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A Pharmacological. Study of the Ephedrine Isomers

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A Pharmacological. Study of the Ephedrine Isomers This dissertation has been 64—1295 microfilmed exactly as received PATIL, Popat Narayan, 1934- A PHARMACOLOGICAL. STUDY OF THE EPHEDRINE ISOMERS. The Ohio State Universityt Ph,Dt, 1963 Pharmacology University Microfilms, Inc., Ann Arbor, Michigan A PHARMACOLOGICAL STUDY OF THE HPHEDRIHE ISOMERS DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Popat Narayan Patil, B. Sc. in Phara., M. Sc. xxxxx The Ohio S tate University 1963 Approved by Adi College of Pharmacy ACKNOWLEDGMENTS The author would Ilka to acknowledge the efforte of Drs. Arthur Tye and Jules B. LaPidus for their valuable advice and Inspiration. The suggestions of Drs* Harold H. Wolf and John W. Nelson are also acknowledged. Special thanks to Mr* Balkrishna Modi for preparing the isomers and Mr. Dalai for the statistical analysis of the data* ii TABLE OF CONTENTS ACKNOWLEDGMENTS .................................................................................. LIST OF TABLES.................................................................................. LIST OF ILLUSTRATIONS ...................................................................... LIST OF ABBREVIATIONS ...................................................................... CHAPTER I. INTRODUCTION AND LITEiiATURS REVIEW G e n e r a l ......................................... .................................... Literature on Optical Isom ers ................................. II. MATERIALS AND METHODS Acute Toxicity .................................................................. Experiments in Dogs ...................................................... Experiments in C a t s ........................ , Isolated Perfused Rabbit Heart ................................. TAIL'S or CONTENTS (Continued) Page IV. DISCUSSION Comparative Potency ..................... ......... 13? Mechanisms of Action of Optical Isomers of Efcihedrine ............................ 139 Effect of D (-) Pseudoephadrine Towards Other Pressor A m in es .................................................. SUMMARY................................................................................................... 153 3I3LI0GRAPHY.......................................................................................... 153 AUTOBIOGRAPHY...................................................................................... 166 iv Activity Ratios of Some Optical Isomers ................. Control B.P. and H.R. in (Atropinized) Anesthetized Dogs .......................................................... Control 3.P. and H.R. in Reserpinized Doge . , Control H.R. of the Isolated Rabbit Heart . Intravenous Acute Toxicity of the Isomers of %>hedrino in M ice ...................................................... Relative Potencies of the Drugs Derived from Equipressor Doses .......................................................... Epinephrine Equivalents at Equip res so r Doses of the Isomers ............................................. .... ■ , Duration of Pressor Action of the Isomers in Dogs B.P. Responses tc D (-) Pseudocphedrine in Anesthetized Dogs ..... ..................................... Comparative Pressor Potency of D (-) I^hcdrina and D (-) Pseudoephedrine in Spinal Cats . Increase of H.R. by the Isomers (In Dogs) . Increase in the H.R. to D (-) Pseudoephedrino in Anesthetized Dogs ......................................... Pressor Effects to the Repeated Doses of Isomers in Dogs .............................................................. Effect of the Isomers on the H.R. and Contractile Force (C.F.) of the Isolated Rabbit Heart , . Effect of D (-) Pseudoephedrine on the H.R. and Contractile Force (C.F.) of the Isolated Rabbit Heart ..................................... Effect of the Isomers on the Coronary Flow of the Isolated Rabbit Heart ..................................... LIST OF TABLES (Continued) Page Summary - Approximate Comparative Potencies of the Isomers ..................................................................... 65 Effect of Reserpine Pre-treatment on the B.P. Effect of the Isomers and Anqphetandne .................. 73 Effect of Reserpine Pre-treatment on the H.R. E ffect o f the Isomers and Amphetamine .................. 7b Summary of the Control B.P. and H.R. and Effect of Reserpine Pre-treatment on it . 75 Effect of D (-) Pseudoephedrine at the Height of Pressor Responses to D (-) Ephedrlne and Vasopressin in D o g s ........................................... 77 The Effect of D (-) Pseudoephedrine at the Height of Pressor Response to D (-) Efc>h- edrine in Anesthetized and Spinal C ats .................. 36 Antagonistic Action of D (-) Pseudoephedrine Towards N.M. E ffect o f D ( - ) i^phedrine in Anesthetized Cats ........................................................ 90 Antagonistic Effect of D (-) Pseudoephedrine Against Norepinephrine on the Rabbit Aortic Strip ......................................................................... 93 Antagonistic Effect of D (-) Pseudoephedrine Against D (-) Ephedrlne on the Rabbit Aortic Strip ......................................................................... 96 Blocking the Pressor Response and I.R. Effect of D (-) Ephedrlne (0 .3 3 mg/kg) by D (-) Pseudoephedrine In Dogs .............................. .... 100 Blocking the Pressor Action ofD ( -) Ephedrlne (0.33 mg/kg) by D (-) Pseudoephedrine in Spinal Cats .................................................................... 103 v i LIST OF TABLES (Continued) Table Page 23. Blocking the Pressor Response and H.R. of D (-) Ephedrlne, L (+) Ephedrlne, L (+) Pseudo­ ephedrine, D (+) Amphetamine, by 30 Minutes Pre-treatment of D (-) Pseudoephedrine (3.3 mg/kg) .................................................................................. 10h 29. Blood Pressure Response to D (-) Pseudoephedrine in Anesthetized Cats , 109 32. Potentiation of Epienphrine Pressor Effects by D (-) Pseudoephedrine .............................. I l l 31. Potentiation of Norepinephrine Pressor Effects by D (-) Pseudoephedrine ........................ l l h 32. Effect of D (-) Pseudoephedrine on C.O. Pressor Response ..... .................. .... 116 33* Effect of D (-) Pseudoephedrine on the Stimulation of the Cervical Sympathe­ t i c Nerve and N ic tita tin g Membrane (N.M.) . 119 3'U Effect of Diphenhydramine (5 mg/kg) on Depressor Responses to Histamine, Iso­ proterenol, and D (-) Pseudoephedrine .... 123 35* Effect of D.C.I. (10 mg/kg) on the Depressor Response to D (-) Pseudoephedrine (9.9 mg/kg) . 12^ 36. Effect of D (-) Pseudoephedrine in Spinal Cats Infused with Norepinephrine ........ 123 37. Effect of D (-) Pseudoephedrine after Hexamethonium C h lo rid e ............................. 131 v ii LIST OF ILLUSTRATIONS Figure Page 1. A Typical Experimental Design Used for the Com­ parative Study of the Isomers in Dogs ..................... 21 2. Graph Showing the Determination of the epinephrine Equivalent for L (+) Pseudoephedrine from Experiment Shown in Fig. 1 .......................................... 24 3. B arb italized Dogs Showing Depressor Response to Graded Doses o f D (-) Pseudoephedrine .... 43 4. Dose Response Curve to Pressor Effects of D (-) Pseudoephedrine in Spinal Cats and D (-) Eph- edrine Equivalent from Graphic Interpolation . 47 5. Gradual Increase in Average Heart Rate of Seven Anesthetized Dogs to D (-) Pseudoephedrine, 3.3 mg/kg, over a Time Period of 30 Minutes . 52 6. Tachyphylaxis to Pressor Effects of D (-) fyhedrine (0.33 mg/kg), L (+) Efchedrine (0.99 mg/kg), D (+) Amphetamine (0.34 ®g/kg), and L (+) Pseudoephedrine (l .65 mg/kg) in Anesthetized Dogs ................. 56 7. Effect of D (-) Pseudoephedrine and D (-) Ephedrlne on the Isolated Rabbit H e a rt ................. 6l 3. Effect of Reserpine Pre-treatment on the B.P. and H.R. Effects of the Isomers in Anesthetized Dogs .............................................................. 67 9. Effect of Reserpine Pre-treatment on the Pressor Effects in Anesthetized D ogs ..................... 69 10. Effect of Reserpine Pre-treatment on the H.R. in Anesthetized D o g s .............................................. 71 11. Antagonistic Effect of D (-) Pseudoephedrine Against the Pressor Effect of D (-) Ephedrlne in Anesthetized D ogs ................................. 78 v iil LIST OF ILLUSTRATIONS (Continued) Figure Page 12. Antagonistic Effect of D (-) Pseudoephedrine on the Pressor Effects of D (+) Amphetamine in Anesthetized Dogs ............................... 30 13. The Effects of L (+) fyhedrine and L ( + ) Pseudoephedrine at the Height of Pressor Effects of D (-) Ephedrlne in Anesthetized Dogs ................................................ 32 14. Effect of D (-) Pseudoephedrine Against the Pressor Effects Induced by D (-) Ephedrine and Vasopressin in Reserpinized D ogs ............................................................... 34 15- Antagonistic Effect of D (-) Pseudoephedrine Against D (-) Ephedrine in Spinal C ats ................... 8? 16. Antagonistic Effect of D (-) Pseudoephedrine Against D (-) Ephedrlne Induced Con­ traction of the Cat N.M ...................................................... 91 17. Antagonistic Effect of D (-) Pseudoephedrine Against Norepinephrine Induced Con­ traction of the Rabbit Aortic S trip s ....................... 9*+ 18. Antagonistic Effect of D (-) Pseudoephedrine Against D (-) Ephedrine on Rabbit Aortic Strips 97 19. Reduction of D (-) Ephedrine Induced Pressor Effects by
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