This unique and much needed textbook meets the rapidly emerging needs of programs training pharmacologic scientists seeking careers in basic research and drug discovery rather than such applied fields as pharmacy and medicine. While the market is crowded with many clinical and therapeutic pharmacology textbooks, the field of pharmacology is booming with the prospects of discovering new drugs, and virtually no extant textbook meets this need at the student level. The market is so bereft of such approaches that many pharmaceutical companies will adopt Hacker, et al. to help train new drug researchers. The boom in pharmacology is driven by the recent decryption of the human genome and enormous progress in controlling genes and synthesizing proteins, making new and even custom drug design possible. This book makes use of these discoveries in presenting its topics, moving logically from drug receptors to the target molecules drug researchers seek, covering such modern topics along the way as side effects, drug resistance, Pharmacogenomics, and even nutriceuticals, one in a string of culminating chapters on the drug discovery process. *Uses individual drugs to explain molecular actions *Full color art program explains molecular and chemical concepts graphically *Logical structure reflecting the current state of pharmacology and translational research, starting with receptors and finishing with target molecules *Covers such intricacies as drug resistance and cell death *Consistent format across chapters and pedagogical strategies make this textbook a superior learning tool
Author(s): Miles Hacker, William S. Messer II, Kenneth A. Bachmann
Edition: 1
Publisher: Academic Press
Year: 2009
Language: English
Pages: 584
Cover Page
......Page 1
Copyright
......Page 2
Dedication
......Page 3
Contributors
......Page 4
Preface
......Page 5
What Is Pharmacology?......Page 6
The Beginnings of Pharmacology......Page 7
Pharmacology and the Middle Ages......Page 8
Pharmacology and the Renaissance......Page 9
The Birth of Modern Pharmacology......Page 10
References......Page 12
Introduction......Page 13
Factors Affecting Dosage......Page 14
DDIs Associated with Alteration of Cytochrome P450 Activity......Page 305
Body Surface Areas......Page 15
Dose Based on Creatinine Clearance......Page 17
Routes of Drug Administration......Page 18
Introduction......Page 19
Ionization of Drugs......Page 20
Miscellaneous Oral Dosage Forms......Page 21
Rectal Route......Page 22
Parenteral Route......Page 23
Transdermal Drug Delivery Systems......Page 24
Topical Solutions and Tinctures......Page 25
Transdermal Drug Delivery Systems......Page 26
Aerosol Delivery Devices for Inhalation, Inhalants, and Sprays......Page 28
Vaporizers and Humidifiers......Page 30
Nanoparticle......Page 32
Review Questions......Page 33
Monographs, Review Articles, and OriginalPapers......Page 171
Drug Transporters and Drug Resistance......Page 34
The Lipid Molecules......Page 35
The Amphipathic Property of Lipid Molecules......Page 42
The Bilayer......Page 43
Trans-bilayer Structure......Page 44
Lateral Structure of a Bilayer......Page 45
The Role of Proteins in a Bilayer......Page 46
Lateral Heterogeneity......Page 48
In Support of Protein Function......Page 49
Role of Drug Polarity......Page 50
Tubular Secretion......Page 52
Vesicle-mediated Transport......Page 53
Pore-forming Peptides......Page 55
General Anesthesia......Page 56
Multiple Drug Resistance......Page 59
Calculating Exposure Doses......Page 60
Review Questions......Page 61
References......Page 63
The Cell Cycle......Page 65
Affinity......Page 66
Efficacy......Page 67
Antagonism......Page 70
Orthosteric Antagonism......Page 71
Allosteric Modulation......Page 73
Extended Ternary Complex Model......Page 74
Conclusions......Page 75
References......Page 76
Pharmacology and the Dose Response......Page 77
Hormesis: Origin of Concept and Terminology......Page 79
Historical Marginalization of Hormesis......Page 80
Rebirth of Scientific Credibility and Centrality......Page 82
Common Terms Used for Hormetic Dose Responses......Page 83
Evidence Supporting Hormesis......Page 84
Hormesis Characteristics......Page 90
The Hormesis Stimulation: Direct or Compensatory Response to Damage?......Page 91
Receptor Tyrosine Kinase-coupled Second Messengers......Page 92
Drugs That Target the Mitotic Spindle......Page 93
The Oral Cavity and Gastro-Intestinal (GI) Tract......Page 94
Hormesis in Drug-Drug Interactions (DDIs) and Mixed Chemical Systems......Page 95
Epidemiological Considerations: Issue of Population Heterogeneity......Page 96
Drug Discovery......Page 97
N-Acetyltransferases (NATs)......Page 98
The Importance of Ligand Alignment......Page 99
Drug Potency and Hormesis......Page 100
Review Questions......Page 101
References......Page 102
References for Figure 5.3.......Page 104
G-Protein-Coupled Receptors......Page 105
G-Protein-Coupled Second Messengers......Page 106
Gs/Gi Coupling to Adenylyl Cyclase......Page 107
Signaling by betagamma Subunits......Page 108
Antimetabolites and Damage During S Phase......Page 427
Ras/MAP Kinase Signaling Cascade......Page 109
Cytokine Receptors (Tyrosine Kinase-Associated Receptors)......Page 111
Development of Drug Allergies......Page 123
Other Classes of Receptors......Page 112
Pharmacokinetic Considerations......Page 313
References and Further Reading......Page 113
Acknowledgements......Page 561
Clinical Correlate: AIDS Pharmacotherapy Movement Across Biological Membranes......Page 115
Overview and History......Page 448
Membrane Proteins......Page 116
Drug Efflux Proteins......Page 367
Dose Response Assessment......Page 352
OAT/OCT......Page 117
Flux Across Biological Membranes......Page 121
Risk Characterization......Page 122
Mechanism of Ion Channel Inhibition......Page 392
Substrate Interactions with Cytochromes P450......Page 124
Absorption and the First-Pass Effect......Page 125
Tubular Transport of Nucleosides and Nucleoside Analogs......Page 126
First-Order Absorption Rate......Page 211
Identifying Hits and Producing Lead Compounds......Page 127
Example......Page 337
Intracellular Membranes......Page 129
Myelosuppression......Page 295
References......Page 130
Overview and History......Page 132
Genomics and Proteomics......Page 553
Biotransformation Pathways......Page 133
Regulation......Page 138
Ion Selectivity......Page 387
Accounting for Cooperativity......Page 309
Microarrays......Page 555
Transcriptional/Posttranscriptional Control......Page 140
Cytochromes P450......Page 141
Structure......Page 143
Topography......Page 144
Origin, Genetics, and Polymorphisms of Cytochromes P450......Page 145
Phenotyping CYP Activity......Page 149
Quantitative Characterization of Drug Metabolizing Enzyme Activities......Page 151
In Silico Methods for Predicting Substrate Specificity......Page 152
Effects of Aging and Disease on Renal Drug Excretion......Page 153
Volume of Distribution......Page 213
Monoamine Oxidases (MAO)......Page 158
Xanthine Oxidase (XO)......Page 159
Flavin Monoxygenases (FMO)......Page 160
Phase II Enzymes......Page 161
Sulfotransferases (SULTs)......Page 162
Glucuronidation......Page 163
Glutathione-S-Transferases (GSTs)......Page 167
Conclusions and Key Points......Page 169
Introduction......Page 175
P-glycoprotein (Pgp, ABCB1)......Page 176
Exponential Function, Exponential Decay, and Half-Life......Page 203
Multidrug Resistant Proteins (MRP, ABCC)......Page 177
Solute Carrier (SLC) Transport Family......Page 178
Organic Anion Transporting Polypeptide Family (OATP, SLC21A)......Page 179
Nucleoside Transporter Families: Concentrative Nucleoside Transporters (CNT, SLC28) and Equilibrative Nucleoside Transporters.........Page 180
Functional Overview of the Kidney......Page 181
Glomerular Filtration......Page 182
Tubular Reabsorption......Page 183
Tubular Transport of Organic Anions......Page 184
Tubular Transport of Organic Cations......Page 186
Renal Drug Interactions......Page 187
The Ultraviolet-Visible Light Detector (the UV-Vis Detector)......Page 188
Drug Transport Across the Hepatocyte......Page 189
Enterohepatic Recycling......Page 191
Hepatobiliary Drug Interactions......Page 193
Using Functional Group Interactions to Track Ligand Binding......Page 493
Intestinal Exsorption......Page 194
Design of Irreversible Inhibitors......Page 298
Other Routes of Drug Excretion......Page 195
Pharmacokinetics of Large Molecules......Page 196
Books......Page 197
Review Articles and Original Papers......Page 198
Pharmacokinetic Modeling......Page 200
Introduction......Page 201
Mathematics in Pharmacokinetics......Page 202
Integration and Area Under the Curve......Page 204
Passive Diffusion Transport Rate......Page 205
Diffusion through a Lipid Bilayer......Page 206
Blood Flow Transport......Page 207
Perfusion versus Permeation Transport Limitations......Page 208
Permeability-Limited Transport......Page 209
Extent of Absorption: Bioavailability......Page 210
Chemical Parameters......Page 212
First-Order Distribution Rate......Page 214
Metabolism......Page 215
First-Order Rate of Metabolism......Page 216
Excretion Clearance and Renal Clearance......Page 217
Overall First-Order Elimination Rate Constant......Page 218
Organization of Single-Dose Pharmacokinetic Model Information......Page 219
One-Compartment Bolus IV Injection (Instantaneous Absorption) Model......Page 220
Setup and Solution of Mass Balance Equations......Page 221
Effect of Basic Model Parameters on the Plasma Concentration versus Time Curve......Page 222
Linear Regression of ln(Cp) versus t......Page 223
Area under the Curve (AUC) Calculations......Page 224
Two-Compartment Instantaneous Drug Absorption Simplification......Page 225
Setup and Solution of Mass Balance Equations......Page 226
Plasma Concentration versus Time Relationships......Page 227
Effect of Basic Model Parameters on the Plasma Concentration versus Time Curve......Page 228
Linear Regression of Postinfusion Data......Page 229
Linear Regression of Infusion Period Data......Page 230
Special Cases of the One-Compartment IV Infusion (Zero-Order Absorption) Model......Page 231
First-Order Absorption......Page 232
Plasma Concentration versus Time Relationships......Page 233
Effect of Basic Model Parameters on the Plasma Concentration versus Time Curve......Page 234
Estimating Model Parameters from Measured Plasma Concentration Data......Page 235
Method of Residuals Analysis of Absorption Phase Plasma Concentration Data......Page 236
Area under the Curve (AUC) Calculations......Page 237
Flip-Flop First-Order Absorption......Page 238
Two-Compartment Bolus IV Injection (Instantaneous Absorption) Model......Page 239
Setup and Solution of Mass Balance Equations......Page 240
Plasma Concentration versus Time Relationships......Page 241
Distribution and Elimination Half-Lives......Page 242
Estimating Model Parameters from Measured Plasma Concentration Data......Page 243
Method of Residuals Analysis of Distribution Phase Plasma Concentration Data......Page 244
Distribution Volume Terms for a Two-Compartment Model......Page 245
Approximation of Two-Compartment Drug by One-Compartment Model......Page 246
Setup and Solution of Mass Balance Equations......Page 247
Distribution and Elimination Half-Lives......Page 248
Effect of Basic Model Parameters on the Plasma Concentration versus Time Curve......Page 249
Method of Residuals Analysis of Distribution Phase Plasma Concentration Data......Page 250
Area under the Curve (AUC) Calculations......Page 251
Two-Compartment First-Order Absorption Model......Page 252
Setup and Solution of Mass Balance Equations......Page 253
Plasma Concentration versus Time Relationships......Page 254
Effect of Basic Model Parameters on the Plasma Concentration versus Time Curve......Page 255
Linear Regression of Terminal Line Plasma Concentration Data......Page 256
Method of Residuals Analysis of Absorption and Distribution Phase Data......Page 257
Area under the Curve (AUC) Calculations......Page 258
Generalized Multicompartment Models......Page 259
Plasma Concentration versus Time Relationships......Page 260
Estimating Model Parameters from Measured Plasma Concentration Data......Page 261
Superposition Principle Assumptions......Page 263
Superposition Principle......Page 264
One-Compartment Instantaneous Absorption......Page 265
One-Compartment First-Order Absorption......Page 267
Generalized Multicompartment Model with Instantaneous or First-Order Absorption......Page 268
Estimating Plasma Drug Concentrations......Page 269
Curve Fitting with Nonlinear Regression Analysis......Page 270
Population Pharmacokinetic Analysis......Page 271
Metabolite Kinetics......Page 272
Nonlinear Kinetics......Page 273
Physiologically-based Pharmacokinetic (PBPK) Models......Page 274
Summary of Key Points......Page 275
References......Page 276
The Scope of Drug Bioanalysis......Page 277
Cell Cycle Checkpoints......Page 278
The Inhibitors of Apoptosis, IAPs......Page 451
Chromatography......Page 279
From LC to GC to HPLC-Comparisons and a History Lesson......Page 280
An Adolescent Heyday of Rational Drug Design......Page 282
Bandbroadening......Page 283
Exposure Setting......Page 286
Extracolumn Bandbroadening......Page 287
Analytical Separations in Practice......Page 288
HPLC Stationary Phases......Page 289
Gradient versus Isocratic Elution......Page 290
Instrumental Aspects of HPLC......Page 291
Gradient Formation......Page 292
Carcinogens......Page 356
A Glossary of Bioanalytical Terms (Source: Adapted from US Food and Drug Administration Guidance for Industry: Bioanalytical Method Validation)......Page 293
Fixed-Wavelength UV-Vis Detectors......Page 294
Agranulocytosis......Page 338
Electrospray Ionization......Page 297
Review Questions......Page 299
References......Page 300
Overview and History......Page 301
A Working Definition......Page 302
Ion Channel Structure and Function: Basic Principles and Mechanisms......Page 303
Sources of Drug Interaction Information......Page 304
Predicting the Clinical Significance of DDIs Associated with CYP Inhibition from In Vitro Data......Page 306
Interactions Resulting from Increased Enzyme Activity......Page 310
Spindle Checkpoint......Page 312
Interactions Involving P-Glycoprotein (PgP)......Page 315
Predicting Clinical DDI Outcomes from In Vitro DDI Data for PgP......Page 316
Predicting DDIs When Victim Drugs Are Processed Both by CYPs and PgP, and When Perpetrators Inhibit Both......Page 317
DDIs Associated with Protein Binding......Page 318
Conclusions and Key Points......Page 320
References......Page 322
Type A ADRs......Page 324
Epidemiology......Page 351
Tools for Searching for Future Drugs......Page 326
Population Distribution and Drug Sensitivity......Page 327
Examples of Type A ADRs......Page 328
Altered Levels of Drug Target......Page 329
Pharmacovigilance and ADR......Page 330
Type B ADRs......Page 331
Classification of Drug Allergies......Page 332
Medicinal Chemistry and the Process of Drug Discovery Today and into the Future......Page 333
Epidemiology of Beta Lactam Drug Allergies......Page 334
Mechanisms of Allergic Responses......Page 335
L-Asparaginase......Page 336
Diclofenac as a Model of Idiosyncratic Hepatotoxicity......Page 339
Anthracycline Cardiotoxicity......Page 341
NSAIDs and Cardiotoxicity......Page 342
Idiosyncratic Pulmonary Damage......Page 343
Idiosyncratic Renal Toxicity......Page 344
Risk Communication......Page 364
Streptomycin-induced Renal Toxicity......Page 345
Review Questions......Page 346
References......Page 365
History......Page 350
Exposure Assessment......Page 353
Soil Sampling......Page 354
Activity Patterns......Page 355
Hazard Index......Page 357
Generic Exposure Dose......Page 358
Plant Models......Page 360
Review Questions......Page 419
Radiological Risk Assessments......Page 361
Risk Management......Page 362
Risk Management Factors in Cost and Feasibility......Page 363
Interplay of Synthetic Chemistry and Advanced Pharmacology......Page 516
Introduction......Page 423
Glutathione and Drug Resistance......Page 371
Structural Modifications......Page 372
DNA Repair and Drug Resistance......Page 374
Resistance to Penicillin: A Story of Two Mechanisms......Page 375
Drug Inactivation by Beta-Lactamases......Page 376
Resistance to Chloroquine: Another Membrane-bound Transporter Protein......Page 377
Antifolate Resistance......Page 378
Tuberculosis Drug Resistance through Decreased Drug Activation......Page 379
Resistance Nodulation Cell Division Superfamily (RND)......Page 380
Drug Metabolism and Excretion versus Side-Effect Toxicity......Page 483
Review Questions......Page 381
Introduction......Page 382
Overview and History......Page 383
Ion Channel Classification and Nomenclature......Page 384
Gating......Page 390
Posttranslational Control......Page 391
Ligand-Gated Channels......Page 393
Calcium Channels......Page 396
Potassium Channels......Page 398
The Systemic Circulation and Blood-Brain Barrier......Page 407
Intracellular and Gap-Junction Ion Channels......Page 408
Conventional ("Sharp") Microelectrodes......Page 409
Patch-Clamp Technique......Page 410
Pharmacological Techniques......Page 412
Crystallographic and Spectroscopic Techniques......Page 413
Genetically Engineered Animal Models......Page 414
Ion Channels and Disease......Page 415
Ion Channels as Drug Targets......Page 416
Abbreviations......Page 420
Monographs, Review Articles, andOriginal Papers......Page 421
Useful Ion Channel Related Web Sites......Page 422
CDKs, Cyclins, CDKIs......Page 424
RB/E2F......Page 425
p21/WAF1/CIP1 and the CDKIs......Page 426
DNA Damage G2 Checkpoint......Page 428
Proteins That Recognize and Respond to Altered DNA Structures......Page 429
Claspin and RAD17 in ATR Signaling......Page 430
Cell Cycle Responses to Cancer Therapies That Damage DNA......Page 431
Mitotic Kinases as Targets of New Chemotherapeutics......Page 436
CPC at the Inner Centromere......Page 437
CPC at the Spindle Midzone......Page 438
Regulation of the CPC......Page 439
Long-term Responses to Aurora Kinase Inhibitors In Vitro......Page 440
Review Questions......Page 441
References......Page 442
Pathways of PCD......Page 449
Caspases......Page 450
The Mechanism of IAP Action......Page 452
Regulation of IAPs......Page 454
IAP Regulatory Proteins......Page 455
Mechanisms of Action of Bcl-2 Protein......Page 456
Apoptosis in Disease......Page 458
Caspase-3 Inhibitors for the Treatment of Stroke......Page 460
Cellular Immunology of MS......Page 462
Induction of Cell Death in Treatment of Cancer......Page 464
Targeting IAPs in Cancer-Proof of Principle Studies......Page 465
Key References and Further Reading......Page 466
Overview......Page 467
Drug Discovery Starting Points......Page 468
Optimizing Pharmacological Profile and Advancing a Preclinical Drug Development Candidate......Page 470
Validating Therapeutic Targets and the First Chance for a New Drug......Page 471
Medicinal Chemistry as an Academic Discipline and Its Adoption by the Industry......Page 473
Birth of a New Drug Discovery Paradigm......Page 474
Pharmacological Media and Biological Surfaces......Page 477
The Bronchopulmonary Circulation and the Second-Pass Effect......Page 480
Efficacy Surfaces: Receptors, Active Sites, and Cell Signaling Clusters......Page 482
Consideration of the Ten Most Prescribed Drugs......Page 487
Experimental Strategies......Page 489
Library-based Drug Design......Page 490
Structure-based Drug Design......Page 491
Site-directed Mutagenesis......Page 492
Inhibiting Proteases......Page 501
Assuring Absorption......Page 503
Directing Distribution......Page 508
Modulating Metabolism......Page 511
Engaging Excretion and Tending to Toxicity......Page 514
Process Chemistry......Page 517
Formulation Chemistry......Page 518
Protecting the Corporate Checkbook......Page 519
Clinical Testing......Page 520
Reconsideration of the Ten Most Prescribed Drugs......Page 521
Background......Page 524
Mechanism of Action......Page 527
The Need for Better Analogs......Page 528
Background......Page 530
Accumulated Structure-Activity Relationships......Page 533
Esmolol Stat......Page 534
Summary......Page 537
Background......Page 538
Today's Approaches......Page 540
Future Approaches......Page 542
Summary......Page 545
Summary......Page 546
Terms......Page 547
Chemical Structures......Page 548
Specific Problems......Page 549
Monographs, Review Articles, and OriginalPapers......Page 550
Web Databases or General Information Starting-Points......Page 552
Computational Proteomics......Page 554
Separation Methods in Proteomics......Page 556
Identification and Validation of Drug Targets......Page 557
Actions of Anticancer Drugs......Page 558
Prediction of Drug Resistance......Page 560
References......Page 562
The Problem......Page 566
Strategies for Searching for Future Drugs......Page 567
The Drugs of the Future......Page 569
References......Page 570
A
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B
......Page 572
C
......Page 573
D
......Page 574
E
......Page 575
H
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I
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M
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O
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P
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S
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V
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Z
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