The in vitro degradation of cisatracurium, the R, cis-R′-isomer of atracurium, in human and rat plasma

Welch, R. M.; Brown, Alan R.; Ravitch, Josh; Dahl, Ray

doi:10.1016/0009-9236(95)90190-6

Cited by 95 publications

(54 citation statements)

References 11 publications

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“…Although the liver and kidneys play only a small role in the excretion of cisatracurium besilate, urinary and hepatic elimination pathways are important for the metabolites of laudanosine. [5][6][7][8] The total body clearance (CL), steady-state Vd and elimination half-life of cisatracurium besilate in patients with normal organ function are approximately 0.27 to 0.34 L/h/kg (4.7 ml/min/kg), 0.11 to 0.16 L/kg and 22 to 35 minutes, respectively. The volume of distribution (Vd) of cisatracurium is small because of its relatively large molecular weight and high polarity.…”

Section: Introductionmentioning

confidence: 99%

A clinical comparative study of two intubating doses of cis-atracurium during general anaesthesia for gynaecological surgery

Jammar

Pathak

Begum

et al. 2017

Int J Basic Clin Pharmacol

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INTRODUCTIONCisatracurium besilate is a cis-cis isomer (51W89:1R-cis 1'R-cis atracurium), one of the 10 stereoisomers of atracurium that constitutes 15% of the atracurium mixture, an intermediate duration non-depolarising neuromuscular blocking drug. It is about three to four times more potent than atracurium and devoid of cardiovascular side effects in doses of upto 8 times of ED95. The ED95 of cisatracurium is 0.05mg/kg. 1-5The rate limiting step in the degradation of cisatracurium is Hoffmann degradation.(organ independent elimination) to form laudanosine and monoquaternary alcohol. 77% of drug is cleared via Hoffmann degradation which is a ph and temperature dependent process, rest 23% of drug get cleared through organ dependent means, and renal elimination accounts for 16% of this. Hydrolysis by non-specific esterases is not an important pathway for cisatracurium degradation. It is not associated with histamine release in humans. Although the liver and kidneys play only a small role in the excretion of cisatracurium besilate, urinary and hepatic elimination pathways are important for the metabolites of laudanosine. 5-8The total body clearance (CL), steady-state Vd and elimination half-life of cisatracurium besilate in patients with normal organ function are approximately 0.27 to 0.34 L/h/kg (4.7 ml/min/kg), 0.11 to 0.16 L/kg and 22 to 35 minutes, respectively. The volume of distribution (Vd) ABSTRACT Background: Cisatracurium is one of the cis-cis isomer of atracurium (51W89:1R-cis 1'R-cis atracurium) an intermediate duration non-depolarising neuromuscular blocking drug and is devoid of histamine release. However, 2× ED95 dose of cisatracurium does not provide satisfactory intubating condition. The recommended intubating dose of cisatracurium is 3 ×ED95. The objective of this study was to evaluate and compare duration of action, hemodynamic effects and any adverse effects for different doses of cisatracurium. Methods: After Institutional Ethical Committee approval and informed patient consent, 80 patients of ASA I and II in the age group of 20-60 years were selected and included in the study. Patients were divided in two groups of 40 each, group A received intravenously 3×ED95 (0.15 mg/kg) loading dose of cisatracurium and group B received intravenously 4×ED95 (0.2 mg/kg) loading dose of cisatracurium. Results: After induction, MAP and HR shows decrease in both groups but neither statistically nor clinically significant. Better hemodynamic stability and longer duration of action was found in group B compared to group A. No adverse effects noted in both groups. Conclusions: 4×ED95 dose of cisatracurium provides longer duration of action and more stable hemodynamic status than 3×ED95. No associated signs of histamine release were detected clinically.

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Section: Introductionmentioning

confidence: 99%

A clinical comparative study of two intubating doses of cis-atracurium during general anaesthesia for gynaecological surgery

Jammar

Pathak

Begum

et al. 2017

Int J Basic Clin Pharmacol

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“…Cisatracurium has been frequently used adjunctively in anesthesia to facilitate endotracheal intubation and to provide muscle relaxation during surgery (Bryson and Faulds, 1997). The drug spontaneously degrades at physiologic pH and temperature via Hofmann elimination to yield laudanosine, which is subsequently metabolized to a number of conjugated metabolites (Dear et al, 1995;Welch et al, 1995;Weindlmayr-Goettel et al, 1998). Therefore, elimination of cisatracurium most likely occurs in both plasma and tissues.…”

Section: Introductionmentioning

confidence: 99%

Altered Cisatracurium Pharmacokinetics and Pharmacodynamics in Patients with Congenital Heart Defects

Wang

Peng

et al. 2015

Drug Metabolism and Disposition

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The neuromuscular blocking agent cisatracurium is frequently used adjunctively in anesthesia to facilitate endotracheal intubation and to provide muscle relaxation during surgery. We aimed to determine the pharmacokinetics (PK)/pharmacodynamics (PD) of cisatracurium in patients with congenital heart defects (CHDs), such as ventricular septal defects and atrial septal defects, and to assess the effects of CHDs on the PK/PD profiles of cisatracurium. A modified two-compartment model with drug clearance from both compartments was best fitted to the PK data to determine the PK parameters. The model suggested that septal defects significantly lowered the rate of cisatracurium distribution from the central to peripheral compartment. The intercompartment rate constants k 12 and k 21 were significantly reduced (35%-60%, P < 0.05) in patients with ventricular septal defects and in patients with atrial septal defects compared with control patients. Consistently, septal defects caused a marked increase (160%-175%, P < 0.001) in the distribution half-life. Furthermore, significantly delayed pharmacodynamic responses to cisatracurium were observed in patients with septal defects. The onset time (i.e., the time to maximal neuromuscular block) was prolonged from 2.2 minutes to 5.0 minutes. PK/PD modeling suggested that reduced concentrations of cisatracurium in the effect compartment due to poorer distribution were the main cause of lagged pharmacodynamic responses. In conclusion, cisatracurium PK/PD were significantly altered in patients with septal defects. Our study should be of use in clinical practice for the administration of cisatracurium to patients with CHDs.

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“…1,21 Several in vitro studies using plasma and blood from different species and in vivo studies in man have reported enantioselective ester hydrolysis of drugs commonly used during anesthesia. [22][23][24] Interestingly, an in vitro study using blood from man reported a slightly shorter half-life of…”

Section: Resultsmentioning

confidence: 99%

Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients

et al. 2001

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The aim of the study was to characterize the individual pharmacokinetics of (-)-R- and (+)-S-clevidipine following intravenous constant rate infusion of rac-clevidipine to essential hypertensive patients. Twenty patients received three out of five randomized treatments with clevidipine. The pharmacokinetics of the separate enantiomers were evaluated by compartmental analysis of blood concentrations vs. time curves using the population approach. The derived pharmacokinetic parameters were used to simulate the time for 50 and 90% postinfusion decline following various infusion times of rac-clevidipine. A two-compartment model was used to describe the dispositions of the enantiomers; there were only minor differences between the estimated pharmacokinetic parameters of the separate enantiomers. The mean blood clearance values of (-)-R- and (+)-S-clevidipine were 0.103 and 0.096 l/min/kg, and the corresponding volumes of distribution at steady state were 0.39 and 0.54 l/kg, respectively. The context-sensitive half-time was approximately 2 min regardless of stereochemical configuration, and a 90% decline in concentration was achieved approximately 8 min postinfusion for (-)-R-clevidipine and 11 min for (+)-S-clevidipine, following clinically relevant infusion times with clevidipine. In conclusion, both enantiomers are high-clearance compounds with similar blood clearance values. The volume of distribution for the enantiomers is slightly different, presumably due to differences in the protein binding. From a pharmacokinetic point of view, the use of a single enantiomer as an alternative to the racemic clevidipine will not offer any clinical advantages.

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The in vitro degradation of cisatracurium, the R, cis-R′-isomer of atracurium, in human and rat plasma

Cited by 95 publications

References 11 publications

A clinical comparative study of two intubating doses of cis-atracurium during general anaesthesia for gynaecological surgery

A clinical comparative study of two intubating doses of cis-atracurium during general anaesthesia for gynaecological surgery

Altered Cisatracurium Pharmacokinetics and Pharmacodynamics in Patients with Congenital Heart Defects

Enantioselective pharmacokinetics of the enantiomers of clevidipine following intravenous infusion of the racemate in essential hypertensive patients

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