acetylcholinesterase inhibitors

Question 1

What holds the AChE to the neuronal surface?

Answer 1

GPI anchoring

Question 2

what forms can AChE exist in?

Answer 2

monomeric, dimeric, or mulitmeric

Question 3

what family does AChE belong to?

Answer 3

the serine hydrolase family

Question 4

how fast is AChE at doing its job?

Answer 4

very very fast. this has one of the highest turnover numbers of any known enzyme and the only thing slowing it down is getting the ACh to bind to the active site fast enough

Question 5

What two things does AChE make ACh into?

Answer 5

acetate and choline

Question 6

what three enzymes are in the AChE binding site?

Answer 6

serine, histadine, and glutamate

Question 7

what amino acid is in the cationic binding site?

Answer 7

tryptophan

Question 8

what is the suffix of all drugs that are acetycholinesterase inhibitors?

Answer 8

“stigmine”

Question 9

do AChE inhibitors resemble ACh in any way?

Answer 9

yes, so they can get into the binding pocket

Question 10

how is neostigmine different than ACh?

Answer 10

it has a benzene ring and a quaternary ammonium compound

Question 11

describe how ACh is eliminated by AChE

Answer 11

ACh goes into the binding pocket and then the OH group on serine acts as a nucleophile and attacks the ester carbon on ACh. Then the choline goes away. the rest of this process happens very fast and the water comes into the binding pocket. it acts as a nucleophile again and attacks the ester carbon and causes acetate to be formed which then diffuses away

Question 12

why does the AChE inhibitor neostigmine do its job?

Answer 12

it has a bulky carbamate group that is harder for water to kick off the serine in the binding pocket, so more ACh stays in the synapse because the AChE enzymes are all full.

Question 13

how do plasma concentrations of neostigmine correlate with its action?

Answer 13

the drug is doing its job as it is getting broken down, so even though plasma concentrations are low, the drug is still doing it job

Question 14

which two AChE inhibitors have quaternary ammonium compounds? what does this mean?

Answer 14

neostigmine and pyrisostigmine, they will not affect the CNS and therfore can not be used to treat Alzheimer’s because they can not increase the ACh in there

Question 15

What is a characteristic of all AChE inhibitors?

Answer 15

they have a carbamate molecule

Question 16

do all AChE inhibitors work through covalent modification at the active site?

Answer 16

no, some are just simply reversible inhibitors

Question 17

what is true about the structure of AChE inhibitors that work as reversible inhibitors?

Answer 17

they do not have carbamate esters

Question 18

How do insecticides work and how are they dangerous?

Answer 18

they look kind of like ACh except they have a flourophosphate molecule on the end. this molecule does not want to unbind to the serine once it has been attached.

Question 19

what is the mechanism of the insecticide binding to the AChE enzyme? what are the two possibilities? which one is bad?

Answer 19

in both circumstances, the serine attacks the phosphate and kicks the fluorine off. in the first scenario, the phosphate serine bod that was formed is broken by water and the enzyme is regenerated. in the second case the phosphate stays bound to the serine and the -OCH(CH3)2 gets kicked off leaving the phosphate permanently bound to the AChE binding site. the latter is dangerous because ACh can no longer be broken down and go through normal muscle function.

Question 20

what is an “aged” enzyme?

Answer 20

this is a really stable molecule that will not come off of the enzyme no matter how hard we try, so the only choice is to wait for the patient to generate new enzyme

Question 21

What can you give to a patient to prevent aging?

Answer 21

2-PAM

Question 22

if the aging has already occurred, can 2-PAM help?

Answer 22

no, it can only prevent it

Question 23

What is 2-PAM

Answer 23

a very strong oxide that is stronger than water and can be used to break the body before aging occurs

Question 24

can 2-PAM treat CNS symptoms?

Answer 24

no, it has a quaternary ammonium compound that can not pass the blood brain barrier

Question 25

what would organophosphates do to the body?

Answer 25

increases SLUD effects because the ACh is piling up, which would mean pupil constriction, salivation, defication, urination, bronchoconstriction, muscle spasms, downregulation of heart rate

Question 26

what is Myasthenia Gravis?

Answer 26

this is an autoimmune disease against the nicotinic receptors at the neuromuscular junction which causes the destruction of the receptors and the inability to contract muscles.

Question 27

how does AChE inhibitors correct myasthenia gravis?

Answer 27

it blocks the destruction of ACh in the junction which causes increased ACh concentration and all the receptors that are left get bound to and can open for normal muscle movement

Question 28

how do AChE blockers help with Alzheimer’s disease?

Answer 28

Alzheimer’s disease is low ACh in the brain. This causes increased ACh and helps treat the problem

Question 29

How do AChE blockers treat glaucoma? is this direct or indirect?

Answer 29

They block AChE from breaking down ACh which increases ACh in the eye and INDIRECTLY treats glaucoma that way

Question 30

what is the direct way to treat glaucoma?

Answer 30

a muscarinic agonist