Chapter 15
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.
5

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.
6

“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.
7

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.
8

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.
9

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.
10

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.
11

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

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.
13

“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.
14

“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 nicotinic
M receptors on skeletal muscle
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
17

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
•
Signs of overmedication
 Excessive salivation and other muscarinic responses
Copyright © 2013, 2010 by Saunders, an imprint of Elsevier Inc.
18

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.
19