Stereopharmacological research in anaesthesiology

Abstract

This thesis is based on a theme of 63 selected publications taken from three of the author’s research programs (on local anaesthetic agents, intravenous anaesthetic agents, and nonsteroidal anti-inflammatory agents) and three individual drug projects (on halothane, ketamine and thalidomide). The publications have been selected to highlight the bearing of the chemistry of the drug, especially the stereochemistry, on some or other aspect of its pharmacology, of which 42 are designated Study (new experimental observations and knowledge), 18 are designated Review (syntheses of ideas from existent knowledge), and 3 are designated Patent (aspects of invention). The thesis is shaped by the narrative relating to the development of anaesthesia as first established by John Snow (1813-1858), and the contemporaneous stereochemical basis of pharmacology first described by Louis Pasteur (1822-1895). It presents each topic as a personal commentary identifying the historical context, rationale and outcome, and recognizing the work of collaborators and others at the institutions where the research was performed. The selected publications originate from research performed at the University of Sydney, the Flinders University of South Australia, and the University of Sheffield (UK), although prior work performed at the University of Washington (USA) also contributed. The ‘concepts and tools’ supporting the research are described in an historical context, corresponding to their evolution. In particular, the dual concepts of pharmacokinetics and pharmacodynamics underpin much of modern pharmacology and run throughout the theme of this thesis. Their investigation required reliable practical tools for physiological data acquisition, numerical data analysis, and drug assay methods, especially for the analytical resolution of chiral drugs used as racemates; however these tools evolved more slowly than the demands of the concepts. Eventually, when they were combined in appropriate ‘whole body’ pharmacological preparations, such as the author’s ‘multicannulated sheep preparation’ that allowed anatomically-correct and physiologically-sound assessment of drug disposition in association with quantitative measures of systemic drug effects, as well as with the ‘Stanford’ quantitative electroencephalography rodent model used for pharmacokineticspharmacodynamics, then real progress became possible, allowing greater insights into drugs used as racemates, such as those described in this thesis. The local anaesthetic program was instrumental in the registration and clinical introduction of two enantiopure substances, ropivacaine and levobupivacaine. The selections from the intravenous anaesthetic program focus on thiopentone and provide evidence of a greater margin of safety of R-thiopentone over the more potent S-thiopentone or the clinically-used racemate. Although the program led to a provisional patent for enantiopure thiopentone, clinical anaesthesia has since largely moved to using propofol which has a preferred pharmacokinetic profile to thiopentone. The selections from the nonsteroidal antiinflammatory drug program focus on ketorolac, but produced inconclusive pharmacokinetic data; given the limited resources available, the program was changed to focus on (achiral) diclofenac. The ketamine project provided useful pharmacokinetic and pharmacodynamic data supporting the current clinical investigations of the pharmacologically preferred esketamine. The halothane project was designed to consider that differential enantiomeric disposition might influence halothane toxicity, but an enantiomeric difference was not found, and the project was terminated due to lack of funds. Finally, the thalidomide project documented that racemization precluded the use of a preferred enantiomer, but also produced a rationale for its use in future combined cancer chemotherapy developments.