Cholinesterase Inhibitors

Question 1

Cholinesterase inhibitors have profound effects on …

How?

Answer 1

Skeletal muscle, ANS, and brain

Enhance action of ACh both at muscarinic and nicotinic receptors

Question 2

Two binding sites on cholinesterase enzyme are important for drug action. What are they?

Answer 2

1. Anionic
   - -attraction site
   - -ACh cation is attracted to the ring system formed by Trp and Phe
2. Esteratic
   - -hydrolysis site
   - -Formed by Ser, His, Glu

Question 3

Neostigmine

Answer 3

A cholinesterase inhibitor that is kind of like ACh

It is a carbamate (carbamic ester)

The carbamate remains bound to Ser portion to prevent/block further hydrolysis
–last a few hours

Question 4

Edrophonium

Answer 4

Simple quaternary alcohol

• -not an ester, no hydrolysis occurs
• -it must be injects (not well absorbed b/c quaternary)

Binds to anionic site and blocks the enzyme
–wont let ACh in

Last a few minutes

Question 5

Organophoasphates

Answer 5

Insecticide that blocks AChase

Interact with esteratic site and produce a firm binding
–no way to recover enzyme, must make more

Question 6

Alzhemiers

Answer 6

• -Most common cause dementia old age
• -Improper processing beta amyloid protein
  
  • -pts generate B-amyloid 42 which is a very toxic substance –> accumulation leads to cell death
• -Loss of cholinergic neurons in brain

Treated with DONEPEZIL
–only helps until neurons die b/c at that point there is no ACh coming off

Question 7

AChase inhibitor used to increase GI activity postoperatively

Answer 7

Neostigmine

• -quaternary but effective PO
• -no CNS effects

What about affects on mm?
–its effect on mm is to just make them stronger, it won’t really have any harmful effects

Question 8

Myasthenia Gravis

Answer 8

• -Disease characterized by skeletal mm weakness
• -Autoimmune loss of nicotinic receptors
• -Loss of 2/3 of receptors leads to the symptoms (like weakness)
• -More common in women

Question 9

Generally, what is used to treat Myasthenia Gravis?

Why/how was it discovered?

Answer 9

Cholinesterase effectors like neostigmine

Mary Walker found neostigmine effective in 1934

Question 10

What specific drugs are used with Myasthenia Gravis (diagnosis, treatment)?

Answer 10

EDROPHONIUM for diagnosis

• -injected; has short duration
• -can also use neostigmine

PYRIDOSTIGMINE p.o. for treatment
–longer duration than neostimgine

Question 11

Aside from diagnosis and treatment, what are drugs also used for in myasthenia gravis?

Answer 11

To distinguish between myasthenia and cholinergic crisis (disease is variable based on amount of AB against receptors)
–use Edrophonium

Myasthenia - disease state getting worse - more autoimmune AB
–with Edrophonium pt will feel better

Cholinergic - too much drug will produce weakness - continuous depolarization and mm weakness
–might get worse for a few minutes

Question 12

What are the catonic (act on anionic site) cholinesterase inhibitors?

Answer 12

edrophonium

donepezil

Question 13

What are the carbamate ester cholinesterase inhibitors?

Answer 13

rivastingmine
physostigmine
neostigmined
pyridostigmine

Question 14

What are irreversible organophosphate cholinesterase inhibitors?

Answer 14

insecticides

Question 15

What are specific examples of non-medical cholinesterase inhibitors?

Answer 15

insecticides

• -chlorpyrifos
• -malathion

nerve gas
–soman

Question 16

Toxicology of cholinesterase inhibitors

–death due to…

Answer 16

asphyxia; four factors are involved

• -bronchoconstriction
• -increased secretions
• -skeletal mm paralysis
• -CNS depression

Question 17

Acronyms for remembering symptoms of cholinesterase inhibitors

Answer 17

DUM BELS (dumb bells)

diarrhea
urination
mm weakness; miosis
bronchoconstriction
excitation
lacrimation
seizures, sweat, salivation

Question 18

How do we treat intoxication with Cholinesterase Inhibitors?

Answer 18

Atropine
AND
Pralidoxime (2-PAM) – works on skeletal mm

Act quickly
–bond increases in strength with time

Question 19

What aspects of Cholinesterase intoxication treatment does atropine work on?

Answer 19

Bronchoconstriction
Increased Secretions
CNS depression

Question 20

What aspects of Cholinesterase intoxication treatment does atropine work on?

Answer 20

Bronchoconstriction
Increased Secretions
Skeletal mm paralysis

Question 21

Malathion

Answer 21

Insecticide that is specific for insects

Mammals and birds can hydrolyze the compound and make it less toxic — so its a good insecticide

Question 22

What is the medical use for malathion?

Answer 22

Used to treat pediulosis capitis (head lice)

• -common in school aged children
• -transmitted by personal contact
• -vector for typhus, trench fever, relapsing fever
• -small ovid gray nits (ova) and mature lice both respond to malathion