title: The relative toxicity of amitriptyline, bupivacaine, and levobupivacaine administered as rapid infusions in rats.
abstract: Intravascular injection of local anesthetics carries the risk of cardiovascular (CV) and central nervous system (CNS) toxicity. Amitriptyline, a tricyclic antidepressant, has local anesthetic potency that is more than that of bupivacaine. In this study, we compared the CV and CNS toxicity of the local anesthetics bupivacaine and levobupivacaine with that of amitriptyline. Twenty-nine Sprague-Dawley rats had their right external jugular vein and carotid artery cannulated under general anesthesia. On Day 2, rats were sedated with midazolam (0.375 mg/kg intraperitoneally) and received rapid infusions of either 1) bupivacaine, levobupivacaine, or amitriptyline at 2 mg x kg(-1) x min(-1) (5 mg/mL concentration) or 2) normal saline (400 micro L x kg(-1) x min(-1)) through an external jugular vein cannula. Electrocardiogram and arterial blood pressure were measured until the dose to cause impending death was reached (heart rate 50 bpm/asystole or apnea for >30 s). The mean dose required to cause apnea and impending death was significantly larger for amitriptyline (74.0 +/- 21 mg/kg and 74.5 +/- 21 mg/kg, respectively) than for levobupivacaine (32.2 +/- 20 mg/kg and 33.9 +/- 22 mg/kg, respectively) or bupivacaine (21.5 +/- 7 mg/kg and 22.7 +/- 7 mg/kg, respectively) (P < 0.05). A significantly larger dose of amitriptyline, given by rapid infusion, is required to cause CV and CNS toxicity in rats, when compared with bupivacaine and levobupivacaine.
  
  
  CONCLUSIONS
  Amitriptyline, a tricyclic antidepressant, has local anesthetic properties and is more potent than bupivacaine. Significantly larger doses of amitriptyline, given by rapid infusion, are required to cause cardiovascular and central nervous system toxicity in rats, when compared with bupivacaine and levobupivacaine.
authors.affiliation: Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Srinivasa
authors.forename: Peter
authors.initials: P
authors.lastname: Gerner
authors.forename: Anna
authors.initials: A
authors.lastname: Haderer
authors.forename: Salahadin
authors.initials: S
authors.lastname: Abdi
authors.forename: Petr
authors.initials: P
authors.lastname: Jarolim
authors.forename: Ging Kuo
authors.initials: GK
authors.lastname: Wang
mesh_terms: D000639:Amitriptyline / Q000008:administration & dosage / Q000633:toxicity*; D000779:Anesthetics, Local / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000929:Antidepressive Agents, Tricyclic / Q000008:administration & dosage / Q000633:toxicity*; D001794:Blood Pressure / Q000187:drug effects; D002045:Bupivacaine / Q000008:administration & dosage / Q000633:toxicity*; D004562:Electrocardiography / Q000187:drug effects; D006323:Heart Arrest / Q000139:chemically induced / Q000503:physiopathology; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D017180:Tachycardia, Ventricular / Q000139:chemically induced / Q000503:physiopathology; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000503:physiopathology
chemical_list: D000779:Anesthetics, Local; D000929:Antidepressive Agents, Tricyclic; D000639:Amitriptyline; D002045:Bupivacaine