Term
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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 |
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Term
| Neostigmine; Pyridostigmine |
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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) |
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Term
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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) |
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Term
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Definition
| Reversible AChE inhibitors |
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Term
| What's the MOA for AChE inhibitors? |
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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 |
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Term
| What happens to acetylcholine in the presence of neostigmine? |
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Definition
ACH won't be broken down and
End result: prolonged activity of ACh at the receptor |
|
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Term
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Definition
| PS ganglia, S ganglia, heart, NMJ |
|
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Term
| what two agents can be used to treat post-operative abdominal distension and urinary retention? |
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Definition
| Bethanechol and neostigmine |
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Term
| What happens in myasthenia gravis? |
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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 |
|
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Term
| how can we increase muscle strength in patients with myasthenia gravis? |
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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 |
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Term
| How can too much neostigmine produce muscle weakness? |
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Definition
| too much neostigmine for too long causes depolarization blockade (i.e. no time for muscle cells to repolarize) |
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Term
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Definition
irreversible AChE inhibitors/organophosphorus compounds
-positively charged; not volatile
therapeutic use (last resort):
-miotic, glaucoma
-adverse effect is lens opacities |
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Term
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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 |
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Term
|
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 |
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Term
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Definition
irreversible AChE inhibitors/organophosphorus compounds
-WAY more toxic than parathion or malathion
-nerve gas |
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Term
| MOA of irreversible AChE inhibitors |
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Definition
| irreversibly phosphorylate (hence inactivate) AChE |
|
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Term
| If we irreversibly inactivate AChE, what effect will that have on ACh? |
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Definition
| ACH will stay around forever until make new ACHE (but you'd be dead by then) |
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Term
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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 |
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Term
| What are AChE inhibitor adverse effects? |
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Definition
| lens opacities (echothiophate), chornic neurotoxicity(?), cholinergic overstimulation or cholinergic crisis (see page 52) |
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Term
| what effects will be caused by excessive simtulation of M receptors? |
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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 |
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Term
| What CNS effects will be caused by excessive stimulation of M receptors? |
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Definition
| confusion, ataxia, slurred speech, loss of reflexes, convulsions, coma, central respiratory paralysis |
|
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Term
| what happens at the NMJ with excessive stimulation of M receptors? |
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Definition
1st thing see is contraction but then get paralysis due to depolarization blockade
-involuntary twitching, severe weakness, paralysis |
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Term
| what's the cause of death in excessive stimulation of M receptor? |
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Definition
| mostly respiratory failure; CV collapse (bp=0) |
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Term
| How do you treat excessive stimulation of M receptor/cholinergic overstimulation? |
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Definition
| Muscarinic blocker (i.e. atropine) and a cholinesterase reactivator (e.g. pralidoxime (2-PAM) |
|
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Term
| will a muscarinic antagonist counteract the effect of sarin on the skeletal m. NMJ? |
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Definition
| No; it's Nm receptors on NMJ |
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Term
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Definition
muscarinic blocker
both central and peripheral effector sites
used for reversible and irreversible AChE inhibitors |
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Term
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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) |
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Term
| What effect will 2-PAM have on a cholinergic crisis that results from an overdose of neostigmine (reversible AChE inhibitor)? |
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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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