Flashcards in Cholinesterase Inhibitors Deck (24):
What does "reversible" AChase inhibitors mean?
They are either poor substrates to AChE enzyme and are hydrolyzed slowly (i.e. 30 minutes), or they are simple competitive inhibitors
How is physostigmine metabolized and what is it used for? Is it tertiary or quaternary?
Tertiary amine - metabolized by ester hydrolysis in plasma
1. Miotic treatment of glaucoma
2. Reversal of toxic CNS and peripheral effects of muscarinic antagonists (but can cause seizures itself)
Is Neostigmine tertiary or quaternary amine? Why is it superior to physostigmine for management of myasthenia gravis?
It is a quaternary amine (poor oral absorption), so it does have a direct agonist effect to nAChR, as well as anti-cholinesterase activity (works well at NMJ).
Other than MG, when else is neostigmine used? When is it contraindicated?
1. Augment the motility of GI tract or lower urinary tract (Same as bethanocol, but longer term)
2. Reversal of skeletal muscle blockade by competitive antagonists
Like bethanocol, it is contraindicated in mechanical obstruction of the GI tract
What is the mechanism of action of Edrophonium? Quaternary or tertiary?
It is a competitive inhibitor of acetylcholinesterase which does not occupy the esterase site, only the negative site of the enzyme (thus it must be a quaternary amine to interact via positive charge)
Think of the edroPHONE booth in sketchy
Why is edrophonium selective for the NMJ?
It is also a direct agonist of nAChR, so will not produce too high acetylcholine levels at other receptors at the doses used therapeutically
Why is edrophonium good for diagnosing MG?
It has a very short course of action (5 min) -> give to patient following exercise test and see if their muscle force is significantly improved during that time
What drug is primarily used for MG treatment and why?
Pyridostigmine, another quaternary AChE-inhibitor like neostigmine, but has a longer halflife
If MG patients suddenly get weaker, what are the two scenarios you must be testing for? How?
1. Myasthenic weakness -> patient's disease is getting worse
2. Cholinergic crisis -> depolarizing blockade due to too much ACh, as disease has gotten better
Determine which one via edrophonium
What is the goal of Alzheimer's anti-AChE pharmacology? Will it slow the course of the disease?
Recover ACh levels in the CNS to improve symptoms, maximizing the ratio of CNS to peripheral inhibition of the enzyme (fewest side effects)
This will not slow the course of the disease
What was the first approved Alzheimer's ACh drug and why is it not used now?
Tacrine -> too many peripheral effects, and caused hepatotoxicity
What drug replaced Tacrine for Alzheimer's and what is its main concern?
Donepezil -> longer duration, less peripheral effects and no hepatotoxicity. (the old people are DONE with the Pezel (puzzle))
Concern: CYP2D6 and CYP3A4 metabolism for drug interactions
What is Rivastigmine used for?
(Reverse the stigma at the alzheimer's gala) Reversible (slowly-metabolized) AChE inhibitor, new Alzheimer's drug, and does not bind plasma proteins -> fewer drug interactions
What is Galantamine?
(Think of the Alzheimer's gala)Reversible AChE inhibitor, used for Alzheimer's
What is the first drug shown to slow rate of deterioration of Alzheimer's, and what is its mechanism of action?
Memantine - glutamate receptor antagonist
What element is contained in all "irreversible" AChE inhibitors? Mechanism? Why they scary?
Phosphates and some organic substitution (organophosphate)
These are resistant to hydrolysis and require enzymatic turnover to stop action. Really scary because they diffuse well through lipid membranes (lipid-soluble)
What is the only clinically useful irreversible cholinesterase inhibitor, and what is it used for? Why is it not good?
Echothiophate - used for sustained miosis of the eye (3 days or longer)
Not good because it causes lens clouding
What are the two pesticides which use the AChE inhibition mechanism which are used in farming?
Malathion and Parathion -> must be bioactivated in liver (or by insect)
What is Malathion used for? Why?
Mosquito control and killing head lice (slowly detoxified in humans, vs Parathion which is not)
What is parathion used for?
What are the three most common causes organophosphate death?
1. Hypotension - due bradycardia and drop in peripheral resistance (elevated levels of ACh, even though you will have more sympathetic action due to ganglionic effects)
2. Difficulty breathing due to bronchial constriction and increased secretions in pulmonary tree + paralysis of respiratory muscles from phase 1 blockade
3. CNS depression due to Phase 1 blockade causes abolishment of respiration and coma
What is the pharmacologic antagonist for excess ACh at nicotinic ACh sites?
There isn't one! (why you can't stop the succinylcholine blockade)
What is given in heroic doses to combat organophosphate poisoning?
Atropine! Blocks muscarinic effects