NMJ

Question 1

How does acetylcholinesterase breakdown acetylcholine?

Answer 1

Two steps:

1) A serine in the active site hydrolyzes the bond between the choline and acetyl groups by forming a covalent bond to the acetyl group
2) water hydrolyzes the bond between the acetyl group and the enzyme

Question 2

What are the classes of acetylcholinesterases?

Answer 2

1) competitive inhibitors that don’t form covalent bonds with acetylcholinesterase
* donepazil, edrophonium, galantamine
2) competitive inhibitors that form covalent bonds with acetylcholinesterase

• carbamates
  
  • carbamyl-enzyme bond
• organophosphates
  
  • phosphate-enzyme bond

Question 3

What are the carbamate drugs? What diseases are they used to treat?

Answer 3

Neostigmine - myasthenia gravis

pyridostigmine - myasthenia gravis (first line)

physostigmine - atropine poisoning/overdose

rivastigmine - dementia

Question 4

What are the acetylcholinesterases used to treat/diagnose myasthenia gravis?

What are the acetylcholinesterases used to treat dementia?

Answer 4

treat MG - pyridostigmine, neostigmine

diagnose MG - edrophonium (Tensilon test)

Dementia - donepezil, galantamine, rivastigmine

Question 5

What is the only clincially approved drug in the organophosphate category of acetylcholinesterases?

Answer 5

Echothiophate - not used clinically except for glaucoma

Question 6

What are the two mechanisms to block the NMJ?

Answer 6

1) non-depolarizing blockade: competitive inhibitors of the nicotinic AChRs block ACh
2) depolarizing blockade: nicotinic agonists produce sustained membrane depolarization so that voltage gated Na+ channels inactivate

Question 7

What drugs are non-depolarizing neuromuscular blockers? What drugs are depolarizing neuromuscular blockers?

Answer 7

non-depolarizing (“-curium”) - cisatracurium, mivacurium, tubocurarine, pancuronium, rocuronium

Depolarizing - succinylcholine

Question 8

What classes of drugs have important interactions with neuromuscular blockers? What are those interactions?

Answer 8

General anesthetics - makes neuromuscular blockers more potent and can lead to malignant hyperthermia

Antibiotics - makes non-depolarizing neuromuscular blockers more potent by decreasing stimulation-induced acetylcholine release

Question 9

What are the adverse effects of neuromuscular blockers?

Answer 9

post-operative pain

histamine release -> increased vascular permeability -> hypotension

effects on ANS ganglia, especially cardiovascular effects