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

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Cholinergic Drugs  Toxicology encompasses  Nicotine  Insecticides  Chemical warfare

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.

5 Tips for Understanding the Cholinergic Drugs  Know the receptors that the drug affects.  Know the normal responses to activation of those receptors.  Know whether the drug in question increases or decreases receptor activation.

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Master Keys to Cholinergic Drugs

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Master Keys to Cholinergic Drugs

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Tips for Understanding the Cholinergic Drugs  Bethanechol (prototype drug)  Selective agonist at muscarinic cholinergic receptors  Refer to Table  Note the effects muscarinic receptors can produce.  Bethanechol activates muscarinic receptors (agonist).  Know which receptors a drug interacts with (Table 14-2) and what those receptors do (Table 14-2).  You can predict the types of responses you might expect from bethanechol.

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Agonists and Antagonists  Muscarinic agonists  Bethanechol  Other muscarinic agonists  Toxicology of muscarinic agonists

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Agonists and Antagonists  Principal structures affected by muscarinic activation  Heart: bradycardia  Exocrine glands: increase sweating, salivation, bronchial secretions, and secretion of gastric acid  Smooth muscles Contraction in lung (constriction) Contraction in lung (constriction) GI tract (increased tone/motility) GI tract (increased tone/motility) Bladder (contraction of detrusor) Bladder (contraction of detrusor) Vascular (relaxation, vasodilation, hypotension) Vascular (relaxation, vasodilation, hypotension) Eye (pupillary constriction and ciliary contraction) Eye (pupillary constriction and ciliary contraction)

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Agonists  Bethanechol  Mechanism of action  Pharmacologic effects  Pharmacokinetics  Therapeutic uses  Urinary retention  Gastrointestinal uses

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Agonists  Adverse effects  Cardiovascular system  Alimentary system  Urinary tract  Exacerbation of asthma  Dysrhythmias in hyperthyroid patients  Preparations, dosage, and administration

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Structures of muscarinic agonists.

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Muscarinic Agonists  Cevimeline  Actions and uses  Adverse effects  Drug interactions  Preparations, dosage, and administration

16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Muscarinic Agonists  Pilocarpine  Glaucoma  Acetylcholine  Miosis  Muscarine  Present in poisonous mushrooms

17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. 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.

18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Overactive Bladder  Affects up to one-third of Americans  Can develop at any age, but is most predominant in elderly patients  Two modes of treatment: behavioral therapy and drug therapy  If ineffective—percutaneous tibial nerve stimulation (PTNS) may be tried.

19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Antagonists (Anticholinergic Drugs)  Competitively block the actions of acetylcholine at muscarinic receptors  Most muscarinic receptors on structures innervated by parasympathetic nerves  Also known as parasympatholytic drugs, antimuscarinic drugs, muscarinic blockers, and anticholinergic drugs  Anticholinergic drugs: produce selective blockade of muscarinic receptors—not all cholinergic receptors

20Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Antagonists (Anticholinergic Drugs)  Certain drugs (antihistamines, tricyclic antidepressants, phenothiazine antipsychotics) have prominent antimuscarinic actions.  Use with caution—or not at all—with patients receiving other muscarinic antagonists.

21Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine  Best known muscarinic antagonist  Found in nature  Mechanism of action No direct effect of its own No direct effect of its own Muscarinic receptor blockade Muscarinic receptor blockade

22Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine  Pharmacologic effects (receptor blockade) Heart Heart Exocrine glands Exocrine glands Smooth muscle Smooth muscle Eye Eye CNS CNS Dose dependency of muscarinic blockade Dose dependency of muscarinic blockade Pharmacokinetics Pharmacokinetics

23Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine (cont’d)  Therapeutic uses Preanesthetic medication Preanesthetic medication Disorders of the eye Disorders of the eye Bradycardia Bradycardia Intestinal hypertonicity and hypermotility Intestinal hypertonicity and hypermotility Muscarinic agonist poisoning Muscarinic agonist poisoning Peptic ulcer disease Peptic ulcer disease Asthma Asthma Biliary colic Biliary colic

24Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine (cont’d)  Adverse effects Xerostomia (dry mouth) Xerostomia (dry mouth) Blurred vision and photophobia Blurred vision and photophobia Elevation of intraocular pressure Elevation of intraocular pressure Urinary retention Urinary retention Constipation Constipation Anhidrosis Anhidrosis Tachycardia Tachycardia Asthma Asthma

25Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Muscarinic Antagonists (Anticholinergic Drugs)  Atropine (cont’d)  Drug interactions Avoid combining atropine with other drugs capable of causing muscarinic blockade Avoid combining atropine with other drugs capable of causing muscarinic blockade  Preparations, dosage, and administration General systemic therapy General systemic therapy AtroPen for cholinesterase inhibitor poisoning AtroPen for cholinesterase inhibitor poisoning Ophthalmology Ophthalmology

26Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Anticholinergic Drugs for Overactive Bladder  Overactive bladder (OAB): characteristics and overview of treatment  Introduction to anticholinergic therapy of OAB  Specific anticholinergic drugs for OAB  Oxybutynin (Ditropan, Oxytrol, Gelnique) Syrup Syrup Extended-release tablets Extended-release tablets Transdermal patch and gel Transdermal patch and gel

27Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Anticholinergic Drugs for Overactive Bladder  Specific anticholinergic drugs for OAB (cont’d)  Darifenacin  Solifenacin  Tolterodine Immediate-release tablets Immediate-release tablets Extended-release capsules Extended-release capsules  Trospium  Fesoterodine

28Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other Muscarinic Antagonists  Scopolamine  Ipratropium bromide  Antisecretory anticholinergics  Dicyclomine  Pirenzepine and telenzepine  Mydriatic-cycloplegics  Centrally acting anticholinergics

29Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Toxicology of Muscarinic Agonists  Source of muscarinic poisoning  Direct-acting muscarinic agonists  Cholinesterase inhibitors  Symptoms  Result from excessive activation of muscarinic receptors  Treatment  Muscarinic blocking agent, such as atropine

30Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Toxicology of Muscarinic Antagonists  Sources of antimuscarinic poisoning  Natural products  Selective antimuscarinic drugs  Drugs with pronounced antimuscarinic properties

31Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Toxicology of Muscarinic Antagonists  Symptoms  Dry mouth  Blurred vision  Photophobia  Hyperthermia  CNS effects  Hot, dry, and flushed skin

32Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Toxicology of Muscarinic Antagonists  Treatment  Physostigmine  Inhibitor of acetylcholinesterase  Warning  Differentiate between poisoning and an actual psychotic episode!