Cholinergics - Acetylcholinesterase Inhibitors Flashcards
What is the basic mechanism of an AChE inhibitor?
Enhance the effects of endogenous ACh due to inhibition of AChE -> prevents ACh degradation
Where is the site of action of AChE inhibitors?
Any place where ACh is the neurotransmitter
post-ganglionic parasympathetic neuroeffective junctions
sympathetic and parasympathetic ganglia
skeletal neuromuscular junction
CNS (If drug can penetrate CNS)
What is the general mechanism of enzymatic hydrolysis of ACh? Relative fast or slow process?
ACh binds AChE -> nucleophilic attack by serine -> hydrolysis of ACh and acetylation of serine (on enzyme) ->acetylated serine is rapidly hydrolyzed to regenerate free enzyme
SUPER FAST 10^4 molecules/second
What is the mechanism of action of Edrophonium?
reversible, competitive enzyme inhibitor
binds enzyme non-covalently
What is the duration of action and route of administration of Edrophonium?
short (minutes)
not orally active -> only IV
What are the therapeutic uses of Edrophonium?
Diagnosis of myasthenia gravis
Distinguish cholinergic crisis from myasthenic crisis
Reversal of paralysis by competitive neuromuscular blocking drugs
What is the significance of the structure of Edrophonium?
Quaternary ammonium -> always (+)ve charge -> cannot get into CNS
What is the mechanism of action of reversible substrate inhibitors?
Drug is hydrolyzed by AChE, but at a slow rate -> keeps AChE inactive so ACh can be around longer
What is the mechanism of action of Physostigmine?
reversible substrate inhibitor of AChE, slowly reversible
What is the significance of the structure of Physostigmine?
lipophillic -> can have CNS effects
What are the therapeutic uses of Physostigmine?
Treatment of chronic wide angle glaucoma
Reverse toxicify by antimuscarinic drug poisoning
What is the duration of action of Neostigmine? (and mechanism of action)
slowly reversible, AChE inhibitor
What is the significance of the structure of Neostigmine?
quaternary amine (+) charge -> cannot get into CNS
What are the therapeutic uses of Neostigmine?
Treatment of myasthenia gravis (oral)
prevention and treatment of post operative atony of gut and bladder (oral)
reversal of paralysis by competitive nt blocking drugs (IV)
What are the side effects of AChE inhibitors?
SLUDGE, hypotension, bradycardia, blurred vision
What is the mechanism of action of an Irreversible Organophosphate Inhibitor?
Irreversibly phosphorylates the serine in the substrate-binding domain of AChE
Return of activity depends on regeneration of enzyme -> slow
What is Sarin?
Organohosphate -> irreversibly inhibits AChE -> very lipophillic -> can penetrate into skin, mucosal membranes, and brain, used as nerve gas in chemical warfare
What is Malathion?
Widely used insecticide -> mammals can detox this, but insects cannot. Organophosphate
What are the toxic effects of organophosphates?
SLUDGE, hypotension, bradycardia, difficulty with visual accommodation,
muscle paralysis due to depolarization block at neuromuscular junction
death due to respiratory failure
Symptoms depend on exposure mechanism too
What is the treatment of organophosphate poisoning?
Atropine -> Muscarinic receptor antagonist, blocks peripheral and central muscarinic effects
Pralidoxime - reactivates AChE peripherally, necessary to use w/in 2-3 hours of exposure