1

Describe the principles underlying antagonism of residual nondepolarizing neuromuscular blockade.

Residual neuromuscular blockade can have serious consequences in the postoperative period. A study of patients during the first 15 minutes after admission to the postanesthesia care unit found that 0.8% developed critical respiratory events. Mean TOF ratio was 0.62 in patients who experienced these events compared with TOF ratios of 0.98 in patients who experienced no event. Complete recovery from neuromuscular blockade should be the goal for every anesthetic. TOF monitoring is an excellent way to assess neuromuscular blockade. Using a peripheral nerve stimulator, one can assess residual blockade by the ratio of the fourth to first twitch amplitude. A TOF ratio greater 0.9 should be achieved before tracheal extubation.

A competitive nondepolarizing neuromuscular block can be terminated spontaneously or pharmacologically. Over time, spontaneous recovery occurs as the NMBD diffuses away from receptor sites and is eliminated by metabolism or excretion. As the concentration of NMBD in plasma and at effect sites decreases, acetylcholine molecules gain greater access to nicotinic cholinergic receptors at the motor end plates.

Pharmacologic agents may be used to increase the amount of acetylcholine at the neuromuscular junction by inhibiting the enzyme acetylcholinesterase. Inhibition of acetylcholinesterase produces a competitive inhibition of the NMBD at receptors. The neuromuscular block can be partially or fully antagonized, depending on the relative amounts of acetylcholine and NMBD molecules present.

2

How is acetylcholinesterase inhibited?

Acetylcholinesterase hydrolyzes acetylcholine at the neuromuscular junction. By inhibiting the action of acetylcholinesterase, increased concentrations of acetylcholine accumulate at the neuromuscular junction. Acetylcholine competes with NMBDs for nicotinic receptor sites at the postjunctional membrane. Acetylcholinesterase inhibition also results in presynaptic generation of an action potential that may spread retrograde up the axon and cause other nerves in the same motor unit to discharge.

Acetylcholinesterase molecules possess an esteratic and an anionic binding site. Anticholinesterases inactivate the enzyme by reversibly binding to one or both of these sites. The stability of the bond determines the duration of the inhibition. Edrophonium binds electrostatically at the anionic site, forming a bond that is weak and resulting in a relatively short duration of action. It also has prejunctional effects, which promote the release of acetylcholine from the motor nerve terminal. Neostigmine and pyridostigmine form covalent bonds at the esteratic site to form a carbamyl ester, which leads to a more prolonged duration of effect.

Organophosphate compounds (e.g., parathion, malathion) inhibit acetylcholinesterase by the formation of irreversible bonds. These compounds are normally used as pesticides but have been used as chemical weapons because they are absorbed by ingestion, inhalation, and transdermally. Occasionally, a patient may present with a cholinergic crisis (see Chapter 24 ) because of organophosphate poisoning.

3

Name clinically relevant acetylcholinesterase inhibitors and their onsets of action.

Edrophonium, neostigmine, and pyridostigmine are the acetylcholinesterase inhibitors used clinically. They are all quaternary ammonium compounds; they do not penetrate the blood-brain barrier. Although in theory, these agents have the ability to affect cholinergic function in the central nervous system, in practice, they do not reach a high enough concentration to do so. However, physostigmine is a tertiary ammonium compound that readily penetrates the blood-brain barrier. For this reason, it is not used for antagonism of neuromuscular blockade. Edrophonium does not inhibit plasma (pseudo-) cholinesterase, whereas neostigmine does.

The onsets of action of the anticholinesterase drugs are as follows:

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  Edrophonium—1 to 2 minutes

  
  
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  Neostigmine—7 to 11 minutes

  
  
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  Pyridostigmine—15 minutes