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Chapter 15

Chapter 15. Cholinesterase Inhibitors and Their Use in Myasthenia Gravis. Cholinesterase Inhibitors. Drugs that prevent the degradation of acetylcholine (ACh) by acetylcholinesterase Viewed as indirect-acting cholinergic agonists Lack selectivity (muscarinic, ganglionic, and neuromuscular)

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Chapter 15

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  1. Chapter 15 Cholinesterase Inhibitors and Their Use in Myasthenia Gravis

  2. 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

  3. Fig. 15-1. Structural formulas of reversible cholinesterase inhibitors.

  4. Fig. 15-2. Hydrolysis of acetylcholine by cholinesterase.

  5. Fig. 15-3. Inhibition of cholinesterase by reversible and “irreversible” inhibitors. (See text for details.)

  6. Cholinesterase Inhibitors • “Reversible” cholinesterase inhibitors • Neostigmine • Other reversible cholinesterase inhibitors • “Irreversible” cholinesterase inhibitors • Basic pharmacology • Toxicology

  7. “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)

  8. Neostigmine (Prostigmin) • Mechanism of action • Pharmacologic effects • Therapeutic administration: muscarinic receptors • Muscarinic responses • Identical to muscarinic agonist response

  9. 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

  10. 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)

  11. 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

  12. Neostigmine (Prostigmin) • Drug interactions • Muscarinic antagonists • Nondepolarizing neuromuscular blockers • Depolarizing neuromuscular blockers

  13. Other “Reversible”Cholinesterase Inhibitors • Physostigmine • Ambenonium, edrophonium, and pyridostigmine • Echothiophate • Drugs for Alzheimer’s disease

  14. “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

  15. “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

  16. Fig. 15-4. Structural formulas of “irreversible” cholinesterase inhibitors.

  17. 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

  18. 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

  19. 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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