Physico-Chemical Aspects of Drug Action (eBook)

Front Cover 1
Physico-Chemical Aspects of Drug Action 4
Copyright Page 5
Table of Contents 6
LIST OF AUTHORS AND PARTICIPANTS 8
CHAPTER 1. INTRODUCTORY REMARKS 12
CHAPTER 2. PHARMACOKINETICS AS A BASIC MEDICAL PROBLEM 16
I. PHARMACOKINETICS AS A MEDICAL PROBLEM 16
II. PHARMACOKINETICS AS A FORMAL PROBLEM 31
ACKNOWLEDGEMENT 35
REFERENCES 35
CHAPTER 3. KINETICS AND IMPLICATIONS OF DISSOLUTION RATE. LIMITED GASTROINTESTINAL ABSORPTION OF DRUGS 44
PHYSICOCHEMICAL FACTORS AFFECTING DISSOLUTION RATE 47
PHYSIOLOGIC FACTORS AFFECTING DISSOLUTION AND ABSORPTION RATE 53
CORRELATION OF IN VITRO DISSOLUTION WITH IN VIVO ABSORPTION KINETICS 59
EFFECT OF ABSORPTION RATE O N DRUG METABOLISM 66
EFFECT OF DISSOLUTION RATE ON PHARMACOLOGIC ACTIVITY 68
REFERENCES 72
CHAPTER 4. PHARMACOKINETICS AND DOSE-CONCENTRATION RELATIONSHIPS 74
1. INTRODUCTION: MODELS, DEFINITIONS AND SYMBOLS 74
LIST OF SYMBOLS 75
2. SINGLE-DOSE ADMINISTRATION 80
3. MULTIPLE-DOSE ADMINISTRATION 98
4. SUMMARY 117
REFERENCES 117
CHAPTER 5. THE TIME COURSE OF THE BIOLOGICAL RESPONSE TO DRUGS :A MATHEMATICAL TREATMENT 126
CHANGE OF DRUG CONCENTRATIONIN THE TARGET TISSUE—A COMPARTMENT MODEL 127
DEPENDENCE OF THE INTENSITY OF RESPONSE ON THE DOSE 127
MATHEMATICAL MODELLING OF THE TIME CHANGE OF RESPONSE 132
RELATIONSHIPS BETWEEN DOSE AND TOTAL RESPONSE 135
REFERENCES 137
CHAPTER 6. MPIRICAL EQUATIONS FOR CORRELATING BIOLOGICAL EFFICIENCY OF ORGANIC COMPOUNDS 138
REFERENCES 149
CHAPTER 7. THE USE OF SUBSTITUENT CONSTANTS IN STRUCTURE-ACTIVITY STUDIES 152
INTRODUCTION 152
LINEAR SINGLE-PARAMETER APPROACHES 152
USE OF ADDITIVE CHARACTER OF log p FOR STRUCTURE-ACTIVITY WORK 156
CORRELATION OF PROTEIN BINDING OF ORGANIC COMPOUNDS WITH log p 158
NONLINEAR DEPENDENCE OF ACTIVITY ON log P 160
SEPARATION OF SUBSTITUENT EFFECTS BY REGRESSION ANALYSIS 164
DISCUSSION 172
ACKNOWLEDGMENTS 177
REFERENCES 177
CHAPTER 8. MOLECULAR BASIS FOR THE ACTIO N OF CHEMOTHERAPEUTIC DRUG STRUCTURE-ACTIVITY STUDIES ON SULFONAMIDES 180
SUMMARY 180
INTRODUCTION 180
CORRELATIONS BETWEEN NMR DATA AND SULFONAMIDE ACTIVITY 186
REFERENCES 191
INFLUENCE OF DIFFERENT DRUGSON THE SULFONAMIDES SERUM BINDING AND ON SULFONAMIDE AQUEOUS HUMOR LEVELS 192
MATERIALS AND METHODS 193
RESULTS 194
DISCUSSION 194
REFERENCES 197
CHAPTER 9. THE STUDY OF DRUG BINDING SITES BY NUCLEAR MAGNETIC RELAXATION 200
REFERENCES 202
DRUG-RECEPTOR INTERACTIONS IN METHEMOGLOBINS AND IN HEMIN MODELS 204
1. THE RECEPTOR OF THE METHEMOGLOBINS 205
2. BINDING FORCES AND AFFINITY 206
3. RECEPTOR-INDUCED CHANGES OF THE INHIBITOR 207
4. INHIBITOR-INDUCED CHANGES OF THE RECEPTOR AND OF THE PROTEIN CONFORMATION 209
5. THE SPECIFICITY OF THE LIGAND-RECEPTOR INTERACTION 211
REFERENCES 215
CHAPTER 10. PATTERNS OF LIGAND-INDUCED CHANGES ON A RECEPTOR SURFACE : THE WATE EXTRUSION HYPOTHESIS 218
INTRODUCTION 218
SUMMARY 245
ADDENDUM 246
ACKNOWLEDGMENTS 246
REFERENCES 246
CAPTER 11. BIOLOGICAL DRUG PARAMETERS FOR STUDIES OF THE RELATIONSHIP BETWEEN STRUCTURE AND ACTIVITY. 248
INTRODUCTION 248
DISCUSSION 269
SUMMARY 270
REFERENCES 270
CHAPTER 12. MATHEMATICAL TREATMENT OF TWO - POINT ATTACHMENT BETWEEN DRUG AND RECEPTOR 272
REFERENCES 280
CHAPTER 13. CHEMICAL STRUCTURE AND BIOLOGICAL ACTIVITY. SOME GENERAL PRINCIPLES 282
REFERENCES 291
CHAPTER 14. MOLECULAR PROPERTIES AND BIOLOGICAL ACTIVITY OF CATECHOLAMINES AND CERTAIN RELATED COMPOUNDS 294
METALLIC ION-CATECHOLAMINE COMPLEXES 296
PHARMACODYNAMIC PROPERTIES OF NON-CATECHOLIC SECONDARY PHENYLETHANOLAMINES 297
A COMPARISON BETWEEN THE PHARMACODYNAMIC PARAMETERS AND THE CHEMICO-PHYSICAL MOLECULAR CONSTANTS 301
NON-CATECHOLIC PRIMARY PHENYLETHANOLAMINES.CONCLUSIONS 304
REFERENCES 305
CHAPTER 15. SOMEEL ECTRONIC ASPECTS OF PHARMACOLOGY 306
INTRODUCTION 306
CHOLINOMIMETIC AGENTS 308
REFERENCES 314
CHAPTER 16. DIARYLCARBINOL ETHERS: STRUCTURE ACTIVITY RELATIONSHIPS. A PHYSICO- CHEMICAL APPROACH 316
REFERENCES 335
CHAPTER 17. QUANTUM MECHANICALLY DERIVED ELECTRONIC DISTRIBUTIONS IN THE CONFORMERS OF 2-PAM 338
INTRODUCTION 338
THEORETICAL METHODS 339
DISCUSSION 361
SUMMARY 364
ACKNOWLEDGMENTS 365
REFERENCES 365
CHAPTER 18. A MOLECULAR BASIS FOR THE ACTION OF CERTAIN DRUGS IN THE CENTRAL NERVOUS SYSTEM1 366
CONCLUDING REMARKS 383
REFERENCES 384
INDEX 388