Pharmacokinetics and Pharmacodynamics of Ketamine as an Analgesic for Rational Intravenous Infusion in Ponies. Graduate School for Cellular and Biomedical Sciences University of Bern PhD Thesis Submitted by Olivier Louis Raymond LEVIONNOIS from Cancale, France Thesis advisor Prof. Dr. Meike Mevissen Division of Veterinary Pharmacology and Toxicology Department of Clinical Research and Veterinary Public Health Vetsuisse Faculty, University of Bern AUTHOR OLIVIER LOUIS RAYMOND LEVIONNOIS Born the 6th September 1977, Paris, France EDUCATION 2003 Academic degree DVM Ecole Nationale Vétérinaire, Agroalimentaire et de l'Alimentation Nantes-Atlantique, Nantes, France 2006 Academic degree Dr. med.vet. Department of Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Switzerland 2006-2011 PhD-student for the DVM-PhD at the Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland POSTGRADUATE TRAINING 2007 Diplomate of the European College of Veterinary Anaesthesia and Analgesia (ECVAA) CURRENT POSITION Clinical educator and Research assistant, Division Anaesthesiology, Department Clinical Veterinary Medicine, Vetsuisse Faculty, University of Bern, Switzerland. LAST PUBLICATIONS Pieper K, Schuster T, Levionnois O, Matis U, Bergadano A. Antinociceptive efficacy and plasma concentrations of transdermal buprenorphine in dogs. Vet J. 2010 Mar 3. [Epub ahead of print] Levionnois OL, Mevissen M, Thormann W, Spadavecchia C. Assessing the efficiency of a pharmacokinetic-based algorithm for target-controlled infusion of ketamine in ponies. Res Vet Sci. 2010 Jun;88(3):512-8. Levionnois OL, Menge M, Thormann W, Mevissen M, Spadavecchia C. Effect of ketamine on the limb withdrawal reflex evoked by transcutaneous electrical stimulation in ponies anaesthetised with isoflurane. Vet J. 2010 Dec;186(3):304-11. Larenza MP, Peterbauer C, Landoni MF, Levionnois OL, Schatzmann U, Spadavecchia C, Thormann W. Stereoselective pharmacokinetics of ketamine and norketamine after constant rate infusion of a subanesthetic dose of racemic ketamine or S-ketamine in Shetland ponies. Am J Vet Res. 2009 Jul;70(7):831-9. Enderle AK, Levionnois OL, Kuhn M, Schatzmann U. Clinical evaluation of ketamine and lidocaine intravenous infusions to reduce isoflurane requirements in horses under general anaesthesia. Vet Anaesth Analg. 2008 Jul;35(4):297-305. Spadavecchia C, Levionnois OL, Kronen P, Andersen OK. The effects of isoflurane minimum alveolar concentration on withdrawal reflex activity evoked by repeated transcutaneous electrical stimulation in ponies. Vet J. 2010 Mar;183(3):337-44. Levionnois OL, Spadavecchia C, Kronen PW, Schatzmann U. Determination of the minimum alveolar concentration of isoflurane in Shetland ponies using constant current or constant voltage electrical stimulation. Vet Anaesth Analg. 2009 Jan;36(1):9-17. Levionnois OL, Kronen P. Development of post-pump syndrome in a sheep after mitral valve stenting. Lab Anim. 2008 Oct;42(4):505-10. Larenza MP, Knobloch M, Landoni MF, Levionnois OL, Kronen PW, Theurillat R, Schatzmann U, Thormann W. Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration in Shetland ponies sedated with xylazine. Vet J. 2008 Sep;177(3):432-5. Larenza MP, Landoni MF, Levionnois OL, Knobloch M, Kronen PW, Theurillat R, Schatzmann U, Thormann W. Stereoselective pharmacokinetics of ketamine and norketamine after racemic ketamine or S-ketamine administration during isoflurane anaesthesia in Shetland ponies. Br J Anaesth. 2007 Feb;98(2):204-12. Knobloch M, Portier CJ, Levionnois OL, Theurillat R, Thormann W, Spadavecchia C, Mevissen M. Antinociceptive effects, metabolism and disposition of ketamine in ponies under target-controlled drug infusion. Toxicol Appl Pharmacol. 2006 Nov 1;216(3):373-86. Spadavecchia C, Levionnois OL, Kronen PW, Leandri M, Spadavecchia L, Schatzmann U. Evaluation of administration of isoflurane at approximately the minimum alveolar concentration on depression of a nociceptive withdrawal reflex evoked by transcutaneous electrical stimulation in ponies. Am J Vet Res. 2006 May;67(5):762-9. Pharmacokinetics and Pharmacodynamics of Ketamine as an Analgesic for Rational Intravenous Infusion in Ponies. Department of Clinical Veterinary Medicine Division of Anaesthesiology, Vetsuisse Faculty, University of Berne, Berne, Switzerland University of Bern | Graduate School for Cellular and Biomedical Sciences Theodor Kocher Institute | Freiestrasse 1 | CH-3012 Bern Olivier Louis Raymond LEVIONNOIS 2011 Accepted by the Faculty of Medicine, the Faculty of Science and the Vetsuisse Faculty of the University of Bern at the request of the Graduate School for Cellular and Biomedical Sciences Bern, Dean of the Faculty of Medicine Bern, Dean of the Faculty of Science Bern, Dean of the Vetsuisse Faculty Bern A ma famille, d’ici et de là bas, tous dans mon cœur. Supervisor: Prof. Meike Mevissen Division of Veterinary Pharmacology and Toxicology Department of Clinical Research and Veterinary Public Health Vetsuisse Faculty, University of Bern, Switzerland Co-referee: Prof. Claudia Spadavecchia Division of Veterinary Anaesthesiology and Pain Medicine Department of Clinical Veterinary Sciences Vetsuisse Faculty, University of Bern, Switzerland Secondary Co-referee and Reviewers: Prof. Wolfgang Thormann Department of Clinical Pharmacology, University of Bern, Switzerland Prof. Christopher Portier Environmental Toxicology Program National Institute of Environmental Health Sciences Research Triangle Park, NC 27709, USA Thesis Mentor: Prof. Mireille Meylan Ruminant Clinic Department of Clinical Veterinary Sciences Vetsuisse Faculty, University of Bern, Switzerland Ketamine pharmacokinetic and pharmacodynamic 0 Ketamine pharmacokinetic and pharmacodynamic Content 1. Abbreviations ......................................................................................................................................................... 2 2. Acknowledgments ................................................................................................................................................. 3 3. Summary ................................................................................................................................................................ 4 (1) Abstract (English) ....................................................................................................................................... 4 (2) Abstract (German) ..................................................................................................................................... 5 (3) Abstract (French) ....................................................................................................................................... 6 4. List of original publications .................................................................................................................................... 7 5. Preface ................................................................................................................................................................... 9 (1) Preliminary notes ....................................................................................................................................... 9 (2) Background ................................................................................................................................................ 9 6. Introduction ......................................................................................................................................................... 13 7. Aims of the PhD project ....................................................................................................................................... 15 (1) Characterization of ketamine pharmacokinetics ..................................................................................... 15 (2) The effect of isoflurane on the Withdrawal Reflex ................................................................................. 16 (3) Effects of ketamine on the Withdrawal Reflex ........................................................................................ 16 8. Methods and Results ........................................................................................................................................... 17 (1) Animals .................................................................................................................................................... 17 (2) Induction of isoflurane general anaesthesia ........................................................................................... 17 (3) Ketamine: stereoselective pharmacokinetics .......................................................................................... 17 (4) Electrophysiological recordings of the Withdrawal Reflexes .................................................................. 27 9. Conclusion and Future applications .................................................................................................................... 31 10. References ......................................................................................................................................................... 35 Declaration of Originality ..................................................................................................................................... 39 Appendix: Publications .......................................................................................................................................