Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Chapter 15 Cholinesterase Inhibitors and Their Use in Myasthenia Gravis

2Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Cholinesterase Inhibitors  Drugs that prevent the degradation of acetylcholine (ACh) by acetylcholinesterase  Viewed as indirect-acting cholinergic agonists  Lack selectivity (muscarinic, ganglionic, and neuromuscular)  Limited therapeutic applications

3Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Structural formulas of reversible cholinesterase inhibitors.

4Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Hydrolysis of acetylcholine by cholinesterase.

5Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Inhibition of cholinesterase by reversible and “irreversible” inhibitors. (See text for details.)

6Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Cholinesterase Inhibitors  “Reversible” cholinesterase inhibitors  Neostigmine  Other reversible cholinesterase inhibitors  “Irreversible” cholinesterase inhibitors  Basic pharmacology  Toxicology

7Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. “Reversible” Cholinesterase Inhibitors  Neostigmine (Prostigmin)  Cannot readily cross membranes  Absorbed poorly with oral administration  Minimal effects on brain and fetus  Poor substrate for cholinesterase (ChE)

8Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Neostigmine (Prostigmin)  Mechanism of action  Pharmacologic effects Therapeutic administration: muscarinic receptors Therapeutic administration: muscarinic receptors  Muscarinic responses Identical to muscarinic agonist response Identical to muscarinic agonist response

9Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Neostigmine (Prostigmin)  Mechanism of action  Neuromuscular effects Therapeutic dose: increases force of contraction in skeletal muscle Therapeutic dose: increases force of contraction in skeletal muscle Toxic levels: decrease force of contraction Toxic levels: decrease force of contraction  Central nervous system Therapeutic levels: mild stimulation Therapeutic levels: mild stimulation Toxic levels: depress the CNS Toxic levels: depress the CNS

10Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Neostigmine (Prostigmin)  Therapeutic uses  Myasthenia gravis  Reversal of nondepolarizing neuromuscular blockade Used postoperatively Used postoperatively Treatment of overdose Treatment of overdose Likely to elicit substantial muscarinic responses Likely to elicit substantial muscarinic responses May need to administer atropine (muscarinic antagonist) May need to administer atropine (muscarinic antagonist)

11Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Neostigmine (Prostigmin)  Adverse effects/acute toxicity  Excessive muscarinic stimulation  Neuromuscular blockade  Treatment with antagonist  Precautions and contraindications  Obstruction of GI or urinary tract  Peptic ulcer disease  Asthma  Coronary insufficiency  Hyperthyroidism

12Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Neostigmine (Prostigmin)  Drug interactions  Muscarinic antagonists  Nondepolarizing neuromuscular blockers  Depolarizing neuromuscular blockers

13Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Other “Reversible” Cholinesterase Inhibitors  Physostigmine  Ambenonium, edrophonium, and pyridostigmine  Echothiophate  Drugs for Alzheimer’s disease

14Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. “Irreversible” Cholinesterase Inhibitors  Highly toxic  Primarily used as insecticides  Only clinical application is glaucoma  All contain an atom of phosphorus  Almost all are highly lipid soluble  Readily absorbed from several routes  Potential use in chemical warfare

15Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. “Irreversible” Cholinesterase Inhibitors  Toxicology  Sources of poisoning  Symptoms Cholinergic crisis Cholinergic crisis  Treatment Mechanical ventilation Mechanical ventilation Pralidoxime Pralidoxime Diazepam Diazepam  Pralidoxime Specific antidote to poisoning Specific antidote to poisoning Effectiveness impacted by early administration Effectiveness impacted by early administration

16Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Fig Structural formulas of “irreversible” cholinesterase inhibitors.

17Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Myasthenia Gravis  Pathophysiology  Characterized by fluctuating muscle weakness and predisposition to rapid fatigue  Common symptoms Ptosis, dysphagia, weakness of skeletal muscles Ptosis, dysphagia, weakness of skeletal muscles  Autoimmune process in which antibodies attack nicotinic M receptors on skeletal muscle

18Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Myasthenia Gravis  Treatment with cholinesterase inhibitors  Beneficial effects Increased muscle strength Increased muscle strength  Side effects Excessive muscarinic response Excessive muscarinic response  Dosage adjustment Start small and adjust to patient response Start small and adjust to patient response May need to modify dosage in anticipation of exertion May need to modify dosage in anticipation of exertion Signs of undermedication Signs of undermedication  Ptosis, difficulty in swallowing Signs of overmedication Signs of overmedication  Excessive salivation and other muscarinic responses

19Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc. Myasthenia Gravis  Myasthenic crisis and cholinergic crisis  Cholinergic crisis Characterized by extreme muscle weakness or frank paralysis and signs of excessive muscarinic stimulation Characterized by extreme muscle weakness or frank paralysis and signs of excessive muscarinic stimulation Treatment with respiratory support and atropine Treatment with respiratory support and atropine  Distinguishing myasthenic crisis from cholinergic crisis History of medication use or signs of excessive muscarinic stimulation assist with differential diagnosis. History of medication use or signs of excessive muscarinic stimulation assist with differential diagnosis.  Use of identification by the patient