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Acetylcholinesterase Inhibitors
pharmacology
28
Pharmacology
Professional
02/21/2012

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Term
Physostigmine
Definition
Reversible AChE inhibitors

site of action: all cholinergic synapses

(not very specific so lots of side effects and not very useful as drug)

-not very large; lipid soluble and CAN cross the BBB (so can have lots of CNS effects)

therapeutic uses:
-miotic; treatment of glaucoma, reverse antimuscarinic effects from lants that contain muscarinic blockers and drugs that have antimuscarinic effects

problem: can cause severe adverse efects-astyole, respiratory problems, seizures
Term
Neostigmine; Pyridostigmine
Definition
Reversible AChE inhibitors

-not lipid soluble; doesn't cross BBB
-direct action on Nm receptors (more selective in NMJ; less effect on autonomic effector sites and ganglia

therapeutic uses:
-postoperative urinary retention and abdominal distension (neostigmine)
-myasthenia gravis (pyridostigmine and neostigmine)

MOA in myasthenia gravis:
-inhibit AChe in the NMJ, which prolongs the life of ACH in the NMJ; N receptors over a greater cross-sectional area of the endplate presumably are exposed to ACH in a sufficient [] for channel opening and production of an postsynaptic EPP

comparatively:
-Neostigmine has 2-4h t1/2 and pyridostigmine is 3-6hr (good for short t1/2 b/c can adjust quickly if take too much); time relased pyridostigmine lasts for ~12hr and good for night use if problem with decrased diaphragm contraction and difficulty breathing

*pyridostigmine can also be used for prevention of nerve gas poisioning (also take muscarinic antagonist to prevent side effects like vasoconstriction)
Term
Edrophonium
Definition
Reversible AChE inhibitors

-analog of neostigmine
-less potent, shorter acting (3-4 min), IV only
-diagnostic test for myasthenia gravis (patient weak-->give drug-->improved muscle strength in 3-5 min and so can diagnose myastenia gravis)
-can assess adequacy of treatment with neostigmine or pyridostigmine
-can differentiate between myasthenic crisis (problems b/c disease) and cholinergic crisis (problem because overdosed drug)
Term
Edrophonium + atropine
Definition
Reversible AChE inhibitors
Term
What's the MOA for AChE inhibitors?
Definition
bind to AChE and are slowly hydrolyzed by the enzyme; this impairs the ability of AChE to hydrolyze acetylcholine; acetylcholine stays in the synaptic terminal for a longer period of time causing increased activity at the receptor
Term
What happens to acetylcholine in the presence of neostigmine?
Definition
ACH won't be broken down and

End result: prolonged activity of ACh at the receptor
Term
where do you see ACH at?
Definition
PS ganglia, S ganglia, heart, NMJ
Term
what two agents can be used to treat post-operative abdominal distension and urinary retention?
Definition
Bethanechol and neostigmine
Term
What happens in myasthenia gravis?
Definition
autoimmune disease

antibodies to the Nm receptor in the NMJ cause down regulation of the receptor; this impairs the action of ACH on skeletal m., causing m. weakness
Term
how can we increase muscle strength in patients with myasthenia gravis?
Definition
increase [] ACH in NMJ

^via AChE inhibitor; wouldn't want to give nicotinic agonist because will activate receptor all the time and not just when want muscle to contract
Term
How can too much neostigmine produce muscle weakness?
Definition
too much neostigmine for too long causes depolarization blockade (i.e. no time for muscle cells to repolarize)
Term
Echothiopate
Definition
irreversible AChE inhibitors/organophosphorus compounds

-positively charged; not volatile

therapeutic use (last resort):
-miotic, glaucoma

-adverse effect is lens opacities
Term
Parathion
Definition
irreversible AChE inhibitors/organophosphorus compounds

-DOES cross BBB
-insecticide
not used clinically; major problem with accidental poisioning

-least toxic compared to malathion and sarin
Term
Malathion
Definition
irreversible AChE inhibitors/organophosphorus compounds

-DOES cross BBB
-insecticide
-low dermal absorption, detox by plasma carboxylesterases more rapidly in mammals and birds than insects;

-used clinically to treat head lice

-more toxic than parathion but way less than sarin
Term
Sarin
Definition
irreversible AChE inhibitors/organophosphorus compounds

-WAY more toxic than parathion or malathion
-nerve gas
Term
MOA of irreversible AChE inhibitors
Definition
irreversibly phosphorylate (hence inactivate) AChE
Term
If we irreversibly inactivate AChE, what effect will that have on ACh?
Definition
ACH will stay around forever until make new ACHE (but you'd be dead by then)
Term
insecticides
Definition
most organophosphates are well absorbed from skin, gut, and conjunctiva; this makes them dangerous to humans and highly effective as insecticides; when dissolved in water they have limited t1/2 in environment
Term
What are AChE inhibitor adverse effects?
Definition
lens opacities (echothiophate), chornic neurotoxicity(?), cholinergic overstimulation or cholinergic crisis (see page 52)
Term
what effects will be caused by excessive simtulation of M receptors?
Definition
cholinergic overstimulation/crisis:

miosis, spasm of accomodiation (can only focus near), extreme salivation, sweating, bronchoconstriction, vomiting (overstim GI tract), diarrhea (overstim gut), bradcardia, hypotension, urinary urgency
Term
What CNS effects will be caused by excessive stimulation of M receptors?
Definition
confusion, ataxia, slurred speech, loss of reflexes, convulsions, coma, central respiratory paralysis
Term
what happens at the NMJ with excessive stimulation of M receptors?
Definition
1st thing see is contraction but then get paralysis due to depolarization blockade

-involuntary twitching, severe weakness, paralysis
Term
what's the cause of death in excessive stimulation of M receptor?
Definition
mostly respiratory failure; CV collapse (bp=0)
Term
How do you treat excessive stimulation of M receptor/cholinergic overstimulation?
Definition
Muscarinic blocker (i.e. atropine) and a cholinesterase reactivator (e.g. pralidoxime (2-PAM)
Term
will a muscarinic antagonist counteract the effect of sarin on the skeletal m. NMJ?
Definition
No; it's Nm receptors on NMJ
Term
Atropine
Definition
muscarinic blocker

both central and peripheral effector sites
used for reversible and irreversible AChE inhibitors
Term
Pralidoxime (2-PAM)
Definition
Cholinesterase Reactivator

-NMJ, autonomic gangalia, peripheral effector sites
-used only for organophosphate poisioning

-breaks P-O bond of irreversible inhibitor, which allows the AChE to break down ACH

(once phosphorylated enzyme complex ages the nucleophilic attach of 2-PAM won't work so want to administer drugs quickly)
Term
What effect will 2-PAM have on a cholinergic crisis that results from an overdose of neostigmine (reversible AChE inhibitor)?
Definition
NO EFFECT

there is no P-O bond, there's a C-O bond so 2-PAM can't break it
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