Cholinergics - Acetylcholinesterase Inhibitors

Question 1

What is the basic mechanism of an AChE inhibitor?

Answer 1

Enhance the effects of endogenous ACh due to inhibition of AChE -> prevents ACh degradation

Question 2

Where is the site of action of AChE inhibitors?

Answer 2

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)

Question 3

What is the general mechanism of enzymatic hydrolysis of ACh? Relative fast or slow process?

Answer 3

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

Question 4

What is the mechanism of action of Edrophonium?

Answer 4

reversible, competitive enzyme inhibitor

binds enzyme non-covalently

Question 5

What is the duration of action and route of administration of Edrophonium?

Answer 5

short (minutes)

not orally active -> only IV

Question 6

What are the therapeutic uses of Edrophonium?

Answer 6

Diagnosis of myasthenia gravis
Distinguish cholinergic crisis from myasthenic crisis
Reversal of paralysis by competitive neuromuscular blocking drugs

Question 7

What is the significance of the structure of Edrophonium?

Answer 7

Quaternary ammonium -> always (+)ve charge -> cannot get into CNS

Question 8

What is the mechanism of action of reversible substrate inhibitors?

Answer 8

Drug is hydrolyzed by AChE, but at a slow rate -> keeps AChE inactive so ACh can be around longer

Question 9

What is the mechanism of action of Physostigmine?

Answer 9

reversible substrate inhibitor of AChE, slowly reversible

Question 10

What is the significance of the structure of Physostigmine?

Answer 10

lipophillic -> can have CNS effects

Question 11

What are the therapeutic uses of Physostigmine?

Answer 11

Treatment of chronic wide angle glaucoma

Reverse toxicify by antimuscarinic drug poisoning

Question 12

What is the duration of action of Neostigmine? (and mechanism of action)

Answer 12

slowly reversible, AChE inhibitor

Question 13

What is the significance of the structure of Neostigmine?

Answer 13

quaternary amine (+) charge -> cannot get into CNS

Question 14

What are the therapeutic uses of Neostigmine?

Answer 14

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)

Question 15

What are the side effects of AChE inhibitors?

Answer 15

SLUDGE, hypotension, bradycardia, blurred vision

Question 16

What is the mechanism of action of an Irreversible Organophosphate Inhibitor?

Answer 16

Irreversibly phosphorylates the serine in the substrate-binding domain of AChE
Return of activity depends on regeneration of enzyme -> slow

Question 17

What is Sarin?

Answer 17

Organohosphate -> irreversibly inhibits AChE -> very lipophillic -> can penetrate into skin, mucosal membranes, and brain, used as nerve gas in chemical warfare

Question 18

What is Malathion?

Answer 18

Widely used insecticide -> mammals can detox this, but insects cannot. Organophosphate

Question 19

What are the toxic effects of organophosphates?

Answer 19

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

Question 20

What is the treatment of organophosphate poisoning?

Answer 20

Atropine -> Muscarinic receptor antagonist, blocks peripheral and central muscarinic effects
Pralidoxime - reactivates AChE peripherally, necessary to use w/in 2-3 hours of exposure