Cholinesterase Inhibitors

Question 1

What does “reversible” AChase inhibitors mean?

Answer 1

They are either poor substrates to AChE enzyme and are hydrolyzed slowly (i.e. 30 minutes), or they are simple competitive inhibitors

Question 2

How is physostigmine metabolized and what is it used for? Is it tertiary or quaternary?

Answer 2

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)

Question 3

Is Neostigmine tertiary or quaternary amine? Why is it superior to physostigmine for management of myasthenia gravis?

Answer 3

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).

Question 4

Other than MG, when else is neostigmine used? When is it contraindicated?

Answer 4

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

Question 5

What is the mechanism of action of Edrophonium? Quaternary or tertiary?

Answer 5

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

Question 6

Why is edrophonium selective for the NMJ?

Answer 6

It is also a direct agonist of nAChR, so will not produce too high acetylcholine levels at other receptors at the doses used therapeutically

Question 7

Why is edrophonium good for diagnosing MG?

Answer 7

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

Question 8

What drug is primarily used for MG treatment and why?

Answer 8

Pyridostigmine, another quaternary AChE-inhibitor like neostigmine, but has a longer halflife

Question 9

If MG patients suddenly get weaker, what are the two scenarios you must be testing for? How?

Answer 9

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

Question 10

What is the goal of Alzheimer’s anti-AChE pharmacology? Will it slow the course of the disease?

Answer 10

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

Question 11

What was the first approved Alzheimer’s ACh drug and why is it not used now?

Answer 11

Tacrine -> too many peripheral effects, and caused hepatotoxicity

Question 12

What drug replaced Tacrine for Alzheimer’s and what is its main concern?

Answer 12

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

Question 13

What is Rivastigmine used for?

Answer 13

(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

Question 14

What is Galantamine?

Answer 14

(Think of the Alzheimer’s gala)Reversible AChE inhibitor, used for Alzheimer’s

Question 15

What is the first drug shown to slow rate of deterioration of Alzheimer’s, and what is its mechanism of action?

Answer 15

Memantine - glutamate receptor antagonist

Question 16

What element is contained in all “irreversible” AChE inhibitors? Mechanism? Why they scary?

Answer 16

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)

Question 17

What is the only clinically useful irreversible cholinesterase inhibitor, and what is it used for? Why is it not good?

Answer 17

Echothiophate - used for sustained miosis of the eye (3 days or longer)

Not good because it causes lens clouding

Question 18

What are the two pesticides which use the AChE inhibition mechanism which are used in farming?

Answer 18

Malathion and Parathion -> must be bioactivated in liver (or by insect)

Question 19

What is Malathion used for? Why?

Answer 19

Mosquito control and killing head lice (slowly detoxified in humans, vs Parathion which is not)

Question 20

What is parathion used for?

Answer 20

Farming

Question 21

What are the three most common causes organophosphate death?

Answer 21

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

Question 22

What is the pharmacologic antagonist for excess ACh at nicotinic ACh sites?

Answer 22

There isn’t one! (why you can’t stop the succinylcholine blockade)

Question 23

What is given in heroic doses to combat organophosphate poisoning?

Answer 23

Atropine! Blocks muscarinic effects

Question 24

What is the drug which must be rapidly administered in order to counteract organophosphates? How does it work?

Answer 24

Pralidoxime -> forms an adduct with the phosphate moeity of the organophosphate. This can be hydrolyzed to regenerate the free enzyme.

If pralidoxime is not administered quickly before water can hydrolyze the bond, an aged adduct will form which cannot be undone (must be administered quickly).