NMJ Pharmacology

Question 1

Botulinum toxin effects @ NMJ

Answer 1

• botulinum toxin lyses synaptobrevin (vesicle-associated membrane protein) ==> inhibits vesicular ACh release
• ==> flaccid paralysis of skeletal muscle

Question 2

Botox uses

Answer 2

• clinical conditions that would benefit from decreased ACh release
• @ NMJ: UMN disease w/spastic paralysis
• @ ANS: overactive bladder, sever underarm sweating
• @ CNS: prevention of migraines

Question 3

Black widow spider venom effects @ NMJ

Answer 3

• forms pores @ terminal axon membrane ==> excessive Ca²⁺ influx ==> explosive ACh release

Question 4

Effect of ACh interaction w/muscle-type nicotonic cholinergic receptor (N_M)

Answer 4

• ==> increased cation conductance ==> depolarization (EPP = End Plate Potential)

Question 5

Curare effects @ NMJ

Answer 5

• = competitive antagonist at N_M
• prevents channel opening and depolarization
• ==> flaccid paralysis

Question 6

Succinylcholine effects @ NMJ

Answer 6

• agonist of N_M receptor w/prolonged binding
• ==> depolarization, but does not allow repolarization
• ==> “depolarization block” ==> no subsequent action potentials ==> flaccid paralysis

Question 7

Effects of nondepolarizing agents @ NMJ (& examples)

Answer 7

• reversible block of N_M ==> prevents channel opening & membrane depolarization
• surmountable blockade that can be reversed by cholinesterase inhibitors
• examples:
  
  • tubocurarine (curare alkaloid)
  • atracurium
  • rocuronium

Question 8

Phase I vs. Phase II block by Succinylcholine (SuCh)

Answer 8

• Phase I block
  
  • prolonged deoplarization ==> prevention of membrane repolarization
  • muscle tension cannot be maintained ==> flaccid paralysis
  • block is potentiated by AChE-i
• Phase II block
  
  • seen w/large or repeated doses
  • unknown mechanism

Question 9

Therapeutic uses of NMJ blocking agents

Answer 9

• surgical muscle relaxation during general anesthesia
• control patients on ventilators
• attenuate convulsion in ECT
• lethal injection

Question 10

AChEIs effects on depolarizing vs. nondepolarizing NMJ blocking agents

Answer 10

• nondepolarizing ==> AChEIs = reversal of block
  
  • allows ACh to remain in synapse longer and produce more effect
• depolarizing ==> AChEIs = increase effects
  
  • increases ACh ==> more depolarization ==> less opportunity to repolarize

Question 11

Depolarizing vs. Non-depolarizing NMJ blocking agents

Answer 11

• non-depolarizing = blocks channels to block APs
  
  • e.g. curare, atracurium, rocuronium
• depolarizing = holds channels open to prevent repolarization to block APs
  
  • e.g. succinylcholine

Question 12

Advantages of nondepolarizing vs. depolarizing NMJ blockers

Answer 12

• non-depolarizing
  
  • can be reversed
  • can last greater than 30 min depending on agent
  • side effects = histamine release, effects on ganglia and muscarinic receptors
• depolarizing
  
  • rapid onset + short effects
  • side effects = hyperkalemia, increased intraocular pressure