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PAUL, Balbir Singh, 1925- a STUDY on the PHARMACODYNAMICS of DIHYDROQUINIDINE in CANINE

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PAUL, Balbir Singh, 1925- a STUDY on the PHARMACODYNAMICS of DIHYDROQUINIDINE in CANINE This dissertation has been microfilmed exactly as received 67-16,326 PAUL, Balbir Singh, 1925- A STUDY ON THE PHARMACODYNAMICS OF DIHYDROQUINIDINE IN CANINE. The Ohio State University, Ph.D,, 1967 Pharmacology University Microfilms, Inc., Ann Arbor, Michigan A STUDY ON THE PHARMACODYNAMICS OF DIHYDROQUINIDINE IN CANINE DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Balbir Singh Paul, B.V.Sc., M.V.Sc. ******* The Ohio State University 1967 Approved by Adviser Department of Veterinary Physiology and Pharmacology ACKNOWLEDGMENTS I am highly indebted to Dr. Thomas E. Powers, Professor in the department of Veterinary Physiology and Pharmacology for his excellent guidance, encouragement and the sincere interest shown by him throughout the entire course of my graduate program-and research. My sincere thanks are due to Drs. S. Dutta and B. Marks for cooperation and affording facilities and guid­ ance during the course of my research. Special thanks are also due to Drs. C. R. Smith, R. W. Redding and R. S. Ray for giving their valid criticism and guidance during the course of my dissertation writing. The numerous illustrations were drawn by Mr. B. Kramer and Miss Diana Walker, medical artists. The statis­ tical computations in part, for this study, were done in the statistical laboratory at The Ohio State University. Technical assistance was given by Mrs. Dassie Sprecher, Messrs. Thomas Heading and Robert Slobody. I am pleased to have been able to fulfill the long desire of my late father. Dr. Ram Singh, in acquiring my graduate education. I also extend my sincere appreciation to my devoted wife, Inder, for her enthusiasm, encourage­ ment and many sacrifices in behalf of my educational pursuit. ii VITA August 5, 1925 Born - Amritsar, India 1946........ B.V.Sc., The University of Panjab, Lahore, India 1946-1948.... Veterinary Surgeon, Veterinary Hospital, Sulu, India 1948-1958.... Instructor, Department of Pharmacology, College of Veterinary Science and Animal Husbandry, Hissar, India 1958-195 9.... Graduate Student, Department of Veterinary Physiology and Pharma­ cology, The (ftiio State University, Columbus, Ohio 1959-196 4 .... Assistant Professor and Professor, of Pharmacology, College of Veterinary Science, Panjab Agricultural University, Hissar, India 1961......... M.V.Sc., Panjab University, Chandigarh, India 1964-1967.... Graduate Student, The Ohio State University, Columbus, Ohio FIELDS OF STUDY Major Field; Veterinary Pharmacology iii CONTENTS Page ACKNOWLEDGMENTS................................. il VITA............................................ iii TABLES....................... vii ILLUSTRATIONS................................... x INTRODUCTION;................. 1 CHAPTER I. REVIEW OF LITERATURE.................... 5 History of cinchona alkaloids Chemical structure of quinidine and dihydroquinidine Comparison of cardiovascular actions of qui-nidine and dihydroquinidine Cardiovascular responses to quinidine with special emphasis on conduction Distribution of cinchona alkaloids in blood and tissues Concentrâtion-Activity relationship of quinidine Metabolism and excretion of cinchona alkaloids II, MATERIAL AND METHODS.................... 32 Purity and identification of DHQ-H^ Methods of preparation of drug solutions dihydroquinidine and dihydroquinidine-H^ XV Page Methods of determination of the specific activity of DHQ-IP Studies on distribution and effects of DHQ on myocardial conduction velocity Surgical technique Electrode assembly Recording system -- Renal clearance Biliary excretion Extraction of unchanged drug from various tissues and biological fluids Radiometric analysis III. RESULTS................................. 54 Identification of DHQ-E? Determination of specific activity of DHQ-H® Effect of dihydroquinidine on myocardial conduction velocity Distribution of dihydroquinidine in various body compartments Disappearance of DHQ from plasma Tissue distribution Excretion of DHQ Renal excretion Renal clearance Biliary excretion Metabolite concentrations of DHQ in various tissues and biological fluids Page Tissues Biological fluids IV, DISCUSSION.............................. 128 Experimental techniques Effect of DHQ on myocardial conduction velocity Distribution in various body compartments Excretion and metabolism SUMMARY.......................................... 167 BIBLIOGRAPHY.................................... 170 Vi TABLES Table Page 1. Determination of the specific activity of DHQ-Hr used in destribution studies........ 57 2« Determination of the specific activity of DHQ-oH^ used in excretion studies. ..... 59 3. Conduction time in milliseconds (msec) from the stimulus to each recording point (1-14) 1 mm apart during different time intervals after DHQ administration in experiment #1, ....... — 60 4. Conduction time in milliseconds (msec) from the stimulus to each recording point (1-14) 1 mm apart during different time intervals after DHQ administration in experiment #2.................. 61 5. Conduction time in milliseconds (msec) from the stimulus to each recording point (1-14) 1 mm apart during different time intervals after DHQ administration in experiment #3............ 62 6. Conduction time in milliseconds (msec) from the stimulus to each recording point (1-14) 1 mm apart during different time intervals after DHQ administration in experiment #4, ..... 63 7. Conduction time in milliseconds (msec) from the stimulus to each recording point (1-14) 1 mm apart during different time intervals after DHQ administration in experiment #5................... 64 8. Effect of DHQ on myocardial conduction velo­ city ......... 72 9. Dosage of DHQ and DHQ-H^ in each experiment of 64 minutes distribution studies.......... 73 vii Table Page 10. Arterial, venous and coronary sinus plasma concentrations of DHQ in experiments 1 to 4 during different time intervals, ••••••••••••• ...... ...... 75 11. Arterial, venous and coronary sinus plasma concentrations of DHQ in experiment number 5 during different time intervals........................... 76 12. Arterial plasma concentrations of DHQ..... 77 13• Venous plasma concentrations of D H Q , 78 14. Coronary sinus plasma concentrations of DHQ...................................... 79 15. Tissue distribution of DHQ at 64 minutes post injection in experiments 1 to 5...... 94 16. Tissue distribution of DHQ at 64 minutes post injection. ....... 95 17. Tissue distribution of DHQ at 6 hours post injection in experiments 6 to 8.,.....,,.., 97 18. Tissue distribution of DHQ at 6 hours post injection................. 98 19. Cumulative renal excretion of DHQ during 64 minutes.............................. 106 20. Dosage of DHQ and DHQ-H^ for experiments on excretion (renal and biliary) . , 108 21. Renal clearance studies on DHQ, Dog #1,.... 110 22. Renal clearance studies on DHQ, Dog #2.... « 111 23. Renal clearance studies on DHQ, Dog #3.... « 112 24. Renal clearance studies on DHQ, Dog #4..... 113 25. Renal clearance studies on DHQ, Dog #5 ..... 114 26. Renal clearance studies on DHQ, Dog #6..... 115 viii Table Page 27. Renal clearance studies on DHQ, Dog #7 ..... 116 28. Cumulative renal excretion of DHQ during 117 29. Cumulative biliary excretion of DHQ diirlnc 6 hours . ... 119 30. Concentration of metabolites of DHQ in various tissues at the end of 64 minutes in the distribution experiments. 123 31. Concentration of metabolites of DHQ in plasma 124 32. Concentration of metabolites of DHQ in urine........................ 125 33. Concentration of metabolites of DHQ in bile......................... 127 ix ILLUSTRATIONS Figure Page 1. Nomenclature used for identification of various quinidine and dihydroquinidine structures............................. ... 10 2. Scheme for the route of metabolism of various cinchona alkaloids (proposed -by Brodie et al. 1951) A, shows the channel adopted by quinidine or quinine. B, shows the channel adopted by cinchonine and cinchonidine ....... .. 29 3. Illustrates the arrangement of the experiment pertaining to the study on the effect of dihydroquinidine on myocardial conduction velocity and its distribution and excretion. The various appliances employed are labeled.., 38 4. Illustrates the schematic diagram on the arrangement of the multipolar electrode assembly and its application on the right myocardium...... .. 41 5. Radio-chromatographic scan of a thin layer chromatoplate of DHQ-H^ and standard DHQ, using a solvent system consisting of chloroform and diethylamine (8:2), Note the radio peak adjacent to the positive area of the standard unlabeled DHQ, marked as U.V (standard DHQ visible under ultra violet light). ........ 56 6. Electrograros recorded from 14 points on the epicardium during control period and at 30 seconds, 1 minute and 2 minutes (after intravenous injection of DHQ (10 mg/kg)... 66 7. Continuation of Figure 6. Electrograms recorded during 4, 16, 32 and 64 minutes post injection period of DHQ admini­ stration are shown. ..... ........ 68 X Figure 3E^ge 8. Graphie representation of distance between electrodes and stimulus artifact (2-15 mm) against the conduction time (msec) between the stimulus artifact and nadir or peak of electrograms from each bipolar electrode. The records are shown both before and during various post injectional periods of DHQ.......... 71 9. Disappearance rate of dihydroquinidine from the arterial blood plasma............ 82 10. Disappearance rate of dihydroquinidine from venous blood plasma. ......
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