Nothing enhances the efficient learning of scientific material more than good artwork. Personal teaching experience has shown us the power of visual learning in the classroom and the positive effect it has on students. A well-done, accurate, and eye-catching illustration captures one's attention and stimulates one's imagination. Visualization of a concept enhances and solidifies one's understanding and internalization of it, and a good illustration becomes the template upon which future learning can be superimposed. We were thus excited when we were approached with the idea of publishing a visual pharmacology book. That is the intent of this book—to provide high-quality illustrative aids that will enhance the learning of the basic principles of pharmacology and present them in a manner that is both scientifically rigorous and enjoyable. It is designed for the visual learner in all of us.
But can there be illustrations of pharmacology? Isn't the study of pharmacology the memorization of innumerable drugs, their trade names, their doses, and other nonvisual material? Hardly. Just as all other basic sciences have their practical side, pharmacology has its application in the use of drugs for treatment of diseases and disorders. But in the past couple of years, there has been a virtual explosion in understanding of the biologic features and events that underlie the therapeutic action of a drug. It is now possible, with the creative input and insight of an artist's eye, to visualize the anatomical, physiologic, biochemical, and molecular underpinnings of pharmacology. This exciting new aspect of pharmacology is the focus of this book.
We believe that this is the first book to place such emphasis on artwork for the explanation of pharmacologic principles. There is, of course, no better starting point for this task than the renowned work of physician-artist Frank H. Net-ter, MD, whose illustrations have educated generations of students. Having access to the Netter collection of illustrations was a rare opportunity to approach the subject of pharmacology visually. To provide illustrations of more recently discovered concepts, we called upon James A. Perkins, MS, MFA, and other talented artists to create dynamic new illustrations of the detailed molecular events that underlie drug action. The translation by these artists of recent complex research findings into clear, precise, and engaging artwork was a pleasure to observe and is a highlight of this book.
Three authors with different but complementary backgrounds and expertise jointly wrote this book. Our collaboration was intended to provide the most authoritative and broadest possible coverage of both the basic science and the clinical applications of pharmacology.
We have written this book with medical, pharmacy, dental, nursing, and other professional students in mind, hoping that it will serve as a valuable adjunct to their more comprehensive textbooks. Each of us has found the illustrations to be useful in our own learning or teaching of the material. However, this book was also designed to be a stand-alone, discussing pharmacologic principles in a manner that allows a great deal of material to be covered in a concise fashion. It is thus also appropriate for use in an introductory course for undergraduate students or even for the interested general reader. We sincerely hope that all find the book useful and the presentation enjoyable. Robert B. Raffa, PhD; Scott M. Rawls, PhD; Elena Portyansky Beyzarov, PharmD

CHAPTER 1. BASIC PRINCIPLES OF PHARMACOLOGY

      Overview 1

Major Ways in Which Drugs Work

      External and Internal Threats 2

      Endogenous Chemical Balance 4

      Modulate Physiologic Processes 5

Chemical Communication

      Chemical Transmission at the Synapse 6

      Synapse Morphology 7

Pharmacodynamics

      Receptors and Signaling 8

      Receptor Subtypes 9

      Agonists 10

      Antagonists 11

      Stereochemistry and 3-Dimensional Fit 12

      Receptor-Effector Coupling 13

      Signal Transduction and Cross Talk 14

      Second-Messenger Pathways 15

      Ligand-Gated Ion Channels 16

      G Protein-Coupled Receptors 17

      Trk Receptors 18

      Nuclear Receptors 19

      Up-regulation and Down-regulation of Receptors 20

      Dose-Response Curves 21

      Potency 22

      Efficacy 22

      Inverse Agonists 23

      Antagonists: Surmountable (Reversible) and Nonsurmountable (Irreversible) 24

Pharmacokinetics

      Routes of Administration 25

      First-Pass Effect 26

      Membrane Transport 27

      Distribution 28

      Barriers 29

      Metabolism (Biotransformation) of Drugs 30

      Cytochrome P-450 (CYP450) Enzymes 31

      Metabolic Enzyme Induction and Inhibition 32

      Elimination 33

CHAPTER 2. DRUGS USED TO AFFECT THE AUTONOMIC AND SOMATIC NERVOUS SYSTEMS

      Overview 35

Organization of the Nervous System

      Organization of the Nervous System 36

      Action of Drugs on Nerve Excitability 37

Somatic Nervous System

      Interface of the Central and Peripheral Nervous Systems and Organization of the Somatic Division 38

      Neuromuscular Transmission 39

      Nicotinic Acetylcholine Receptor 40

      Physiology of the Neuromuscular Junction 41

      Pharmacology of the Neuromuscular Junction 42

      Mechanism of Action of Acetylcholinesterase Inhibitors 43

      Neuromuscular Blocking Agents: Nondepolarizing and Depolarizing 44

Autonomic Nervous System

      Autonomic Nervous System: Schema 45

      Sympathetic Fight or Flight Response 46

      Cholinergic and Adrenergic Synapses 47

      Example of Cholinergic and Adrenergic Drug Treatment: Glaucoma 48

      Cholinergic Receptors 49

      Cholinergic Drugs 50

      Example of Cholinergic Drug Treatment: Myasthenia Gravis 52

      Adrenergic Receptors 53

      Adrenergic Drugs 54

      Drugs That Act on the Autonomic Nervous System 55

      Drug Side Effects 56

CHAPTER 3. DRUGS USED IN DISORDERS OF THE CENTRAL NERVOUS SYSTEM AND TREATMENT OF PAIN

      Overview 57

Introduction to the CNS and Drug Action

      Development of the Nervous System 58

      Anatomy of the Nervous System 59

      Functional Correlations and Visualization of Brain Structures 60

      Resting Membrane and Action Potentials 61

      Excitatory and Inhibitory Postsynaptic Potentials 62

      Central Nervous System Neurotransmitters, Receptors, and Drug Targets 63

Sedative-Hypnotic Drugs

      GABA_A Receptor Complex and Sedative-Hypnotic Drugs 64

Anxiolytic Agents

      Clinical Anxiety 65

      Anxiolytic Agents 66

Antiepileptic Agents

      Causes of Seizures and Their Treatment 67

      Epilepsy: Generalized Seizures and Status Epilepticus 68

      Epilepsy: Partial and Absence Seizures 69

Antidepressants

      Clinical Depression 71

      Antidepressants: Mechanisms of Action 72

Drugs Affecting Bipolar Disorder and OCD

      Bipolar Disorder and Compulsive Behavior 73

Antipsychotic Agents

      Psychosis and Dopamine Pathways 74

Drugs Affecting Movement Disorders and Other Neurodegenerative Disorders

      Motor Tracts, Basal Ganglia, and Dopamine Pathways 75

      Parkinsonism: Symptoms and Defect 77

      Parkinsonism: Levodopa, Carbidopa, and Other Drugs 78

      Huntington Disease and Tourette Syndrome 79

      Alzheimer Disease: Symptoms, Course, and Pathology 80

      Alzheimer Disease: Cholinergic Involvement and Drugs 81

      Stroke: Symptoms and Drug Treatment 83

CNS Skeletal Muscle Relaxants

      Motor Neurons and Drugs 84

Analgesics and Anesthetics

      Pain Pathways 85

      Local Anesthetics: Spinal Afferents and Local Anesthetic Mechanisms of Action 86

      General Anesthetics: Properties 87

      Opioids: Endogenous Opioid Pathway 88

      Opioids: Receptor-Transduction Mechanisms 89

      Nonopioids: NSAIDs, Selective Cyclooxygenase-2 Inhibitors, and Acetaminophen 90

      Sumatriptans and Reuptake Inhibitors 91

CHAPTER 4. DRUGS USED IN DISORDERS OF THE CARDIOVASCULAR SYSTEM

      Overview 93

Cardiovascular System: Anatomy, Function, and Regulation of the Heart

      Cardiovascular Function: Anatomy 94

      Cardiovascular Function: Definition of Terms and Regulation 95

      Role of Catecholamines in Heart Function 96

      Sympathetic and Parasympathetic Regulation of Heart Function 97

      Synthesis and Storage of Catecholamines 98

      Regulation of Norepinephrine Release 99

      Inactivation of Norepinephrine 100

Hypercholesterolemia and Atherosclerosis

      Hypercholesterolemia: Causes 101

      Hypercholesterolemia: Pharmacologic Therapy 102

Angina

      Angina Overview 103

      Nitrates for Angina Treatment: Classes, Administration Routes, Pharmacology, and Adverse Effects 104

      Nitroglycerin in Angina Treatment 105

      Nitroglycerin: Mechanism of Action 106

      Calcium Channel Antagonists 107

      Drug Summary for Angina 108

Heart Failure

      Heart Failure Overview 109

      Heart Failure: Treatment 110

      Heart Failure Treatment: β-Adrenergic Stimulators and Blockers 111

      Heart Failure Treatment: Cardiac Glycosides 112

Arrhythmias

      Cardiac Arrhythmias: General 113

      Cardiac Arrhythmias: Treatment 115

      Cardiac Arrhythmias: Drug Classification 117

Hypertension

      Hypertension Overview 118

      Hypertension: Causes 119

      Hypertension Treatment: Diuretics 120

      Hypertension Treatment: Angiotensin-Converting Enzyme Inhibitors 121

      Hypertension Treatment: (3 and a Blockers 122

      Hypertension Treatment: Minoxidil 123

      Hypertension Treatment: Clonidine 124

      Hypertension in Elderly Patients 125

      Pheochromocytoma-lnduced Hypertension 126

      Hypertension in Cushing Syndrome 127

Peripheral Vascular Disease

      Peripheral Vascular Disease 128

CHAPTER 5. DRUGS USED IN DISORDERS OF THE ENDOCRINE SYSTEM

      Overview 129

Hypothalamic and Pituitary Disorders

      Regulation of Hypothalamic and Pituitary Hormones 130

      Hypopituitarism 132

      Growth Hormone Deficiency and Treatment 133

      Growth Hormone Excess (Acromegaly) and Treatment 134

Thyroid Disorders

      Thyroid Hormones 135

      Thyroid Hormones: Synthesis, Release, and Regulation 136

      Hypothyroidism 137

      Hypothyroidism: Treatment of Choice 138

      Liothyronine and T_4/T_3 Combinations 139

      Hyperthyroidism 140

      Hyperthyroidism: Treatment 141

      Thioamides 142

      Thioamides: Adverse Effects 143

      Radioactive Iodine 144

      Iodide 145

      Adrenergic Antagonists 146

Corticosteroids and Adrenocortical Dysfunction

      Regulation of Adrenal Hormones 147

      Mineralocorticoids and Glucocorticoids 148

      Corticosteroids 149

      Cushing Syndrome 150

      Ketoconazole 151

      Metyrapone 152

      Aminoglutethimide 153

      Addison Disease, or Primary Adrenal Insufficiency 154

Diabetes Mellitus

      The Pancreas and Insulin Production 155

      Insulin Secretion 156

      Lack of Insulin 157

      Type 1 Diabetes Mellitus 158

      Type 2 Diabetes Mellitus 159

      Insulin Therapy 160

      Reactions to Insulin: Hypoglycemia and Adipose Tissue Changes 161

      Sulfonylureas 162

      Biguanides 163

      Meglitinides 164

      α-Glucosidase Inhibitors 165

      Thiazolidinediones 166

      Thiazolidinediones: Clinical Rationale and Adverse Effects 167

CHAPTER 6. DRUGS USED IN DISORDERS OF THE GASTROINTESTINAL SYSTEM

      Overview 169

Function and Regulation of the Gl System

      Enteric Nervous System 170

      Integration of the Autonomic and Enteric Nervous Systems 171

      Gastrointestinal Motility 172

      Control of Peristalsis 174

      Hormones of the Gastrointestinal Tract 175

      Parietal Cell Function Regulation 176

      Pancreatic Secretion 177

      Defecation 178

      Protein Digestion 179

      Fat Digestion 180

Disorders of Colonic Motility

      Colonic Motility and Treatment of Diarrhea 181

      Antidiarrheal Drugs and Their Adverse Effects 182

      Causes of Constipation 183

      Treatment of Constipation 184

Functional Disorder of the Large Intestine

      Treatment of Irritable Bowel Syndrome 185

Protozoal Gl Infection

      Giardiasis 187

Peptic Ulcer

      Helicobacter pylori Infection Overview 188

      Treatment of Helicobacter pylori Infection 189

      Peptic Ulcer Treatment 190

Gastroesophageal Reflux Disease

      Gastroesophageal Reflux Disease Overview 191

      Gastroesophageal Reflux Disease Treatment 192

Pancreatitis

      Treatment of Pancreatitis 193

Cholelithiasis

      Pathologic Features of Gallstones 195

      Gallstone Pathogenesis and Treatment 196

Liver Physiology and Pathology

      Liver Function 197

      Bilirubin Production and Excretion 198

      Cirrhosis 199

      Ascites 200

Nausea and Vomiting

      Physiology of Emesis 202

      Antiemetics 204

CHAPTER 7. DRUGS USED IN DISORDERS OF THE RESPIRATORY SYSTEM

      Overview 205

Respiration: Physiology and Pathology

      Respiration Overview 206

      Respiratory Diseases 207

Allergy

      Allergy 208

      Leukocyte Function 209

      Allergic Rhinitis 210

Asthma

      Introduction to Asthma 211

      Extrinsic and Intrinsic Asthma 212

      Asthma Pharmacotherapy 214

      Anti-lgE Antibodies 215

      Mast Cell Degranulation Blockers 216

      Bronchodilators 217

      Methylxanthines 218

      Methylxanthines: Adverse Effects 219

      β-Adrenergic Agonists 220

      Nonselective β-Adrenergic Agonists 221

      Selective β_2-Adrenergic Agonists 222

      Antimuscarinic Antagonists 223

Antiinflammatory Agents: Corticosteroids

      Corticosteroids 224

      Corticosteroids: Clinical Uses 225

      Corticosteroids: Adverse Effects 226

Antiinflammatory Agents: Leukotriene Antagonists

      Leukotrienes 227

      Leukotriene Antagonists 228

Cough

      Cough 229

      Cough Suppressants (Antitussive Agents) 230

Chronic Obstructive Pulmonary Disease

      Chronic Obstructive Pulmonary Disease 231

      Emphysema 232

      Emphysema: Causes 233

      Inherited Emphysema 234

      Chronic Bronchitis 235

      COPD: General Treatment Measures 236

      COPD: Specific Drug Treatments 237

Restrictive Pulmonary Disease

      Restrictive Pulmonary Disease 238

Pneumonia

      Pneumonia 239

      Viral Pneumonia 241

      Bacterial Pneumonia 243

CHAPTER 8. DRUGS USED IN DISORDERS OF THE REPRODUCTIVE SYSTEM

      Overview 245

Organization and Function of the Reproductive System

      Organization of the Reproductive System 246

      Regulation of Estrogen and Testosterone 247

      Events of the Normal Menstrua! Cycle 248

Contraception

      Combination Oral Contraceptives 249

      Major Adverse Effects of Combination Oral Contraceptives 250

      Estrogen and Coagulation 251

      Progestin-Only Contraceptives 252

      The Morning-After Pill 253

      The Abortion Pill 254

Endometriosis and Treatment

      Endometriosis 255

      Danazo 256

      Gonadotropin-Releasing Hormone Agonists, Combination Oral Contraceptives, and Progestin 257

Postmenopausal Hormone Changes and Therapy

      Estrogen Decline 258

      Vasomotor Symptoms 259

      Genitourinary Atrophy 260

      Osteoporosis and Estrogen 261

      Role of Progestins in Hormone Replacement Therapy 262

      Route of Hormone Administration 263

      General Adverse Effects 264

      Cardiovascular and Neurologic Risks 265

      Cancer Risks 266

Selective Estrogen Receptor Modulators and Antiestrogens

      Selective Estrogen Receptor Modulators 267

      Antiestrogens 268

Hypogonadism

      Hypogonadism 269

      Hypogonadism Treatment and Adverse Effects 270

CHAPTER 9. DRUGS USED TO AFFECT RENAL FUNCTION

      Overview 271

Organization and Functions of the Renal System

      Macroscopic Anatomy 272

      The Nephron 273

      Blood Vessels Surrounding Nephrons 274

      The Glomerulus 275

      Practical Application: Measuring the Glomerular Filtration Rate 276

      Tubular Segments 277

      Ion and Water Reabsorption 278

      Bicarbonate Reabsorption 279

      Potassium Excretion 280

Volume Regulation

      Antidiuretic Hormone 281

      Renin-Angiotensin-Aldosterone System 282

Diuretics

      General Considerations: Volume Homeostasis 283

      Mercurial Diuretics 285

      Carbonic Anhydrase Inhibitors 286

      Thiazide Diuretics 287

      Potassium-Sparing Agents 288

      Loop (High-Ceiling) Diuretics 289

      Osmotic Agents 290

      Summary of Therapeutics 291

Urinary Incontinence

      Urinary Incontinence 293

Urinary Tract Calculi

      Urinary Tract Calculi (Kidney Stones) 294

Renal Insufficiency and Dialysis

      Effect of Renal Insufficiency on Drug Action 295

      Effect of Hemodialysis on Drug Action 296

CHAPTER 10. DRUGS USED IN INFECTIOUS DISEASE

      Overview 297

Bacterial Infections: Antibiotics

      Classification of Antibiotics 298

      Definitions: Bacteriostatic Versus Bactericidal 299

      Spectrum of Activity 300

      Mechanisms of Resistance 301

      Examples of Resistance 302

      Natural Penicillins: Penicillin G and Penicillin V 303

      Aminopenicillins: Amoxicillin and Ampicillin 304

      Antipseudomonal Penicillins: Carbenicillin, Piperacillin, and Ticarcillin 305

      β-Lactamase Inhibitors 306

      β Lactamase-Resistant Penicillins: Cloxacillin, Dicloxacillin, Oxacillin, and Nafcillin 307

      Adverse Effects of Penicillins 308

      Cephalosporins 309

      Carbapenems: Imipenem-Cilastatin, Ertapenem, and Meropenem 310

      Monobactams: Aztreonam 311

      Vancomycin 312

      Vancomycin Treatment Difficulties: Resistance and Adverse Effects 313

      Tetracyclines 314

      Aminoglycosides 315

      Macrolides: Erythromycin, Azithromycin, and Clarithromycin 316

      Clindamycin 317

      Quinolones 318

      New-Generation Quinolones 319

      Quinupristin/Dalfopristin 321

      Linezolid 322

      Sulfonamides 323

Fungal Infections: Antifungal Drugs

      Nature of Fungal Infections and Therapy 324

      Amphotericin В 325

      Azole Antifungal Agents and Other Antifungal Agents 326

Viral Infections and Antiviral Agents

      Nature of Viral Infections 327

      Herpesviruses 328

      Acyclovir and Famciclovir 329

      Ganciclovir 330

      Influenza and Its Treatment 331

HIV Infection: Antiretroviral Agents

      HIV Infection 332

      Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Non-NRTIs 333

      Protease Inhibitors 334

      Other Antiretroviral Agents for AIDS: Tenofovir and Enfuvirtide 335

CHAPTER 11. DRUGS USED IN NEOPLASTIC DISORDERS

      Overview 337

Introduction to Chemotherapy

      Cell Cycle 338

      Combination Chemotherapy 339

      Adverse Effects of Chemotherapy 340

Antimetabolites

      Folate Analogs: Methotrexate 341

      Purine Analogs: Mercaptopurine and Thioguanine 342

      Pyrimidine Analogs: 5-Fluorouracil 343

      Pyrimidine Analogs: Capecitabine 344

      Pyrimidine Analogs: Cytarabine and Fludarabine 345

      Pyrimidine Analogs: Gemcitabine 346

      Substituted Ureas: Hydroxyurea 347

Alkylating Agents

      Nitrogen Mustards: Mechlorethamine and Melphalan 348

      Cyclophosphamide and Ifosfamide 349

      Nitrosoureas: Carmustine and Lomustine 350

      Platinum Compounds: Cisplatin, Carboplatin, and Oxaliplatin 351

Microtubule Inhibitors

      Vinca Alkaloids: Vincristine, Vinblastine, and Vinorelbine 352

      Taxanes 353

Antibiotics

      Anthracyclines: Doxorubicin and Daunorubicin 354

Hormonal Therapies

      Estrogen Antagonists: Tamoxifen and Toremifene 355

      Aromatase Inhibitors: Anastrozole, Letrozole, and Exemestane 356

      Gonadotropin-Releasing Hormone Analogs: Leuprolide and Goserelin 357

      Antiandrogens: Flutamide, Bicalutamide, and Nilutamide 358

Monoclonal Antibodies

      Unconjugated Antibodies: Trastuzumab, Alemtuzumab, and Rituximab 359

      Conjugated Antibodies: Ibritumomab Tiuxetan and Tositumomab and Iodine I 131 Tositumomab 360

Newer Miscellaneous Agents

      Imatinib Mesylate 361

      Gefitinib 362

      Bortezomib 363

CHAPTER 12. DRUGS USED FOR SKIN DISORDERS

      Overview 365

Organization of the Skin

      Anatomy of the Skin 366

Hair Loss

      Alopecia 367

Blister Diseases

      Bullous (Blister) Skin Diseases 368

Eczema

      Common Dermatoses Including Eczema 369

Psoriasis

      Psoriasis 370

Mite and Louse Infestations

      Scabies and Pediculosis 371

Hives

      Urticaria 372

CHAPTER 13. VITAMINS: DEFICIENCIES AND DRUG INTERACTIONS

      Overview 373

Fat-Soluble Vitamins

      Deficiency of Vitamin A (Retinol) and Other Fat-Soluble Vitamins 374

Water-Soluble Vitamins

      Deficiency of Thiamine (B_1) and Other В Vitamins 375

      Niacin or Nicotinic Acid Deficiency (Pellagra) 376

      Vitamin С Deficiency (Scurvy) 377

Vitamin-Drug Interactions

      Fat-Soluble Vitamin-Drug Interactions 378

      Water-Soluble Vitamin-Drug Interactions 379

CHAPTER 14. DRUG ALLERGY, ABUSE, AND POISONING OR OVERDOSE

      Overview 381

Drug Allergy

      Allergic Reactions to Drugs 382

      Type I (Acute, Anaphylactic) Reactions 383

      Type II (Cytotoxic, Autoimmune) Reactions 384

      Type III (Immune Complex, Serum Sickness, Arthus) Reactions 385

      Type IV (Cell-Mediated, Delayed-Hypersensitivity, Contact Dermatitis) Reactions 386

Drug Abuse

      Brain Reward Circuit 387

      Ethanol: Deleterious Effects 388

      Ethanol Abuse: Treatment 389

      Withdrawal: Opioids, Benzodiazepines, and Barbiturates 390

Poisoning or Overdose

      Sympathomimetic Drugs 392

      Cholinergic Drugs 393

      Anticholinergic Drugs 394

      Serotonergics 395

      Opioids 396

      Over-the-Counter Products 397

      Management of Poisoning and Overdose 398

Index 399

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