title: The effects of general anesthesia on whole body and regional pharmacokinetics of local anesthetics at toxic doses.
abstract: BACKGROUND
  Local anesthetic toxicity is often studied experimentally in anesthetized subjects, but clinical toxicity usually occurs in conscious patients. In this study, we determined the influence of general anesthesia on the pharmacokinetics of six local anesthetics administered i.v. at approximately the highest recommended doses.
  
  
  METHODS
  Chronically instrumented ewes (approximately 45-50 kg, n = 18) were infused over 3 min with (base doses as HCl salts) bupivacaine (100 mg), levobupivacaine (125 mg), ropivacaine (150 mg), lidocaine (350 mg), mepivacaine (350 mg), or prilocaine (350 mg), on separate occasions when conscious and halothane anesthetized. Serial arterial, heart, and brain venous blood drug concentrations were measured by achiral/chiral high-performance liquid chromatography, as relevant. Whole body pharmacokinetics were assessed by noncompartmental analysis; heart and brain pharmacokinetics were assessed by mass balance. Drug blood binding, in the absence and presence of halothane, was assessed by equilibrium dialysis in vitro.
  
  
  RESULTS
  Blood local anesthetic concentrations were doubled with anesthesia because of decreased whole body distribution and clearance (respectively, to 33% and 52% of values when conscious). Heart and brain net drug uptake were greater under anesthesia, reflecting slower efflux from both regions. Clearances of R-bupivacaine > S-bupivacaine and R-prilocaine > S-prilocaine, but, mepivacaine clearance was not enantioselective. Halothane did not influence blood binding of the local anesthetics.
  
  
  CONCLUSIONS
  General anesthesia significantly changed whole body and regional pharmacokinetics of each local anesthetic as well as the systemic effects. General anesthesia is thus an important but frequently overlooked factor in studies of local anesthetic toxicity.
authors.affiliation: Department of Anaesthesia and Pain Management, University of Sydney at Royal North Shore Hospital, Sydney NSW 2065, Australia.
authors.forename: Susan E
authors.initials: SE
authors.lastname: Copeland
authors.forename: Leigh A
authors.initials: LA
authors.lastname: Ladd
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Gu
authors.forename: Laurence E
authors.initials: LE
authors.lastname: Mather
mesh_terms: D000577:Amides / Q000493:pharmacokinetics; D018685:Anesthetics, Inhalation / Q000494:pharmacology*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity; D000818:Animals; D002045:Bupivacaine / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D002319:Cardiovascular System / Q000187:drug effects / Q000378:metabolism; D002490:Central Nervous System / Q000187:drug effects / Q000378:metabolism; D004347:Drug Interactions; D005260:Female; D006221:Halothane / Q000494:pharmacology*; D007262:Infusions, Intravenous; D000077554:Levobupivacaine; D008012:Lidocaine / Q000493:pharmacokinetics; D008619:Mepivacaine / Q000493:pharmacokinetics; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D011318:Prilocaine / Q000493:pharmacokinetics; D011485:Protein Binding; D000077212:Ropivacaine; D012756:Sheep; D014018:Tissue Distribution
chemical_list: D000577:Amides; D018685:Anesthetics, Inhalation; D000779:Anesthetics, Local; D011318:Prilocaine; D000077212:Ropivacaine; D008012:Lidocaine; D000077554:Levobupivacaine; D008619:Mepivacaine; D006221:Halothane; D002045:Bupivacaine