Hofman degradation

Hofmann degradation is a spontaneous process in plasma at normal pH and temperature and does not depend on any circulating enzyme. In a Hofmann elimination reaction, a quaternary ammonium group is converted to a tertiary amine by cleavage of a carbon-nitrogen bond.

This is a pH- and temperature-dependent reaction in which higher pH and temperature favor elimination. Among drugs used in anesthesia, Atracurium besylate and its 1R‐cis, 1R′‐cis isomer (cisatracurium) undergo Hofmann elimination. This unique pharmacological property provides an organ‐independent degradation pathway.

Atracurium is a bis-benzyltetrahydroisoquinolinium with isoquinolinium nitrogens connected by a diester-containing hydrocarbon chain. The presence (in duplicate) of two-carbon separations between quaternary nitrogen and ester carbonyl provides the basis for a Hofmann elimination reaction.

The marketed form of atracurium has 10 isomers. These isomers have been separated into three geometric isomer groups that are designated cis-cis, cis-trans, and trans-trans according to their configuration about the tetrahydroisoquinoline ring system. The ratio of the cis-cis, cis-trans, and trans-trans isomers is approximately 10 : 6 : 1.

Atracurium is metabolised via Hofmann elimination and nonspecific ester hydrolysis (60%-90%). Laudanosine is the major metabolite of both pathways of metabolism of atracurium, with Hofmann elimination resulting in two molecules of laudanosine and ester hydrolysis resulting in one molecule of laudanosine for every molecule of atracurium that is metabolized.

Cisatracurium is the 1R cis–1′R cis isomer of atracurium and represents about 15% of the marketed atracurium mixture by weight but more than 50% in terms of potency or neuromuscular blocking activity. Cisatracurium is metabolized by Hofmann elimination. It is approximately four times as potent as atracurium, but unlike atracurium, it does not cause release of histamine in the clinical dose range.

In contrast to atracurium, nonspecific plasma esterases do not seem to be involved in the clearance of cisatracurium. Hofmann elimination accounts for 77% of the clearance of cisatracurium, whereas renal clearance is responsible for another 16%. Because of the greater potency of cisatracurium, laudanosine quantities produced by Hofmann elimination are 5 to 10 times lower than in the case of atracurium, thus making this not an issue in practice.