Transcript Chapter_015
Chapter 15
Cholinesterase Inhibitors and
Their Use in Myasthenia Gravis
Copyright © 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
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Fig. 15-1. Structural formulas of reversible cholinesterase inhibitors.
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Fig. 15-2. Hydrolysis of acetylcholine by cholinesterase.
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Fig. 15-3. Inhibition of cholinesterase by reversible and “irreversible” inhibitors.
(See text for details.)
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Cholinesterase Inhibitors
“Reversible” cholinesterase inhibitors
Neostigmine
Other reversible cholinesterase inhibitors
“Irreversible” cholinesterase inhibitors
Basic pharmacology
Toxicology
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“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)
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Neostigmine (Prostigmin)
Mechanism of action
Pharmacologic effects
• Therapeutic administration: muscarinic
receptors
Muscarinic
responses
• Identical to muscarinic agonist response
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Neostigmine (Prostigmin)
Mechanism of action
Neuromuscular effects
• Therapeutic dose: increases force of
contraction in skeletal muscle
• Toxic levels: decrease force of contraction
Central
nervous system
• Therapeutic levels: mild stimulation
• Toxic levels: depress the CNS
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Neostigmine (Prostigmin)
Therapeutic uses
Myasthenia gravis
Reversal of nondepolarizing neuromuscular
blockade
• Used postoperatively
• Treatment of overdose
• Likely to elicit substantial muscarinic responses
• May need to administer atropine (muscarinic antagonist)
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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
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Neostigmine (Prostigmin)
Drug interactions
Muscarinic antagonists
Nondepolarizing neuromuscular blockers
Depolarizing neuromuscular blockers
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Other “Reversible”
Cholinesterase Inhibitors
Physostigmine
Ambenonium, edrophonium, and
pyridostigmine
Echothiophate
Drugs for Alzheimer’s disease
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“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
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“Irreversible”
Cholinesterase Inhibitors
Toxicology
Sources of poisoning
Symptoms
• Cholinergic crisis
Treatment
• Mechanical ventilation
• Pralidoxime
• Diazepam
Pralidoxime
• Specific antidote to poisoning
• Effectiveness impacted by early administration
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Fig. 15-4. Structural formulas of “irreversible” cholinesterase inhibitors.
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Myasthenia Gravis
Pathophysiology
Characterized by fluctuating muscle weakness
and predisposition to rapid fatigue
Common symptoms
• Ptosis, dysphagia, weakness of skeletal muscles
Autoimmune process in which antibodies attack
nicotinicM receptors on skeletal muscle
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Myasthenia Gravis
Treatment with cholinesterase inhibitors
Beneficial effects
• Increased muscle strength
Side effects
• Excessive muscarinic response
Dosage adjustment
• Start small and adjust to patient response
• May need to modify dosage in anticipation of exertion
• Signs of undermedication
Ptosis, difficulty in swallowing
Excessive salivation and other muscarinic responses
• Signs of overmedication
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Myasthenia Gravis
Myasthenic crisis and cholinergic crisis
Cholinergic crisis
• Characterized by extreme muscle weakness or frank
paralysis and signs of excessive muscarinic stimulation
• 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.
Use of identification by the patient
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