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Cardioactive Agents : Metoprolol, Sotalol and Milrinone. Influence of Myocardial Content and Systolic Interval

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Cardioactive Agents : Metoprolol, Sotalol and Milrinone. Influence of Myocardial Content and Systolic Interval 3Õ' î'qt ACUTE HAEMODYNAMIC EFFECTS OF THREE CARDIOACTIVE AGENTS : METOPROLOL, SOTALOL AND MILRINONE. INFLUENCE OF MYOCARDIAL CONTENT AND SYSTOLIC INTERVAL. by Rebecca Helen Ritchie, B.Sc (Hons) A thesis submitted for the degree of Doctor of Philosophy ln The University of Adelaide (Faculty of Medicine) February 1994 Department of Medicine (Cardiology Unit, The Queen Elizabeth Hospital) The University of Adelaide Adelaide, SA, 5000. ll ¡ r -tL',. r,0';(', /1L.)/'t :.: 1 TABLE OF CONTENTS Table of contents 1 Declaration vtl Acknowledgements v111 Publications and communications to learned societies in support of thesis D( Summary xl Chapter 1: General Introduction 1 1.1 Overview 2 1.2 Acute effeots of cardioactive drugs 3 1.2.1 Drug effects 4 l.2.2Determnants of drug effects 5 1.3 Myocardial drug gPtake of cardioactive agents 8 1.3.1 Methods of assessment in humans invívo 9 1.3.2 Results of previous studies 10 1.4Influence of cardioactive drugs on contractile state 11 1.4. 1 Conventional indices 11 I.4.2 The staircase phenomenon t2 1.4.3 The mechanical restitution curve t2 1.5 The present study t4 1.5.1 Current relevant knowledge of the acute haemodynamic effects of the cardioactive drugs under investigation r4 1.5.1.1 Metoprolol 15 1.5.1.2 Sotalol 28 1.5.1.3 Milrinone 43 1.5.2 Cunent relevant knowledge of the short-term pharmacokinetics of the cardioactive drugs under investigation 59 1.5.2.1Metoprolol 59 1.5.2.2 Sotalol 7I ll 1.5.2.3 Milrinone 78 1.5.3 Current relevant knowledge of the potential for rate-dependence of the effects of these cardioactive drugs on contractile state 82 1.5.3.1 MetoProlol 82 1.5.3.2 Sotalol 82 1.5.3.3 Milrinone 83 1.6 Objectives of the curent investigation 84 Chapter 2: Materials and Methods 86 2.1 Methods utilized for invivo (human) and invitro (animat) experimentation 87 2.1.1 Protocol for cardiac catheterization for determination of myocardial drug uptake and measurement of acute effects in humans 87 2.l.ZProtocol for isolated perfused rat hearts 90 2.2 Analyfical methods 92 2.2.1IfPLC quantitation of metoprolol in human whole blood and rat heart homogenates 92 z.z.2LfPLcquantitation of sotalol enantiomers in human whole blood 97 2.2.3L+Lccluantitation of milrinone in human whole btood 103 2.2.3.1Analysis of milrinone in biological samples - results of previous investigations 103 2.2.3.2 Methodology developed for analysis of milrinone in human whole blood samples in the current investigation 104 2.2.41-owry protein assay in rat heart homogenates 109 2.2.5 RIA determination of cAMP concentrations in human plasma 111 2.3 Quantitation of haemodynamic, electrocardiographic and electrophysiologic effects Il4 2.4 Calculation of myocardial drug uptaks ll4 2.5 Correlation between myocardiat drug content and simultaneous effects 117 2.6 Pharmacokinetic and pharmacodynamic models utilized for examining the relationship between myocardial drug content and effect l2O 2.7 Statistical analyses utilized in this thesis 123 lll Chapter 3: Determination of rate-related inotropic effects in humans 128 3.1 Mechanical restitution curve construction 129 3.2 Development of a quantitafive model for the mechanical restitution curve 131 3.2.L Background t3l 3.2.2 Methods 131 3.2.3 Results 132 3.2.3.1Theoretical considerations I32 3.2.3.2 The present investigation 136 3.2.4 Discussion 142 3.3 Other methods of examining the potential for rate-dependence of drug effects on contractile state 149 Chapter 4: Acute myocardial metoprolol uptake : correlation with acute effects and influence of hypoxia 152 4.1 Background and Aims 153 4.2 Methods r54 4.3 Results 155 4.3. 1 Patient characteristics 155 4.3.2 Acute haemodynamic effecs of metoprolol in humans r57 4.3.3 Acute electrocardiographic effects of metoprolol in humans 158 4.3.4 Validity of utilizing femoral arterial metoprolol concentrations as a swrogate for those in the aorta 165 4.3.5 Acute myocardial metoprolol uptake in huma¡rs 165 4.3.6 Acute myocardial metoprolol uptake by isolated Langendorff- perfused rat hearts : influence of hypoxia 1ó8 4.3.7 Conelation between myocardial metoprolol content and acute effects in humans 168 4.3.8 Pharmacokinetic - pharmacodynamic link models between myocardial metoprolol content and effect in humans 174 lv 4.3.9 Metoprolol redistribution into other vascula¡ beds in humans 174 4.3.10 Formation of active metoprolol metabolites in humans 179 4.3.I1Concenffation of metoprolol by red blood cells in humans I79 4.3.12 Serial mechanical restitution curye construction in humans 179 4.3.13 Post-extrasystolic potentiation without a compensatory pause in humans 193 4.3.L4 Application of the curve-fitting model to mechanical restitution curves obtained post-metoprolol administration in humans 183 4.3.15 Examination of hysteresis between myocardial metoprolol content and the rate-dependence index following metoprolol administration in humans 196 4.3.16 Rapid atrial pacing before and after metoprolol injection 191 4.3.L7 Summary of results I93 4.4 Discussion 194 Chapter 5: Acute myocardial uptake of d- and l-sotalol: correlation with acute effects in humans 201 5.1 Background and Aims 202 5.2 Methods 203 5'3 Results 204 5.3.1 Patient cha¡acteristics 204 5.3.2 Acute haemodynamic effects of sotalol 206 5.3.3 Acute electrocardiographic effects of sotalol 206 5.3.4 Acute electrophysiologic effects of sotalol 214 5.3.5 Validity of utilizing femoral arte¡ial sotalol concentrations as a surrogate for those in the aorta 214 5.3.6 Acute myocardial sotalol uptake 214 5.3.7 Correlation between myocardial sotalol content and acute effects 222 5.3.8 Pharmacokinetic - pharmacodynamic link models between myocardial sotalol content and effect 226 5.3.9 Sotalol redistribution into other vascular beds 226 5.3.10 Serial mechanical restitution curve construction 231 v 5.3.11 Post-extrasystolic potentiation without a compensatory pause 234 5.3.12 Application of the curve-frtting model to mechanical restitution curyes obtained post-sotalol injection 237 5.3.L3 Rapid atrial pacing before and after sotalol injection 237 5.3.L4 Submaximal coronary vasodilator reserve 24t 5.3.15 Summary of results 242 5.4 Discussion 243 Chapter 6: Acute myocardial uptake of milrinone : correlation with acute effects and a biochemical marker in humans 249 6.1 Background and Aims 25O 6.2 Methods 251 6.3 Results , 252 6.3.1 Patient characteristics 252 6.3.2 Acute haemodynamic effects of milrinone 252 6.3.3 Acute electrocardiographic effects of milrinone 257 6.3.4 Acute electrophysiologic effects of milrinone 257 6.3.5 Influence of milrinone on plasma cAMP concentrations 257 6.3.6 Validity of utilization of femoral arterial milrinone concentrations as a surogate for those in ttre aorta 266 6.3.7 Acute myocardial milrinone uptake 266 6.3.8 Correlation benveen myocardial milrinone content and acute effects 268 6.3.9 Milrinone redistribution into other vascular beds 273 6.3.10 Serial mechanical restitution curve construction 273 6.3.11 Post-extrasystolic potentiation without a compensatory pause 216 6.3.I2Post-extrasystolic potentiation with a compensatory pause 276 6.3.13 Application of the curve-fitting model to mechanical restitution curyes obtained post-milrinone injection 279 6.3.14 Examination of hysteresis between myocardial milrinone content and the rate dependence index 279 6.3.15 Influence of rapid atrial pacing on LV+dP/dt before and after milrinone injection 283 vl 6.3.16 Submaximal coronary vasodilator reserve 285 6.3.L7 Summary of results 286 6.4 Discussion 287 Chapter 7: General Discussion 294 7.lOverview 295 7.2 Acute effects of cardioactive drugs 296 7.3 Determinants of drug effects : influence of myocardial drug conteht in the present investigation 297 7.4 Myocardial drug uptake of cardioactive agents : comparison with previous studies 2gg 7.5 Influence. of ca¡dioactive drugs on contractile state : modulation by changes in cycle length 301 7.6 Conctusions 304 Bibliography s06 vll DECLARATION This work contains no material which has been accepted for the award of any other degree or diploma in any university or other tertiary institution and, to the best of my knowledge and belief, contains no material previously published or written by any other person, except where due reference has been made in the text. I give consent to this copy,of my thesis, when deposited in the University Library, being available for loan and photocopytng. ret.?.qtt- Signed Date vlll ACKNOWLEDGEMENTS I would like to thank my supervisor Prof John Horowitz for his supervision and guidance. My sincere thanks also to Prof Ivan de la Lande for his advice, encouragement, critical evaluation of the work, and especially his practical assistance with the Langendorff isolated rat heart preparation. The assistance of Dr Dennis Morgan (Victorian College of Pharmacy) and Prof Richard Jarrett (Department of Statistics) was also appreciated, in the pharmacokinetic / pharmacodynamic modelling, and the development of a model for the mechanical restitution curve, respectively. I also wish to thank Dr Yi Zhang for her assistance with data collation for postextrasystolic potentiation, Dr John Hii for his assistance with measurement of the electrophysiologic patameters, and the staff of the Cardiology Research and Cardiac Catheterization Laboratories, and the Department of Clinical Pharmacology for their valuable assistance in the research protocol. My thanks also to the many patients who took part in the study, without whose voluntary participation this work would not have been possible. Finally, I would like to thank Steven, and my close friends, for their support and encouragement during this time.
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