrants bind to bile acids in the intestine, thus inhibits uptake of intestinal bile salts into the blood and increases the fecal loss of bile saltbound LDL 23
  • 479. Bile Acid Sequestrants(2) 1) Cholestyramine (Questran®): Usual dose: 4 g by mouth 1-2 times a day with meal to a maximum of 24 g per day 2) Colesevelam (Welchol®) Usual dose: 3 tablets by mouth twice daily with meals or 6 tablets once daily with a meal 3) Colestipol (Colestid®)  Usual dose:   Granules: 5-30 g by mouth daily given once or 2-4 times a day with meal Tablets: 2-16 g by mouth daily 24
  • 480. Bile Acid Sequestrants(3) Effectiveness:  Reduces LDL cholesterol by 15-30%  Increases HDL cholesterol by 3-5%  Increases TG Drug interaction:  Decreased absorption of fat soluble Vitamins: A, D, E, K, C and folic acid  Decreased absorption of other drugs: tetracycline, thiazide diuretics, aspirin, phenobarbital, pravastatin, digoxin 25
  • 481. Bile Acid Sequestrants(4) Side effects:  Stomach upset, constipation accompanied by heart burn, nausea, and bloating Avoid use in:  A disease called dysbetalipoproteinemia  Triglycerides >400 mg/dL Use caution if:  Triglycerides >200 mg/dL  Colesevalam is much better tolerated than cholestyramine or colestipol  Statins and other drugs should be taken 1-2 hours before and 4-5 hours after bile acid sequestrants 26
  • 482. Nicotinic Acid Mechanism of action:  Nicotinic acid decreases the clearance of ApoA1 to increase HDL; it inhibits the synthesis of VLDL Effectiveness:     Decreases LDL cholesterol by 5-25 % Increases HDL cholesterol by 15-35% Decreases TG by 20-50% Nicotinic acid is the most potent drug that increases HDL cholesterol 27
  • 483. Nicotinic Acid(2) Side effects:  Flushing (taking aspirin or ibuprofen can reduce symptoms)  Increases blood glucose due to impaired insulin sensitivity  Gout  Liver toxicity associates with sustained release form (Niaspan)  Upper stomach distress and muscle weaknes Avoid use in:  Chronic liver disease  Severe gout Use with caution in:  Type 2 diabetes (high dose)  Gout  Peptic ulcer disease 28
  • 484. Fibric Acids Mechanism of action:  Fibric acid up-regulates fatty acid transport protein and fatty acid oxidation; thus it reduces the formation of VLDL, increases formation of HDL, and enhances the breakdown of TG Agents: Gemfibrozil (Lopid®) Fenofibrate (Tricor®) 29
  • 485. Fibric Acids(2) Effectiveness:  Reduces LDL cholesterol by 20-50% with normal TG  Increases LDL cholesterol with high TG  Reduces TG by 20-50%  Increases HDL cholesterol by 10-20%  Fibric acids are very effective in lowering TG and preventing pancreatitis  Fibric acids reduce VLDL, but fibric acids might increase LDL and total cholesterol 30
  • 486. Fibric Acids(3) Side effects:    Dyspepsia, gallstones, muscle ache, rash Unexplained non-coronary heart disease deaths seen in a World Health Organization (WHO) study Weakness, tiredness, elevations in muscle enzyme Avoid use in:   Severe renal disease Severe hepatic disease Drug interaction:  Fibric acids bind to albumin and increase the effect of anticoagulants 31
  • 487. Ezetimibe (Zetia) Mechanism of action:  Inhibits absorption of cholesterol in the small intestine; thus it decreases the delivery of cholesterol to the liver and increases the clearance of cholesterol from the blood Side effects: chest pain, dizziness, diarrhea, abdominal pain Drug interaction:  Bile acid sequestrants decrease ezetimibe concentrations  Ezetimibe should be spaced 2 hours before or 4 hours after bile acid sequestrants administration  Fibric acids increase ezetimibe concentrations 32
  • 488. For Further Study Recommended Reading: Management of Hyperlipidemic States Formative Assessment Practice question Clinical: E-Medicine Articles Hypertriglyceridemia 33
  • 489. CV Pharmacology Diuretic Agents Illustration Hot-Linked to Renal Physio and Pharm/Pharm2000 Prepared and presented by: Marc Imhotep Cray, M.D. Professor Pharmacology and BMS Recommended Reading: Renal Pharmacology Formative Assessment Practice question set #1 Clinical: E-Medicine Article Hypokalemia
  • 490. This illustration shows where some types of diuretics act, and how Source: http://en.wikipedia.org/wiki/Diuretics 2
  • 491. Diuretic Agents   Drugs that accelerate the rate of urine formation Result: removal of sodium and water 3
  • 492. Sodium As goes sodium so goes water  20 to 25% of all sodium is reabsorbed into the bloodstream in the loop of Henle  5 to 10% in the distal tubules,  3% in collecting ducts  If not absorbed, it is excreted with the urine 4
  • 493. Diuretic Agents 1. 2. 3. 4. 5. Carbonic anhydrase inhibitors Loop diuretics Osmotic diuretics Potassium-sparing diuretics Thiazide and thiazide-like diuretics 5
  • 494. Carbonic Anhydrase Inhibitors (CAIs) 1. acetazolamide (Diamox) 2. methazolamide 3. Dichlorphenamide  MOA: these agents block formation of H+ and HCO3- from CO2 and H2O.  The end result is that bicarbonate is excreted in the urine. (see notes page for more) 6
  • 495. Carbonic Anhydrase Inhibitors: Mechanism of Action   The enzyme carbonic anhydrase helps to make H+ ions available for exchange with sodium and water in the proximal tubules CAIs block the action of carbonic anhydrase, thus preventing the exchange of H+ ions with sodium and water 7
  • 496. Carbonic Anhydrase Inhibitors: Mechanism of Action    Inhibition of carbonic anhydrase reduces H+ ion concentration in renal tubules As a result, there is increased excretion of bicarbonate, sodium, water, and potassium Reabsorption of water is decreased and urine volume is increased 8
  • 497. Carbonic Anhydrase Inhibitors: Therapeutic Uses   Adjunct agents in the long-term management of open-angle glaucoma Used with miotics to lower intraocular pressure before ocular surgery in certain cases  Also useful in the treatment of:  Glaucoma  Edema  Epilepsy  High-altitude sickness 9
  • 498. Carbonic Anhydrase Inhibitors: Therapeutic Uses   Acetazolamide is used in the management of edema secondary to CHF when other diuretics are not effective CAIs are less potent diuretics than loop diuretics or thiazides—metabolic acidosis they induce reduces their diuretic effect in 2 to 4 days 10
  • 499. Carbonic Anhydrase Inhibitors: Side Effects hyperchloremic metabolic acidosis Drowsiness Anorexia Paresthesias Hematuria Urticaria Photosensitivity Melena 11
  • 500. Loop Diuretics    bumetanide (Bumex) ethacrynic acid (Edecrin) furosemide (Lasix) 12
  • 501. Loop Diuretics: Mechanism of Action   Act directly on the ascending limb of the loop of Henle to inhibit sodium and chloride reabsorption Increase renal prostaglandins, resulting in the dilation of blood vessels and reduced peripheral vascular resistance 13
  • 502. Loop Diuretics: Drug Effects  Potent diuresis and subsequent loss of fluid  Decreased fluid volume causes:   Reduced pulmonary vascular resistance  Reduced systemic vascular resistance  Reduced central venous pressure   Reduced BP Reduced left ventricular end-diastolic pressure Potassium depletion 14
  • 503. Loop Diuretics: Therapeutic Uses   Edema associated with CHF or hepatic or renal disease Control of hypertension 15
  • 504. Loop Diuretics: Side Effects Body System CNS Effect Dizziness headache tinnitus blurred vision GI Nausea/vomiting, diarrhea 16
  • 505. Loop Diuretics: Side Effects Body System Hematologic Metabolic Effect Agranulocytosis, neutropenia, thrombocytopenia Hypokalemia, hyperglycemia, hyperuricemia 17
  • 506. Osmotic Diuretics  mannitol (Resectisol, Osmitrol) 18
  • 507. Osmotic Diuretics: Mechanism of Action    Work in the proximal tubule Nonabsorbable, producing an osmotic effect Pull water into the blood vessels and nephrons from the surrounding tissues 19
  • 508. Osmotic Diuretics: Drug Effects     Reduced cellular edema Increased urine production, causing diuresis Rapid excretion of water, sodium, and other electrolytes, as well as excretion of toxic substances from the kidney Reduces excessive intraocular pressure 20
  • 509. Osmotic Diuretics: Therapeutic Uses     Used in the treatment of patients in the early, oliguric phase of ARF To promote the excretion of toxic substances Reduction of intracranial pressure Treatment of cerebral edema 21
  • 510. Osmotic Diuretics: Side Effects    Convulsions Thrombophlebitis Pulmonary congestion Also headaches, chest pains, tachycardia, blurred vision, chills, and fever 22
  • 511. Potassium-Sparing Diuretics    amiloride (Midamor) spironolactone (Aldactone) triamterene (Dyrenium) 23
  • 512. Potassium-Sparing Diuretics: Mechanism of Action     Work in collecting ducts and distal convoluted tubules Interfere with sodium-potassium exchange Competitively bind to aldosterone receptors Block the reabsorption of sodium and water usually induced by aldosterone 24
  • 513. Potassium-Sparing Diuretics: Drug Effects    Prevent potassium from being pumped into the tubule, thus preventing its secretion Competitively block the aldosterone receptors and inhibit its action The excretion of sodium and water is promoted 25
  • 514. Potassium-Sparing Diuretics: Therapeutic Uses spironolactone and triamterene  Hyperaldosteronism  Hypertension  Reversing the potassium loss caused by potassium-losing drugs amiloride  Treatment of CHF 26
  • 515. Potassium-Sparing Diuretics: Side Effects Body System CNS GI Other Effect Dizziness, headache Cramps, nausea, vomiting, diarrhea Urinary frequency, weakness **hyperkalemia 27
  • 516. Potassium-Sparing Diuretics: Side Effects spironolactone  gynecomastia, amenorrhea, irregular menses 28
  • 517. Thiazide and Thiazide-Like Diuretics  hydrochlorothiazide (Esidrix, HydroDIURIL)  chlorothiazide (Diuril)  trichlormethiazide (Metahydrin)  chlorthalidone (Hygroton)  metolazone (Mykrox, Zaroxolyn) 29
  • 518. Thiazide and Thiazide-Like Diuretics: Mechanism of Action   Inhibit tubular resorption of sodium and chloride ions Action primarily in the ascending loop of Henle and early distal tubule  Result: water, sodium, and chloride are excreted  Potassium is also excreted to a lesser extent  Dilate the arterioles by direct relaxation 30
  • 519. Thiazide and Thiazide-Like Diuretics: Drug Effects   Lowered peripheral vascular resistance Depletion of sodium and water 31
  • 520. Thiazide and Thiazide-Like Diuretics: Therapeutic Uses  Hypertension (one of the most prescribed group of agents)  Edematous states  Idiopathic hypercalciuria  Diabetes insipidus  Adjunct agents in treatment of CHF, hepatic cirrhosis 32
  • 521. Thiazide and Thiazide-Like Diuretics: Side Effects Body System Effect CNS Dizziness, headache, blurred vision, paresthesias, decreased libido Anorexia, nausea, vomiting, diarrhea GI 33
  • 522. Thiazide and Thiazide-Like Diuretics: Side Effects Body System Effect GU Integumentary Metabolic Impotence Urticaria, photosensitivity Hypokalemia, glycosuria, hyperglycemia 34
  • 523. Reference Resources    Drug Monitor - Diuretics Diagram at cvpharmacology.com Renal Physiology And Disease 35
  • 524. Introduction to EKG Interpretation Marc Imhotep Cray, M.D. Professor of Basic Medical Sciences Companion Study Resource : MicroEKG Manual Video Education: 12 Lead ECG Placement Part I 12 Lead ECG Placement Part II IVMS Cloud Resource :
  • 525. The Electrocardiogram  Propagation of Electrical Activity Through the Heart  The Cardiac Action Potential  Generation of the Cardiac Pacemaker  The Electrocardiogram  Cardiac Vectors
  • 526. Electrical Conductivity in the Heart Within the atria and ventricles myocardial cells are connected by gap junctions. Gap junctions allow the cardiac action potential to propagate from cell to cell through a low resistance pathway. 3
  • 527. Electrical Conductivity in the Heart  Electrical activity can pass from cell to cell in the atria and ventricles.  The atria and ventricles are electrically isolated by the hearts fibrous skeleton the Annulus fibrosus.  The heart has specialized electrically active cells in addition to contractile myocardium.  These cells form the Sinatorial (SA) node, Atrioventricular (AV) node, Bundle of His and Purkinje Fibres  Electrical activity normally originates in the SA node.  The AV node forms the only site of electrical connection between the atria and ventricles. 4
  • 528. Specialized Conductive Tissue in the Heart 5
  • 529. Autorhythmicity  Some heart cells (SA, AV node and Purkinje) show automaticity, the ability to generate a heart beat.  These cells have an intrinsic rhythmicity which generates a pacemaker potential.  The heart does not require nerve or hormonal input to beat.  The heart transplant patients the nerves are severed but the heart beats on. 6
  • 530. Propagation of the Cardiac Action Potential Action potential (AP) starts at SA node. AP conducted through atrial muscle, interatrial band and internodal pathways. The AP is delayed at the AV node before entering the Bundle of His. Conduction through the Bundle of His and Purkinje fibres is extremely rapid. The ventricles depolarise from endo to epicardium and from apex to base. 7
  • 531. The Cardiac Action Potential The cardiac action potential has several distinct phases. The cardiac action potential is different in the ventricles, atria and conductive tissue. Cells in the specialised electoral pathways of the heart are spontaneously active and show automaticity. These cells do not have a true resting membrane potential. 8
  • 532. Cardiac versus Skeletal Muscle AP 9
  • 533. The Phases of the Ventricular AP The rapid depolarization is due to the opening of voltage gated Na+ channels. Inactivation of the Na+ channels and opening of slow Ca2+ channels produces the plateau. During the cardiac AP K+ conductance falls. Repolarization occurs by a return of the Ca2+ and K+ permeability to resting values. 10
  • 534. Mechanism of the Pacemaker Potential The rapid depolarization phase of the AP in cardiac pacemaker cells is due to opening of slow Ca2+ channels. Repolsarisation after the AP is due to opening of K+ channels. Spontaneous depolarization is produced by a progressive fall in the K+ permeability combined with an inward current if (the nature of if is still under investigation). 11
  • 535. Cardiac Pacemakers  The sinoatrial has the fastest pacemaker potential (~90100 beats/min) and is the normal pacemaker  The atrioventricular node is the next fastest (~40-60 beats/min) followed by cells in the bundle of His (15-30).  The fastest pacemaker normally drives the heart and suppresses other pasemakers (overdrive suppression).  A beat generated outside the normal pacemaker is an ectopic beat.  The site that generates an ectopic beat is known as an ectopic focus (foci pl.) or ectopic pacemaker. 12
  • 536. Neural Control of Heart Rate Noradrenaline (NA) from sympathetic nerves and circulating adrenaline, increase the heart rate and enhances conduction of the AP. Acetylcholine (ACh) released from parasympathetic nerves reduces the heart rate and conduction across the AV node. 13
  • 537. Neural Control of Heart Rate  Agents that alter heart rate are chronotropic.  Positive chronotropic agents increase heart rate.  Adrenaline and NA act on b-adrenergic receptors on the heart.  Isoprenaline (isoproterenol) is b-adrenergic agonist which increases heart rate.  Propranolol is a b-adrenergic antagonist that blocks the actions of adrenaline, NA and isoprenaline.  Adrenergic stimulation increases the Na+ and Ca2+ permeability of cardiac cells, hypopolarising them and increasing the pacemaker potential rise.  At rest the heart is under week sympathetic tone. 14
  • 538. Neural Control of Heart Rate  Agents with negative chronotropic actions slow the heart.  Acetylcholine acts on M-cholinergic (muscarinic) receptors on the heart.  Methacholine, carbachol (carbamylcholine) and muscarin are pharmacological stimulants of muscarinic receptors.  Atropine is a muscarinic antagonist that blocks the actions of ACh and other muscarinic receptor agonists  ACh increases K+ permeability of cardiac cell hyperpolarising them and reducing the rise in the pacemaker potential  At rest the heart is under parasympathetic tone which slows the natural rhythm of the heart. 15
  • 539. Resting Autonomic Control of Heart Rate At rest heart rate is under both sympathetic and parasympathetic tone. Normally the parasympathetic inhibition of rate is larger than the sympathetic stimulation. 16
  • 540. Some Other Agents.  Nifedipine and Verapamil are calcium channel blocking agents that reduce heart rate.  Increased extracellular K+ (hyperkalaemia): hyperpolarises cardiac myocytes, shortens the AP and slows the heart. Arrhythmia or heart block is often produced with fibrillation at higher levels. Only a 5-10mM rise in extracellular K+ can cause death.  Excessive extracellular Ca2+ (hypercalcaemia) can produce spastic contractions of the heart.  Reduced Ca2+ (hypocalcaemia) concentrations inhibit heart contraction and can trigger ectopic foci. 17
  • 541. The Electrocardiogram (EKG/ECG) P wave is due to atrial depolarisation. The QRS complex is due to ventricular depolarisation. T wave is Ventricular repolarisation. U wave is often seen in hypokalaemia. An atrial T wave is occasionally seen in complete heart block 18
  • 542. EKG Intervals P-R interval: delay between atial and ventricular depolarisation. QRS: time for ventricular depolarisation. Q-T:Duration of electrical systole. 19
  • 543. Normal EKG Intervals  P-R interval is normally 0.12-0.20 sec, most of this time is delay at the AV node. An increased P-R interval (>0.28 sec) is characteristic of 1st degree heart block.  QRS complex normally lasts less than 0.10 sec. Increased width of the complex is a characteristic of defects in the branch bundles or Purkinje fibres i.e. branch bundle block.  Q-T interval varies inversely with heart rate. 20
  • 544. Extracellular Action Potential 21
  • 545. The Cardiac Vector The Heart is a three dimensional object so the mean axis of polarity in the heart exists as a vector. A vector has both an orientation and a magnitude. Both the direction and magnitude of the cardiac vector change during the heart beat. 22
  • 546. The Cardiac Vector 23
  • 547. EKG Limb Leads 24
  • 548. 25
  • 549. Normal EKG recorded on the Bipolar Limb Leads 26
  • 550. Uses of the EKG Heart Rate Conduction in the heart Arrhythmias Direction of the cardiac vector Damage to the heart muscle Provides NO (direct) information about pumping or mechanical events in the heart. 27
  • 551. EKG Interpretation http://www.pana.org/Power%20Point%20Prese ntations/12-lead%20EKG%20Interpretation.pdf
  • 552. The Basics • • • • • • PQRST Rate Rhythm Axis Intervals Ischemia 29
  • 553. PQRST waves R P Name the waves T PR QT Q Name the intervals 30
  • 554. PQRST waves P PR QT R S Name the waves T Name the intervals 31
  • 555. Rate – The Paper 150 300 75 100 60 Or look at the right upper corner for the rate or look at the monitor for the rate Measure the rate by the distance between QRS complexes 32
  • 556. Rate – The Paper 0.2 sec 200 msec 0.04 sec 40 msec Normal paper speed is 25 mm/sec What are the time intervals between lines? 33
  • 557. Rhythm Questions • Is this sinus rhythm? • Are there P waves present? – If not…Atrial fibrillation • Is this sinus rhythm? – P before every QRS – PR interval the same for every beat – PR less than 0.2 sec (one big box) • Not sinus rhythm… – AV block – Tachydysrhythmia – Bradydysrhythmia 34
  • 558. Is this sinus rhythm? 1. P in front of every QRS? 2. PR interval > 0.12 and < 0.20 sec? 3. P upright in I, II, and III? • Yes to all 3 indicates sinus rhythm 35
  • 559. The AV Blocks • 1st Degree AVB – PR interval fixed – PR interval > 200 msec 36
  • 560. The AV Blocks • Type 1 Second Degree Block – Wenkebach – Watch for grouped beating – PR lengthens – RR shortens – Dropped beat 37
  • 561. The AV Blocks • Type 2 Second Degree Block – PR interval fixed – P without QRS – Dropped beat often in a fixed ratio 38
  • 562. The AV Blocks • Third Degree Block – AV dissociation – Escape beat • AV nodal – rate normal – Narrow complex • Junctional – rate 40-60’s – Narrow complex • Ventricular – rate 30-40’s – Wide complex, bizarre shape 39
  • 563. Fill in the table with the correct rhythms Narrow Wide Regular Irregular 40
  • 564. Filled in the Table Narrow Regular Irregular Wide Sinus rhythm Supraventricular tachy (SVT) Re-entrant tachycardia (WPW) Ventricular tachycardia SVT with BBB SVT with aberrancy Atrial fibrillation (AF) Multifocal Atrial Tachy (MAT) AF with BBB AF with aberrancy Torsade du Pointes 41
  • 565. The Normal Axis -30° to 90° -30° 90° 42
  • 566. The Axis – Lead I 0° 43
  • 567. The Axis – Lead II 60° 44
  • 568. The Axis – Lead III 120° 45
  • 569. The Axis – Lead aVF 90° 46
  • 570. The Axis – Lead aVL -30° 47
  • 571. The Axis – Lead aVR -150° 48
  • 572. The Axis -150° aVR -30° aVL 0° I 60° II 120° III 90° aVF 49
  • 573. How to find the axis… • Find the most isoelectric limb lead (R=S) • The mean axis is perpendicular to this lead. • If the QRS is positive then the axis is in that direction. • If the QRS is negative then the axis is away from that lead. 50
  • 574. Axis Practice – What is the axis? Most isoelectric lead? Lead aVF Positive or negative? Positive aVF is 90° The axis is perpendicular to this and is 0° 51
  • 575. Axis Practice – What is the axis? Most isoelectric lead? Lead II Positive or negative? Positive II is +60° The axis is perpendicular to this and is -30° 52
  • 576. Axis Practice – What is the axis? Most isoelectric lead? Lead aVR Positive or negative? Negative aVR is -150° The axis is perpendicular to this and is -60° 53
  • 577. Intervals PR interval Normal range 0.12 to 0.20 sec QT interval Normal range <.45 sec 54
  • 578. QT interval The normal QT interval will vary with heart rate and a corrected score is the most accurate measure. RR interval QTc = QT ÷ preceding RR interval 55
  • 579. Bundle Branch Blocks • • • • Left (LBBB) Right (RBBB) Left Anterior Fascicular Block (LAFB) Left Posterior Fascicular Block (LPFB) 56
  • 580. Wide QRS = Bundle Branch Block • RBBB – Rabbit ears in V1 – Tall R in V6 with slurred S – Normal or right axis (90 to 110) • LBBB – V1 – small R and deep, wide S – V6 – Tall, wide, slurred R – Normal or left axis (-30 to -90) 57
  • 581. Fascicular Blocks • LAFB – – – – Left axis (-30 to -90) I and aVL = small Q II, III, aVF = small R and deep S q1r3 • LPFB – – – – Right axis (110 to 180) I, aVL, V5-6 = no Q, small R, deep S II, III, aVF = small Q, tall R q3r1 58
  • 582. Ischemia or Infarction • ST segment = depression Infarction • ST segment = elevation Ischemia 59
  • 583. Where do you see EKG changes for the following areas of ischemia? • • • • • • • Anterior Septal Anteroseptal Inferior Lateral Posterior Right ventricular 60
  • 584. Anterior Ischemia • ST segment elevation – V3 and V4 • Reciprocal changes (ST depression) – II, III, AVF 61
  • 585. Septal Ischemia • ST segment elevation – V1 and V2 62
  • 586. Anteroseptal • ST segment elevation – V1 through V4 • Reciprocal changes (ST depression) – II, III, AVF 63
  • 587. Inferior Ischemia • ST segment elevation – II, III, aVF • Reciprocal changes (ST depression) – V1 through V4 64
  • 588. Lateral Ischemia • ST segment elevation – I, aVL, V5 and V6 • Often associated with anterior ischemia • Reciprocal changes (ST depression) – II, III, AVF 65
  • 589. Posterior Ischemia • • • • Easy to miss! Tall R wave in V1 and V2 ST segment depression in V1 through V4 If you hold the EKG up to a bright light and turn it over you will see the classic ST elevation. 66
  • 590. Right Ventricular • ST segment elevation – II, III, aVF • Tall R – II, III, aVF • Reciprocal changes (ST depression) – I and aVL – Check right sided leads • Expect hypotension with nitroglycerine or morphine 67
  • 591. Which coronary artery? 68
  • 592. High Yield Data and ECG Tracings 69
  • 593. 70
  • 594. 71
  • 595. 72
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  • 602. Resources for Further Study Electrocardiogram, EKG, or ECG – Explanation of what an ECG is, who needs one, what to expect during one, etc. Written by the National Heart Lung and Blood Institute (a division of the NIH) University of Maryland School of Medicine Emergency Medicine Interest Group – Introduction to EKG's as written by a medical student and a cardiologist ECG in 100 steps: Slideshow ECG Lead Placement – A teaching guide "designed for student nurses who know nothing at all about Cardiology" ECGpedia: Course for interpretation of ECG 12-lead ECG library Simulation tool to demonstrate and study the relation between the electric activity of the heart and the ECG Minnesota ECG Code openECGproject - help develop an open ECG solution EKG Review: Arrhythmias – A guide to reading ECG's written by a college (not medical school) professor 79
  • 603. CV Pharmacology Antiarrhythmic Agents Recommended Reading: Antiarrhythmic Drugs Formative Assessment Practice question set #1 Prepared and Presented by: Marc Imhotep Cray, M.D. Professor Pharmacology EKG Tutorial RnCeus Interactive “Has good EKG tracings” Clinical: E-Medicine Article Ventricular Fibrillation
  • 604. 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
  • 605. Electrophysiology and Cardiac Arrhythmias  Cardiac Rhythm Normal rate: 60-100 beats per minute Impulse Propagation: sinoatrial node atrioventricular (AV node) His-Purkinje distribution throughout the ventricle  Normal AV nodal delay (0.15 seconds) -- sufficient to allow atrial ejection of blood into the ventricles  See Animated-Interactive Cardiac Cycle Hyper heart by Knowlege Weavers Adobe Shockwave Player 3
  • 606. Electrophysiology and Cardiac Arrhythmias(2)  Definition: arrhythmia -- cardiac depolarization different from previous slide sequence - abnormal origination (not SA nodal)  abnormal rate/regularity/rhythm  abnormal conduction characteristics See: http://www.rnceus.com/ekg/ekgframe.html 4
  • 607. Cardiac Electrophysiology  The cardiac action potential is a specialized action potential in the heart, with unique properties necessary for function of the electrical conduction system of the heart  The cardiac action potential differs significantly in different portions of the heart  This differentiation of action potentials allows different electrical characteristics of different portions of the heart  For instance, the specialized conduction tissue of heart has special property of depolarizing without any external influence known as cardiac muscle automaticity See: Interactive animation illustrating the generation of a cardiac action potential 5
  • 608. Cardiac Electrophysiology(2)   In cardiac myocytes, the release of Ca2+ from the sarcoplasmic reticulum is induced by Ca2+ influx into cell through voltage-gated calcium channels on the sarcolemma This phenomenon is called calcium-induced calcium release and increases myoplasmic free Ca2+ concentration causing muscle contraction 6
  • 609. Cardiac Electrophysiology(3) http://www.zuniv.net/physiology/book/chapter11.html 7
  • 610. Cardiac Electrophysiology(4) Note that there are important physiological differences between nodal cells and ventricular cells;  the specific differences in ion channels and mechanisms of polarization give rise to unique properties of SA node cells,  most importantly the spontaneous depolarizations (cardiac muscle automaticity) necessary for the SA node's pacemaker activity  8
  • 611. Cardiac Electrophysiology(5) Calcium channels  Two voltage-dependent calcium channels play critical roles in the physiology of cardiac muscle: 1. L-type calcium channel ('L' for Long-lasting) and 2. T-type calcium channels ('T' for Transient) voltage-gated calcium channels  These channels respond differently to voltage changes across the membrane:  L-type channels respond to higher membrane potentials, open more slowly, and remain open longer than T-type channels Also See Notes Page 9
  • 612. Cardiac Electrophysiology(6)   The resting membrane potential is caused by difference in ionic concentrations and conductances across the membrane of the cell during phase 4 of the action potential. The normal resting membrane potential in ventricular myocardium is about -85 to -95 mV    This potential is determined by the selective permeability of the cell membrane to various ions The membrane is most permeable to K+ and relatively impermeable to other ions The resting membrane potential is therefore dominated by the K+ equilibrium potential according to the K+ gradient across the cell membrane The cardiac action potential has five phases 10
  • 613. Cardiac Electrophysiology(7) The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, including the  Na+-K+ ion exchange pump, the  Na+-Ca2+ exchanger current  Remember: Intracellularly K+ is the principal cation, and phosphate and the conjugate bases of organic acids are the dominant anions. Extracellularly Na+ and Cl- predominate 11
  • 614. Cardiac Electrophysiology(8)   Transmembrane potential -- determined primarily by three ionic gradients: Na+, K+, Ca 2+  water-soluble, -- not free to diffuse through the membrane in response to concentration or electrical gradients: depended upon membrane channels (proteins)  Movement through channels depend on controlling "molecular gates"  Gate-status controlled by:     Ionic conditions Metabolic conditions Transmembrane voltage Maintenance of ionic gradients:   Na+/K+ ATPase pump termed "electrogenic" when net current flows as a result of transport (e.g., three Na+ exchange for two K+ ions) 12
  • 615. Cardiac Electrophysiology(9) Initial permeability state -- resting membrane potential  sodium -- relatively impermeable  potassium -- relatively permeable Cardiac cell permeability and conductance:  conductance: determined by characteristics of ion channel protein  current flow = voltage X conductance  voltage = (actual membrane potential - membrane potential at which no current would flow, even with channels open) 13
  • 616. Cardiac Electrophysiology(10) Sodium  Concentration gradient: 140 mmol/L Na+ outside: 10 mmol/L Na+ inside;  Electrical gradient: 0 mV outside; -90 mV inside  Driving force -- both electrical and concentration -tending to move Na+ into the cell  In the resting state: sodium ion channels are closed therefore no Na+ flow through the membrane  In the active state: channels open causing a large influx of sodium which accounts for phase 0 depolarization 14
  • 617. Cardiac Electrophysiology(11) Cardiac Cell Phase 0 and Sodium Current •Note the rapid "upstroke" characteristic of Phase 0 depolarization. •This abrupt change in membrane potential is caused by rapid, synchronous opening of Na+ channels. •Note the relationships between the the ECG tracing and phase 0 Source: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm 15
  • 618. Cardiac Electrophysiology(12) Potassium:  Concentration gradient (140 mmol/L K+ inside; 4 mmol/L K+outside)  Concentration gradient -- tends to drive potassium out  Electrical gradient tends to hold K+ in  Some K+ channels ("inward rectifier") are open in resting state -- however, little K+ current flows because of the balance between the K+ concentration and membrane electrical gradients  Cardiac resting membrane potential: mainly determined   By the extracellular potassium concentration and Inward rectifier channel state 16
  • 619. Cardiac Electrophysiology(13) Spontaneous Depolarization (pacemaker cells)-phase 4 depolarization  Spontaneous Depolarization occurs because:     Gradual increase in depolarizing currents (increasing membrane permeability to sodium or calcium) Decrease in repolarizing potassium currents (decreasing membrane potassium permeability) Both Ectopic pacemaker: (not normal SA nodal pacemakers) -  Facilitated by hypokalemic states Increasing potassium: tends to slow or stop ectopic pacemaker activity 17
  • 620. Cardiac Electrophysiology(14) Ca2+: Channel Activation Sequence similar to sodium; but occurring at more positive membrane potentials (phases 1 and 2) •Following intense inward Na+ current (phase 0), Ca2+currents: •Phases 1 & 2, are slowly inactivated. (Ca2+channel activation occurred later than for Na+) Source: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm 18
  • 621. Cardiac Electrophysiology(15) Channel Inactivation, Re-establishing the Resting Membrane Potential •Final repolarization (phase 3): •complete Na+ and Ca2+ channel inactivation •Increased potassium permeability •Membrane potential approaches K+ equilibrium potential -- which approximates the normal resting membrane potential Source: http://www.pharmacology2000.com/Cardio/antiarr/antiarrtable.htm 19
  • 622. Cardiac Electrophysiology(15)   Five Phases:cardiac action potential associated with HISpurkinje fibers or ventricular muscle See Notes Page for Explainations 20
  • 623. Influence of Membrane Resting Potential on Action Potential Properties Factors that reduce the membrane resting potential & reduce conduction velocity  Hyperkalemia  Sodium pump block  Ischemic cell damage 21
  • 624. Influence of Membrane Resting Potential on Action Potential Properties(2) Factors that may precipitate or exacerbate arrhythmias  Ischemia  Hypoxia  Acidosis  Alkalosis  Abnormal electrolytes  Excessive catecholamine levels  Autonomic nervous system effects (e.g., excess vagal tone)  Excessive catecholamine levels     Autonomic nervous system effects (e.g., excess vagal tone) Drug effects: e.g., antiarrhythmic drugs may cause arrhythmias) Cardiac fiber stretching (as may occur with ventricular dilatation in congestive heart failure) Presence of scarred/diseased tissue which have altered electrical conduction properties 22
  • 625. Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? Reference Resource Reader: Teaching Cardiac Arrhythmias: A Focus on Pathophysiology and Pharmacology/ PDF Anti-arrhythmic drugs may work by:  (a) Suppressing initiation site (automaticity/after-depolarizations) and/or  (b) Preventing early or delayed afterdepolarizations and/or  (c) By disrupting a re-entrant pathway 23
  • 626. Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? (a) Automaticity: Automaticity may be diminished by:  (1) increasing the maximum diastolic membrane potential  (2) decreasing the slope of phase 4 depolarization  (3) increasing action potential duration  (4) raising the threshold potential  All of these factors make it take longer or make it more difficult for the membrane potential to reach threshold.     (1) The diastolic membrane potential may be increased by adenosine and acetylcholine. (2) The slope of phase 4 depolarization may be decreased by beta receptor blockers (3) The duration of the action potential may be prolonged by drugs that block cardiac K+ channels (4) The membrane threshold potential may be altered by drugs that block Na+ or Ca2+ channels. 24
  • 627. Intro to Arrhythmias and Drug Therapy How do Antiarrhythmic Drugs Work? (b) Delayed or Early Afterdepolarizations:  Delayed or early afterdepolarizations may be blocked by factors that   (1) prevent the conditions that lead to afterdepolarizations. (2) directly interfere with the inward currents (Na+, Ca2+) that cause afterdepolarizations. 25