Palawan State University BIO 117 - Basic Pharmacology PDF

PALAWAN STATE UNIVERSITY College of Sciences BIO 117 - BASIC PHARMACOLOGY Drugs Affecting the Autonomic Nervous System MODULE 3  Table of Contents Content Page Learning Objectives …...

PALAWAN STATE UNIVERSITY College of Sciences BIO 117 - BASIC PHARMACOLOGY Drugs Affecting the Autonomic Nervous System MODULE 3  Table of Contents Content Page Learning Objectives ………………………………………………………. 2 Overview ………………………………………………………………....... 3 I. Introduction to the Nervous System …………………….................. 4 Learning Check 3.1.……………………………………………………. 23 II. Drugs affecting the Autonomic Nervous System..…………………...24 Learning Check 3.2.………………………………………………….....56 Evaluation ………………………………………………………………….. 84 Written Output Grading Rubric.................................................................................... 86 Reflection............................................................................................ 87 References ……………………………………………………………….... 88 2 Page 1  Learning Objectives After going through in this module, you should be able to:  Identify the anatomical and functional divisions of the nervous system and give their corresponding functions;  Differentiate between cholinergic and adrenergic agonists and antagonists;  Describe the therapeutic uses and adverse effects of drugs commonly used in the treatment of autonomic nervous system disorder/diseases. 3 Page 2  Overview In this module you will be introduced to the Autonomic Nervous System and Central Nervous System. We will also discuss drugs which act as agonists and antagonists of both adrenergic and cholinergic receptors, as well as drugs which affect the CNS such as the sedative hypnotics, antipsychotics, anesthetics, muscle relaxants, antiseizure, opioids, and alcohol. YouTube links are also provided to facilitate your learning. At the end of this module, you will create an infographic of the topics we have discussed in this module. Always visit our Google classroom and view the announcements and other requirements for submission. Be sure to submit the requirements on the due date. When possible, the Module Quiz will administered face to face at the College of Sciences. 4 Page 3  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM The nervous system is anatomically divided into the central nervous system (CNS; the brain and spinal cord) and the peripheral nervous system (PNS; neuronal tissues outside the CNS). The peripheral nervous system is subdivided into: (1) efferent division, the (motor) neurons of which carry signals away from the brain and spinal cord to the peripheral tissues; (2) afferent division, the (sensory) neurons of which bring information from the periphery to the CNS. Functionally, the nervous system (PNS) can be divided into two major subdivisions: autonomic and somatic. The efferent ANS is divided into the: sympathetic and the parasympathetic nervous systems, and enteric nervous system. 5 Figure 2.1 Organization of the Nervous System Source: https://www.physio-pedia.com/File:Nervous_System.jpg Page 4  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM The somatic efferent neurons are involved in the voluntary control of functions such as contraction of the skeletal muscles essential for locomotion. The motor portion of the somatic subdivision is largely concerned with consciously controlled functions such as movement, respiration, and posture. The autonomic nervous system (ANS) is largely independent (autonomous) in that its activities are not under direct conscious control. It is composed of efferent neurons that innervate smooth muscle of the viscera, cardiac muscle, vasculature, and the exocrine glands. The ANS is concerned primarily with control and integration of visceral functions necessary for life such as cardiac output, blood flow distribution, glandular secretions, and digestion. 6 Figure 2.2 The Nervous System Source: https://www.docsity.com/en/organization-of-the-nervous-system-drugs-brain-and-behavior- lecture-slides/226060/ & https://www.biologyonline.com/dictionary/afferent-nerve Page 5  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Evidence is accumulating that the ANS, especially the vagus nerve, also influences immune function and some CNS functions such as seizure discharge. Some evidence indicates that autonomic nerves can also influence cancer development and progression. Figure 2.3 Vagus nerve Source: https://teachmeanatomy.info/head/c ranial-nerves/vagus-nerve-cn-x/. Anatomy of the Autonomic Nervous System 1. Efferent neurons The ANS carries nerve impulses from the CNS to the effector organs by way of two types of efferent neurons (Figure 2.4). Preganglionic neuron: its cell body is located within the CNS. Preganglionic neurons emerge from the brainstem or spinal cord and make a synaptic connection in ganglia (an aggregation of nerve cell bodies located in the peripheral nervous 7 system). These ganglia function as relay stations between a preganglionic neuron and a second nerve cell, the postganglionic neuron. Postganglionic neuron: it has a cell body originating in the ganglion. It is generally nonmyelinated and terminates on effector organs, such as smooth muscles of the viscera, cardiac muscle, and the exocrine glands. Figure 2.4 Efferent neurons of the autonomic nervous system Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 6  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Anatomy of the Autonomic Nervous System 2. Afferent neurons They are important in the reflex regulation of the ANS (for example, by sensing pressure in the carotid sinus and aortic arch) and signaling the CNS to influence the efferent branch of the system to respond. 3. Sympathetic neurons Anatomically, they originate in the CNS and emerge from two different spinal cord regions. The preganglionic neurons of the sympathetic system come from thoracic and lumbar regions of the spinal cord, and they synapse in two cord-like chains of ganglia that run in parallel on Figure 2.5 Afferent neurons each side of the spinal cord. The preganglionic neurons are short Source: in comparison to the postganglionic ones. Axons of the https://doctorlib.info/physiology/ganon g-review-medical-physiology/37.html postganglionic neuron extend from these ganglia to the tissues that they innervate and regulate. Note: The adrenal medulla receives preganglionic fibers from the sympathetic system. Lacking axons, the adrenal medulla, in response to stimulation by the ganglionic neurotransmitter 8 acetylcholine, influences other organs by secreting the hormone epinephrine, also known as adrenaline, and lesser amounts of norepinephrine into the blood. Figure 2.7 Adrenal Figure 2.6 Sympathetic and medulla and the parasympathetic neurons sympathetic neurons Source: Source: https://ortholibrary.in/orthoPharmaHome https://www.slideshare.ne t/AkayaEmerk/adrenal- Page 7 medulla-46410701  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Anatomy of the Autonomic Nervous System 4. Parasympathetic neurons The parasympathetic preganglionic fibers arise from the cranium (from cranial nerves III, VII, IX, and X) and from the sacral region of the spinal cord and synapse in ganglia near or on the effector organs. Thus, in contrast to the sympathetic system, the preganglionic fibers are long, and the postganglionic ones are short, with the ganglia close to or within the organ innervated. Figure 2.7 Sympathetic versus parasympathetic neurons Source: https://www.sciencedirect.com/topics/v eterinary-science-and-veterinary- medicine/parasympathetic-nervous- system Figure 2.8 The vertebral/spinal column Source: https://teachmeanatomy.info/back/bone s/vertebral-column/ Page 8  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Anatomy of the Autonomic Nervous System 5. Enteric neurons The enteric nervous system is the third division of the autonomic nervous system. It is a collection of nerve fibers that innervate the gastrointestinal tract, pancreas, and gallbladder, and it constitutes the “brain of the gut.” This system functions independently of the CNS and controls the motility, exocrine and endocrine secretions, and microcirculation of the gastrointestinal tract. It is modulated by both the sympathetic and parasympathetic nervous systems. 10 Figure 2.9 The enteric nervous system Source:https://www.keentween.org/ens-enteric-nervous-system.html Page 9  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Functions of the Sympathetic Nervous System The sympathetic division has the property of adjusting in response to stressful situations, such as trauma, fear, hypoglycemia, cold, or exercise. 1. Effects of stimulation of the sympathetic division The effect of sympathetic output is to increase heart rate and blood pressure, to mobilize energy stores of the body, and to increase blood flow to skeletal muscles and the heart while diverting flow from the skin and internal organs. Sympathetic stimulation results in dilation of the pupils and the bronchioles (Figure 3.3). It also affects gastrointestinal motility and the function of the bladder and sexual organs. 11 Figure 2.10 Action of sympathetic and parasympathetic nervous systems on effectors organs Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 10  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Functions of the Sympathetic Nervous System 2. Fight or flight response These are the changes experienced by the body during emergencies (Figure 2.11). These reactions are triggered both by direct sympathetic activation of the effector organs and by stimulation of the adrenal medulla to release epinephrine and lesser amounts of norepinephrine. These hormones enter the bloodstream and promote responses in effector organs that contain adrenergic receptors. The sympathetic nervous system tends to function as a unit, and it often discharges as a complete system - for example, during severe exercise or in reactions to fear. This system, with its diffuse distribution of postganglionic fibers, is involved in a wide array of physiologic activities, but it is not essential for life. D. Functions of the parasympathetic nervous system It maintains essential bodily functions, such as digestive 12 processes and elimination of wastes, and is required for life. It usually acts to oppose or balance the actions of the sympathetic division and is generally dominant over the sympathetic system in “rest and digest” situations. The parasympathetic system is not a functional entity and it never discharges as a complete system. If it did, it would Figure 2.11 Sympathetic produce massive, undesirable, and unpleasant symptoms. and parasympathetic Instead, discrete parasympathetic fibers are activated actions are elicited by separately, and the system functions to affect specific different stimuli organs, such as the stomach or eye. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 11  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Functions of the Sympathetic Nervous System E. Role of the CNS in autonomic control functions The ANS, a motor system, also require sensory input from peripheral structures to provide information on the state of affairs in the body. This feedback is provided by streams of afferent impulses, originating in the viscera and other autonomically innervated structures, that travel to integrating centers in the CNS - that is, the hypothalamus, medulla oblongata, and spinal cord. These centers respond to the stimuli by sending out efferent reflex impulses via the ANS (Figure 2.12). 1. Reflex arcs Most of the afferent impulses are translated into reflex responses without involving consciousness. For example, a fall in blood pressure causes pressure- sensitive neurons (baroreceptors in the heart, vena cava, aortic arch, and carotid sinuses) to send fewer impulses to cardiovascular centers in the brain. This prompts a reflex 13 response of increased sympathetic output to the heart and vasculature and decreased parasympathetic output to the heart, which results in a compensatory rise in blood pressure and tachycardia (Figure 2.12). Note: In each case, the reflex arcs of the ANS comprise a sensory (or afferent) arm, and a motor (or efferent, or effector) arm. Figure 2.12 Baroreceptor reflex arc responds to a 2. Emotions and the autonomic nervous system decrease in blood pressure. Source: Lippincott’s Illustrated Stimuli that evoke feelings of strong emotion, such as Reviews: Pharmacology. 4th rage, fear, or pleasure, can modify the activity of the ANS. ed. Page 12  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Functions of the Sympathetic Nervous System F. Innervation by the autonomic nervous system 1. Dual innervation Most organs in the body are innervated by both divisions of the ANS. Thus, vagal parasympathetic innervation slows the heart rate, and sympathetic innervation increases the heart rate. Despite this dual innervation, one system usually predominates in controlling the activity of a given organ. For example, in the heart, the vagus nerve is the predominant factor for controlling rate. This type of antagonism is considered to be dynamic and is fine-tuned at any given time to control homeostatic organ functions. 2. Organs receiving only sympathetic innervation Although most tissues receive dual innervation, some effector organs, such as the adrenal medulla, kidney, pilomotor muscles, and sweat glands, receive innervation only from the sympathetic system. The control of blood pressure is also mainly a sympathetic activity, with essentially no participation by the parasympathetic system. G. Somatic nervous system The efferent somatic nervous system differs from the autonomic 14 system in that a single myelinated motor neuron, originating in the CNS, travels directly to skeletal muscle without the mediation of ganglia. Remember! The somatic nervous system is under voluntary control, whereas the autonomic is an involuntary system. Figure 2.13 Comparison of somatic and autonomic nervous systems Source: https://sites.psu.edu/intropsychf19grp8/2019/09/12/the-somatic-nervous-system/ Page 13  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Chemical Signaling Between Cells Neurotransmission in the ANS is an example of the more general process of chemical signaling between cells. In addition to neurotransmission, other types of chemical signaling are the release of local mediators and the secretion of hormones. A. Local mediators Most cells in the body secrete chemicals that act locally - that is, on cells in their immediate environment. These chemical signals are rapidly destroyed or removed; therefore, they do not enter the blood and are not distributed throughout the body. Examples are histamine and the prostaglandins. B. Hormones Specialized endocrine cells secrete hormones into the bloodstream, where they travel throughout the body exerting effects on broadly distributed target cells in the body. Examples include adrenocorticotropic hormone (corticotropin) and growth hormone (somatotropin). C. Neurotransmitters All neurons are distinct anatomic units, and no structural continuity exists between most neurons. Communication between nerve cells - and between nerve cells and effector organs - occurs through the release of specific chemical signals, called 15 neurotransmitters, from the nerve terminals. This release is triggered by the arrival of the action potential at the nerve ending, leading to depolarization. Uptake of Ca2+ initiates fusion of the synaptic vesicles with the presynaptic membrane and release of their contents. The neurotransmitters rapidly diffuse across the synaptic cleft or space (synapse) between neurons and combine with specific receptors on the postsynaptic (target) cell. Figure 2.14 Action potential Source: https://www.osmosis.org/learn/Neuron_acti on_potential Page 14  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Chemical Signaling Between Cells C. Neurotransmitters 1. Membrane receptors All neurotransmitters and most hormones and local mediators are too hydrophilic to penetrate the lipid bilayer of target-cell plasma membranes. Instead, their signal is mediated by binding to specific receptors on the cell surface of target organs. Remember! A receptor is a recognition site for a substance. It has a binding specificity, and it is coupled to processes that eventually evoke a response. Most receptors are proteins. They need not be located in the membrane. 2. Types of neurotransmitters Although over fifty signal molecules in the nervous system have tentatively been identified, six signal compounds - norepinephrine (and the closely related epinephrine), acetylcholine, dopamine, serotonin, histamine, and GABA - are most commonly involved in the actions of therapeutically useful drugs. Each of these chemical signals binds to a specific family of receptors. Acetylcholine and norepinephrine are the primary chemical signals in the ANS, whereas a wide variety of neurotransmitters function in the CNS. Not only are these neurotransmitters released on nerve stimulation, co-transmitters, such as adenosine, often accompany them and modulate the transmission process. a) Acetylcholine 16 The autonomic nerve fibers can be divided into two groups based on the chemical nature of the neurotransmitter released. If transmission is mediated by acetylcholine, the neuron is termed cholinergic. Acetylcholine mediates the transmission of nerve impulses across autonomic ganglia in both the sympathetic and parasympathetic nervous systems. It is the neurotransmitter at the adrenal medulla. Transmission from the autonomic postganglionic nerves to the effector organs in the parasympathetic system and a few sympathetic system organs also involves the release of acetylcholine. In the somatic nervous system, transmission at the neuromuscular junction (that is, between nerve fibers and voluntary muscles) is also cholinergic (Figure 2.14). Page 15  Discussion I. INTRODUCTION TO THE AUTONOMIC NERVOUS SYSTEM Chemical Signaling Between Cells C. Neurotransmitters 2. Types of neurotransmitters b) Norepinephrine and epinephrine When norepinephrine or epinephrine is the transmitter, the fiber is termed adrenergic (adrenaline being another name for epinephrine). In the sympathetic system, norepinephrine mediates the transmission of nerve impulses from autonomic postganglionic nerves to effector organs. Note: A few sympathetic fibers, such as those involved in sweating, are cholinergic. 17 Figure 2.14 Adrenergic versus cholinergic receptors Sourcehttps://www.quora.com/How-do-adrenergic-receptors-and-cholinergic-receptors-differ Page 16  Learning Check LEARNING CHECK 2.1 Provide the required information in the figure/diagram below. Choose from the given phrases/description to correctly fill-in the numbered and lettered blanks below: Numbered blanks choices Lettered blanks choices Somatic nervous system voluntary Autonomic nervous system involuntary Sensory division brain & spinal cord Motor division cranial nerves & spinal nerves Central nervous system mobilizes body systems during activity Peripheral nervous system promotes house-keeping functions during rest Sympathetic division somatic & visceral sensory nerve fibers Parasympathetic division motor nerve fibers conducts impulses from receptors to the CNS conducts impulses from the CNS to cardiac & smooth muscles & glands conducts impulses from the CNS to skeletal muscles conducts impulses from the CNS to muscles & glands 1. _____ 2. _____ a. _____ b. _____ 3. _____ 4. _____ c. _____ e. _____ d. _____ f. _____ Somatic sensory fiber 5. _____ 6. _____ g. _____ i. _____ 18 h. _____ j. _____ Visceral sensory fiber Motor fiber of SNS 7. _____ 8. _____ k. _____ l. _____ Sympathetic motor fiber of ANS Afferent division of PNS parasympathetic motor fiber of ANS Efferent division of PNS Page 23  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Drugs affecting the autonomic nervous system are divided into two groups according to the type of neuron involved in their mechanism of action. Cholinergic drugs - act on receptors that are activated by acetylcholine. Adrenergic drugs - act on receptors that are stimulated by norepinephrine or epinephrine. Both act by either stimulating or blocking receptors of the ANS. The Cholinergic Neuron What uses acetylcholine as neurotransmitter? (Figure 2.18) the preganglionic fibers terminating in the adrenal medulla; the autonomic ganglia (both parasympathetic and sympathetic); the postganglionic fibers of the parasympathetic division; neurons that innervate the muscles of the somatic system. Trivia: Patients with Alzheimer's disease have a significant loss of cholinergic neurons in the temporal lobe and entorhinal cortex. Most of the drugs available to treat the disease are acetylcholinesterase inhibitors. Neurotransmission at cholinergic neurons Neurotransmission in cholinergic neurons involves sequential six steps. The first four - synthesis, storage, release, and binding of acetylcholine to a receptor - are followed by the fifth step, degradation of the neurotransmitter in the synaptic gap (that is, the space 19 between the nerve endings and adjacent receptors located on nerves or effector organs), and the sixth step, the recycling of choline (Figure 2.19). 1. Synthesis of acetylcholine Choline is transported from the extracellular fluid into the cytoplasm of the cholinergic neuron by an energy-dependent carrier system that cotransports sodium. The uptake of choline is the rate-limiting step in acetylcholine synthesis. Choline acetyltransferase catalyzes the reaction of choline with acetyl coenzyme A (CoA) to form acetylcholine – an ester - in the cytosol.. Note: Choline has a quaternary nitrogen and carries a permanent positive charge, and thus, cannot diffuse through the membrane. Page 24  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM 20 Figure 2.18 Sites of actions of cholinergic agonists in the autonomic and somatic nervous system Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 25  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Neurotransmission at cholinergic neurons 21 Figure 2.19 Synthesis and release of acetylcholine from the cholinergic neuron. AcCoA = acetyl CoA Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 26  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Neurotransmission at cholinergic neurons 2. Storage of acetylcholine in vesicles The acetylcholine is packaged into presynaptic vesicles by an active transport process coupled to the efflux of protons. The mature vesicle contains not only acetylcholine but also ATP and proteoglycan. Most synaptic vesicles contain the primary neurotransmitter, here acetylcholine, as well as a cotransmitter (i.e., ATP) that will increase or decrease the effect of the primary neurotransmitter. The neurotransmitters in vesicles will appear as bead-like structures, known as varicosities, along the nerve terminal of the presynaptic neuron. 3. Release of acetylcholine When an action potential propagated by the action of voltage-sensitive sodium channels arrives at a nerve ending, voltage-sensitive calcium channels on the presynaptic membrane open, causing an increase in the concentration of intracellular calcium. Elevated calcium levels promote the fusion of synaptic vesicles with the cell membrane and release of their contents into the synaptic space. This release can be blocked by botulinum toxin. In contrast, the toxin in black widow spider venom causes all the acetylcholine stored in synaptic vesicles to empty into the synaptic gap. 4. Binding to the receptor Acetylcholine released from the synaptic vesicles diffuses across the synaptic space, and it binds to either of two postsynaptic receptors on the target cell or to presynaptic 22 receptors in the membrane of the neuron that released the acetylcholine. Two classes of postsynaptic cholinergic receptors on the surface of the effector organs (Figure 2.25): a) muscarinic receptor b) nicotinic receptor Binding to a receptor leads to a biologic response within the cell, such as the initiation of a nerve impulse in a postganglionic fiber or activation of specific enzymes in effector cells as mediated by second-messenger molecules. Page 27  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Neurotransmission at cholinergic neurons 5. Degradation of acetylcholine The signal at the postjunctional effector site is rapidly terminated, because acetylcholinesterase cleaves acetylcholine to choline and acetate in the synaptic cleft (Figure 2.19). 6. Recycling of choline Choline may be recaptured by a sodium-coupled, high-affinity uptake system that transports the molecule back into the neuron, where it is acetylated into acetylcholine that is stored until released by a subsequent action potential. Cholinergic Receptors (Cholinoceptors) Muscarinic and nicotinic receptors can be distinguished from each other on the basis of their different affinities for agents that mimic the action of acetylcholine (cholinomimetic agents or parasympathomimetics). 23 Figure 2.20 Types of cholinergic receptors. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 28  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Cholinergic Receptors (Cholinoceptors) Muscarinic receptors These receptors bind acetylcholine and also recognize muscarine, an alkaloid that is present in certain poisonous mushrooms. However, these show only a weak affinity for nicotine (Figure 2.20A). Five subclasses of muscarinic receptors: M1, M2, M3, M4, and M5. Locations: These receptors have been found on ganglia of the peripheral nervous system and on the autonomic effector organs, such as the heart, smooth muscle, brain, and exocrine glands. M1 receptors are also found on gastric parietal cells; M2 receptors on cardiac cells and smooth muscle; and M3 receptors on the bladder, exocrine glands, and smooth muscle. Note: Drugs with muscarinic actions preferentially stimulate muscarinic receptors on these tissues, but at high concentration they may show some activity at nicotinic receptors. Mechanisms of acetylcholine signal transduction: A number of different molecular mechanisms transmit the signal generated by acetylcholine occupation of the receptor. For example, when the M1 or M3 receptors are activated, the receptor undergoes a conformational change and interacts with a G protein, designated Gq, which in turn activates phospholipase C. This leads to the hydrolysis of phosphatidylinositol-(4,5)- 24 bisphosphate (PIP2) to yield diacylglycerol and inositol (1,4,5)-trisphosphate (formerly called inositol (1,4,5)-triphosphate), which cause an increase in intracellular Ca2+ (Figure 2.20C). This cation can then interact to stimulate or inhibit enzymes, or cause hyperpolarization, secretion, or contraction. In contrast, activation of the M2 subtype on the cardiac muscle stimulates a G protein, designated Gi, that inhibits adenylyl cyclase and increases K+ conductance (Figure 2.20B), to which the heart responds with a decrease in rate and force of contraction. Page 29  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Cholinergic Receptors (Cholinoceptors) Nicotinic receptors These receptors bind to acetylcholine and also recognize nicotine but show only a weak affinity for muscarine (Figure 2.17B). Mechanism of signal transduction: The nicotinic receptor is composed of five subunits, and it functions as a ligand-gated ion channel (Figure 2.20A). Binding of two acetylcholine molecules elicits a conformational change that allows the entry of sodium ions, resulting in the depolarization of the effector cell. Nicotine (or acetylcholine) initially stimulates and then blocks the receptor. Locations: Nicotinic receptors are located in the CNS, adrenal medulla, autonomic ganglia, and the neuromuscular junction. Those at the neuromuscular junction are sometimes designated NM and the others NN. The nicotinic receptors of autonomic ganglia differ from those of the neuromuscular junction. For example, ganglionic receptors are selectively blocked by hexamethonium, whereas neuromuscular junction receptors are specifically blocked by tubocurarine. 25 Figure 2.20Three mechanisms whereby binding of a neurotransmitter leads to a cellular effect. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 30  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Cholinergic Agonist (Cholinoreceptor Stimulants) Figure 2.21 Three mechanisms whereby binding of a neurotransmitter leads to a cellular effect. Source: Katzung BG. 2017. Basic & Clinical Pharmacology. Direct-acting Cholinergic Agonists Cholinergic agonists (or parasympathomimetics) mimic the effects of acetylcholine by binding directly to cholinoceptors. 26 These agents may be broadly classified into two groups: a) Choline esters, including acetycholine and synthetic esters of choline (carbachol and bethanechol) b) naturally occurring alkaloids, such as pilocarpine Some of the more therapeutically useful drugs (pilocarpine and bethanechol) preferentially bind to muscarinic receptors and are sometimes referred to as muscarinic agents. However, as a group, the direct-acting agonists show little specificity in their actions, which limits their clinical usefulness. Note: Muscarinic receptors are located primarily, but not exclusively, at the neuroeffector junction of the parasympathetic nervous system. Page 31  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Direct-acting Cholinergic Agonists Figure 2.22 Molecular structures of four choline esters. Acetylcholine and methacholine are acetic acid esters of choline and β-methylcholine, respectively. Carbachol and bethanechol are carbamic acid esters of the same alcohols Source: Katzung BG. 2017. Basic & Clinical Pharmacology. 27 Figure 2.23 Structures of some cholinomimetic alkaloids Page 32 Source: Katzung BG. 2017. Basic & Clinical Pharmacology..  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHOLINERGIC AGONISTS (CHOLINORECEPTOR STIMULANTS) DRUGS ACTIONS THERAPEUTIC USES ADVERSE EFFECTS DIRECT-ACTING Decreases heart rate & None None cardiac output; Decreases blood pressure; Increases salivary secretion; Acetylcholine Stimulates intestinal secretions & motility; Enhances bronchial secretions; Increases tone of detrusor urinae muscle (bladder); Miosis; Vasodilation Increases intestinal Sweating motility & tone; Salivation Flushing Bethanecol Stimulates detrusor Decreased blood pressure muscle of bladder Nausea causing expulsion of Abdominal pain urine Treatment of urinary retention Diarrhea Bronchospasm 28 Miosis during ocular surgery; Release of epinephrine Little to no side effect at Carbachol Topically to reduce doses used Miosis intraocular pressure in open- opthalmologically angle or narrow-angle glaucoma, particularly in patients who have become tolerant to pilocarpine Miosis CNS disturbances Pilocarpine Reduce intraocular pressure Stimulate secretions of in open-angle and narrow – Profuse sweating & sweat, tears, & saliva angle glaucoma salivation Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 33  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHOLINERGIC AGONISTS (CHOLINORECEPTOR STIMULANTS) DRUGS ACTIONS THERAPEUTIC USES ADVERSE EFFECTS INDIRECT-ACTING: REVERSIBLE (ANTICHOLINESTERASES) Contraction of visceral Increase intestinal and Convulsion at high smooth muscle bladder motility; doses Physostigmine Miosis Reduce intraocular pressure Bradycardia in glaucoma; Hypotension Fall in cardiac output Reverse CNS and cardiac bradycadia effects of tricyclic Paralysis of skeletal antidepressants; muscle Reverse CNS effects of atropine Prevent postoperative Stimulates contractility abdominal distention and Salivation Neostigmine before it paralyzes; urinary retention; Flushing Decreased blood Stimulates bladder and Treat myasthenia gravis; pressure GIT Nausea As antidote to tubocurarine Abdominal pain Diarrhea Pyridostigmine Chronic management of Bronchospasm & Ambenomium myasthenia gravis 29 Rapid increase in muscle For diagnosis of myasthenia Edrophonium strength gravis; As antidote for tubocurarine Tacrine, Hepatotoxic (tacrine) Donezepil, Remedy for loss of cognitive Rivastigmine & function in Alzheimer disease Gastrointestinal distress Galantamine Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 34  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHOLINERGIC AGONISTS (CHOLINORECEPTOR STIMULANTS) DRUGS ACTIONS THERAPEUTIC USES INDIRECT-ACTING: IRREVERSIBLE (ANTICHOLINESTERASES) Generalized cholinergic stimulation Paralysis of motor function (causing Isoflurophate breathing difficulties) Treatment of open-angle glaucoma Convulsions Intense miosis Figure 2.25 Some adverse effects observed with cholinergic drugs Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Figure 2.22 Mechanism of action of cholinergic agonists Source: https://biology-forums.com/index.php?action=gallery;sa=view;id=28434 Page 35  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Cholinergic Antagonists The cholinergic antagonists (also called cholinergic blockers, parasympatholytics or anticholinergic drugs) bind to cholinoceptors, but they do not trigger the usual receptor-mediated intracellular effects. 1. Antimuscarinic agents These agents (for example, atropine and scopolamine) selectively block muscarinic synapses/receptors of the parasympathetic nerves causing inhibition of all muscarinic functions (Figure 2.24). These drugs also block the few exceptional sympathetic neurons that are cholinergic, such as those innervating salivary and sweat glands. In contrast to the cholinergic agonists, which have limited usefulness therapeutically, the cholinergic blockers are beneficial in a variety of clinical situations. Because they do not block nicotinic receptors, the antimuscarinic drugs have little or no action at skeletal neuromuscular junctions or autonomic ganglia. Note: A number of antihistaminic and antidepressant drugs also have antimuscarinic activity. 2. Ganglionic blockers These show a preference for the nicotinic receptors of the sympathetic and 31 parasympathetic autonomic ganglia. Clinically, they are the least important of the anticholinergic drugs. Some also block the ion channels of the autonomic ganglia. These drugs show no selectivity toward the parasympathetic or sympathetic ganglia and are not effective as neuromuscular antagonists. Thus, these drugs block the entire output of the ANS at the nicotinic receptor. The responses observed are complex and unpredictable, making it impossible to achieve selective actions. Therefore, ganglionic blockade is rarely used therapeutically. However, ganglionic blockers often serve as tools in experimental pharmacology. Page 36  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Cholinergic Antagonists 32 Figure 2.26 Sites of action of cholinergic antagonists Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Figure 2.27 Competition of atropine and scopolamine with acetylcholine for the muscarinic receptor Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed Page 37  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHOLINERGIC ANTAGONISTS (CHOLINERGIC BLOCKERS) DRUGS ACTIONS THERAPEUTIC USES ADVERSE EFFECTS ANTIMUSCARINIC AGENTS Atropine Eye: mydriasis, In ophthalmology, to unresponsiveness to light, produce mydriasis and cycloplegia cycloplegia prior to refraction GIT: antispasmodic, reduce gastric motility To treat spastic disorders of Dry mouth the GIT & lower urinary tract Urinary system: reduce Blurred vision hypermotility of urinary To treat organophosphate bladder poisoning “sandy eyes’ Cardiovascular: To suppress respiratory Tachycardia bradycardia (at low secretions prior to surgery doses); increase heart rate Constipation (at high doses), dilate cutaneous vasculature (at Restlessness toxic doses) Confusion Secretions: blocks salivary glands, drying Hallucination effect on mouth, affect sweat & lacrimal glands Delirium 33 Scopolamine Blocks short-term memory In obstetrics, with morphine to produce amnesia and Produces sedation but at sedation higher doses, it produces excitement To prevent motion sickness Ipratropium Treatment of asthma Management of chronic obstructive pulmonary disease Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 38  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM CHOLINERGIC ANTAGONISTS (CHOLINERGIC BLOCKERS) DRUGS ACTIONS THERAPEUTIC USES ADVERSE EFFECTS GANGLIONIC BLOCKERS Increases blood pressure None At higher doses, blood Nicotine pressure falls and Increases cardiac rate activity in both GIT and bladder ceases Increases peristalsis Short-term treatment Trimethaphan (emergency) of hypertension Treatment of moderately Mecamylamine severe to severe hypertension NEUROMUSCULAR BLOCKING DRUGS A. Nondepolarizing (competitive) blockers Tubocurarine Release histamine Adjuvant drugs in anesthesia Tubocurarine: may Mivacurium Decrease blood pressure during surgery to relax induce histamine release Atracurium Flushing skeletal muscle and promote ganglionic Bronchoconstriction blockade 34 B. Depolarizing blockers Adjuvant drugs in anesthesia Postoperative muscle succinylcholine during surgery to relax pain skeletal muscle Hyperkalemia Increased intraocular and intragastric pressure Malignant hyperthermia Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 39  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Cholinergic Antagonists 3. Neuromuscular blocking agents These drugs block cholinergic transmission between motor nerve endings and the nicotinic receptors on the neuromuscular end plate of skeletal muscle (Figure 2.24). These neuromuscular blockers are structural analogs of acetylcholine, and they act either as antagonists (nondepolarizing type) or agonists (depolarizing type) at the receptors on the end plate of the neuromuscular junction. A. Nondepolarizing (competitive) blockers The first drug found capable of blocking the skeletal neuromuscular junction was curare, which the native hunters of the Amazon in South America used to paralyze game. The drug tubocurarine was introduced into clinical practice in the early 1940s. Although tubocurarine is considered to be the prototype agent in this class, it has been largely replaced by other agents due to side effects. The neuromuscular blocking agents have significantly increased the safety of anesthesia, because less anesthetic is required to produce muscle relaxation, allowing patients to recover quickly and completely after surgery. These agents are 35 also useful in facilitating intubation. Figure 2.28 Adverse effects commonly At low doses: Nondepolarizing neuromuscular blocking drugs observed with interact with the nicotinic receptors to prevent the binding cholinergic of acetylcholine (Figure 2.25). These drugs thus prevent antagonists. Source: depolarization of the muscle cell membrane and inhibit Lippincott’s Illustrated muscular contraction. Because these agents compete with Reviews: Pharmacology. acetylcholine at the receptor without stimulating the receptor, 4th ed. they are called competitive blockers. Page 40  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Cholinergic Antagonists Neuromuscular blocking agents B. Depolarizing agents The depolarizing neuromuscular blocking drug succinylcholine attaches to the nicotinic receptor and acts like acetylcholine to depolarize the junction (Figure 2.25). Unlike acetylcholine, which is instantly destroyed by acetylcholinesterase, the depolarizing agent persists at high concentrations in the synaptic cleft, remaining attached to the receptor for a relatively longer time and providing a constant stimulation of the receptor. Phase I. The depolarizing agent first causes the opening of the sodium channel associated with the nicotinic receptors, which results in depolarization of the receptor. This leads to a transient twitching of the muscle (fasciculations). Phase II. Continued binding of the depolarizing agent renders the receptor incapable of 36 transmitting further impulses. With time, continuous depolarization gives way to gradual repolarization as the sodium channel closes or is blocked. This causes a resistance to depolarization and a flaccid paralysis. Figure 2.29 Mechanism of action of depolarizing neuromuscular blocking agents. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 41  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM The Adrenergic Neuron Adrenergic neurons release norepinephrine as the primary neurotransmitter. These neurons are found in the central nervous system (CNS) and also in the sympathetic nervous system, where they serve as links between ganglia and the effector organs. The adrenergic neurons and receptors, located either presynaptically on the neuron or postsynaptically on the effector organ, are the sites of action of the adrenergic drugs (Figure 2.28) Neurotransmission at adrenergic neurons Neurotransmission in adrenergic neurons closely resembles that of cholinergic neurons except that norepinephrine is the neurotransmitter instead of acetylcholine. Neurotransmission takes place at numerous bead-like enlargements called varicosities. The process involves five steps: synthesis, storage, release, and receptor binding of norepinephrine, followed by removal of the neurotransmitter from the synaptic gap (Figure 2.29). 1. Synthesis of norepinephrine 37 Tyrosine is transported by a Na+-linked carrier into the axoplasm of the adrenergic neuron, where it is hydroxylated to dihydroxyphenylalanine (DOPA) by tyrosine hydroxylase. This is the rate-limiting step in the formation of norepinephrine. DOPA is then decarboxylated by the enzyme dopa decarboxylase (aromatic L-amino acid decarboxylase) to form dopamine in the cytoplasm of the presynaptic neuron. Figure 2.30 Sites of actions of adrenergic agonists. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 42  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Neurotransmission at adrenergic neurons 38 Figure 2.31 Synthesis and release of norepinephrine from the adrenergic neuron. Page 43 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed.  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Neurotransmission at adrenergic neurons 2. Storage of norepinephrine in vesicles Dopamine is then transported into synaptic vesicles by an amine transporter system that is also involved in the reuptake of preformed norepinephrine. Dopamine is hydroxylated to form norepinephrine by the enzyme, dopamine β-hydroxylase. Note: Synaptic vesicles contain dopamine or norepinephrine plus ATP and β-hydroxylase, as well as other cotransmitters. In the adrenal medulla, norepinephrine is methylated to yield epinephrine, both of which are stored in chromaffin cells. On stimulation, the adrenal medulla releases about 80% epinephrine and 20% norepinephrine directly into the circulation. 3. Release of norepinephrine An action potential arriving at the nerve junction triggers an influx of calcium ions from the extracellular fluid into the cytoplasm of the neuron. The increase in calcium causes vesicles inside the neuron to fuse with the cell membrane and expel (exocytose) their contents into the synapse. 4. Binding to a receptor Norepinephrine released from the synaptic vesicles diffuses across the synaptic space and binds to either postsynaptic receptors on the effector organ or to presynaptic receptors on the nerve ending. 39 The recognition of norepinephrine by the membrane receptors triggers a cascade of events within the cell, resulting in the formation of intracellular second messengers that act as links (transducers) in the communication between the neurotransmitter and the action generated within the effector cell. Adrenergic receptors use both the cyclic adenosine monophosphate (cAMP) second- messenger system, and the phosphatidylinositol cycle, to transduce the signal into an effect. Page 44  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Neurotransmission at adrenergic neurons 5. Removal of norepinephrine Norepinephrine may: 1) diffuse out of the synaptic space and enter the general circulation; 2) be metabolized to O-methylated derivatives by postsynaptic cell membrane- associated catechol O-methyltransferase (COMT) in the synaptic space; or 3) be recaptured by an uptake system that pumps the norepinephrine back into the neuron. The uptake by the neuronal membrane involves a sodium/potassium-activated ATPase that can be inhibited by tricyclic antidepressants, such as imipramine, or by cocaine (Figure 2.29). Uptake of norepinephrine into the presynaptic neuron is the primary mechanism for termination of norepinephrine's effects. 6. Potential fates of recaptured norepinephrine Once norepinephrine reenters the cytoplasm of the adrenergic neuron, it may be taken up into adrenergic vesicles via the amine transporter system and be sequestered for release by another action potential, or it may persist in a protected pool. Alternatively, norepinephrine can be oxidized by monoamine oxidase (MAO) present in neuronal mitochondria. The inactive products of norepinephrine metabolism are excreted in the urine as vanillylmandelic acid, metanephrine, and normetanephrine. 40 Page 45  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Adrenergic receptors (adrenoceptors) In the sympathetic nervous system, several classes of adrenoceptors can be distinguished pharmacologically. Two families of receptors, designated α and β, were initially identified on the basis of their responses to the adrenergic agonists epinephrine, norepinephrine, and isoproterenol. α1 and α2 receptors The α adrenoceptors show a weak response to the synthetic agonist isoproterenol, but they are responsive to the naturally occurring catecholamines epinephrine and norepinephrine (Figure 2.30). For α receptors, the rank order of potency is epinephrine > norepinephrine >> isoproterenol. The α adrenoceptors are subdivided into two subgroups α1 and α2, based on their affinities for α agonists and blocking drugs. For example, the α1 receptors have a higher affinity for phenylephrine than do the α2 receptors. Also, 41 Conversely, the drug clonidine selectively binds to α2 receptors and has less effect on α1 receptors. The α1 receptors are present on the postsynaptic membrane of the effector organs and mediate many of the classic effects involving constriction of smooth muscle. Figure 2.32 Types of adrenergic receptors. Source: Lippincott’s Illustrated The α2 receptors are located primarily on Reviews: Pharmacology. 4th ed. presynaptic nerve endings and on other cells, such as the β cell of the pancreas, and on certain vascular smooth muscle cells, control adrenergic neuromediator and insulin output, respectively. Page 46  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Adrenergic receptors (adrenoceptors) β receptors These receptors exhibit a set of responses different from those of the α receptors. These are characterized by a strong response to isoproterenol, with less sensitivity to epinephrine and norepinephrine (Figure 2.30). For β receptors, the rank order of potency is isoproterenol > epinephrine > norepinephrine. The β-adrenoceptors can be subdivided into three major subgroups, β1, β2, and β3, based on their affinities for adrenergic agonists and antagonists. It is known that β3 receptors are involved in lipolysis but their role in other specific reactions are not known. β1 receptors have approximately equal affinities for epinephrine and norepinephrine, whereas β2 receptors have a higher affinity for epinephrine than for norepinephrine. Thus, tissues with a predominance of β2 receptors (such as the vasculature of skeletal muscle) are particularly responsive to the hormonal effects of circulating 42 epinephrine released by the adrenal medulla. Binding of a neurotransmitter at any of the three β receptors results in activation of adenylyl cyclase and, therefore, increased concentrations of cAMP within the cell. Figure 2.33 Second messengers mediate the effects of α receptors. DAG=diacylglycerol; IP3=inositol triphosphate. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 47  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Adrenergic receptors (adrenoceptors) Figure 2.34 Major effects mediated by α and β adrenoreceptors. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Characteristics of Adrenergic Agonists Most of the adrenergic drugs are derivatives of β-phenylethylamine (Figure 2.33). Substitutions on the benzene ring or on the ethylamine side chains produce a great variety of compounds with varying abilities to differentiate between α and β receptors and to penetrate the CNS. 43 Two important structural features of these drugs: (1) number and location of OH substitutions on the benzene ring; (2) nature of the substituent on the amino nitrogen. Page 48  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Characteristics of Adrenergic Agonists A. Catecholamines Sympathomimetic amines that contain the 3,4- dihydroxybenzene group (such as epinephrine, norepinephrine, isoproterenol, and dopamine) are called catecholamines. These compounds share the following properties: 1. High potency: Drugs that are catechol derivatives (with -OH groups in the 3 and 4 positions on the benzene ring) show the highest potency in directly activating α or β receptors. 2. Rapid inactivation: Not only are the catecholamines metabolized by COMT postsynaptically and by MAO intraneuronally, they are also metabolized in other tissues. For example, COMT is in the gut wall, and MAO is in the liver and gut wall. Thus, catecholamines have only a brief period of action when given parenterally, and they are ineffective when administered orally because of inactivation. 3. Poor penetration into the CNS: Catecholamines are polar and, therefore, do not readily penetrate into the CNS. Nevertheless, most of these drugs have some clinical effects (anxiety, tremor, and headaches) that are attributable to action on the CNS. 44 B. Noncatecholamines Compounds lacking the catechol hydroxyl groups have longer half-lives, because they are not inactivated by COMT. These include phenylephrine, ephedrine, and amphetamine. These are poor substrates for MAO and, thus, show a prolonged duration of action, because MAO is an important route of detoxification. Increased lipid solubility of many of the noncatecholamines (due to lack of polar hydroxyl groups) permits greater access to the CNS. Figure 2.35 Structures of several important adrenergic agonists. Drugs containing the catechol ring are shown in yellow.. Page 49 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed.  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Characteristics of Adrenergic Agonists C. Substitution on the amine nitrogen The nature and bulk of the substituent on the amine nitrogen is important in determining the β selectivity of the adrenergic agonist. For example, epinephrine, with a -CH3 substituent on the amine nitrogen, is more potent at β receptors than norepinephrine, which has an unsubstituted amine. Similarly, isoproterenol, with an isopropyl substituent - CH(CH3)2 on the amine nitrogen (Figure 2.33), is a strong β agonist with little α activity (Figure 2.30). D. Mechanism of action of the adrenergic agonists 1. Direct-acting agonists These drugs act directly on α or β receptors, producing effects similar to those that occur following stimulation of sympathetic nerves or release of the hormone epinephrine from the adrenal medulla (Figure 2.34). Examples of direct-acting agonists include epinephrine, norepinephrine, isoproterenol, and phenylephrine. 45 2. Indirect-acting agonists These agents, which include amphetamine, cocaine and tyramine, may block the uptake of Figure 2.36 Sites of action of norepinephrine (uptake blockers) or are taken up into direct-, indirect-, and mixed-acting the presynaptic neuron and cause the release of agonists. norepinephrine from the cytoplasmic pools or vesicles Source: Lippincott’s Illustrated Reviews: of the adrenergic neuron (Figure 2.34). As with neuronal Pharmacology. 4th ed. stimulation, the norepinephrine then traverses the synapse and binds to the α or β receptors. 3. Mixed-action agonists Some agonists, such as ephedrine, pseudoephedrine and metaraminol, have the capacity both to stimulate adrenoceptors directly and to release norepinephrine from the adrenergic neuron (Figure 2.34). Page 50  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM ADRENERGIC AGONISTS DRUGS RECEPTOR THERAPEUTIC USES ADVERSE EFFECTS SPECIFICITY DIRECT-ACTING α1, α2 Acute asthma CNS disturbances: β1, β2 anxiety, fear, tension, Treatment of open-angle glaucoma headache, tremor Epinephrine Anaphylactic shock Hemorrhage Cardiac arrythmias In local anesthetics, to increase Pulmonary edema duration of action Norepinephrine α1, α2 Treatment of shock β1 Isoproterenol β1, β2 As a cardiac stimulant Same as epinephrine dopaminergic Treatment of shock Nausea Dopamine α1, β1 Treatment of congestive heart failure Hypertension Raise blood pressure Arrhythmias Dobutamine β1 Treatment of congestive heart failure Same as epinephrine α1 As a nasal decongestant Hypertension Phenylephrine Raise blood pressure Headache 46 Treatment of paroxysmal Cardiac irregularities supraventricular tachycardia Methoxamine α1 Treatment of supraventricular Hypertension tachycardia Headache vomiting Clonidine α2 Treatment of hypertension Metaproterenol Β1 > β2 Treatment of bronchospasm and asthma Albuterol β2 Treatment of bronchospasm (short- Terbutaline acting) Salmeterol β2 Treatment of bronchospasm (long- Formoterol acting) Page 51 Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed.  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM ADRENERGIC AGONISTS DRUGS RECEPTOR THERAPEUTIC USES ADVERSE EFFECTS SPECIFICITY INDIRECT-ACTING As a CNS stimulant in treatment of Its use in pregnancy Amphetamine α, β, CNS children with attention deficit syndrome, should be avoided narcolepsy, and appetite control because of adverse effects on development of the fetus MIXED-ACTION Treatment of asthma Ephedrine α, β, CNS Life-threatening As a nasal decongestant cardiovascular reactions Raise blood pressure Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. 47 Figure 2.37 Some adverse effects observed with adrenergic agonists. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 52  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM Adrenergic Antagonists The adrenergic antagonists (also called blockers or sympatholytic agents) bind to adrenoceptors but do not trigger the usual receptor-mediated intracellular effects. These drugs act by either reversibly or irreversibly attaching to the receptor, thus preventing its activation by endogenous catecholamines. Like the agonists, the adrenergic antagonists are classified according to their relative affinities for α or β receptors in the peripheral nervous system. α-Adrenergic Blocking Agents Drugs that block α-adrenoceptors profoundly affect blood pressure. Because normal sympathetic control of the vasculature occurs in large part through agonist actions on α- adrenergic receptors, blockade of these receptors reduces the sympathetic tone of the blood vessels, resulting in decreased peripheral vascular resistance. This induces a reflex tachycardia resulting from the lowered blood pressure. Note: β receptors, including β1-adrenoceptors on the heart, are not affected by α blockade. The α-adrenergic blocking agents, phenoxybenzamine and phentolamine, have limited clinical applications. β-Adrenergic Blocking Agents All the clinically available β-blockers are competitive antagonists. Nonselective β- 48 blockers act at both β1 and β2 receptors, whereas cardio-selective β antagonists primarily block β1 receptors Note: There are no clinically useful β2 antagonists. Although all β-blockers lower blood pressure in hypertension, they do not induce postural hypotension, because the α-adrenoceptors remain functional. Therefore, normal sympathetic control of the vasculature is maintained. β-Blockers are also effective in treating angina, cardiac arrhythmias, myocardial infarction, congestive heart failure, hyperthyroidism, and glaucoma, as well as serving in the prophylaxis of migraine headaches. Note: The names of all β-blockers end in ”-olol” except for labetalol and carvedilol. Page 53  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM ADRENERGIC ANTAGONISTS DRUGS RECEPTOR THERAPEUTIC USES ADVERSE EFFECTS SPECIFICITY α-ADRENERGIC BLOCKING AGENTS α1, α2 Treatment of pheochromocytoma Postural hypotension Nasal stuffiness Chronic management of tumors Nausea Phenoxybenzamine Vomiting Treatment of Raynaud disease Tachycardia Treatment of hypertension Treatment of Raynaud disease Postural hypotension Phentolamine Arrhythmia α2 Treatment of hypertension Anginal pain Prazosin α1 Treatment of hypertension Dizziness Terazosin Lack of energy Doxazosin Nasal congestion Tamsulosin Headache Drowsiness Orthostatic hypotension β-ADRENERGIC BLOCKING AGENTS β1, β2 Hypertension Arrhythmia Glaucoma Bronchoconstriction Propranolol Migraine Sexual dysfunction Angina pectoris Myocardial infarction 49 Hyperthyroidism Timolol β1, β2 Glaucoma Nadolol Hypertension Acebutolol β1 Atenolol Hypertension Metoprolol Esmolol Pindolol β1, β2 Hypertension acebutolol Labetalol α1 , β1, β2 Hypertension Drowsiness Carvedilol Congestive heart failure Orthostatic hypotension Page 54  Discussion III. DRUGS AFFECTING THE AUTONOMIC NERVOUS SYSTEM 50 Figure 2.38 Comparison of agonists, antagonists, and partial agonists of β adrenoreceptors. Source: Lippincott’s Illustrated Reviews: Pharmacology. 4th ed. Page 55  Learning Check LEARNING CHECK 2.2 Explain the drug development and testing processes required to bring a drug to market: 51 Page 56  Learning Check LEARNING CHECK 2.3 Provide the correct information to the numbered boxes using the following phrases or terms: (15 points) 52 Page 83  Evaluation Performance Task Infographic Create an infographic on the topics discussed in Module 2, focusing on the Drugs affecting the Autonomic Nervous System and Central Nervous System. The Tips for Creating Infographic and the Grading Rubric for Infographic will be posted in our google classroom. (20 points) 53 Page 84  Evaluation Written Work Module Quiz An online chapter/module quiz will be given which will cover all learning outcomes. 54 Page 85 Rubrics 55 Page 86  Reflection Post-lesson Self-Reflection: What students think they learned? 1. What concept or skill did you learn in this module? 2. What is unclear or confusing? 3. Does the information you learned today connect to something else you’ve learned in the past? 4. What did I learn from this module that will help me in the future? 56 Page 87  References Textbooks  Brunton L, Hilal-Dandan R, Knollman BC. 2018. Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 13th ed. McGraw Hill-Education, United States of America.  Katzung, Bertram G. 2018. Basic and Clinical Pharmacology. 14th ed. McGraw Hill- Education, United States of America Online References  Autonomic Nervous System at https://courses.lumenlearning.com/epcc-austincc-ap1- 2/chapter/divisions-of-the-autonomic-nervous-system/ YouTube links  Introduction to Autonomic Nervous System at https://www.youtube.com/watch?v=7EkB9obPnM0  Autonomic Nervous System: Sympathetic vs Parasympathetic, Animation at https://www.youtube.com/watch?v=D96mSg2_h0c  AUTONOMIC NERVOUS SYSTEM at https://www.youtube.com/watch?v=qeXP_ricT4s  Action Potential in the Neuron at https://www.youtube.com/watch?v=oa6rvUJlg7o  Action Potential in Neurons at https://www.youtube.com/watch?v=iBDXOt_uHTQ  Nerve impulse Animation at https://www.youtube.com/watch?v=dSkxlpNs3tU  Chemical Synapse Animation at https://www.youtube.com/watch?v=mItV4rC57kM  Cholinergic Drugs - Pharmacology, Animation at https://www.youtube.com/watch?v=EwsVmTOBZrc  Cholinergic Agonists and Antagonists animation video at https://www.youtube.com/watch?v=TVFQ7YbKZBE 57  Pharmacology - ADRENERGIC RECEPTORS & AGONISTS at https://www.youtube.com/watch?v=KtmV-yMDYPI  Adrenergic Drugs - Pharmacology, Animation at https://www.youtube.com/watch?v=FCOJq_G-1TE  Adrenergic Synthesis And Metabolism animation at https://www.youtube.com/watch?v=H1qUpuf0ZP4  Nerve Synapse Animation at https://www.youtube.com/watch?v=ecGEcj1tBBI  central nervous system at https://www.youtube.com/watch?v=0yXMGQaVVXg Page 88  References YouTube links  A Journey Through Your Nervous System at https://www.youtube.com/watch?v=VAEmxt78bBI  The Influence of Drugs on Neurotransmitters at https://www.youtube.com/watch?v=mVJjWYXS4JM  How do drugs affect the brain? at https://www.youtube.com/watch?v=8qK0hxuXOC8  Drugs and the Nervous System at https://www.youtube.com/watch?v=3LTPX5yZYqk  Understanding Parkinson's disease at https://www.youtube.com/watch?v=ckn9zybpYZ8  Inside Alzheimer’s disease at https://www.youtube.com/watch?v=zTd0-A5yDZI  Mechanisms and secrets of Alzheimer's disease: exploring the brain at https://www.youtube.com/watch?v=dj3GGDuu15I  Neuroscience Basics: GABA Receptors and GABA Drugs at https://www.youtube.com/watch?v=MRr6Ov2Uyc4  How do antidepressants work? at https://www.youtube.com/watch?v=ClPVJ25Ka4k  What causes panic attacks, and how can you prevent them? at https://www.youtube.com/watch?v=IzFObkVRSV0  What is schizophrenia? at https://www.youtube.com/watch?v=K2sc_ck5BZU  OPIOIDS (MADE EASY) at https://www.youtube.com/watch?v=t2tKyjj7u5Y  This Is What Happens to Your Brain on Opioids | Short Film Showcase at https://www.youtube.com/watch?v=NDVV_M__CSI  How Do Pain Relievers Work? at https://www.youtube.com/watch?v=9mcuIc5O-DE  Epilepsy: Types of seizures, Symptoms, Pathophysiology, Causes and Treatments at https://www.youtube.com/watch?v=RxgZJA625QQ 58  ANTIEPILEPTIC DRUGS (MADE EASY) at https://www.youtube.com/watch?v=xFUHE9gX6W8 Page 89