Atracurium elimination reactions

Atracurium, a curare-like muscle relaxant that is metabolized via an elimination reaction... 

Recent developments have led to agents with a built-in functional group that allows more rapid metabolism. Initially, the presence of ester groupings, as in suxamethonium, allowed fairly rapid metabolism in the body via esterase enzymes that hydrolyse these linkages. The enzyme involved appears to be a non-specific serum acetylcholinesterase (see Box 13.4). Even better is the inclusion of functionalities that allow additional degradation via an elimination reaction. Such an agent is atracurium. 

Atracurium is a synthetic bisquaternary benzylisoquinolinium compound with a novel method of metabolism, the Hofmann elimination reaction. This reaction takes place at a pH of 7.4 and a temperature of 37°C. It is thus metabolised at body temperature and pH, and has to be stored in a refrigerator. The usual intubating dose of atracurium is 0.5-0.75 mg-kg-1 (2-3xED95). The onset of action with this dose is 2-3 minutes and intubating conditions are acceptable in 90-120 seconds. Spontaneous recovery occurs reliably from an atracurium neuromuscular block, such that an intubating dose of about 0.5 mg-kg-1 can be expected to provide surgical muscle relaxation for 25-40 minutes in the normal healthy patient. Repeated administration of atracurium leads only to a small increase in the duration of action. 

Figure 17-20 Hoffman elimination and hydrolysis reactions of atracurium.

There is one important reaction of quaternary amines that has heen exploited in dmg design the Hofinarm elimination (Fig. 3.28). The reaction is promoted by strongly basic conditions and the more acidic a P-hydro-gen atom the more readily the reaction occurs. Atracurium is based upon tubocurarine that was discovered as an arrow poison that paralyses muscles. Thus atracurium is used as a neuromuscular blocker that acts at the acetyl choline receptor and is used to relax muscles such as the abdominal muscles in preparation for surgery. The P-hydrogens in atracurium are particularly acidic and thus atracurium breaks down spontaneously at physiological pH and thus has a short duration of action and is less likely to produce cardiac side effects (see Ch. 16). 

A particular reaction of quaternary amines, the Hofmann elimination, was used to determine the design of atracurium, a muscle relaxant which falls apart spontaneously and thus does not require metabolic elimination. 

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