Atracurium Besilate - Clinical Pharmacology

Clinical Pharmacology

Atracurium is susceptible to degradation by Hofmann elimination and ester hydrolysis as components of the in vivo metabolic processes. The initial in vitro studies appeared to indicate a major role for ester hydrolysis but, with accumulation of clinical data over time, the preponderence of evidence indicated that Hofmann elimination at physiological pH is the major degradation pathway vindicating the premise for the design of atracurium to undergo an organ-independent metabolism.

Hofmann elimination is a temperature- and pH-dependent process, and therefore atracurium's rate of degradation in vivo is highly influenced by body pH and temperature: An increase in body pH favors the elimination process, whereas a decrease in temperature slows down the process. Otherwise, the breakdown process is unaffected by the level of plasma esterase activity, obesity, age, or by the status of renal or hepatic function. On the other hand, excretion of the metabolite, laudanosine, and, to a small extent, atracurium itself is dependent on hepatic and renal functions that tend to be less efficient in the elderly population. The pharmaceutical presentation is a mixture of all ten possible stereoisomers. Although there are four stereocentres, which could give 16 structures, there is a plane of symmetry running through the centre of the diester bridge, and so 6 meso structures (structures that can be superimposed by having the opposite configuration then 180° rotation) are formed. This reduces the number from sixteen to ten. There are three cis-cis isomers (an enantiomeric pair and a meso structure), four cis-trans isomers (two enantiomeric pairs), and three trans-trans isomers (an enantiomeric pair and a meso structure). The proportions of cis−cis, cis−trans, and trans−trans isomers are in the ratio of 10.5 :6.2 :1. . One of the three cis-cis structures is marketed as a single-isomer preparation, cisatracurium (trade name Nimbex); it has the configuration 1R, 2R, 1′R, 2′R at the four stereocentres