title: Altered Cisatracurium Pharmacokinetics and Pharmacodynamics in Patients with Congenital Heart Defects.
abstract: 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 k12 and k21 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.
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (Z.W., B.W.); Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (S.W., X.Y.); and Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China (X.P., C.L.).
authors.forename: Zhufeng
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (Z.W., B.W.); Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (S.W., X.Y.); and Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China (X.P., C.L.).
authors.forename: Sheng
authors.initials: S
authors.lastname: Wang
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (Z.W., B.W.); Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (S.W., X.Y.); and Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China (X.P., C.L.).
authors.forename: Xuemei
authors.initials: X
authors.lastname: Peng
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (Z.W., B.W.); Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (S.W., X.Y.); and Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China (X.P., C.L.).
authors.forename: Chunying
authors.initials: C
authors.lastname: Lu
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (Z.W., B.W.); Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (S.W., X.Y.); and Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China (X.P., C.L.).
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Ye
authors.affiliation: Division of Pharmaceutics, College of Pharmacy, Jinan University, Guangzhou, China (Z.W., B.W.); Department of Anesthesiology, Guangdong Cardiovascular Institute, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China (S.W., X.Y.); and Department of Anesthesiology, First Affiliated Hospital of Jinan University, Guangzhou, China (X.P., C.L.) bj.wu@hotmail.com.
authors.forename: Baojian
authors.initials: B
authors.lastname: Wu
mesh_terms: D000328:Adult; D001279:Atracurium / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D005260:Female; D006344:Heart Septal Defects, Atrial / Q000097:blood / Q000378:metabolism*; D006345:Heart Septal Defects, Ventricular / Q000097:blood / Q000378:metabolism*; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008954:Models, Biological; D009466:Neuromuscular Blocking Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D009469:Neuromuscular Junction / Q000187:drug effects*; D061886:Neuromuscular Monitoring; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D009466:Neuromuscular Blocking Agents; D001279:Atracurium; C101584:cisatracurium