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The Cerebral Pharmacokinetics and Pharmacodynamics of Propofol in Sheep

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The Cerebral Pharmacokinetics and Pharmacodynamics of Propofol in Sheep 12-ß .aì The Cerebral Pharmacokinetics and Pharmacodynamics of Propofol in Sheep Guy Lawrence Ludbrook Department of Anaesthesia and lntensive Care Faculty of Medicine Division of Health Sciences University of Adelaide Adelaide, S.A. 5005 Australia Thesis submitted for the Degree of Doctor of Philosophy May 1997 1 2 Abstract 9 Declaration 11 Acknowledgements 13 Publications produced during candidacy 15 Published Papers and Chapters 15 Abstracts 16 Abbreviations 19 Chapter 1. A literature review of studies of the cerebral pharmacokinetics and pharmacodynamics of propofol 21 1.1 lntroduction 21 1.2 Pharmacokinetics 23 1.2.1 General Pharmacokinetic approaches 23 1 .2.1 .1 Pharmacokinetic modelling 23 1 .2.1 .2 Compartmental modelling 24 1.2.1.2.1 Effect compartment modelling 25 1 .2.1 .3 Physiological modelling 27 1 .2.2 Pharmacokinetics of propofol 28 1.2.2.1 Systemic pharmacokinetics of propofol 28 1 .2.2.2 Cerebral pharmacokinetics 29 1 .2.2.3 Concentration-eff ect relationsh ips 30 1.2.2.4 Effect compartment modelling of propofol 32 1.2.2.5 Specific pharmacokinetic problems at induction 32 1.2.2.5.1 Blood sampling 32 1.2.2.5.2 Rate of administration 33 1 .2.2.5.3 Extra-hepatic metabol ic clearance 34 1.2.2.5.4 Variability in calculated parameters 35 1 .2.2.5.5 Co-adm in istration at induction 36 1.2.2.6 Summary 37 1.3 Pharmacodynamics 38 1.3.1 Pharmacodynamic modelling 38 1.3.1.1 Linear ând log linear models 38 1.3.1.2 Emax models 38 1.3.1.3 Sigmoid Emax models 39 1.3.2 Cerebral pharmacodynamics of propofol 39 1.3.2.1 Effect of propofol on neuronal function 40 1 .3.2.2 Cerebral metabol ism 41 1.3.2.3 Cerebral blood flow 42 1.3.2.4 Blood pressure 43 1.4 Methods available for studies of cerebral pharm acokínetics and pharm acodynam ics 45 1 .4. 1 Cerebral pharmacokinetic methods 45 1.4.1.1 Tissue biopsies 45 1 .4.1 .2 Autoradiographic studies 46 1.4.1.3 Microdialysis 46 1 .4.1 .4 lsolated organs 47 1.4.1.5 Mass balance principles 47 1.4.1.5.1 Vascular anatomy 47 1 .4.1.5.2 Non-vascular drug loss 48 1.4.1.5.3 Transit times 48 1.4.1.5.4 Blood sampling and assay 49 1.4.1.5.5 Organ blood f low 49 3 1 .4.2 Cerebral pharmacodynamic methods 1.4.2.1 Cerebral blood flow 1.4.2.1.1 lndicator methods 1.4.2.1 .2 Flowmeter methods 1 .4.2.2 Cerebral m etabol ism 1.4.2.3 Depth of anaesthesia 1.4.2.3.1 Clinical signs 1.4.2.3.2 Electrical activity of the brain 1 .4.2.3.3 Su rface Electromyography (EMG) 1 .4.2.3.4 Oesophageal manometry 1.5.2.3.5 Algesimetry 1.4.2.4 Minimum alveolar concentration (MAC) 1.5 Summary and aíms of research Chapter 2. General methods and materials for studies in sheep 2.1 Ethical approval 2.2 Animal selection and handling 2.3 Preparation and instrumentation 2.3.1 Anaesthesia 2.3.2lnstrumentation 2.4 Maintenance of instrumented sheep 2.5 Drug studies 2.6 Blood sample handling 2.7 Propofol assays 2.7. 1 Storage stability 2.7.1.1 Methods 2.7.1.2 Results 2.7.1.3 Discussion 2.8 Blood gas and oxygen content analysis 2.9 Data handling Chapter 3. A method for the frequent measurement of the antinociceptive effects of drugs 3.1 lntroduction 3.1.1 ldeal characteristics of the proposed technique 3.1.1.1 Stimulus 3.1.1.2 Response 3.1.2 Development of an algesimetry device 3.1.2.1 Current Generator 3.1.2.2 Pilot study in man 3.1.2.2.1 Methods 3.1.2.2.2 Results 3.1.2.3 Pilot study in sheep 3.1.2.3.1 Method 3.1.2.3.2 Results 3.1 .2.4 Electronic modifications 3.2 Methods 3.2.1 Animal preparation 3.2.2 Study design 3.2.2.1 Measurement protocol 3.2.2.1. 1 Current delivery 3.2.2.1.2 Response 3.2.2.1.3. Operator 3.2.2.2 Determination of optimal current delivery regimen 4 3.2.2.2.1 Cu rrent f req uency 84 3.2.2.2.2 Ram p duration 84 3.2.2.2.3 Measu rement interval 84 3.2.2.2.4 Baseline stabil ity 84 3.2.2.3 Effects of analgesic and sedative/anaesthetic agents on threshold current 84 3.2.2.3.1. Propofol 85 3.2.2.3.2 Sodium th iopentone 85 3.2.2.3.3 Xylazine 85 3.2.2.3.4 Opioids 85 3.3 Results 85 3.3.1 Determination of optimal current delivery regimen 85 3.3.1.1 Current frequency 85 3.3.1.2 Ramp duration 85 3.3. 1 .3 Measurement interval 85 3.3.1.4 Baseline stability 86 3.3.2 Effects of analgesic and sedative/anaesthetic agents on threshold current 86 3.3.2.1 Sedative/anaesthetic agents 86 3.3.2.2 Effects of analgesic agents 87 3.4 Discussion 88 3.4.1 Baseline stability 91 3.4.2 Optimal stimulus pattern 92 3.4.3 Drug administration 93 3.4.3.1 Response to propofol and thiopentone 93 3.4.3.2 Response to xylazine 95 3.4.3.3 Response to opioids 95 Chapter 4. Development of a cerebral blood flow method for studies of cerebral pharmacokinetics and pharmacodynamics in unrestrained sheep. 97 4.1 ldentification of a suitable anatomical site 98 4.1.1 lntroduction 98 4.1.2 Methods 99 4.1.2.1 ln vivo angiography studies 99 4.1.2.2 Retrograde dye studies 99 4.1.3 Results 99 4.1.3.1 Digital subtraction angiography 99 4.1.3.2 Retrograde dye studies 100 4.1.4 Discussion 100 4.2 Validation of the CBF method 103 4.2.1 lntroduction 103 4.2.2 Methods 103 4.2.2.1 Equipment 103 4.2.2.2 Surgical placement of the flow probe 104 4.2.2.3 Validation and calibration of the flow measurement 104 4.2.2.3.1 Vessel diameter over a range of CBF values 104 4.2.2.3.2 The relationship between Doppler velocity and sagittal sinus blood flow 105 4.2.2.3.3 The time-course of CBF and its response to perturbations 106 4.2.2.3.4 Control measu rements 106 4.2.2.3.5 CO2 reactivity 106 4.2.2.3.6 The response to hyper- and hypotension 107 5 4.2.3 Results 107 4.2.3.1 Validation and calibration of the flow measurement 107 4.2.3.1.1 The influence of CBF on vessel diameter 107 4.2.3.1.2 Relationship between Doppler velocity and sagittal sinus flow 108 4.2.3.2 The time-course of CBF and its response to perturbations 108 4.2.3.2.1 Control measurements 108 4.2.3.2.2 CO2 reactivity 110 4.2.3.2.3 The response to hyper- and hypotension 111 4.4.4 Discussion 111 Chapter 5. The relationship between brain and blood concentrat¡ons of propofol, and cerebral effects after rapid intravenous injection in sheep. 117 5.1 lntroduction 117 5.2 Methods 118 5.2.1 Animal preparation 118 5.2.2 Study design 118 5.2.2.1 Parameter measurement 119 5.2.2.2 Blood sampling 119 5.2.2.3 General design 119 5.2.3 Data handling and statistical analysis 119 5.2.3. 1 Pharmacokinetic analysis 120 5.3 Results 121 5.3. 1 Pharmacodynamics 121 5.3.2 Pharmacokinetics 122 5.3.3 Concentration-Effect Relationsh ips 123 5.3.3.1 Depth of anaesthesia 123 5.3.3.2 Cerebral blood flow 124 5.4 Discussion 124 5.4. 1 Pharmacokinetics 124 5.4.1.1 Arterial kinetics 125 5.4.1 .2 Cerebral kinetics 128 5.4. 1 .3 Concentration-effect relationships 129 5.4.2 Pharm acodynam ics 132 5.4.2.1CBF and CMR '132 5.4.2.2 Depth of anaesthesia 134 Ghapter 6. Prolonged administration of propofol: concentrations and effect 137 6.1 lntroduction 137 6.2 Methods 138 6.2.1 Animal preparation 138 6.2.2 Study design 138 6.2.3 Data handling and statistical analysis 139 6.3 Results 139 6.3. 1 Pharmacodynamics 139 6.3.2 Pharmacoki netics 140 6.3.3 Concentration- Effect Relationsh ips 141 6.3.4 Mass balance 141 6.4 Discussion 141 6.4.1 Cerebral blood flow 141 6.4.2 Propof ol concentrations 143 6.4.3 Acute tolerance 145 6.4.4 Mass balance 148 6 Chapter 7. The effect of rate of administration on brain concentrations of propofol 151 7.1 lntroduction 151 7.2 Methods 152 7 .2.1 Animal preparation 152 7.2.2 Study design 152 7.2.3 Data handling and statistical analysis 153 7.3 Results 153 7.3.1 Propofol concentrations 153 7.3.2 Effects on blood pressure 154 7.3.3 Titration to effect: Effects on dose and time to onset of anaesthesia 154 7.4 Discussion 155 7.4.1 Ellects of administration rate on propofol concentrations 155 7.4.2 Effects of administration rate on blood pressure 158 7.4.3 Effects of administratiorr rate on administered dose and onset time 1s9 Chapter 8.
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