Influence of extreme obesity on the body disposition and neuromuscular blocking effect of atracurium

Abstract

The pharmacokinetics and pharmacodynamics of atracurium, a nondepolarizing neuromuscular blocking agent, were compared between morbidly obese patients and nonobese patients. Atracurium besylate (0.2 mg/kg) was administered intravenously as a bolus to patients who had received anesthesia. The force of contraction of the adductor pollicis was measured and plasma samples were collected for a 2-hour period. The concentrations of atracurium and its major end product, laudanosine, were determined by use of a chromatographic method. The pharmacokinetic-pharmacodynamic relationship was characterized by use of several models. No difference was observed between obese patients and nonobese patients in atracurium elimination half-life (19.8 +/- 0.7 versus 19.7 +/- 0.7 minutes), volume of distribution at steady state (8.6 +/- 0.7 versus 8.5 +/- 0.7 L), and total clearance (444 +/- 29 versus 404 +/- 25 ml/min). However, if values were expressed on a total body weight basis, there was a difference between obese and nonobese patients in the volume of distribution at steady state (0.067 versus 0.141 L/kg) and total clearance (3.5 +/- 0.2 versus 6.6 +/- 0.5 ml/min/kg). Although atracurium concentrations were consistently higher in obese patients than in nonobese patients, there was no difference in the time of recovery from neuromuscular blockade between the two groups. Consequently, the median effective concentration was higher in obese than in nonobese patients (470 +/- 46 versus 312 +/- 33 ng/ml).

Altered Drug Metabolism and Transport in Pathophysiological Conditions

“…Animal studies performed using a diabetes mellitus rat model (induced by alloxan or streptozotocin treatment) have reported altered PK of drugs such as acetaminophen, chlorzoxazone, theophylline, clarithromycin, furosemide, and methotrexate (Baek et al, 2006;Kim et al, 2005aKim et al, , 2005bPark et al, 1996Park et al, , 1998Watkins & Sherman, 1992). Although, no changes in PD of atracurium were reported in obese animals compared to lean control (Varin et al, 1990), triazolaminduced sedation in obese humans increased significantly compared to normal weight men (Derry et al, 1995). We also observed similar disparities in the PD of midazolam, CYP3A substrate, (increased sleep time) and zoxazolamine, CYP2E1 substrate (no change) in DIO mice (Ghose et al, 2011b).…”

Pharmacokinetic Considerations in Obesity

“…In one study, it was shown that the absolute volume of distribution (V dss ) of atracurium is unchanged in obese individuals. 41 At the same time, the volume of distribution corrected for TBW decreased. Some lipophilic substances, such as the -adrenergic receptor blockers bisoprolol and nebivolol, also have volumes of distribution that decrease when corrected for TBW.…”

“…46 The same dose of triazolam was used for both obese and nonobese individuals. Varin et al 41 showed that even though obese individuals were exposed to significantly higher plasma concentrations of atracurium, no change was seen in the duration of neuromuscular blockade. The authors attributed this change in sensitivity to a combination of protein binding effects and desensitization of acetycholine receptors.…”

Anesthesia in the obese patient: Pharmacokinetic considerations

“…It has been reported that obese patients require significantly more pancuronium than nonobese subjects for the maintenance of 90% paralysis throughout surgery [89]. Varin et al [90] evaluated the pharmacokinetics and pharmacodynamics of atracurium in morbidly obese and nonobese patients and reported no difference in elimination half-life (19 F 0.7 minutes in both obese and nonobese patients), volume of distribution at steady state (8.6 F 0.7 L in obese and 8.5 F 0.7 L in control patients), and total clearance (444 F 29 mL/min in obese and 440 F 25 mL/min in control patients). In the same study, the authors also observed that although atracurium concentrations were higher in the obese than nonobese patients, there was no difference between the 2 groups in the time of recovery from neuromuscular blockade.…”