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Pharmacology: Pharmacodynamics: Cisatracurium is a nondepolarizing skeletal muscle relaxant. Cisatracurium binds competitively to Cholinergic receptors on the motor end-plate to antagonize the action of acetylcholine, resulting in block of neuromuscular transmission. This action is antagonized by acetyl cholinesterase inhibitors, such as neostigmine.
Pharmacokinetics: Absorption: During infusion of cisatracurium peak plasma concentrations of laudanosine and the monoquaternary alcohol metabolites are approximately 6% and 11% of the parent compound, respectively.
Distribution: The volume of distribution of cisatracurium is limited by its large molecular weight and high polarity. The Vss was equal to 145 ml/kg in healthy 19-to 64-year-old surgical patients receiving opioid anesthesia. The Vss was 21% larger in similar patients receiving inhalation anesthesia.
Protein binding: The binding of cisatracurium to plasma proteins has not been successfully studied due to its rapid degradation at physiologic pH. Inhibitor of degradation requires nonphysiological conditions of temperature and pH which are associated with changes in protein binding.
Metabolism: The degradation of cisatracurium is largely independent of liver metabolism. Results from in vitro Experiments suggest the cisatracurium undergoes Hofmann elimination (a pH- and temperature-dependent chemical process) to form laudanosine and the monoquaternary acrylate metabolite. The monoquaternary acrylate undergoes hydrolysis by non-specific plasma esterases to form the monoquaternary alcohol (MQA) metabolite. The MQA metabolite can also undergo Hofmann elimination but at a much slower rate than cisatracurium. Laudanosine is further metabolized to desmethyl metabolites which are conjugated with glucuronic acid and excreted in the urine.
Organ-independent Hofmann elimination is the predominant pathway for the elimination of cisatracurium. The liver and kidney play a minor role in the elimination of cisatracurium but are primary pathways for the elimination of metabolites. Because cisatracurium is 3 times more potent than atracurium and lower dose are required, the corresponding laudanosine concentrations following cisatracurium one-third of those that would be expected following an equipotent dose of atracurium.
Elimination: Mean clearance values for cisatracurium ranged from 4.5 to 5.7 mL/min/kg in studies of healthy surgical patients. Compartmental pharmacokinetic modeling suggests that approximately 80% of the clearance is accounted for the Hofmann elimination and the remaining 20% by renal and hepatic elimination. These findings are consistent with the low magnitude of interpatient variability in clearance (16%) estimated as part of the population pharmacokinetic/pharmacodynamics analyses and with the recovery of parent and metabolites in urine. Following 14C-cisatracurium administration to 6 healthy male patients, 95% of the dose was recovered in the urine (mostly as conjugated metabolites) and 4% in the feces; less than 10% of the dose was excreted as unchanged parent drug in the urine. In 12 healthy surgical patients receiving non-radiolabeled cisatracurium who had Foley catheters placed for surgical management, approximately 15% of the dose was excreted unchanged in the urine.
Special populations: Renal function impairment: Pharmacokinetic/pharmacodynamics profile similar to that in healthy adults; concentration of metabolites may be increased after prolonged administration.
Hepatic function impairment: Minor alterations in pharmacokinetics, but no substantial differences in recovery profile. Concentration of metabolites may be increased after prolonged administration.
Pharmacokinetic/pharmacodynamics profile similar to that in healthy adults; concentration of metabolites may be increased after prolonged administration.
Elderly: The minor differences in pharmacokinetic/pharmacodynamics parameters of cisatracurium between elderly patients and young patients were not associated with clinically significant differences in the recovery profile of cisatracurium.
