Chapter_015

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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
2
Fig. 15-1. Structural formulas of reversible cholinesterase inhibitors.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
3
Fig. 15-2. Hydrolysis of acetylcholine by cholinesterase.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
4
Fig. 15-3. Inhibition of cholinesterase by reversible and “irreversible” inhibitors.
(See text for details.)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Cholinesterase Inhibitors

“Reversible” cholinesterase inhibitors



Neostigmine
Other reversible cholinesterase inhibitors
“Irreversible” cholinesterase inhibitors


Basic pharmacology
Toxicology
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Neostigmine (Prostigmin)

Mechanism of action
 Pharmacologic effects
• Therapeutic administration: muscarinic
receptors
 Muscarinic
responses
• Identical to muscarinic agonist response
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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)
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Neostigmine (Prostigmin)

Drug interactions



Muscarinic antagonists
Nondepolarizing neuromuscular blockers
Depolarizing neuromuscular blockers
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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Other “Reversible”
Cholinesterase Inhibitors




Physostigmine
Ambenonium, edrophonium, and
pyridostigmine
Echothiophate
Drugs for Alzheimer’s disease
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
15
Fig. 15-4. Structural formulas of “irreversible” cholinesterase inhibitors.
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
16
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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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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
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
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