Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Chapter 14 Muscarinic Agonists and Antagonists

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Principles of Neuropharmacology  Neuropharmacologic agents can be divided into two broad categories:  Peripheral nervous system drugs  Central nervous system drugs 2

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Overview of the Nervous System 3

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Principles of Neuropharmacology  Neuropharmacologic drugs can modify many diverse processes:  Skeletal muscle contraction  Cardiac output  Vascular tone  Respiration  Gastrointestinal function  Uterine motility  Glandular secretion  Ideation, mood, and perception of pain 4

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. PNS: Sympathetic Nervous System Fight-or-Flight  ↑ HR, ↑ BP  ↑ Glucose  Blood shunted to skeletal muscles  Bronchi dilate  Pupils dilate

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. PNS: Parasympathetic Nervous System Rest-and-Digest  ↓ HR, ↓ BP  ↑ Gastric secretion  Emptying of bowel & bladder  Pupils constrict  Contraction of bronchial smooth muscle

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Figure 13.2 Effects of the sympathetic and parasympathetic nervous systems. Source: Biology Guide to the Natural World, 2 nd ed (p. 558) by David Krogh, 2002 Upper Saddle River, NJ, Prentice Hall. Reprinted by permission.

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Principles of Neuropharmacology  How neurons regulate physiologic processes  Basic mechanisms by which neuropharmacologic agents act:  Sites of action: Axons vs. synapses  Steps in synaptic transmission  Effects of drugs on the steps of synaptic transmission 8

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Mechanisms of Neuropharmacologic Agents  Sites of action: Axons vs. synapses  Axonal conduction  Synaptic transmission  Receptors 9

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Mechanisms: Steps in Synaptic Transmission Steps in synaptic transmission: 1. Transmitter synthesis 2. Transmitter storage 3. Transmitter release 4. Receptor binding 5. Termination of transmission 10

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Effects of drugs on the steps of synaptic transmission  Transmitter synthesis  Increase transmitter synthesis  Decrease transmitter synthesis  Cause synthesis of transmitter molecules  Transmitter storage  Cause receptor activation to decrease  Transmitter release  Promote or inhibit release  Receptor binding  Cause activation  Block activation  Enhance activation  Termination of transmission  Block transmitter reuptake  Inhibit transmitter degradation 11

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Multiple Receptor Types and Selectivity of Drug Action  Selectivity  Most desirable quality a drug can have  Able to alter a disease process while leaving other physiologic processes largely unaffected  Act by altering synaptic transmission = greater selectivity 12

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. An Approach to Learning About Peripheral Nervous System Drugs  Three types of information needed:  Type (or types) of receptor(s) through which the drug acts (for example, alpha 1, alpha 2, beta 1 )  Normal response to the activation of those receptors (agonist vs. antagonist)  What the drug in question does to receptor function 13

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Basic Principles of Neuropharmacology  An approach to learning about peripheral nervous system drugs:  Knowing the receptors that the drug affects  Knowing the normal responses to the activation of those receptors  Knowing whether the drug in question increases or decreases receptor activation 14

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Cholinergic Drugs  Agents that influence the activity of cholinergic receptors  Most mimic or block the actions of acetylcholine  Cholinesterase inhibitors  Indirectly prevent the breakdown of acetylcholine 15

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Cholinergic Drugs  Toxicology encompasses the following:  Nicotine  Insecticides  Chemical warfare 16

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 17

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Tips for Understanding the Cholinergic Drugs  Know the receptors that the drug affects  Know the normal responses to the activation of those receptors  Know whether the drug in question increases or decreases receptor activation  Know the master keys to cholinergic drugs (see Tables 14-1 and 14-2 in the text) 18

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Agonists and Antagonists  Muscarinic agonists  Bethanechol  Other muscarinic agonists  Toxicology of muscarinic agonists  Muscarinic antagonists (anticholinergic drugs)  Atropine  Anticholinergic drugs for overactive bladder (urge incontinence)  Other muscarinic antagonists  Toxicology of muscarinic antagonists 19

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Agonists  Bethanechol  “Parasympathomimetic agent”  Selective agonist at muscarinic cholinergic receptors  Heart: Bradycardia  Smooth muscle: Lung: Constriction of the bronchi Gastrointestinal system: Increased tone and motility Bladder: Contraction of detrusor muscle and relaxation of the trigone and sphincter  Exocrine glands: Increased sweating, salivation, bronchial secretions, and secretion of gastric acid  Eye: Miosis and contraction of the ciliary muscle 20

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Agonists  Bethanechol  Therapeutic uses: Urinary retention and investigational gastrointestinal uses  Adverse effects: Cardiovascular system: Hypotension Gastrointestinal system: Increased tone and motility Exacerbation of asthma Dysrhythmias in patients with hyperthyroidism 21

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Agonists  Other muscarinic agonists  Cevimeline: Derivative of acetylcholine  Pilocarpine: Used mainly for topical therapy of glaucoma  Acetylcholine: Used for rapid miosis (pupil constriction) after delivery in cataract surgery 22

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Agonists  Toxicology of muscarinic agonists  Source: Ingestion of certain mushrooms, direct- acting muscarinic agonists, and cholinesterase inhibitors  Symptoms: Profuse salivation, lacrimation (tearing), visual disturbances, bronchospasm, diarrhea, bradycardia, and hypotension with possible cardiovascular collapse  Treatment: Atropine and supportive therapy 23

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Agonists  Principal structures affected by muscarinic activation  Heart: Bradycardia  Exocrine glands: Increased sweating, salivation, bronchial secretions, and secretion of gastric acid  Smooth muscles Contraction in lung (constriction) Gastrointestinal tract (increased tone/motility) Bladder (contraction of detrusor) Vascular (relaxation, vasodilation, and hypotension) Eye (pupillary constriction and ciliary contraction) 24

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. 25

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Overactive Bladder  Also known as urgency incontinence, detrusor instability, and sometimes “can’t- hold-it-anymore” incontinence  Four major symptoms: Urinary urgency, urinary frequency, nocturia, and urge incontinence  Urge incontinence often results from involuntary contractions of the bladder detrusor 26

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Overactive Bladder  Affects up to one third of Americans  Can develop at any age but is most predominant among older adults  Two modes of treatment: Behavioral therapy and drug therapy  If therapy is ineffective, percutaneous tibial nerve stimulation (PTNS) may be tried 27

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Antagonists (Anticholinergic Drugs)  Competitively block the actions of acetylcholine at muscarinic receptors  Most muscarinic receptors are on structures innervated by parasympathetic nerves  Also known as parasympatholytic drugs, antimuscarinic drugs, muscarinic blockers, and anticholinergic drugs  Anticholinergic drugs: Produce the selective blockade of muscarinic receptors (not all cholinergic receptors) 28

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Antagonists (Anticholinergic Drugs)  Certain drugs (antihistamines, tricyclic antidepressants, phenothiazine antipsychotics) have prominent antimuscarinic actions  Use these with caution – or not at all – for patients receiving other muscarinic antagonists 29

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Cholinergic-Blocking Drugs Mnemonic

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine  Best-known muscarinic antagonist  Found in nature  Mechanism of action: No direct effect of its own Muscarinic receptor blockade 31

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine  Pharmacologic effects (receptor blockade) Heart: Increases heart rate Exocrine glands: Decreases secretions Smooth muscle: Relaxes the bronchi, decreases the tone of the urinary bladder detrusor, and decreases the tone and motility of the gastrointestinal tract Eyes: Mydriasis and cycloplegia Central nervous system: Mild excitation to hallucinations and delirium 32

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine (Cont.)  Therapeutic uses Preanesthetic medication Disorders of the eye Bradycardia Intestinal hypertonicity and hypermotility Muscarinic agonist poisoning Peptic ulcer disease Asthma Biliary colic 33

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine (Cont.)  Adverse effects Xerostomia (dry mouth) Blurred vision and photophobia Elevation of intraocular pressure Urinary retention Constipation Anhidrosis Tachycardia Asthma 34

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine (Cont.)  Drug interactions Avoid combining atropine with other drugs capable of causing muscarinic blockade  Preparations, dosage, and administration General systemic therapy AtroPen for cholinesterase inhibitor poisoning Ophthalmology 35

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Anticholinergic Drugs for Overactive Bladder  Overactive bladder (OAB): Characteristics and overview of treatment  Specific anticholinergic drugs for OAB:  Oxybutynin [Ditropan XL, Oxytrol, Gelnique] Syrup Extended-release tablets Transdermal patch and gel MOA: Anticholinergic agent that acts primarily at M 3 muscarinic receptors 36

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Anticholinergic Drugs for Overactive Bladder  Darifenacin  Solifenacin  Tolterodine  Fesoterodine  Trospium  Differs in degree of selectivity  Side effect profile: Dry mouth, QT interval, constipation 37

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Other Muscarinic Antagonists  Scopolamine  Anticholinergic drug with actions much like those of atropine  Therapeutic doses of atropine produce mild central nervous system excitation; therapeutic doses of scopolamine produce sedation  Scopolamine suppresses emesis and motion sickness, whereas atropine does not  Principal uses for scopolamine: Motion sickness, production of cycloplegia and mydriasis for ophthalmic procedures, and production of preanesthetic sedation and obstetric amnesia 38

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Other Muscarinic Antagonists  Ipratropium bromide  Anticholinergic drug  Used to treat asthma, chronic obstructive pulmonary disease (COPD), and rhinitis caused by allergies or the common cold  Inhalation or nasal spray routes: Not associated with typical antimuscarinic side effects (dry mouth, blurred vision, urinary hesitancy, constipation) 39

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Other Muscarinic Antagonists  Antisecretory anticholinergics  Glycopyrrolate [Robinul, Cuvposa], mepenzolate [Cantil], methscopolamine [Pamine], and propantheline  Reduced salivation 40

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Other Muscarinic Antagonists  Dicyclomine  Indicated for irritable bowel syndrome (spastic colon, mucous colitis) and functional bowel disorders (diarrhea, hypermotility) 41

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Other Muscarinic Antagonists  Mydriatic-cycloplegics  Atropine, homatropin, scopolamine, cyclopentolate, and tropicamide  Used to produce mydriasis and cycloplegia during ophthalmic procedures 42

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Other Muscarinic Antagonists  Centrally acting anticholinergics  Parkinson’s disease  Drug-induced parkinsonism  Benefits derive from the blockade of muscarinic receptors in the central nervous system 43

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Toxicology of Muscarinic Agonists  Source of muscarinic poisoning  Direct-acting muscarinic agonists  Cholinesterase inhibitors  Symptoms  Result from the excessive activation of muscarinic receptors  Treatment  Muscarinic blocking agent, such as atropine 44

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Toxicology of Muscarinic Antagonists  Sources of antimuscarinic poisoning  Natural products  Selective antimuscarinic drugs  Drugs with pronounced antimuscarinic properties 45

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Toxicology of Muscarinic Antagonists  Symptoms  Dry mouth  Blurred vision  Photophobia  Hyperthermia  Central nervous system effects  Hot, dry, and flushed skin 46

Copyright © 2016, 2013, 2010 by Saunders, an imprint of Elsevier Inc. All rights reserved. Toxicology of Muscarinic Antagonists  Treatment  Physostigmine  Inhibitor of acetylcholinesterase  Warning  Differentiate between poisoning and an actual psychotic episode 47