PHAR 370 Module 02 Companion Guide PDF

PHAR 370 FUNDAMENTALS OF PHARMACOLOGY AND THERAPEUTICS MODULE 02 INTRODUCTION TO THE NERVOUS SYSTEM Please note: This course was designed to be interacted and engaged with using the online modules. This Module Companion Guide is a resource created to complement the online slides. If there is a discrepancy between this guide and the online module, please refer to the module. How can you help protect the integrity and quality of your Queen’s University course? Do not distribute this Module Companion Guide to any students who are not enrolled in PHAR 370 as it is a direct violation of the Academic Integrity Policy of Queen’s University. Students found in violation can face sanctions. For more information, please visit https://www.queensu.ca/academic- calendar/health-sciences/bhsc/. MODULE 02 COMPANION GUIDE PHAR 370 TABLE OF CONTENTS INTRODUCTION..................................................................................................................................................... 7 Learning Outcomes........................................................................................................................................... 7 Course Icons...................................................................................................................................................... 7 Module Assignments........................................................................................................................................ 7 Virtual Ileum Lab........................................................................................................................................... 8 Module Outline.................................................................................................................................................. 8 SECTION 01: Introduction to Autonomic Pharmacology.................................................................................. 9 The Nervous System......................................................................................................................................... 9 Review of the Nervous System and Neurotransmission.............................................................................. 9 Video: Neurotransmission and Termination of Response........................................................................... 9 Question: Neurotransmission.......................................................................................................................10 Organization of the Nervous System............................................................................................................10 Peripheral Nervous System............................................................................................................................10 Autonomic Nervous System...........................................................................................................................11 ANS: A Two Neuron System............................................................................................................................11 Divisions of the ANS.........................................................................................................................................12 Parasympathetic vs Sympathetic Nervous Systems...................................................................................12 Question 1 of 2: End of Section Quiz 1 of 2..................................................................................................13 Question 2 of 2: End of Section Quiz............................................................................................................13 SECTION 02: Parasympathetic Nervous System..............................................................................................14 Introduction to the Parasympathetic Nervous System..............................................................................14 Parasympathetic Neurons.............................................................................................................................14 Organization of the Parasympathetic Nervous System..............................................................................14 Video: Parasympathetic Nervous System.....................................................................................................15 Question: The Parasympathetic Nervous System.......................................................................................15 Parasympathetic Neurotransmitters and Receptors..................................................................................15 Parasympathetic Receptors...........................................................................................................................16 Termination of Response...............................................................................................................................16 Question: Activators and Inhibitors..............................................................................................................16 Activation of the Parasympathetic Nervous System (PSNS).......................................................................17 Activation: Specificity of Target Receptors...................................................................................................18 Clinical Use of Activators................................................................................................................................18 Glaucoma.....................................................................................................................................................18 PAGE 2 MODULE 02 COMPANION GUIDE PHAR 370 Poor Muscle Tone in the Bladder..............................................................................................................18 Asthma.........................................................................................................................................................19 Inhibitors..........................................................................................................................................................19 Clinical Use of Inhibitors.................................................................................................................................20 Question 1 of 2: Clinical Application: Inhibitors...........................................................................................20 Question 2 of 2: Clinical Application: Inhibitors...........................................................................................21 Answer: Clinical Application: Inhibitor Feedback.........................................................................................21 Question: 1 of 2: End of Section Quiz...........................................................................................................21 Question 2 of 2: End of Section Quiz............................................................................................................22 SECTION 03: Sympathetic Nervous System......................................................................................................23 Introduction to the Sympathetic Nervous System......................................................................................23 Fight or Flight Response.................................................................................................................................23 Sympathetic Neurons.....................................................................................................................................23 Organization of the Sympathetic Nervous System.....................................................................................24 The Adrenal Medulla.......................................................................................................................................24 Location of the Adrenal Medulla...............................................................................................................25 Release of Epinephrine and Norepinephrine..........................................................................................25 Question: The Sympathetic Nervous System...............................................................................................26 Video: Sympathetic Nervous System............................................................................................................26 Sympathetic Neurotransmitters and Receptors..........................................................................................26 Alpha (α) Receptors.....................................................................................................................................27 Beta (β) Receptors.......................................................................................................................................27 Question 1 of 2: Location of Sympathetic Receptors..................................................................................27 Question 2 of 2: Response of Sympathetic Receptors................................................................................28 Recall: Norepinephrine...................................................................................................................................28 Activation of the Sympathetic Nervous System...........................................................................................29 Clinical Indications for Adrenergic Drugs.....................................................................................................29 Adrenergic Drugs: Clinical Indications..........................................................................................................29 Question: Adrenergic Drugs...........................................................................................................................30 Adrenergic Drugs: Adverse Effects................................................................................................................30 Clinical Indications of Antiadrenergic Drugs................................................................................................31 Pheochromocytoma...................................................................................................................................31 Benign Prostatic Hyperplasia.....................................................................................................................31 Angina and Congestive Heart Failure.......................................................................................................32 PAGE 3 MODULE 02 COMPANION GUIDE PHAR 370 Glaucoma.....................................................................................................................................................32 Neurological Diseases................................................................................................................................33 Adverse Effects: Antiadrenergic Drugs.........................................................................................................33 Summary: Drugs that Target the ANS...........................................................................................................33 Question: Chemical Buffers and their Primary Roles.................................................................................33 Drugs Affecting the ANS Through their Action on the Brain......................................................................34 Question 1 of 2: End of Section Quiz............................................................................................................34 Question 2 of 2: End of Section Quiz............................................................................................................35 SECTION 04: Neuromuscular Blocking Drugs and Anesthetics.....................................................................36 Introduction to the Somatic Nervous System..............................................................................................36 The Somatic Nervous System........................................................................................................................36 Organization of the Somatic Nervous System.............................................................................................36 Neuromuscular Junction................................................................................................................................36 Neuromuscular Blocking Drugs.....................................................................................................................37 Analogy: Non-Depolarizing vs. Depolarizing Neuromuscular Blockers....................................................38 Example of Non-Depolarizing Neuromuscular Blockers: Tubocurarine..................................................39 Overcoming Non-Depolarizing Blocking Agents..........................................................................................39 Video: Non-Depolarizing Neuromuscular Blockers.....................................................................................40 Example of Depolarizing Blocking Agents: Succinylcholine.......................................................................40 Succinylcholine............................................................................................................................................40 Phases of Depolarizing Blockers Action.......................................................................................................41 Phase 2: Desensitization.................................................................................................................................41 Video: Depolarizing Muscular Blockers........................................................................................................42 Adverse Effects of Depolarizing Blockade....................................................................................................42 Clinical Indications for Neuromuscular Blockers........................................................................................43 Question: Review of the Autonomic Nervous System................................................................................43 Anesthesia........................................................................................................................................................43 General Anesthesia.........................................................................................................................................44 Anesthesia Mechanism of Action..................................................................................................................44 Categories of Anesthesia................................................................................................................................45 Inhaled Anesthetics....................................................................................................................................45 Types of Inhaled Anesthetics.....................................................................................................................45 Intravenous Anesthetics.............................................................................................................................46 Types of Intravenous Anesthetics.............................................................................................................46 PAGE 4 MODULE 02 COMPANION GUIDE PHAR 370 Balanced Anesthesia.......................................................................................................................................46 Local Anesthesia..............................................................................................................................................47 Local Anesthetic and the ANS.........................................................................................................................47 Clinical Applications of Local Anesthesia......................................................................................................47 Clinical Applications of Local Anesthesia......................................................................................................48 Question: Summary of Anesthetics...............................................................................................................48 Question 1 of 2: End of Section Quiz............................................................................................................48 Question 2 of 2: End of Section Quiz............................................................................................................49 SECTION 05: Substance Use Disorders.............................................................................................................50 Introduction to Substance Use Disorders....................................................................................................50 What is SUD?.....................................................................................................................................................50 Stigma of SUD...................................................................................................................................................51 Factors Influencing SUD.................................................................................................................................51 Potential for Misuse of a Drug.......................................................................................................................52 Drug Tolerance, Withdrawal, and Addiction................................................................................................53 1) Drug Tolerance........................................................................................................................................53 The Extent of Drug Tolerance....................................................................................................................54 Mechanisms of Drug Tolerance.................................................................................................................54 Cellular Tolerance...................................................................................................................................55 Down-Regulation of Endogenous Systems..........................................................................................55 Video: Tolerance..........................................................................................................................................56 Cross Tolerance...........................................................................................................................................56 2) Drug Dependence and Withdrawal......................................................................................................56 Withdrawal Symptoms...............................................................................................................................57 Video: Drug Withdrawal.............................................................................................................................57 3) Drug Addiction........................................................................................................................................58 The Dopamine Hypothesis.........................................................................................................................58 Characteristics of Addictive Drugs............................................................................................................59 Question: Clinical Application: Drug Addiction........................................................................................60 Answer: Clinical Application: Pain Management.....................................................................................60 Prescription Use vs Misuse of Substances...................................................................................................61 Question 1 of 2: End of Section Quiz............................................................................................................61 Question 2 of 2: End of Section Quiz............................................................................................................61 CONCLUSION.......................................................................................................................................................63 PAGE 5 MODULE 02 COMPANION GUIDE PHAR 370 End of Module 02: Complete!........................................................................................................................63 PAGE 6 MODULE 02 COMPANION GUIDE PHAR 370 INTRODUCTION Please see the online learning module for the full experience of interactions within this document. This content was retrieved from Introduction, Slide 1 of 5 of the online learning module. Module 02 is the first of two modules that will cover the nervous system. In this module, you will be introduced to the nervous system and its organization throughout the body. You will explore the two divisions of the autonomic nervous system, the parasympathetic and sympathetic nervous systems, and learn about receptors that are used to target these body systems. Furthermore, you will discuss factors that influence substance use disorders. This foundational knowledge will assist you as you move onto Module 03, where you will learn about drugs used to excite and/or depress the nervous system, as well as drugs to treat neurodegenerative diseases. LEARNING OUTCOMES This content was retrieved from Introduction, Slide 2 of 5 of the online learning module. On successful completion of Module 02, students will be able to: Describe the sympathetic and parasympathetic nervous systems. Explain how drugs are used to target these nervous systems. Describe the use of drugs to produce muscle paralysis and anesthesia. Discuss the factors that influence substance use disorders. COURSE ICONS This content was retrieved from Introduction, Slide 3 of 5 of the online learning module. Throughout PHAR 370, you should watch for several icons throughout the course modules. Learn about its role in the course. Did You Know? This icon lives in the sidebar of the slide. Clicking this icon will reveal additional non-testable information related to the concept presented on the slide. Click For An Example This icon lives inline with the slide text. When you see this icon, click it to reveal an example related to content you just learned. References This icon lives in the sidebar. Clicking it will reveal the sources of course content and/or images. MODULE ASSIGNMENTS This content was retrieved from Introduction, Slide 4 of 5 of the online learning module. PAGE 7 MODULE 02 COMPANION GUIDE PHAR 370 These assessments must be completed as part of Module 02. Continue to view details. Virtual Ileum Lab – Refer to page 8 Activities throughout the Module: Note that text responses and interactions will not be graded unless otherwise notified. However, they are recorded within the module and viewable by your instructor. VIRTUAL ILEUM LAB Subpage of Introduction Slide 4 of 5 – Virtual Ileum Lab 1/1 Each student will be given an unknown drug that affects the autonomic nervous system. Students will individually work through the virtual ileum lab to determine the identity of their unknown drug, by comparing the unknown drug response to the responses of known drugs within the rabbit ileum tissue. Students will discuss their results and conclusions within an assigned group. After discussion, the written lab report will be completed individually and submitted for evaluation by TAs or the course instructor. For specific details about this assessment, visit the assignment page in your online learning environment. MODULE OUTLINE Section 01: Introduction to Autonomic Pharmacology Section 02: Parasympathetic Nervous System Section 03: Sympathetic Nervous System Section 04: Neuromuscular Blocking Drugs and Anesthetics Section 05: Substance Use Disorders PAGE 8 MODULE 02 COMPANION GUIDE PHAR 370 SECTION 01: INTRODUCTION TO AUTONOMIC PHARMACOLOGY This content was retrieved from Section 01, Slide 1 of 13 of the online learning module. THE NERVOUS SYSTEM This content was retrieved from Section 01, Slide 2 of 13 of the online learning module. The nervous system is the body’s control and communication system. It consists of the brain, spinal cord, sensory organs, and all the nerves within the body. The nervous system functions to control all bodily functions, both voluntary and involuntary. Therefore, it should come as no surprise that a vast number of drugs have been developed to target the nervous system. In this section, you will review the organization of the nervous system and neurotransmission. Note: some of this information may be review from previous courses. REVIEW OF THE NERVOUS SYSTEM AND NEUROTRANSMISSION This content was retrieved from Section 01, Slide 3 of 13 of the online learning module. The nervous system has three basic functions, or steps, through which it responds to the environment. Review these three basic functions. Recognize The nervous system recognizes changes in the internal or external environment. For example, an increase in the external temperature (28oC vs 0°C). Process and Integrate The nervous system perceives the changes in the environment. For example, the body feels hot. React The nervous system reacts to changes in the environment by producing a response or an action to counteract the change. For example, the body will sweat to compensate for increases in temperature. Once the body compensates for a change, it returns to baseline and prepares to recognize further changes. References: (Thermometer): Icon made by EpicCoders from www.flaticon.com (https://www.flaticon.com/free- icon/thermometer_134125#term=thermometer&page=1&position=3) (Brain): Nervous System. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/category/anatomy-and-the-human-body/nervous-system/) (Sweat): https://sinicropispine.com/sweating-spine-surgery/ VIDEO: NEUROTRANSMISSION AND TERMINATION OF RESPONSE PAGE 9 MODULE 02 COMPANION GUIDE PHAR 370 This content was retrieved from Section 01, Slide 4 of 13 of the online learning module. Neurons, the functional unit of the brain, are nerve cells capable of generating and transmitting electrical signals. Neurons within the nervous system communicate by way of synaptic transmission, or neurotransmission. Synaptic transmission is usually chemical in nature, meaning that the release of a substance is required in order to activate the other neuron or pass on the message. Watch the video for a brief overview of neurotransmission. As you watch: Focus on the general sequence of events that occurs during neurotransmission. Page Link: https://player.vimeo.com/video/181966458?title=0&byline=0&portrait=0 QUESTION: NEUROTRANSMISSION This content was retrieved from Section 01, Slide 5 of 13 of the online learning module. Answer the question about neurotransmission. Which one of the mechanisms listed is the most common mechanism by which neurotransmitters are removed from the synaptic cleft? Neurotransmitters can be taken back up into the presynaptic neuron through transporters Neurotransmitters can change conformation after a certain period of time to become inactive Neurotransmitters can be broken down by enzymes in the synaptic cleft Neurotransmitters can be taken up by adjacent glial cells Feedback: The correct answer is Neurotransmitters can be taken back into the presynaptic neurons through transporters. ORGANIZATION OF THE NERVOUS SYSTEM This content was retrieved from Section 01, Slide 6 of 13 of the online learning module. The nervous system is broadly divided into two main systems: the central nervous system and the peripheral nervous system. Learn about the two divisions of the nervous system. CNS The central nervous system (CNS) consist of the brain and the spinal cord. PNS The peripheral nervous system (PNS) contains all the nerve fibres outside of the CNS. PERIPHERAL NERVOUS SYSTEM This content was retrieved from Section 01, Slide 7 of 13 of the online learning module. PAGE 10 MODULE 02 COMPANION GUIDE PHAR 370 The PNS can be further divided into sensory and motor divisions. The motor division consists of the somatic nervous system and the autonomic nervous system (ANS). The ANS is made up of the parasympathetic and sympathetic nervous systems - as shown in the figure. Review the functions of each subdivision of the PNS. The rest of this section will focus primarily on the organization and function of the autonomic nervous system. Sensory (afferent) Transmits sensory information from the periphery to the CNS Motor (efferent) Transmits motor commands from the CNS to the periphery Autonomic Nervous System Involuntary motor control of smooth and cardiac muscle Somatic Nervous System Voluntary motor control of skeletal muscle Parasympathetic Nervous System Rest and digest response Sympathetic Nervous System Fight or flight response AUTONOMIC NERVOUS SYSTEM This content was retrieved from Section 01, Slide 8 of 13 of the online learning module. As you just learned, the ANS is a division of the PNS that controls involuntary responses. It does this by influencing organs, glands, and smooth muscle, and is often involved in maintaining a stable internal environment. In other words, the ANS governs vital bodily functions that are normally carried out without conscious effort. The ANS helps to control blood pressure, heart rate, bowel movement, urinary output, and sweating. Because these processes are controlled without conscious effort, the autonomic nervous system is often called the involuntary nervous system. ANS: A TWO NEURON SYSTEM This content was retrieved from Section 01, Slide 9 of 13 of the online learning module. Within the ANS, two neurons are required to reach the target organ. The first neuron’s cell body is in the CNS, and the second neuron’s cell body is in the ganglion*. PAGE 11 MODULE 02 COMPANION GUIDE PHAR 370 The neuron before the ganglia is termed the preganglionic nerve, while the neuron after the ganglia is termed the postganglionic nerve. Definition*: Ganglion: A mass of nerve cell bodies. DIVISIONS OF THE ANS This content was retrieved from Section 01, Slide 10 of 13 of the online learning module. The ANS has two distinct parts: the parasympathetic nervous system and the sympathetic nervous system. Learn about the two divisions of the ANS. Parasympathetic Nervous System The parasympathetic nervous system is responsible for the “Rest and Digest” response and is activated under non-stressful conditions. The effects of the parasympathetic nervous system include pupil constriction, decreased heart rate, and increased digestive intestinal activity. Sympathetic Nervous System The sympathetic nervous system is responsible for the “Fight or Flight” response and is activated under conditions of stress. The effects of the sympathetic nervous system include pupil dilation, increased sweating, heart rate, and blood pressure. Reference: Adapted from: Nervous System. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/category/anatomy-and-the-human-body/nervous-system/) PARASYMPATHETIC VS SYMPATHETIC NERVOUS SYSTEMS This content was retrieved from Section 01, Slide 11 of 13 of the online learning module. Both the parasympathetic and sympathetic nervous systems have their higher centres in the brain which act to monitor and control the ANS. These two systems normally act in a balanced and opposed fashion. In fact, the activity of an organ at any one time is the result of the two opposing influences exerted by the two systems. Note: most organs have dual innervation from both the parasympathetic and sympathetic nervous systems, but not all. Many medical conditions involve abnormal autonomic nervous system function, such as hypertension, congestive heart failure, and atrial fibrillation. An overview of the organization, neurotransmitters, and receptors involved with the sympathetic and parasympathetic nervous systems is shown in the figure. Note: the paravertebral ganglia are sometimes referred to as the sympathetic trunk or sympathetic chain. Reference: PAGE 12 MODULE 02 COMPANION GUIDE PHAR 370 21953518430a51180e2a965ac977ee41—autonomic-nervous-system-human-development.jpg (236x215). (n.d.). Retrieved August 14, 2017, from https://i.pinimg.com/236x/21/95/35/21953518430a51180e2a965ac977ee41--autonomic-nervous- system-human-development.jpg QUESTION 1 OF 2: END OF SECTION QUIZ 1 OF 2 This content was retrieved from Section 01, Slide 12 of 13 of the online learning module. Answer the question about neurotransmission. Select whether each organ is or is not a target of the autonomic nervous system. Cardiac Muscle Yes No Skeletal Muscle Yes No Blood Vessels Yes No Sweat Glands Yes No Feedback: The correct answers are: Cardiac Muscle - Yes Skeletal Muscle - No Blood Vessels - Yes Sweat Glands - Yes QUESTION 2 OF 2: END OF SECTION QUIZ This content was retrieved from Section 01, Slide 13 of 13 of the online learning module. Answer the question about the autonomic nervous system. Which of the organs listed is a target of the autonomic nervous system? Cardiac Muscle Skeletal Muscle Pituitary Gland Neurons in the forebrain Feedback: The correct answer is cardiac Muscle PAGE 13 MODULE 02 COMPANION GUIDE PHAR 370 SECTION 02: PARASYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 02, Slide 1 of 20 of the online learning module. INTRODUCTION TO THE PARASYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 02, Slide 2 of 20 of the online learning module. As you just learned, the parasympathetic nervous system is a division of the ANS. General stimulation of the parasympathetic nervous system promotes, or increases, vegetative functions of the body. As such, parasympathetic activity is the predominant activity at rest. Vegetative functions of the body include: Decreased heart rate Decreased blood pressure Increased digestion PARASYMPATHETIC NEURONS This content was retrieved from Section 02, Slide 3 of 20 of the online learning module. The neurons of the parasympathetic nervous system originate from two places in the spinal cord. Learn where parasympathetic neurons originate in the spinal cord. Cervical, or top, region of the spinal cord Sacral, or bottom, region of the spinal cord Reference: Nervous System. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/category/anatomy-and- the-human-body/nervous-system/) ORGANIZATION OF THE PARASYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 02, Slide 4 of 20 of the online learning module. The parasympathetic nervous system has long preganglionic fibres that release acetylcholine, which binds to the nicotinic receptors (NN) in the ganglia. Activation of NN receptors on the postsynaptic membrane results in depolarization and propagation of the impulse along the postganglionic fibre. The postganglionic fibres are short and also release acetylcholine, which binds to muscarinic receptors (M) on the target organ. Axons of the parasympathetic nervous system have few branches, which produces a localized effect. The large N in NN receptors designates that this is a nicotinic receptor. The subscript N designates that the receptor is neuronal and is found on the ganglionic post-synaptic membrane. This is in comparison to NM receptors that are found in the neuromuscular junction of skeletal muscle. PAGE 14 MODULE 02 COMPANION GUIDE PHAR 370 VIDEO: PARASYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 02, Slide 5 of 20 of the online learning module. Watch the video for an overview of the parasympathetic nervous system. As you watch: Focus on the neurotransmitters that function within the parasympathetic nervous system to elicit a response. Page Link: https://player.vimeo.com/video/283789606 QUESTION: THE PARASYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 02, Slide 6 of 20 of the online learning module. Answer the question about the parasympathetic nervous system. Which function is mediated by the parasympathetic nervous system? Stimulation of the digestive system Increased heart rate Bronchodilation Increased cell metabolism Feedback: The correct answer is stimulation of the digestive system. PARASYMPATHETIC NEUROTRANSMITTERS AND RECEPTORS This content was retrieved from Section 02, Slide 7 of 20 of the online learning module. All parasympathetic nerves release the same neurotransmitter - acetylcholine. Synapses and receptors that release and bind acetylcholine are described as cholinergic. Within the parasympathetic system, acetylcholine can bind to two receptors: nicotinic (N) and muscarinic (M) receptors. Here is an introduction to muscarinic and nicotinic receptors. 1. Nicotinic receptors are ligand-gated ion channels 2. Muscarinic receptors are typical G-protein coupled receptors Note: for a review of the signalling mechanisms utilized by different types of receptors, refer to Module 01. PAGE 15 MODULE 02 COMPANION GUIDE PHAR 370 PARASYMPATHETIC RECEPTORS This content was retrieved from Section 02, Slide 8 of 20 of the online learning module. Here is an overview of the location and responses of the nicotinic and muscarinic receptors. Receptor Primary Locations Response Nicotinic (NN) Ganglia Impulse conducted to postganglionic neuron Muscarinic (M) Heart Decreased heart rate and force of contraction Smooth muscle Smooth muscle contraction Glands Gland secretion TERMINATION OF RESPONSE This content was retrieved from Section 02, Slide 9 of 20 of the online learning module. To terminate the acetylcholine-mediated response within the parasympathetic nervous system, acetylcholinesterase (A c h E) breaks down acetylcholine in the synaptic cleft into acetate and choline - as shown in the figure. Reference: Adapted from: Neural cells, Intracellular Components, and Receptors and Channels. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image-set-download/) QUESTION: ACTIVATORS AND INHIBITORS This content was retrieved from Section 02, Slide 10 of 20 of the online learning module. In Module 01, you learned that drugs can be classified into five groups (agonist, partial agonist, allosteric activator, competitive antagonist, and non-competitive antagonist) based on their interaction PAGE 16 MODULE 02 COMPANION GUIDE PHAR 370 with the receptor. Classify the drug groups as activators or inhibitors of the receptor. Word Bin: Agonist, Competitive Antagonist, Allosteric Activator, Partial Agonist, Non-Competitive Antagonist Feedback: Activator: Agonist Partial Agonist Allosteric Activator Inhibitor: Competitive Antagonist Non-Competitive Antagonist ACTIVATION OF THE PARASYMPATHETIC NERVOUS SYSTEM ( PSNS) This content was retrieved from Section 02, Slide 11 of 20 of the online learning module. Drugs can stimulate or activate the parasympathetic nervous system through three main actions. Review how drugs activate the PSNS. Drugs can bind to and activate nicotinic receptors. Drugs can bind to and activate muscarinic receptors. Drugs can block the metabolism of acetylcholine (by inhibiting A c h E) thereby increasing the concentration of acetylcholine in the synaptic cleft. Drugs that block the metabolism of acetylcholine are called indirect acting agents and drugs that bind receptors are called direct acting agents. Both types of drugs are termed parasympathomimetic or cholinomimetic agents. Reference: PAGE 17 MODULE 02 COMPANION GUIDE PHAR 370 Adapted from: Nervous System. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/category/anatomy-and-the-human-body/nervous-system/) ACTIVATION: SPECIFICITY OF TARGET RECEPTORS This content was retrieved from Section 02, Slide 12 of 20 of the online learning module. Drugs that stimulate the parasympathetic nervous system produce characteristics of rest and relaxation. Direct and indirect acting agents can be referred to as cholinomimetics since they mimic the actions of acetylcholine (at NN or M receptors). Activation of the NN receptors activates the postganglionic neurons of both the parasympathetic and sympathetic nervous systems. Therefore, to activate specifically the parasympathetic nervous system, the drug must bind to and activate just M receptors. CLINICAL USE OF ACTIVATORS This content was retrieved from Section 02, Slide 13 of 20 of the online learning module. Clinically, cholinergic drugs are not widely used as they have a variety of adverse effects, such as slowing the heart rate and/or constricting respiratory passages. However, some clinical indications for cholinergic drugs do exist. Learn about three examples where cholinergic activators are used clinically. Glaucoma - Refer to page 18 Poor muscle tone in the bladder - Refer to page 18-19 Asthma - Refer to page 19 GLAUCOMA Subpage of Section 02 Slide 13 of 20 – Glaucoma 1/1 Glaucoma is a condition where the patient experiences an increase in intraocular pressure due to poor drainage of the fluid of the eye. The increased pressure can lead to optic nerve damage, which will affect vision and eventually lead to blindness if not treated. One treatment for glaucoma is a muscarinic receptor agonist, such as pilocarpine. Administration of a muscarinic receptor agonist increases parasympathetic nervous system activation, which leads to contraction of the ciliary body of the eye. This facilitates drainage of the fluid and decreases the pressure in the eye. While muscarinic agonists can be used to treat glaucoma, often beta antagonists are preferred - you will learn about beta antagonists in Section 03 of this module. Reference: Glaucoma.png (1000x459). (n.d.). Retrieved August 16, 2017, from http://www.evadeopro.com/wp- content/uploads/2017/07/glaucoma.png POOR MUSCLE TONE IN THE BLADDER PAGE 18 MODULE 02 COMPANION GUIDE PHAR 370 Subpage of Section 02 Slide 13 of 20 – Poor muscle tone in the bladder 1/1 Patients who are postoperative or postpartum sometimes experience poor muscle tone in the bladder. Poor muscle tone in the bladder can also be experienced secondary to spinal cord injury or disease. The inability to urinate is uncomfortable and can become painful. The administration of a muscarinic agonist will cause the bladder to contract, allowing the patient to urinate. ASTHMA Subpage of Section 02 Slide 13 of 20 – Asthma 1/1 The diagnostic test for asthma is called the methacholine challenge. Methacholine is a muscarinic agonist, and when inhaled it causes the bronchioles to constrict, which inhibits breathing. Patients are given increasing doses of methacholine, with each dose being followed by a pulmonary function test. Patients who have asthma are hypersensitive to methacholine, meaning that their breathing will become restricted due to methacholine at a lower dose than patients who do not have asthma. Once the methacholine challenge is completed, patients are given a beta 2 agonist to relax the bronchioles and return the lungs to normal functioning – you will learn more about beta receptors in Section 03 of this module. Reference: By United States-National Institute of Health: National Heart, Lung, Blood Institute – http://www.nhlbi.nih.gov/health/health-topics/topics/asthma/, Public Domain, https://commons.wikimedia.org/w/index.php?curid=24760677 INHIBITORS This content was retrieved from Section 02, Slide 14 of 20 of the online learning module. Drugs can also inhibit the activity of the parasympathetic nervous system. The most common drugs that perform this function are anticholinergic drugs - drugs that antagonize or block M or NN receptors. These drugs are more common than cholinergic drugs. By inhibiting the parasympathetic nervous system, anticholinergic drugs cause effects of “fight or flight”. These drugs are also associated with high incidences of adverse effects, which has limited their clinical use. In particular, anticholinergic drugs can cause tachycardia (i.e. a fast heart rate), which can be dangerous. Learn about the two types of anticholinergic drugs. Ganglion-blocking drugs Ganglion-blocking drugs, which are drugs that specifically antagonize or inhibit the NN receptors found in all autonomic ganglia, are important for physiological and pharmacological research, as they block all autonomic outflow. However, ganglion-blocking drugs (e.g. hexamethonium) have limited clinical use because of the broad range of adverse effects associated with them. Selective autonomic blocking agents are much more PAGE 19 MODULE 02 COMPANION GUIDE PHAR 370 useful clinically. Muscarinic receptor blockers Muscarinic receptor blockers are used more commonly. The prototypical muscarinic receptor antagonist is atropine, which is a competitive antagonist of all muscarinic receptors, and when administered as a liquid drop to the eyes, will dilate pupils for a week or more! CLINICAL USE OF INHIBITORS This content was retrieved from Section 02, Slide 15 of 20 of the online learning module. As you can imagine, people today do not wish to have their pupils dilated for a week at a time. Therefore shorter-acting muscarinic antagonists have been developed to dilate the pupils. These drugs also have other clinical indications for respiratory, GI, and urinary disorders. Learn about the clinical uses of muscarinic antagonists. Respiratory Disorders People who have asthma or chronic obstructive pulmonary disease can sometimes be prescribed muscarinic antagonists. When inhaled, these drugs have a good safety profile and will produce moderate bronchodilation and decreased airway secretion. Urinary Disorders Some patients experience urgency to urinate due to conditions such as minor bladder inflammation and incontinence. A muscarinic antagonist will inhibit the contraction of the bladder, providing respite to a patient who feels the need to urinate frequently. GI Disorders GI cramps, hypermotility, and diarrhea can be treated with muscarinic antagonists, which will decrease intestinal motility. Reference: Adapted from: Main Organs. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image0set- download/) QUESTION 1 OF 2: CLINICAL APPLICATION: INHIBITORS This content was retrieved from Section 02, Slide 16 of 20 of the online learning module. Answer the clinical application question about acetylcholine. Cholinergic poisoning, meaning poisoning due to excess acetylcholine, can occur due to toxic nerve gas. In August 2013, toxic nerve gas was released in Syria. Specifically, this toxic nerve gas was Sarin, which is a colourless, odourless gas that is a potent acetylcholinesterase inhibitor. Remember that acetylcholinesterase is responsible for breaking down acetylcholine in the synaptic cleft into acetate and choline, thereby terminating the response to acetylcholine. Using your previous knowledge, discuss the role of acetylcholine in the parasympathetic nervous system. PAGE 20 MODULE 02 COMPANION GUIDE PHAR 370 Feedback: Instructor’s Answer: Acetylcholine is a neurotransmitter released by pre- and post-ganglionic neurons in the parasympathetic nervous system (acetylcholine is also released from the preganglionic neurons in the sympathetic nervous system - you will learn about the sympathetic nervous system in Section 03 of this module). Acetylcholine can bind to nicotinic or muscarinic receptors to activate the parasympathetic nervous system and induce the “rest-and-digest” response. QUESTION 2 OF 2: CLINICAL APPLICATION: INHIBITORS This content was retrieved from Section 02, Slide 17 of 20 of the online learning module. Answer the clinical application question about inhibitors. Sarin blocks acetylcholinesterase, thereby inhibiting the breakdown of acetylcholine. The result is an exaggerated parasympathetic response, including constriction of pupils, tightness in the chest, nausea, drooling, defecation, and urination. Death is due to asphyxiation, and in this incidence in Syria, hundreds of people died due to cholinergic poisoning. Now that you have learned about the parasympathetic nervous system, if you were asked how to treat people with toxic nerve gas poisoning, what type of drug would you suggest? Navigate to the next slide for feedback on the clinical application question. ANSWER: CLINICAL APPLICATION: INHIBITOR FEEDBACK This content was retrieved from Section 02, Slide 18 of 20 of the online learning module. Instructor’s Answer People suffering with cholinergic poisoning have too much acetylcholine in their system, producing exaggerated parasympathetic nervous system responses. As such, one good drug to use would be a muscarinic receptor antagonist. This would inhibit some of the exaggerated parasympathetic effects observed. A good choice would be atropine, since it blocks all muscarinic receptors and is long-acting. Atropine would help delay the symptoms, however the major problem of acetylcholine not being broken down still remains. In other words, we need to somehow regenerate acetylcholinesterase. The drug pralidoxime will bind to the Sarin gas and remove it from the acetylcholinesterase, thereby regenerating enzyme activity. Note: The antidote for cholinergic poisoning is atropine and pralidoxime, however pralidoxime has to be administered within five hours of poisoning for the acetylcholinesterase to be regenerated. QUESTION: 1 OF 2: END OF SECTION QUIZ This content was retrieved from Section 02, Slide 19 of 20 of the online learning module. Answer the question about the parasympathetic nervous system. An indirect activator of the parasympathetic nervous system initiates a response or alters a response by: Directly binding to muscarinic receptors Directly binding to alpha receptors PAGE 21 MODULE 02 COMPANION GUIDE PHAR 370 Directly binding to beta receptors Directly binding to acetylcholinesterase Feedback: The correct answer is directly binding to acetylcholinesterase. QUESTION 2 OF 2: END OF SECTION QUIZ This content was retrieved from Section 02, Slide 20 of 20 of the online learning module. Which one of the items listed is an appropriate therapeutic use of an antagonist of the parasympathetic nervous system? To dilate pupils To diagnose asthma To treat poor muscle tone in the bladder To treat gastrointestinal paralysis Feedback: The correct answer is to dilate pupils. PAGE 22 MODULE 02 COMPANION GUIDE PHAR 370 SECTION 03: SYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 03, Slide 1 of 24 of the online learning module. INTRODUCTION TO THE SYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 03, Slide 2 of 24 of the online learning module. The sympathetic nervous system is a second division of the autonomic nervous system, alongside the parasympathetic nervous system. Although both activation and inactivation are important in terms of regulating the autonomic nervous system, in response to a perceived threat the body specifically activates the sympathetic nervous system and prepares for fight or flight. FIGHT OR FLIGHT RESPONSE This content was retrieved from Section 03, Slide 3 of 24 of the online learning module. General stimulation of the sympathetic nervous system results in the mobilization of resources to prepare the body to meet emergencies. The mass sympathetic discharge results in increased activity of many functions of the body. Review some of these functions. Activation of the sympathetic nervous system results in increases in: Heart rate Blood pressure Blood supply to the tissues Rate of cell metabolism Blood glucose The sum of these effects permits the body to perform physical tasks that otherwise would not be possible. SYMPATHETIC NEURONS This content was retrieved from Section 03, Slide 4 of 24 of the online learning module. The neurons of the sympathetic nervous system originate from two places in the spinal cord: The thoracic region, and The lumbar region. These two sections constitute the middle portions of the spinal cord - as indicated in the figure. PAGE 23 MODULE 02 COMPANION GUIDE PHAR 370 Reference: Nervous System. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/category/anatomy-ant- the-human-body/nervous-system/) ORGANIZATION OF THE SYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 03, Slide 5 of 24 of the online learning module. The sympathetic nervous system is organized in a slightly different manner than the parasympathetic. Review the organization of the sympathetic nervous system. 1. The sympathetic nervous system has short preganglionic neurons that release acetylcholine at the ganglia. 2. Acetylcholine binds to and activates NN receptors at the sympathetic ganglia, conducting the signal to the long postganglionic neurons of the sympathetic nervous system. 3. The sympathetic postganglionic neurons predominantly release norepinephrine at the target organ, which binds to alpha (α) or beta (β) receptors. 4. Exceptions to this rule are the sympathetic postganglionic neurons that innervate sweat glands and renal vascular smooth muscle. These neurons release acetylcholine, which binds to M receptors, and dopamine, which binds to D receptors, respectively. 5. Axons of the sympathetic nervous system are highly branched, and therefore influence many organs. Some of these organs influenced by the sympathetic nervous system are shown in the figure. THE ADRENAL MEDULLA This content was retrieved from Section 03, Slide 6 of 24 of the online learning module. You will now learn about the adrenal medulla and its role in the sympathetic nervous system. The adrenal medulla is a specialized organ that essentially functions as a sympathetic autonomic ganglion. Learn about the location and function of the adrenal medulla. PAGE 24 MODULE 02 COMPANION GUIDE PHAR 370 The Adrenal Medulla - Refer to page 25-26 LOCATION OF THE ADRENAL MEDULLA Subpage of Section 03 Slide 6 of 24 – The Adrenal Medulla 1/2 You may recall from previous anatomy or physiology courses that the adrenal medulla is the centre portion of the adrenal gland, surrounded by the adrenal cortex. It is innervated by short sympathetic preganglionic fibers. When these sympathetic preganglionic fibres are activated, they release acetylcholine, which binds to NN receptors on the adrenal medulla. Activation of these NN receptors results in the release of predominantly epinephrine (80%; also known as adrenaline), but also norepinephrine (20%) from the adrenal medulla. Switch between a diagram outlining the location of the adrenal gland and a transverse section of the gland. Location of the adrenal gland above the kidney Transverse section of adrenal gland Reference: Adapted from: Endocrinology. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image-set- download/) RELEASE OF EPINEPHRINE AND NOREPINEPHRINE Subpage of Section 03 Slide 6 of 24 – The Adrenal Medulla 2/2 The released epinephrine and norepinephrine travel through the blood and interact with α and β receptors throughout the body, causing varying effects. Since the neurotransmitters released by the PAGE 25 MODULE 02 COMPANION GUIDE PHAR 370 adrenal medulla act via the circulation at distant sites, they are considered to act like hormones. Stress can also stimulate the adrenal medulla, releasing epinephrine and norepinephrine, leading to a prolonged sympathetic effect. QUESTION: THE SYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 03, Slide 7 of 24 of the online learning module. Answer the question about the sympathetic nervous system. Which one of the effects listed is mediated by increased activity of the sympathetic nervous system? Inhibition of adrenal glands Increased digestion Increased heart rate Constriction of the pupils Feedback: The correct answer is increased heart rate. VIDEO: SYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 03, Slide 8 of 24 of the online learning module. Watch the video for an overview of the sympathetic nervous system. As you watch: Focus on the neurotransmitters that function within the sympathetic nervous system to elicit a response. Page Link: https://player.vimeo.com/video/283789859 SYMPATHETIC NEUROTRANSMITTERS AND RECEPTORS This content was retrieved from Section 03, Slide 9 of 24 of the online learning module. As indicated previously, the neurotransmitter released by the sympathetic preganglionic neurons is acetylcholine, which binds to the NN receptors on the ganglia. The neurotransmitter at the postganglionic sympathetic nerve ending is predominantly norepinephrine, which can bind to α or β receptors. These receptors have been designated adrenergic receptors and are typical G-protein coupled receptors, as you learned in Module 01. Multiple subtypes of adrenergic receptors exist, however, this lesson will focus on two main subtypes of each of alpha and beta receptors. Learn about alpha and beta receptors. Alpha (α) Receptors - Refer to page 27 Beta (β) Receptors - Refer to page 27 Note: The neurotransmitter released from all preganglionic neurons (both sympathetic and PAGE 26 MODULE 02 COMPANION GUIDE PHAR 370 parasympathetic) is acetylcholine, and the receptor at all ganglia is NN. ALPHA (Α) RECEPTORS Subpage of Section 03 Slide 9 of 24 – Alpha (α) Receptors 1/1 Alpha (α) receptors can be subdivided into two main types: α1 and α2. Learn about α1 and α2 receptors. α1 receptors Located post-synaptically, predominantly on smooth muscle (i.e. blood vessels, gastrointestinal muscle, and the uterus) Activation of α1 receptors predominantly leads to contraction of the muscle Multiple subtypes of α1 receptors exist The different subtypes are organ selective and drugs can be designed to target a specific subtype of α1 receptors, allowing for drug selectivity α2 receptors Located post-synaptically on smooth muscle as well as pre-synaptically on the neuronal membrane. Those receptors located pre-synaptically are considered autoreceptors autoreceptors* The effects listed for activation of α1 receptors also apply to activation of α2 receptors that are located post-synaptically Activation of α2 autoreceptors, however, leads to a decrease in the release of norepinephrine from the presynaptic nerve, thereby decreasing sympathetic activation These receptors are only targeted in specific situations. Definition*: Autoreceptors: A type of receptor located in the membranes of presynaptic nerves that acts as part of a negative feedback loop in signal transduction. It is only sensitive to the neurotransmitters released from the neuron on which it resides. BETA (Β) RECEPTORS Subpage of Section 03 Slide 9 of 24 – Beta (β) Receptors 1/1 Beta (β) receptors can be sub-divided into two main types: β1 and β2. Learn about β1 and β2 receptors. β1 receptors β1 receptors are found predominantly in the heart and gastrointestinal muscle Activation leads to increased force and rate of contraction of the heart, and relaxation of the gastrointestinal smooth muscle. β2 receptors β2 receptors are found in the lungs, blood vessels, gastrointestinal muscle, and uterus Activation of these receptors leads to muscle relaxation QUESTION 1 OF 2: LOCATION OF SYMPATHETIC RECEPTORS This content was retrieved from Section 03, Slide 10 of 24 of the online learning module. PAGE 27 MODULE 02 COMPANION GUIDE PHAR 370 Using the drop down menu, answer the question about sympathetic receptors. Which receptor corresponds with the primary locations listed? Drop down options: α2, β1, β2 Pre-synaptic neuronal membrane Heart and gastrointestinal muscle Lungs, blood vessels, gastrointestinal muscle, and uterus Feedback: Pre-synaptic neuronal membrane: α2 Heart and gastrointestinal muscle: β1 Lungs, blood vessels, gastrointestinal muscle, and uterus: β2 QUESTION 2 OF 2: RESPONSE OF SYMPATHETIC RECEPTORS This content was retrieved from Section 03, Slide 11 of 24 of the online learning module. Using the drop down menu, answer the question about sympathetic receptors. Which receptor causes each of the listed responses? Drop down options: α1, α2, β1, β2 Relaxes uterine and bronchial smooth muscle Decreases the release of norepinephrine from the presynaptic neuron Increases heart rate and force of contraction Contracts smooth muscle in the vasculature and uterus and decreases motility and tone in the gastrointestinal tract Feedback: Relaxes uterine and bronchial smooth muscle: β2 Decreases the release of norepinephrine from the presynaptic neuron: α2 Increases heart rate and force of contraction: β1 Contracts smooth muscle in the vasculature and uterus and decreases motility and tone in the gastrointestinal tract: α1 RECALL: NOREPINEPHRINE This content was retrieved from Section 03, Slide 12 of 24 of the online learning module. Recall that the sympathetic postganglionic neurons predominantly release norepinephrine at the target organ. Norepinephrine binds to α or β1 receptors in the postsynaptic membrane to exert its action. The activity of norepinephrine is terminated by reuptake back into the presynaptic neuron followed by enzyme degradation within the neuron. PAGE 28 MODULE 02 COMPANION GUIDE PHAR 370 ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM This content was retrieved from Section 03, Slide 13 of 24 of the online learning module. Drugs acting directly or indirectly on the sympathetic nervous system can mimic the actions of norepinephrine, thereby appearing to increase the activity of the sympathetic nervous system. Three mechanisms are indicated: Review the three mechanisms by which drugs can target the sympathetic nervous system. Direct stimulation The drug binds directly to the receptor and produces an effect. An example is epinephrine, which works by directly binding to alpha and beta receptors. Indirect stimulation The drug increases the release of norepinephrine from the presynaptic neuron. Amphetamines act in this way. Combination of the two The drug binds directly to the receptor AND increases release of norepinephrine. Drugs can stimulate one or both of alpha and beta receptors. An example is the drug ephedrine which is used as a decongestant. CLINICAL INDICATIONS FOR ADRENERGIC DRUGS This content was retrieved from Section 03, Slide 14 of 24 of the online learning module. Clinically, drugs that activate processes normally controlled by the sympathetic nervous system are primarily used for their effects on the heart, blood pressure, bronchial tree, and nasal passages. These drugs produce similar effects to the anticholinergics, but due to the receptor subtypes (α 1, β1, and β2), the actions of these drugs are more specific and predictable depending on which receptor subtype is activated. Continue to the next slide for examples of clinical use of adrenergic drugs. ADRENERGIC DRUGS: CLINICAL INDICATIONS This content was retrieved from Section 03, Slide 15 of 24 of the online learning module. Learn about the role of adrenergic drugs in each clinical indication. Anaphylaxis Anaphylaxis is a severe immune reaction affecting both respiratory and cardiovascular systems. Hypersensitivity to food, drug, or other substances (i.e. bee stings) can trigger anaphylaxis, which results in severe bronchospasm and mucous membrane congestion, among other symptoms. The treatment for these severe allergic reactions is epinephrine (i.e. EpiPen), which causes bronchodilation and constriction of blood vessels, relieving the symptoms. Epinephrine will also increase heart rate and the force of contraction of the heart, thereby increasing blood pressure if the person happens to go into shock. PAGE 29 MODULE 02 COMPANION GUIDE PHAR 370 Cardiac Applications Adrenergic drugs, such as epinephrine, increase heart rate and the force of contraction of the heart by activating β1 receptors. As such, these drugs can be used for temporary emergency management of complete heart block or cardiac arrest. Nasal Congestion α1 agonists constrict blood vessels and are therefore useful in the treatment of nasal congestion. Phenylephrine and pseudoephedrine are examples of α1 agonists that are used as nasal decongestants. Ophthalmic When given in the eye, α1 agonists such as phenylephrine dilate the pupil, facilitating retinal examination. Pulmonary β2-selective drugs, such as salbutamol, produce bronchodilation, which is an effective treatment for someone suffering from asthma. Both short-acting and long-acting β2 agonists are available. These drugs can also be used to treat chronic obstructive pulmonary disease (COPD) QUESTION: ADRENERGIC DRUGS This content was retrieved from Section 03, Slide 16 of 24 of the online learning module. Answer the question about the clinical indications of adrenergic drugs. Which one of the conditions listed is the correct clinical indication for a β2 receptor agonist? Congestive heart failure Asthma Nasal congestion Benign prostatic hyperplasia Feedback: The correct answer is asthma ADRENERGIC DRUGS: ADVERSE EFFECTS This content was retrieved from Section 03, Slide 17 of 24 of the online learning module. Adrenergic drugs, like all drugs, can result in adverse effects. Adverse effects are often the result of stimulation of receptors in another area of the body. Learn about the common adverse effects of adrenergic drugs. CNS Stimulation of adrenergic receptors in the CNS may lead to headaches, restlessness, mild tremors, PAGE 30 MODULE 02 COMPANION GUIDE PHAR 370 nervousness, dizziness, excitement, insomnia, or euphoria. Cardiovascular Stimulation in the cardiovascular system may cause palpitations, tachycardia, vasoconstriction, or hypertension. Other Stimulation of adrenergic receptors in other areas may cause anorexia, dry mouth, nausea, vomiting, or muscle cramps. Remember: Whenever giving a drug to a patient, keep in mind the characteristics of the patient. Patients who are elderly or very young will react differently to drugs based on their ability to biotransform and excrete drugs. In addition, information such as drug allergies and other illnesses, such as hypertension, cardiac dysrhythmias, or angina pectoris may change the therapeutic management of a patient. CLINICAL INDICATIONS OF ANTIADRENERGIC DRUGS This content was retrieved from Section 03, Slide 18 of 24 of the online learning module. Antiadrenergic drugs are used clinically for a variety of different indications. Drugs that inhibit the function of the sympathetic nervous system produce characteristics of “rest and relaxation” and have a wide therapeutic application. The most widely prescribed drugs that target the autonomic nervous system are those that block the sympathetic nervous system, called antiadrenergic drugs. Antiadrenergic drugs can specifically block either α or β receptors, or they can block both classes of receptors. Learn about the common clinical indications for antiadrenergic drugs. Pheochromocytoma - Refer to page 31 Benign Prostatic Hyperplasia - Refer to pages 31-32 Angina and Congestive Heart Failure - Refer to page 32 Glaucoma - Refer to pages 32-33 Neurological Diseases - Refer to page 33 PHEOCHROMOCYTOMA Subpage of Section 03 Slide 18 of 24 – Pheochromocytoma 1/1 Pheochromocytoma is a tumour of the adrenal medulla, the organ responsible for secreting epinephrine and norepinephrine in response to stress. The tumour secretes epinephrine and norepinephrine without the stimulus of stress, resulting in unwanted increases in sympathetic activity. Surgical resection of the tumour is the first-line treatment for pheochromocytoma, however, an antiadrenergic is first given to block the sympathetic receptors to prevent intra-operative hypertension. BENIGN PROSTATIC HYPERPLASIA PAGE 31 MODULE 02 COMPANION GUIDE PHAR 370 Subpage of Section 03 Slide 18 of 24 – Benign Prostatic Hyperplasia 1/1 Benign prostatic hyperplasia (BPH) is a non-cancerous growth of the prostate gland that is common in older men. Symptoms include frequent urination, difficulty starting urination, urgency to void, and voiding at night. Treatment includes α1 receptor antagonists, which work by relaxing smooth muscle in the prostate and bladder, facilitating urination. A comparison of a normal vs enlarged prostate. When the prostate is enlarged, the urethra is constricted and this results in difficulty urinating. Reference: By Unknown – National Cancer Institute, AV Number: CDR462221, Public Domain, https://commons.wikimedia.org/w/index/php?curid=5581217 ANGINA AND CONGESTIVE HEART FAILURE Subpage of Section 03 Slide 18 of 24 – Angina and Congestive Heart Failure 1/1 Angina is chest pain due to poor oxygen supply to the heart, while congestive heart failure is a condition where cardiac pumping is impaired due to weakening or death of part of the heart muscle. Treatment for both conditions can include selective β1 receptor antagonists. Blocking β1 receptors in the heart reduces heart rate and the force of contraction of the heart, resulting in a decrease in oxygen demand and blood pressure, thereby relieving the pain. GLAUCOMA Subpage of Section 03 Slide 18 of 24 – Glaucoma 1/1 Recall from Section 01 that glaucoma is a disease of the eye, often associated with increased intraocular pressure, which can damage the optic nerve and lead to loss of vision. β-blocking drugs are also useful in the treatment of glaucoma. Topical application of either non- selective or β1-selective beta blockers reduce the production of the aqueous humor, which in turn reduces intraocular pressure. Reference: PAGE 32 MODULE 02 COMPANION GUIDE PHAR 370 Glaucoma.png (1000x459). (n.d.). Retrieved August 16, 2017, from http://www.evadeopro.com/wp- content/uploads/2017/07/glaucoma.png NEUROLOGICAL DISEASES Subpage of Section 03 Slide 18 of 24 – Neurological Diseases 1/1 β-blockers are also useful in the treatment of a number of neurological diseases. For example, β-blockers can reduce the frequency and intensity of migraines, reduce tremors in Parkinson’s Disease, and reduce anxiety. β-blockers may also benefit patients undergoing alcohol withdrawal, as they slow the heart rate, ease anxiety, and reduce tremors associated with alcohol withdrawal. ADVERSE EFFECTS: ANTIADRENERGIC DRUGS This content was retrieved from Section 03, Slide 19 of 24 of the online learning module. Adverse effects also exist with the use of antiadrenergic drugs. For the purposes of this course, you will learn about the most common adverse effect for antiadrenergic drugs - orthostatic hypotension. Learn about an adverse effect of antiadrenergic drugs. Orthostatic hypotension is the decrease in blood pressure that occurs when moving from a laying or sitting position to a standing position. This is a common adverse effect, as constriction of blood vessels is a normal process for maintaining blood pressure. With the use of antiadrenergic drugs, the ability of blood vessels to constrict is impaired, as is the ability of the heart to increase contractions, leading to decreased blood pressure. SUMMARY: DRUGS THAT TARGET THE ANS This content was retrieved from Section 03, Slide 20 of 24 of the online learning module. Since the transmission of messages in the synaptic junctions of the autonomic nervous system is chemical in nature, these junctions can be targets for drug action. Many drugs modify these systems, but they are often categorized into four general types. Here is an overview of the four types of drugs that target the ANS. 1. Drugs that block the effects of the sympathetic system. 2. Drugs that mimic the effects of the sympathetic system. 3. Drugs that mimic the effects of the parasympathetic system. 4. Drugs that block the effects of the parasympathetic system. Because there is a balance between the parasympathetic and sympathetic nervous systems, drugs that block the activity of one system can often "unmask" the activity of the other system. QUESTION: CHEMICAL BUFFERS AND THEIR PRIMARY ROLES This content was retrieved from Section 03, Slide 21 of 24 of the online learning module. PAGE 33 MODULE 02 COMPANION GUIDE PHAR 370 You are provided with the mechanism of action for four drugs. Using the dropdown menu, apply knowledge gained from this module to categorize the drugs according to the types of drugs that target the ANS. Drop down options: Drugs that blocks the effects of the parasympathetic system, Drugs that mimics the effects of the parasympathetic system, Drugs that blocks the effects of the sympathetic system, Drugs that mimics the effects of the sympathetic system Epinephrine: activates α and β receptors Propranolol: blocks β receptors in the heart Methacholine: activates M receptors Atropine: blocks M receptors Feedback: Epinephrine: activates α and β receptors: Drugs that mimics the effects of the sympathetic system Propranolol: blocks β receptors in the heart: Drugs that blocks the effects of the sympathetic system Methacholine: activates M receptors: Drugs that mimics the effects of the parasympathetic system Atropine: blocks M receptors: : Drugs that blocks the effects of the parasympathetic system DRUGS AFFECTING THE ANS THROUGH THEIR ACTION ON THE BRAIN This content was retrieved from Section 03, Slide 22 of 24 of the online learning module. The activity of the autonomic nervous system also can be modified by drugs acting on the brain. These drugs can be organized into two categories. Review the two categories of drugs that affect the ANS by acting on the brain. Central Stimulants Drugs that increase sympathetic and parasympathetic activity (excitation). For example, amphetamine. Central Depressants Drugs that decrease sympathetic and parasympathetic activity (inhibition). For example, benzodiazepines. QUESTION 1 OF 2: END OF SECTION QUIZ This content was retrieved from Section 03, Slide 23 of 24 of the online learning module. Answer the question about the sympathetic nervous system. Which neurotransmitter and receptor are correctly matched? Acetylcholine: α1 receptors Norepinephrine: β1 receptors Dopamine: β2 receptors Epinephrine: nicotinic receptors PAGE 34 MODULE 02 COMPANION GUIDE PHAR 370 Feedback: The correct answer is norepinephrine: β1 receptors. QUESTION 2 OF 2: END OF SECTION QUIZ This content was retrieved from Section 03, Slide 24 of 24 of the online learning module. Answer the question about the sympathetic nervous system. Which one of the statements regarding the sympathetic nervous system is correct? β1 receptors are predominantly found in the heart The sympathetic nervous system has long preganglionic fibres The adrenal medulla secretes epinephrine during relaxed states β2 receptors are found on pre-synaptic neuronal membranes Feedback: The correct answer is β1 receptors are predominantly found in the heart. PAGE 35 MODULE 02 COMPANION GUIDE PHAR 370 SECTION 04: NEUROMUSCULAR BLOCKING DRUGS AND ANESTHETICS This content was retrieved from Section 04, Slide 1 of 29 of the online learning module. INTRODUCTION TO THE SOMATIC NERVOUS SYSTEM This content was retrieved from Section 04, Slide 2 of 29 of the online learning module. Historically, undergoing surgery was a dreaded procedure, as it often consisted of excruciating pain. The advent of neuromuscular blocking drugs and anesthetics greatly benefited surgical procedures. As a result of these drugs, patients were protected from the pain of surgery and their muscles were relaxed during the procedure, which provided a still operative field for surgeons. In this section, you will begin by learning about the somatic nervous system and the neuromuscular junction, before learning about drugs that can influence the neuromuscular junction. THE SOMATIC NERVOUS SYSTEM This content was retrieved from Section 04, Slide 3 of 29 of the online learning module. Recall from Section 01 that the peripheral nervous system is composed of the autonomic nervous system and the somatic nervous system. The autonomic nervous system innervates smooth and cardiac muscle, while the somatic nervous system innervates skeletal muscle, which is under voluntary control and consists primarily of the muscles of posture and movement. The somatic nervous system will be the focus of this section. ORGANIZATION OF THE SOMATIC NERVOUS SYSTEM This content was retrieved from Section 04, Slide 4 of 29 of the online learning module. Unlike the autonomic nervous system, which consists of two neurons to reach the target organ, the somatic nervous system requires just one neuron to reach the target skeletal muscle. Therefore, in the somatic nervous system, the voluntary motor nerves extend from the CNS all the way to the skeletal muscle. This means that some neurons in the somatic nervous system can be very long. At the skeletal muscle, the neuron releases acetylcholine, which binds to nicotinic receptors on skeletal muscle (designated NM, where the subscript ‘M’ is for muscle). Receptor activation on the skeletal muscle causes contraction of the muscle. NEUROMUSCULAR JUNCTION This content was retrieved from Section 04, Slide 5 of 29 of the online learning module. The synapse between a motor neuron and skeletal muscle is called the neuromuscular junction. When the NM receptors on the skeletal muscle are activated, they cause the muscle to contract. In order for a muscle to contract, multiple NM receptors on the muscle fibre have to be activated at once, causing depolarization of the skeletal muscle membrane followed by muscle fibre contraction. Full muscle contraction is achieved when many NM receptors on many muscle fibers are activated simultaneously. Continue to view the animation. PAGE 36 MODULE 02 COMPANION GUIDE PHAR 370 ACh is released from the motor neuron ACh binds to and activates NM receptors The muscle contracts! Reference: Adapted from: Neural cells, Intracellular Components, and Receptors and Channels. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image-set-download/) NEUROMUSCULAR BLOCKING DRUGS This content was retrieved from Section 04, Slide 6 of 29 of the online learning module. Drugs that target skeletal muscle act by interfering with neurotransmission at the neuromuscular junction. These drugs are called neuromuscular blocking drugs. You will learn about two classes of neuromuscular blocking drugs in this course. Learn about the function of the two classes of neuromuscular blocking drugs. Non-Depolarizing Neuromuscular Blockers PAGE 37 MODULE 02 COMPANION GUIDE PHAR 370 Non-depolarizing neuromuscular blockers act like competitive antagonists, blocking the N M receptors, thereby inhibiting the binding of acetylcholine to the receptors. Since less NM receptors are available for acetylcholine to bind to, the muscle is unable to depolarize and muscle contraction is inhibited. Depolarizing Neuromuscular Blocking Depolarizing neuromuscular blockers function like agonists, activating the N M receptors, thereby initially causing muscle contraction. However, these drugs are resistant to acetylcholinesterase breakdown and therefore cause continual activation of the NM receptors without allowing time for the muscle to repolarize, leading to muscle paralysis. Reference: Adapted from: Neural cells, Intracellular Components, and Receptors and Channels. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image-set-download/) ANALOGY: NON-DEPOLARIZING VS. DEPOLARIZING NEUROMUSCULAR BLOCKERS This content was retrieved from Section 04, Slide 7 of 29 of the online learning module. Navigate through the analogy and help further your understanding of non-depolarizing vs depolarizing neuromuscular blockers. Turn on your sound for this analogy. A simple analogy to help understand the difference between non-depolarizing and depolarizing neuromuscular blockers is to compare stopping a car by using the brakes to not being able to start a car because of a flooded engine. A non-depolarizing neuromuscular blocker is similar to using the brakes to stop your car. PAGE 38 MODULE 02 COMPANION GUIDE PHAR 370 It inhibits the acetylcholine (i.e. gas) from activating the receptors (i.e. engine), thereby stopping muscle contraction (i.e. the car). A depolarizing neuromuscular blocker is similar to flooding the engine, as too much acetylcholine is in the neuromuscular junction activating the receptors (i.e. too much gas is in the engine), which results in a desensitization of the receptors (i.e. engine will not start), and therefore the muscle becomes paralyzed (i.e. the car cannot run). Although not a perfect comparison, this analogy helps illustrate how two seemingly opposite actions can cause the same result (i.e. muscle paralysis, or a stopped car). Reference: Adapted from: Neural cells, Intracellular Components, and Receptors and Channels. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image-set-download/) EXAMPLE OF NON -DEPOLARIZING NEUROMUSCULAR BLOCKERS: TUBOCURARINE This content was retrieved from Section 04, Slide 8 of 29 of the online learning module. The majority of clinically relevant neuromuscular blockers are non-depolarizing blocking agents. The prototypical example drug in this class is tubocurarine. The onset of action of tubocurarine is about four minutes and its pharmacological effect lasts 45-60 minutes. Clinically, tubocurarine is no longer commonly used, as it has been predominantly replaced by related drugs that have better safety profiles. However, the agents currently used clinically act in the same manner as tubocurarine. Reference: Adapted from: Neural cells, Intracellular Components, and Receptors and Channels. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image-set-download/) OVERCOMING NON-DEPOLARIZING BLOCKING AGENTS This content was retrieved from Section 04, Slide 9 of 29 of the online learning module. Importantly, the effect of non-depolarizing blocking agents can be overcome by using acetylcholinesterase inhibitor drugs (e.g. physostigmine). By inhibiting acetylcholinesterase, the buildup of acetylcholine is able to out compete the non- PAGE 39 MODULE 02 COMPANION GUIDE PHAR 370 depolarizing blocking drug, resulting in muscle contraction. Reference: Adapted from: Neural cells, Intracellular Components, and Receptors and Channels. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image-set-download/) VIDEO: NON-DEPOLARIZING NEUROMUSCULAR BLOCKERS This content was retrieved from Section 04, Slide 10 of 29 of the online learning module. Watch the video for an overview of non-depolarizing neuromuscular blocking drugs. As you watch: Focus on how you can overcome the neuromuscular blockers in the synaptic cleft. Page Link: https://player.vimeo.com/video/283790423 EXAMPLE OF DEPOLARIZING BLOCKING AGENTS: SUCCINYLCHOLINE This content was retrieved from Section 04, Slide 11 of 29 of the online learning module. Depolarizing blocking agents activate the NM receptors similar to acetylcholine, depolarizing the plasma membrane of the muscle fiber. However, the drugs are more resistant to the enzyme acetylcholinesterase. Therefore, the drug is not broken down in the synapse and the muscle fibers are persistently depolarized. The result is paralysis of muscle fibers. Here is an example of a depolarizing blocking agent. Example: Succinylcholine - Refer to pages 40-41 SUCCINYLCHOLINE Subpage of Section 04 Slide 11 of 29 – Succinylcholine1/1 The only depolarizing blocking agent used clinically is succinylcholine. Here is an overview of the mechanism of action for succinylcholine. PAGE 40 MODULE 02 COMPANION GUIDE PHAR 370 1. Succinylcholine has rapid onset (~30-60 seconds) 2. It has a short duration of action (5-10 minutes) 3. The short duration of action is due to the fact that succinylcholine is metabolized by cholinesterase in the plasma of the blood, which is why the duration of action is short compared to non-depolarizing blocking agents (e.g. rocuronium, shown in the figure) The percentage of peak effect after a single ED50 of succinylcholine and rocuronium as a function of time. Reference: Kopman, A. F., Klewicka, M. M., Kopman, D. J., & Neuman, G. G. (1999). Molar Potency Is Predictive Of the Speed of Onset of Neuromuscular Blod for Agents of Intermediate, Short, and Ultrashort Duration. Anesthesiology: The Journal of the American Society of Anesthesiologists, 90(2), 425-431. (http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1946476) PHASES OF DEPOLARIZING BLOCKERS ACTION This content was retrieved from Section 04, Slide 12 of 29 of the online learning module. Two phases exist to the depolarizing block: the depolarizing and desensitizing phase. Learn about each of the phases. Depolarizing Phase The muscle fibers depolarize in a disorganized manner, resulting in muscular fasciculation (i.e. twitching). Once the muscle fibers depolarize, they are unable to repolarize due to the continual presence of the drug activating the receptors, resulting in paralysis. Desensitizing Phase This occurs after prolonged exposure to the depolarizing blocking agent. The muscle membrane eventually repolarizes, but it is now desensitized. Therefore, the muscle is no longer responsive to acetylcholine and full neuromuscular block has been achieved. The result is flaccid paralysis, a condition where your muscles are unable to contract. Full depolarizing neuromuscular block is achieved within 60 seconds. PHASE 2: DESENSITIZATION PAGE 41 MODULE 02 COMPANION GUIDE PHAR 370 This content was retrieved from Section 04, Slide 13 of 29 of the online learning module. During the desensitization phase, once the NM receptors become desensitized to the depolarizing blocker, the NM receptors act as if an antagonist is binding instead of an agonist. Consequently, binding of acetylcholine to the NM receptors also no longer activates them. Because of this desensitization, the effect of depolarizing blocking agents is prolonged by the use of acetylcholinesterase inhibitor drugs, since neither acetylcholine nor the depolarizing blocking drug can activate the NM receptors. Reference: Adapted from: Neural cells, Intracellular Components, and Receptors and Channels. (2018) Servier Medical Art. CC 3.0 (https://smart.servier.com/image-set-download/) VIDEO: DEPOLARIZING MUSCULAR BLOCKERS This content was retrieved from Section 04, Slide 14 of 29 of the online learning module. Watch the video for an overview of depolarizing neuromuscular blocking drugs. As you watch: Focus on the two phases of depolarizing blocking agents. Page Link: https://player.vimeo.com/video/283790148 ADVERSE EFFECTS OF DEPOLARIZING BLOCKADE This content was retrieved from Section 04, Slide 15 of 29 of the online learning module. Depolarizing neuromuscular blockers can have some adverse effects, including muscle pain, and malignant hyperthermia. Learn more about each condition. Muscle Pain Use of depolarizing blockers, such as succinylcholine, are associated with postoperative pain. This is more common for heavily muscled patients. Malignant Hyperthermia PAGE 42 MODULE 02 COMPANION GUIDE PHAR 370 This is an uncommon, genetically linked condition that can occur after exposure to succinylcholine and manifests as a rise in body temperature, tachycardia, and muscle rigidity. Symptoms usually develop within an hour of exposure. CLINICAL INDICATIONS FOR NEUROMUSCULAR BLOCKERS This content was retrieved from Section 04, Slide 16 of 29 of the online learning module. Not many drugs target skeletal muscle. However, a few therapeutic indications for targeting skeletal muscle exist, such as during surgical procedures (e.g. to produce muscle paralysis as adjuncts to anesthetics) or to reduce spasticity (e.g. muscle relaxants for chronic back pain or fibromyalgia). Review specific examples of how neuromuscular blockers are used clinically. Surgery: The most common use of neuromuscular blockers is during surgical procedures. By using drugs to target skeletal muscle, it is possible to achieve adequate muscle relaxation for all types of surgical procedures, especially during intra-abdominal and intra-thoracic procedures, without the cardiorespiratory depressant effects of deep anesthesia. Endotracheal intubation: Relaxation of the tracheal and pharyngeal muscles, facilitating the insertion of an endotracheal tube, which maintains airways during surgery. Succinylcholine is often used, as short term paralysis is needed for endotracheal intubation. Control of ventilation: For critically ill patients who have respiratory failure. By administering a neuromuscular blocker, chest wall resistance and ineffective spontaneous ventilation is eliminated, allowing the ventilator to maintain respiration. QUESTION: REVIEW OF THE AUTONOMIC NERVOUS SYSTEM This content was retrieved from Section 04, Slide 17 of 29 of the online learning module. Answer the question about the peripheral nervous system. What are the neurotransmitters used in the parasympathetic, sympathetic, and somatic nervous systems? Feedback: Instructor’s Answer: The parasympathetic nervous system releases acetylcholine from the presynaptic neurons and the postsynaptic neurons. The sympathetic nervous system releases acetylcholine from the presynaptic neurons and norepinephrine from the postsynaptic neurons. The somatic nervous system, a one- neuron system, relea

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