TY - JOUR
T1 - Direct cardiac effects of intracoronary bupivacaine, levobupivacaine and ropivacaine in the sheep
AU - Chang, Dennis Hsu-Tung
AU - Ladd, Leigh A.
AU - Copeland, Susan E.
AU - Iglesias, Miguel A.
AU - Plummer, John Lewis
AU - Mather, L.
PY - 2001
Y1 - 2001
N2 - 1. The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. 2. In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant effects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) effects. 3. To study CVS effects over a wide range of doses with minimal CNS and other influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (~50 Kg body weight). After dose-ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 µmol ([approximate]amp;2.5 mg) in 8 µmol increments, to either a fatal outcome or a 40 µmol ([approximate]amp;12.5 mg) maximum. 4. All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: four of six with bupivacaine (mean±s.e.mean actual fatal dose: 21.8±6.4 ��mol), five of seven with levobupivacaine (22.9±3.5 µmol), four of six with ropivacaine (22.9±5.9 µmol). No significant differences in survival or in fatal doses between these drugs were found. 5. The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage.
AB - 1. The racemic local anaesthetic agent bupivacaine is widely used clinically for its long duration of action. Levobupivacaine and ropivacaine are bupivacaine enantiopure congeners, developed to improve upon the clinical safety of bupivacaine, especially the risk of fatal arrhythmogenesis. 2. In previous preclinical studies of the safety of these drugs with intravenous administration in conscious ewes over a wide dose range, we found that central nervous system (CNS) excito-toxicity reversed the cardiac depressant effects when doses approached the convulsant threshold and thus precluded accurate comparison of their cardiovascular system (CVS) effects. 3. To study CVS effects over a wide range of doses with minimal CNS and other influences, brief (3 min) infusions of bupivacaine, levobupivacaine or ropivacaine were administered into the left main coronary arteries of previously instrumented conscious ewes (~50 Kg body weight). After dose-ranging studies, the drugs were compared in a randomized, blinded, parallel group design. Equimolar doses were increased from 8 µmol ([approximate]amp;2.5 mg) in 8 µmol increments, to either a fatal outcome or a 40 µmol ([approximate]amp;12.5 mg) maximum. 4. All three drugs produced tachycardia, decreased myocardial contractility and stroke volume and widening of electrocardiographic QRS complexes. Thirteen of 19 animals died of ventricular fibrillation: four of six with bupivacaine (mean±s.e.mean actual fatal dose: 21.8±6.4 ��mol), five of seven with levobupivacaine (22.9±3.5 µmol), four of six with ropivacaine (22.9±5.9 µmol). No significant differences in survival or in fatal doses between these drugs were found. 5. The findings suggest that ropivacaine, levobupivacaine and bupivacaine have similar intrinsic ability to cause direct fatal cardiac toxicity when administered by left intracoronary arterial infusion in conscious sheep and do not explain the differences between the drugs found with intravenous dosage.
KW - bupivacaine
KW - coronary circulation
KW - levobupivacaine
KW - myocardial contractility
KW - ropivacaine
KW - ventricular arrhythmias
UR - http://handle.uws.edu.au:8081/1959.7/10695
M3 - Article
SN - 0007-1188
JO - British Journal of Pharmacology
JF - British Journal of Pharmacology
ER -