1. Cholinesterase Inhibitors (Indirect acting cholinergic agonists)
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Saja Hamed, Ph.D

2. prevent the degradation of ACh by acetylcholinesterase
limited therapeutic applications
they lack selectivity.
two basics category:
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Saja Hamed, Ph.D

3. 19/03/1440
Saja Hamed, Ph.D

4. Reversible inhibitors:
Neostigmine:
absorbed poorly from the GI tract, and has minimal effect on the brain and fetus
one molecule of ChE can break down a huge amount of ACh in a very short time
ChE splits neostigmine more slowly than it splits Ach
19/03/1440
Saja Hamed, Ph.D

5. Pharmcologic effects:
In sufficient doses it intensify transmission at junctions where ACh is the transmitter  skeletal muscle stimulation, activation of muscarinic receptors, ganglionic stimulation, activation of cholinergic receptors in the CNS
At therapeutic doses it affects only the muscarinic receptors and nicotinic receptors of the NMJ
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Saja Hamed, Ph.D

6. Pharmacokinetics: administered orally poorly absorbed
Duration of action: 2-4 hours
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Saja Hamed, Ph.D

7. Therapeutic Uses: Oral therapy of myasthenia gravis:
neuromuscular disorders: antibodies against nicotinicM receptors on skeletal muscles
muscle weakness: Drooping eyelids, difficulty swallowing, weakness of skeletal muscle, difficulty breathing
 Myasthenia crisis vs. cholinergic crisis all share the muscle weakness and paralysis
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Saja Hamed, Ph.D

8. Adverse effects:
excessive muscarinic stimulation: excessive salivation, increased gastric secretions, increased tone and motility of the GI, urinary urgency, bradycardia, sweating, miosis
Neuromuscular blockade : at therapeutic doses they inc force of contraction, in toxic doses they reduce the force of contraction because excessive amount of ACh at he NMJ keep the motor end plate in a state of constant depolarization. Paralysis of respiratory muscle can be fatal
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Saja Hamed, Ph.D

9. Precautions and contraindications:
same as direct-acting muscarinic agonists: Obstruction of the GI, obstruction of the UT, peptic ulcer, asthma, coronary insufficiency, hyperthyroidism
Acute toxicity:
excessive muscarinic stimulation and respiratory depression
IV atropine and mechanical ventilation with oxygen (Respiratory depression cannot be managed by drug)
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Saja Hamed, Ph.D

10. b. Physotigmine: readily crosses membranes[A1]
drug of choice for treating poisoning by atropine and other drugs that cause muscarinic blockade[A3]
IM or slow IV injection
It counteract antimuscarinic poisoning by causing ACh to build up at muscarinic receptors. The accumulated ACh compete with muscarinic blockade for receptor binding and thereby reverse receptor blockade
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Saja Hamed, Ph.D

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Saja Hamed, Ph.D

12. Edrophonium for diagnosis of myasthenia gravis
Edrophonium for diagnosis of myasthenia gravis. IV injection lead to a rapid increase in muscle strength
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Saja Hamed, Ph.D

13. Irreversible inhibitors:
highly toxic
insecticides
nerve agents (World war II)
known as organophosphate cholinesterase inhibitors
lipid soluble (Easily absorbed from the skin that is why they are useful insecticides and chemical warfare)
effects persist until new molecules of cholinesterase is synthesized
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Saja Hamed, Ph.D

14. Toxicology: agricultural workers
excessive muscarinic stimulation and depolarizing neuromuscular blockade  paralysis and death from apnea
treatment: mechanical ventilation, giving atropine to reverse muscarinic stimulation, giving pralidoxime to reverse inhibition of cholinesterase  
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Saja Hamed, Ph.D

15. Pralidoxime:
Antidote
Effective at NMJ
Cannot cross BBB
Must be administered soon after poisoning otherwise aging take place
The bond bet organophosphate and cholinesterase increases in strength. Once aging take place pralidoxime unable to dissociate inhibitor from the enzyme. Aging varies according to nerve agents from 2 minutes up to 13 hours
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Saja Hamed, Ph.D

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Saja Hamed, Ph.D

17. Neuromuscular blocking agents
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Saja Hamed, Ph.D

18. All act by competing with ACh at nicotinicM receptors
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Saja Hamed, Ph.D

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Saja Hamed, Ph.D

20. Muscle relaxation during surgery:
block nicotinicM receptors at the NMJ (Prevent Ach from binding causing muscle relaxation)
Muscle relaxation during surgery:
a. relaxation of skeletal muscles to make the surgeon’s work easier.
b. allow us to decrease the dosage of general anesthetic thereby decreasing the risk associated with anesthesia (Dec. the risk of respiratory depression and recovery occurs fast)
See attached information
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Saja Hamed, Ph.D

21. a. Nondepolarizing Neuromuscular blockers:
1. Tubocurarine:
curare: an arrow poison used for hunting by South American Indian (Cause relaxation (paralysis) of skeletal muscle. Death from paralysis of respiration muscles)
carry a positive charge
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Saja Hamed, Ph.D

22. Pharmacologic effects:
Muscle relaxation: produces a state of flaccid paralysis
Hypotension: by release of histamine and partial ganglionic blockade[A3]
Have no effect on CNS (Do not diminish consciousness or perception of pain even with complete paralysis)
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Saja Hamed, Ph.D

23. IV: paralysis develops in minutes Several hours for complete recovery
Pharmacokinetics:
IV: paralysis develops in minutes
Several hours for complete recovery
Therapeutic uses:
muscle relaxation during surgery, mechanical ventilation, endotracheal intubation
Adverse effects:
respiratory arrest: facilities for artificial ventilation must be immediately available
hypotension, bradycardia, and cardiac arrest
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Saja Hamed, Ph.D

24. Precautions and contraindications: Myasthenia Gravis
The dosage of neuromuscular blocker should be reduced when combined with general anesthetics
Toxicology:
Overdose lead to apnea
Apnea managed by respiratory support and a cholinesterase inhibitor (e.g. neostigmine)
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Saja Hamed, Ph.D

25. b. Depolarizing neuromuscular blockers:
1. Succinylcholine:
 binds to nicotinicM receptors and causes depolarization muscle contractions remains bound prevent repolarizing paralysis
The end plate must repeatedly depolarize and repolarize to maintain contraction
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Saja Hamed, Ph.D

26. Pharmacologic effects: muscle relaxation
no effect on CNS: Causes complete paralysis without decreasing consciousness or pain
Pharmacokinetics:
short duration of action
IV injection: solutions unstable  use within 24hours. Multidose vials are stable up to 2 weeks
Rapidly degraded by plasma cholinesterase
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Saja Hamed, Ph.D

27. apnea in patients with low pseudocholinesterase activity
Therapeutic Uses:
Muscle relaxation during short procedures (Endotracheal intubation, endoscopy, electroconvulsive therapy)
Adverse effects:
apnea in patients with low pseudocholinesterase activity
postoperative muscle pain (neck, shoulders, back): hours after surgery and may persists several hours or even days
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Saja Hamed, Ph.D

28. Cholinesterase inhibitors potentiate the effects of succinylcholine
Drug interactions:
Cholinesterase inhibitors potentiate the effects of succinylcholine
No antidote to succinylcholine poisoning (Supportive management)
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Saja Hamed, Ph.D