Case 22 - Antagonism of nondepolarizng neuromuscular blockade

Question 1

What train-of-four value should be achieved prior to extubation?

Answer 1

• A TOF ratio greater than 0.9 should be achieved before extubation
• TOF monitoring is an excellent way to assess neuromusuclar blockade via peripheral nerve stimulator
• TOF is the ratio of the fourth to the first twitch amplitude

Question 2

How are competitive NMBDs terminated?

Answer 2

• Terminated either spontaneously or pharmacologically
• Spontaneous
  
  • recovery occurs as NMBD diffuse away from receptor site and eliminated by metabolism or excretion. As concentration of NMBD at NMJ decreases, AcH molecules gain greater access to nicotinic cholinergic receptors at motor end plates
• Pharmacological - acetylcholinesterase inhibitors –> block and inhibit acetylcholinesterase at NMJ, resulting in increased amounts of AcH at NMJ, which can competitively bind to AcH nicotinic receptors at motor end plates

Question 3

How is acetylcholinesterase inhibited?

Answer 3

• acetylcholinesterase inactivates AcH at NMJ
• inhibition of acetylcholinesterase (**ACH-I) **results in increased concentration of AcH at NMJ, which competes with NMBDs for nicotinic recpetor sites at postjunctional membrane
• Endrophonium (short acting), neostigmine and pyridostigmine (intermediate-long acting).

Question 4

Describe Organophosphate MOA

Answer 4

• form irreversible bonds with acetylcholinesterase
• result -> increase AcH concetration at synapse

Toxicity produces cholinergic crisis. Used in chemical weapons, pesticides.

Question 5

Name clinically relevant ACH-I and onset of action

Answer 5

• Endrophonium, neostigmine, pyridostigmine, and physostigmine

Endrophonium

• quaternary ammonium compound, does not cross BBB, onset 1 - 2 min

Neostigmine

• quaternary ammonium compound, does not cross BBB, onset 7 - 11 min

Pyridosigmine

• quaternary ammonium compound, does not cross BBB, onset 15 min

Physostigmine

• TERTIARY ammonium compound, crosses BBB, can affect cholinergic function in CNS and this is why it is not used as antagonism for NMBDs. used for anticholinergic crisis

Question 6

What are usual doses and expected duration of action for ACH-I?

Answer 6

• Dose recommendations depend on the particular NMBD to be anatognized and intensity of neuromusclar blockade.
• if ACH-I is given to early (when no twitches are elicited), duration of recovery is unknown, and attempts to antagonize the block are likely to be unsuccessful
• Neostigmine dose - 0.04 - 0.07 mg/kg
• Endrophonium dose - 0.5 to 1 mg/kg
• ACH - I have ceiling effect –> additional doses are ineffective.

Question 7

Why is it necessary to administer an anticholinergic drug with an acetylcholinesterase inhibitor?

Answer 7

• **AcH has both nicotinic and muscarinc agonist effects. **
  
  • acetylcholinesterase located at NMJ and autonomic nervous system synapse
• Increasing AcH at NMJ is desierable for NMBD reversal; however, muscarinc effects are undesirable.
• Symptoms of muscarinc effects: think of DUMBELLS - Diarrhea, Urination, Miosis, Bradycardia, Bronchospasm, Emesis, Lacrimation, Lethargy and Salivation and seizures.

Question 8

Pair anticholinergic with ACH-I

Answer 8

• Atropine should be paired with endrophonium since they have rapid onset of action.
  
  • Administer atropine before endrophonium.
• Glycopyrrolate and neostigmine or pyridostigmine should be paired as they both have similar delays to onset.

Question 9

Briefly describe Sugammadex

Answer 9

• binds to steroidal NMBDs (-onium)
• binds and encapsulates steroidal NMBDs to form a stable complex that has no neuromsuclar blocking properities
• time to complete recovery in a patient with steroidal NMBD and no response to TOF is 2-3 min after administering Sugammadex.