General and Molecular Pharmacology

Name: General and Molecular Pharmacology | Principles of Drug Action
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Principles of Drug Action

Francesco Clementi Guido Fumagalli(Herausgeber*in)

Wiley (Verlag)

Erschienen am 1. Juli 2015

786 Seiten

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Intro
Title Page
Copyright Page
Contents
List of Contributors
Preface
SECTION 1 INTRODUCTION TO PHARMACOLOGY
CHAPTER 1 ESSENTIAL LEXICON OF PHARMACOLOGY
THE SOCIAL IMPACT OF PHARMACOLOGY
ESSENTIAL LEXICON
Active Substances
Pharmacological Disciplines
Drug-Receptor Interactions
Measure of the Clinical Response
TAKE-HOME MESSAGE
CHAPTER 2 A SHORT HISTORY OF PHARMACOLOGY
BIRTH AND HISTORICAL DEVELOPMENTS OF PHARMACOLOGY
From Magical and Natural Remedies of Ancient Medicine to Arabic Alchemy
From Monastic Medicine to Botanical Gardens
From Anatomical Renaissance to the "Experienz": Paracelsus' Spagyric
From Iatrochemistry to the Age of Enlightenment
From the Search of the Active Principle to the Discovery of Alkaloids and Glucosides
The Drug Synthesis Revolution: From Handmade to Industrial Production
MODERN PHARMACOLOGY
Ehrlich and Chemotherapy: The Concept of Receptor
The Birth of Modern Pharmacology
THE BIOTECHNOLOGY ERA AND THE PHARMACOLOGY IN THE THIRD MILLENNIUM
The Impact of New Biotechnologies: Molecular Biology, Bioinformatics, and Combinatorial Chemistry
Biological Drugs and Pharmacology Perspectives
Personalized Therapies and New Sceneries in Pharmaceutical Industry
TAKE-HOME MESSAGE
FURTHER READING
SECTION 2 GETTING THE DRUG TO ITS SITE OF ACTION
CHAPTER 3 CELLULAR BASIS OF PHARMACOKINETICS
A QUICK JOURNEY WITH THE DRUG IN THE BODY
Absorption
Distribution
Drug Elimination
CROSSING CELL MEMBRANES
Passive Diffusion across Cell Membranes
Drug Transport across Cell Membranes
Endocytosis
DRUG DIFFUSION TO ORGANS AND TISSUES
Properties of the Most Important Cell Barriers
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 4 DRUG ABSORPTION AND ADMINISTRATION ROUTES
GENERAL RULES ABOUT DRUG ABSORPTION RATE
Partition Coefficient
Drug Dispersion
Extension of the Absorbing Surface
Permeability of the Absorbing Surface
Vascularization
ENTERAL ROUTES OF ADMINISTRATION
Oral Route
Sublingual and Rectal Routes
SYSTEMIC PARENTERAL ROUTES OF ADMINISTRATION
The Intravascular Route
i.m. Injection
Subcutaneous and Intradermal Injections
OTHER ROUTES OF DRUG ADMINISTRATION
Inhalation Route
Topical/Regional Routes
Intracavity Routes
Dermal or Transcutaneous Route
Mucosal Routes
ABSORPTION KINETICS
General Rules
Interrelation between Gene Therapy and Drug Delivery Techniques
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 5 DRUG DISTRIBUTION AND ELIMINATION
DISTRIBUTION
Tissues and Avidity for Drugs
The Apparent Distribution Volume
Drug Binding to Plasma Proteins
Factors That Determine the Distribution Rate of Drugs to the Various Compartments
ELIMINATION
The Concept of Half-Life
The Concept of Clearance
RENAL EXCRETION OF DRUGS
Glomerular Filtration
Tubular Functions and Pharmacokinetics
Active Transport of Organic Anions and Cations
Factors Determining Renal Clearance of Drugs
HEPATIC EXCRETION AND ENTEROHEPATIC CYCLE
Perfusion, Binding to Plasma Proteins, Enzymatic Activity, and Hepatic Clearance
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 6 DRUG METABOLISM
METABOLIC MODIFICATION OF DRUG ACTIVITY
TWO PHASES OF DRUG METABOLISM
Phase I Reactions
Phase II Enzymatic Reactions
EXTRAHEPATIC BIOTRANSFORMATIONS
Biotransformation by the Intestinal Flora
PHARMACOMETABOLIC INDUCTION AND INHIBITION
Induction of Drug Metabolism
Inhibition of Drug Metabolism
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 7 CONTROL OF DRUG PLASMA CONCENTRATION
TIME COURSE OF DRUG PLASMA CONCENTRATION FOLLOWING A SINGLE ADMINISTRATION
DRUGS DISTRIBUTE TO ORGANS AND TISSUES AND THEN ARE ELIMINATED
Description of Drug Plasma Concentration Time Course Following a Single Administration
Area under the Plasma Concentration Curve (AUC)
The Plasma Concentration Peak
DRUG PLASMA CONCENTRATION TIME COURSE DURING REPETITIVE ADMINISTRATIONS
During Repetitive Administrations, the Drug Plasma Concentration Time Course Is Given by the Sum of the Time Courses of the Single Doses
In a Chronic Therapy at Steady State, Each New Dose Replaces the Drug Amount that has been Eliminated Since the Last Administration
The Time to Reach the Steady State Depends on the Drug Half-Life
Plasma Concentration at Steady State
The Single Dose to Administer is Computed as a Function of the Interval between Successive Administrations
Fluctuations of Drug Plasma Concentration at Steady State
Absorption Kinetics Influence the Amplitude of Oscillations in Plasma Concentration at Steady State
Loading (Attack) Doses to Rapidly Attain Steady-State Concentration
MULTICOMPARTMENTAL KINETICS
Drug Binding to Plasma Proteins and Tissue Equilibration with Plasma
The Particular Case of the Nephron
Drugs Redistribution among Compartments
CORRECTIONS OF THE THERAPEUTIC REGIMEN
Normally Available Pharmacokinetic Data Are Average Values
Varying Dosage as a Function of Body Weight and Physical Constitution
Varying Dosage as a Function of Age
Dosage Correction in the Presence of Hepatic Pathologies
Dosage Correction in the Presence of Renal Pathologies
TAKE-HOME MESSAGE
FURTHER READING
SECTION 3 RECEPTORS AND SIGNAL TRANSDUCTION
CHAPTER 8 DRUG-RECEPTOR INTERACTIONS: QUANTITATIVE AND QUALITATIVE ASPECTS
GENERAL PROPERTIES OF DRUG RECEPTORS
Drug Receptors Are Molecules Relevant for Cellular Functions
Not All Drugs Interact with a Receptor
Drug Activity Follows to Drug-Receptor Complex Formation
Drug-Receptor Interaction Is Mostly Mediated by Weak Chemical Bonds
Reversible or Irreversible Drug-Receptor Interactions
CHARACTERISTICS OF DRUG-RECEPTOR INTERACTION
The Relationship between Drug Concentration and Drug-Receptor Complex Is Similar to the Michaelis-Menten Equation
The Binding Isotherm and Its Linear Transformations Allow to Obtain the Parameters of the Drug-Receptor Interaction
Receptors Can Be Heterogeneous
Drug Competition for a Same Receptor Binding Site
QUANTITATIVE ASPECTS OF DRUG EFFECTS: DOSE-RESPONSE CURVES
Potency and Efficacy
FROM DRUG-RECEPTOR INTERACTION TO DRUG RESPONSE
Occupancy Theory
Modifications to the Occupancy Assumption
Efficacy Theory
Nonlinear Function between Receptor Occupancy and Tissue Response: EC50 Different from Kd
Constitutively Active Receptors and Inverse Agonists
Two-State Receptor Model and Beyond: Multiple Receptor States and "Biased" Signaling
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 9 RECEPTORS AND MODULATION OF THEIR RESPONSE
CLASSES OF RECEPTORS AND STRATEGIES OF SIGNAL TRANSDUCTION
Intracellular/Intranuclear Receptors
Membrane Receptors
CONTROL OF RECEPTOR LOCALIZATION IN THE CELL MEMBRANE
INTRACELLULAR TRAFFIC OF CELL RECEPTORS
How Receptors Reach the Cell Membrane and how Their Number is Regulated
MODULATION OF RECEPTOR RESPONSES
RECEPTOR MODULATION BY DRUGS
TAKE-HOME MESSAGE
FURTHER READING
General
Intracellular Receptors
Ligand-gated Ion Channels
G Protein-Coupled Receptors
Catalytic Receptors
Chemokine Receptors
Toll-Like Receptors
Death Receptors
CHAPTER 10 ADAPTATION TO DRUG RESPONSE AND DRUG DEPENDENCE
MOLECULAR, CELLULAR, AND SYSTEMIC ADAPTATION
Cellular Adaptation
Effects of Repeated Drug Exposure
DRUG ADDICTION AS A PARADIGM OF ALLOSTATIC ADAPTATION
Adaptation and Stages of Drug Addiction
Research on Drug Addiction
THERAPY FOR DRUG DEPENDENCE
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 11 PHARMACOLOGICAL MODULATION OF POSTTRANSLATIONAL MODIFICATIONS
PROTEIN PHOSPHORYLATION
Protein Kinases
Protein Phosphatases
SUMOylation
UBIQUITINATION
GLYCOSYLATION
ACETYLATION
HYDROXYLATION
CARBOXYLATION
METHYLATION
S-NITROSYLATION
DISULFIDE BONDS
LIPID MODIFICATIONS
Myristoylation
Prenylation
Palmitoylation
Attachment of Glycosylphosphatidylinositols
PHARMACOLOGICAL MODULATION OF POST TRANSLATIONAL MODIFICATIONS
Deacetylase Inhibitors
Glycosylation Inhibitors
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 12 CALCIUM HOMEOSTASIS WITHIN THE CELLS
THE CYTOSOL: A CROSSROAD OF Ca2+ FLUXES
Free Ca2+ in the Cytosol and Total Cell Calcium
The High-Affinity Buffering of Cytosolic Proteins
THE PLASMA MEMBRANE: CHANNELS, PUMPS, AND TRANSPORTERS
Surface Channels Permeable to Ca2+
Surface Pumps and Transporters
Ca2+ IN INTRACELLULAR ORGANELLES
The ER: A Rapidly Exchanging Ca2+ Pool
Mitochondria as Local Buffers of [Ca2+]i
ER and Mitochondria Allow Rapid Changes of [Ca2+]i within Cells
[Ca2+]i Control in Other Intracellular Structures
Local Relevance of Organelle Calcium Pools
Ca2+ IN CELL PATHOLOGY
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 13 PHARMACOLOGY OF MAP KINASES
THE MAPK FAMILY AND THE ACTIVATION MECHANISM
The ERK Family
The JNK Family
The p38 Family
ERK5
MAPK SPECIFICITY
Duration of Action
Multiple Enzyme Isoforms
Subcellular Localization and Interaction with Scaffold Proteins
miRNAs
PHARMACOLOGICAL INHIBITION OF MAPK
Inhibition of the Ras/RAF/MEK/ERK Cascade
MEK
RAF
JNKs
p38
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 14 SMALL G PROTEINS
STRUCTURE AND FUNCTION OF SMGs
PHYSIOLOGICAL ROLES OF COMPONENTS OF MAJOR SMG FAMILIES
POSTTRANSLATIONAL MODIFICATION AND SUBCELLULAR LOCALIZATION OF SMGs
REGULATORY PROTEINS
GEFs
GAPs
GDIs
MODULATION OF SMG SIGNALING BY BACTERIAL TOXINS AND DRUGS
Bacterial Toxins
Bacterial Toxins Modifying Host RhoGTPases
Bacterial Toxins Acting as GEFs or GAPs for Host GTPases
Modulation of the Prenylation Process
Modulation of GEFs
Modulation of GAPs
FUTURE PERSPECTIVES
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 15 INTEGRATION IN INTRACELLULAR TRANSDUCTION OF RECEPTOR SIGNALS
DUALISM OF RECEPTORS IN THE NUCLEUS AND IN THE CYTOPLASM
HETEROGENEITY OF RECEPTOR ASSEMBLY
TRANSDUCTION CASCADES DEPEND ON CROSSTALK AND COMPLEMENTARITY AMONG RECEPTORS
A Comprehensive Scenario of Signal Transduction: From GSKß3 to AKT and mTOR
DEVELOPMENT OF NEW DRUGS AND THERAPIES
TAKE-HOME MESSAGE
FURTHER READING
SECTION 4 RECEPTOR CLASSES
CHAPTER 16 LIGAND-GATED ION CHANNELS
TISSUE DISTRIBUTION AND SUBCELLULAR LOCALIZATION OF LGICs
MOLECULAR ORGANIZATION OF LGICs
Classification of LGICs
TOPOLOGY OF LGICs
The Binding Sites for Endogenous Ligands
Structure and Localization of the Channel
Functions of the Cytoplasmic Domain
MODULATION OF LGIC ACTIVITY
Desensitization
Subunit Composition and Biophysical and Pharmacological Properties of LGICs
CROSSTALK WITH OTHER RECEPTOR SYSTEMS
MECHANISMS OF ACTION OF DRUGS THAT MODULATE LGICs
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 17 G-PROTEIN-COUPLED RECEPTORS
MOLECULAR ORGANIZATION OF GPCRs
The Ligand Binding Site
Dimerization
GPCR Mutations and Human Diseases
MOLECULAR ORGANIZATION AND FUNCTION OF G PROTEIN
Signaling by G Proteins
Structural and Functional Properties of a-Subunits
The ß? Complex
Regulation of Multiple Effectors Through G Proteins
EFFECTOR PATHWAYS OF GPCRs
The Adenylyl Cyclase System
The Phospholipase C System
INTERACTION OF GPCRs WITH OTHER PROTEINS
GPCR-Interacting Proteins: Control of Receptor Function, Intracellular Trafficking, and Localization
G-Protein-Independent Signaling
PERSPECTIVES
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 18 GROWTH FACTOR RECEPTORS
MOLECULAR STRUCTURE OF GROWTH FACTOR RECEPTORS
Growth Factor Receptors are Tyrosine Kinases with Modular Structure
Modulatory Functions of the Transmembrane and Juxtamembrane Domains of Growth Factor Receptors
RECEPTOR ACTIVATION AND SIGNAL TRANSDUCTION
Receptor Dimerization and Activation
Signal Transducers Binding to Phosphorylated Tyrosines
RAS-Dependent Transduction Pathway in Cell Proliferation and Neoplastic Transformation
Activation of Enzymes Generating Lipid Second Messengers
Cytoplasmic Tyrosine Kinases
Tyrosine Phosphatases Modulating Tyrosine Kinase Activity
STATs
PHARMACOLOGICAL APPROACHES TO THE CONTROL OF GROWTH FACTOR RECEPTOR ACTIVITY
mAbs and Small Kinase Inhibitors
Growth Factor Receptors as Targets for Anticancer Drugs
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 19 CYTOKINE RECEPTORS
CLASSIFICATION OF CYTOKINES AND THEIR RECEPTORS
Hematopoietin Receptors
Tyrosine Kinase Receptors
The IL-1/IL-18 Receptor Family
The TNFR Family (Jelly Roll Motif Cytokines)
Chemokine Receptors
CYTOKINES IN THEIR BIOLOGICAL SETTINGS
Hematopoietic Cytokines
Cytokines in Innate Immunity
Cytokines of Adaptive Immunity
Anti-inflammatory Cytokines
PHARMACOLOGY OF CYTOKINES AND THEIR RECEPTORS
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 20 ADHESION MOLECULE RECEPTORS
ADHESION RECEPTORS
Classification
Functions
SIGNAL TRANSDUCTION BY ADHESION RECEPTORS
FAK and Src-Family Kinases in Integrin Signal Transduction
Signal Transduction by Cadherins
Signal Transduction by CD44
ADHESION RECEPTORS AS DRUG TARGETS
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 21 SOLUBLE CYTOKINE RECEPTORS AND MONOCLONAL ANTIBODIES IN PATHOPHYSIOLOGY AND THERAPY
SOLUBLE RECEPTORS
The Paradigm of Viral Receptors for Cytokines
"Decoy" Receptors: Molecular Traps for Agonists
Soluble Receptors: Mechanisms of Generation and Action
Soluble Receptors: Antagonist Effects
Soluble Receptors: Agonist Effects
Soluble Receptors as Pharmacological Agents
MONOCLONAL ANTIBODIES
TAKE-HOME MESSAGE
FURTHER READING
SECTION 5 MODULATION OF GENE ESPRESSION
CHAPTER 22 PHARMACOLOGY OF TRANSCRIPTION
INTRODUCTION TO THE MECHANISMS OF TRANSCRIPTIONAL REGULATION
General Transcription Factors
The Promoter: A Multifunctional Region with Positive and Negative Regulatory Elements
Additional Factors Required to Stabilize PIC Structure
Mediator
Control of Specificity and Inducibility of Gene Expression
Coregulatory Complexes and Covalent Modification of Histones
Toward a Unified Theory of Transcriptional Regulation
TRANSCRIPTIONAL REGULATION BY EXTRACELLULAR STIMULI
Three Classes of Inducible Transcription Factors
FROM THE PHARMACOLOGY OF TRANSCRIPTION TO PHARMACOEPIGENOMICS
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 23 PHARMACOGENETICS AND PERSONALIZED THERAPY
VARIATION OF DRUG RESPONSES AND THE DEFINITION OF PHARMACOGENETICS
GENETIC BASIS OF VARIABILITY IN DRUG RESPONSE
Genes and Pharmacogenetics
Allelic Variants of Genes Involved in Drug Response
Copy Number Variation
GENETIC POLYMORPHISMS AND DRUG METABOLISM
GENETIC POLYMORPHISMS IN GENES ENCODING PHASE I ENZYMES
Polymorphisms of CYP2D6
Allelic Variants in the CYP2C Subfamily
Role of Phase I Enzymes in Prodrug Activation
Thiopurine Methyltransferase
UGT1A1 and Irinotecan: A Case Already under Evaluation by the Regulatory Agencies
GENETIC POLYMORPHISMS IN GENES ENCODING TRANSPORTERS INVOLVED IN DRUG ABSORPTION, DISTRIBUTION, AND EXCRETION
ABCB1 and Multidrug Resistance
The OAT1B1 Transporter and Statin-Induced Myopathy
GENETIC POLYMORPHISMS IN GENES ENCODING MOLECULAR TARGETS OF DRUG ACTION
ß1 Receptor Polymorphism and the Response to ß-Blockers in Heart Failure
ß2 Receptor Polymorphism and the Response to Antiasthma Therapy
METHODS OF PHARMACOGENETIC STUDIES
THE FUTURE OF PHARMACOGENETIC
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 24 INTRACELLULAR RECEPTORS
STRUCTURAL FEATURES OF INTRACELLULAR RECEPTORS
Intracellular Receptor Classification
Molecular Organization and Functional Domains
INTRACELLULAR RECEPTORS AS LIGAND-REGULATED TRANSCRIPTION FACTORS
Classification of Ligands
Ligand-Dependent Transcriptional Activation
Ligand-Dependent Transrepression
Transcriptional Activation of Intracellular Receptors in the Absence of Ligand
Temporal Oscillations of DNA Binding of Intracellular Receptors
PHYSIOLOGICAL ACTIVITIES AND PHARMACOLOGICAL CONTROL OF INTRACELLULAR RECEPTORS
Specificity of Action of Homologous Receptors
Tissue Specificity of Nuclear Receptor Activity
Receptor Agonists and Antagonists
CAR and SXR Receptors
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 25 RNA MOLECULE AS A DRUG: FROM RNA INTERFERENCE TO APTAMERS
MECHANISMS OF ACTION OF RNA DRUGS
RNA Interference
Inhibition of miRNA Biological Activity by Complementary Oligonucleotides
Antisense Oligonucleotide to Modify the Splicing Patterns
Aptamers
DELIVERY
GENERAL CHEMICAL STRUCTURE
Phosphorothioates
Phosphoramidates
2'-O-Alkyl-Ribonucleotides
LNAs
PNA
Modifications of Purine and Pyrimidine Bases
PHARMACOTOXICOLOGY
Cellular Pharmacokinetics and Toxicology
Systemic Pharmacokinetics and Toxicology
PRESENT USE AND FUTURE PERSPECTIVES
TAKE-HOME MESSAGE
FURTHER READING
SECTION 6 REGENERATIVE MEDICINE
CHAPTER 26 REGENERATIVE MEDICINE AND GENE THERAPY
PRINCIPLES OF REGENERATIVE MEDICINE
DEFINITION, CLASSIFICATION, AND FEATURES OF STEM CELLS
Pluripotent Stem Cells
Multipotent (or Adult) Stem Cells
STEM CELL-BASED DRUGS
CELL THERAPY AND REGENERATIVE MEDICINE
Regenerative Medicine Approaches to Epithelial Lesions
Regenerative Medicine to Treat Cardiac Dysfunctions
Stem Cell-Based Therapies for Skeletal Muscle Diseases
Stem Cell-Based Therapies for Brain Diseases
GENE THERAPY
Protocols for Gene Therapy
Gene Therapy for Monogenic Inherited Diseases
FUTURE PERSPECTIVES
TAKE-HOME MESSAGE
FURTHER READING
SECTION 7 PHARMACOLOGICAL CONTROL OF MEMBRANE TRANSPORT
CHAPTER 27 ION CHANNELS
ION CHANNELS AND TRANSPORTERS
CHARACTERIZATION AND FUNCTION OF ION CHANNELS
Channel Classification According to Permeating Ions and Gating Mechanisms
Permeation and Concentration Gradients
Transmembrane Voltage Triggers Conformational Changes
Current-Voltage Relationships and The Rectification Process
STRUCTURAL ORGANIZATION OF ION CHANNELS
The Voltage Sensor of VGICs
Inactivation
Ion Selectivity
DRUGS AND ION CHANNELS
Drugs Interacting Directly with Ion Channels
Modulation of Ion Channel Activity by Drugs Acting on Receptors Functionally Coupled to Ion Channels
SODIUM CHANNELS
Molecular Structure and Modulation
Cellular Localization of VGSCs
Pharmacology of VGSCs
CALCIUM CHANNELS
Localization and Physiological Functions of VGCCs
Structural Organization of VGCC
VGCC Pharmacology
POTASSIUM CHANNELS
Structural Organization of Potassium Channels
NONSELECTIVE CHANNELS, ANIONIC CHANNEL, AND OTHERS
Cationic Channels Modulated by Cyclic Nucleotides
TAKE-HOME MESSAGE
REFERENCES
FURTHER READING
CHAPTER 28 MEMBRANE TRANSPORTERS
TRANSPORTER CLASSIFICATION
ATP-Dependent Active Transporters
ATP-Independent Transporters
Na+/K+-ATPase
Structure
Biophysical Properties and Involvement in Intracellular Signaling
Pharmacology of Na+/K+-ATPase
H+/K+-ATPase
Structure, Distribution, and Function
Regulation of the Gastric Proton Pump
Pharmacology of the Gastric Proton Pump
PLASMA MEMBRANE Ca2+-ATPase
SARCOPLASMIC/ENDOPLASMIC RETICULUM Ca2+-ATPase
Structure, Distribution, and Regulatory Mechanisms of SERCA
Physiological Properties and Pharmacological Modulation
Na+/Ca2+ EXCHANGER
Structure and Distribution
Biophysical Properties and Physiological Role
NCX in Pathologies and Pharmacological Modulation
Na+/H+ EXCHANGER
Structure, Distribution, and Functional Properties
Functional Significance and Pharmacological Modulation
Na+/K+/Cl- COTRANSPORTER
Structure and Distribution
Functional Properties
Role in Cell Physiology and Pathology
Pharmacology
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 29 NEUROTRANSMITTER TRANSPORTERS
NEUROTRANSMITTER TRANSPORTERS AND SYNAPTIC FUNCTION
Regulation of Transporter Activity and Traffic
NEUROTRANSMITTER TRANSPORTER FAMILIES
Na+/K+-Dependent Transporters for Excitatory Amino Acids
Na+/Cl--Dependent Plasma Membrane Transporters
Molecular Mechanism of Transport
GABA Transporters
The Serotonin Transporter
The Dopamine Transporter
The Noradrenaline and Adrenaline Transporters
H+-Dependent Vesicular Transporters
The Vesicular Monoamine Transporters
The Vesicular Acethylcholine Transporter
The Vesicular Transporters for Excitatory Amino Acids, GABA, and Glycine
TAKE-HOME MESSAGE
FURTHER READING
SECTION 8 CONTROL OF PROTEOLYSIS
CHAPTER 30 INTRACELLULAR PROTEOLYSIS
GENERAL CHARACTERISTICS OF PROTEASES
Classification
CHARACTERISTICS AND REGULATION OF INTRACELLULAR PROTEOLYSIS
Function and Pharmacological Modulation of the Main Intracellular Proteolytic Systems
LYSOSOMAL PROTEASES
Types and Families of Lysosomal Enzymes
COMPARTMENTALIZED PROTEASES WITH SPECIFIC FUNCTIONS
Signal Proteases
Maturation Proteases
Plasma Membrane Proteases
CYTOPLASMIC PROTEASES
The Proteasome
PROTEASOME INHIBITORS AS ANTI-INFLAMMATORY AND ANTITUMORAL DRUGS
Other Serine Proteases for Protein Quality Control
Caspases: Initiators and Executors of Apoptosis
Calpain
EXOGENOUS INTRACELLULAR PROTEASES
HIV and Inhibitors of Viral Proteases
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 31 EXTRACELLULAR PROTEOLYSIS
THE EXTRACELLULAR MATRIX PROTEOLYTIC DEGRADATION SYSTEMS
PLASMINOGEN SYSTEM AND ITS ACTIVATORS
PAs as Fibrinolytic Agents
Localized Activation of uPA by Interaction with a Specific Receptor
Function and Pharmacological Modulation of the PA System
Pharmacological Inhibition of the PA System in Neoplastic Processes
MATRIX METALLOPROTEASES
Modular Structure of MMPs
MMP Activation at the Plasma Membrane
Function and Pharmacological Modulation of MMP
TAKE-HOME MESSAGE
FURTHER READING
SECTION 9 CONTROL OF CELL CYCLE AND CELLULAR PROLIFERATION
CHAPTER 32 CELL CYCLE AND CELL DEATH
CELL CYCLE
Timely Regulated Expression of Cyclins and Cell Cycle Progression
Role of Retinoblastoma Binding Protein during G1-S Transition
Cdk Inhibitors and Cell Cycle "Checkpoints"
CELL DEATH
PROGRAMMED CELL DEATH OR APOPTOSIS
Apoptotic Bodies
Apoptotic Biochemical Pathways
NECROSIS
Morphological Features of Necrosis
Role of Mitochondria in the Necrotic Process
DRUGS AND APOPTOSIS
Proapoptotic Drugs
Drugs That Inhibit Apoptosis
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 33 MECHANISMS OF ACTION OF ANTITUMOR DRUGS
CONVENTIONAL ANTITUMOR DRUGS
Alkylating Agents
Platinum Compounds
Antimetabolites
Drugs Acting on Microtubules
DNA Topoisomerase Inhibitors
TARGET-SPECIFIC ANTITUMOR DRUGS
Inhibitors of Survival Factors
Proteasome Inhibitors
Epigenetic Factors as Drug Targets
Telomeres and Telomerase
MONOCLONAL ANTIBODIES IN CLINICAL USE
Mechanism of Action
Trastuzumab
Cetuximab
Bevacizumab
TAKE-HOME MESSAGE
FURTHER READING
SECTION 10 CONTROL OF CELLULAR METABOLISM
CHAPTER 34 MITOCHONDRIA, OXIDATIVE STRESS, AND CELL DAMAGE: PHARMACOLOGICAL PERSPECTIVES
REACTIVE OXYGEN SPECIES (ROS)
Mitochondrial Formation of ROS
Physiological Role of ROS
Pathophysiological Role of ROS in Mitochondrial Ca2+ Homeostasis
THE MITOCHONDRIAL PTP
DRUGS AND MITOCHONDRIA
Antioxidants Directed to Mitochondria
Drugs Acting on Mitochondrial Channels to Prevent Mitochondrial Dysfunction
Drugs Promoting Mitochondrial Dysfunction for Possible Antineoplastic Treatments
Drugs Acting on the Mitochondrial Metabolism
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 35 PHARMACOLOGICAL CONTROL OF LIPID SYNTHESIS
CHOLESTEROL BIOSYNTHESIS
Statins: Inhibitors of the HMG-CoA Reductase
Farnesyl Pyrophosphate Synthase Inhibitors (Nitrogen-Containing Bisphosphonates)
Squalene Synthase Inhibitors
BIOSYNTHESIS OF FATTY ACIDS
Fatty Acid Synthase and Its Inhibitors
Fatty Acid Desaturases and Their Inhibitors
TRIGLYCERIDE BIOSYNTHESIS
Inhibitors of Diacylglycerol Acyltransferase
TRANSCRIPTIONAL CONTROL OF GENES INVOLVED IN LIPID METABOLISM
Liver X Receptors and Liver X Receptor Synthetic Ligands
Peroxisome Proliferator-Activated Receptors and Their Pharmacological Modulation
LIPID TRANSFER PROTEINS
ACAT and Its Inhibitors
CETP and Its Inhibitors
The MTP and Its Inhibitors
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 36 GLUCOSE TRANSPORT AND PHARMACOLOGICAL CONTROL OF GLUCOSE METABOLISM
MECHANISMS OF GLYCEMIC CONTROL
Modulation of GLUT4 Transporter Function by Insulin and Physical Activity
Insulin Receptors and Signal Transduction Pathway
PHARMACOLOGY OF GLYCEMIC CONTROL
Pharmacological Stimulation of ß-Cell Activity
Modulation of Insulin Signaling
Modulation of Intestinal Glucose Absorption
INSULIN RESISTANCE AND NEW THERAPEUTIC PERSPECTIVES
TAKE-HOME MESSAGE
FURTHER READING
SECTION 11 INTERCELLULAR COMMUNICATION
CHAPTER 37 PHARMACOLOGICAL REGULATION OF SYNAPTIC FUNCTION
THE SYNAPSE
Synaptic Organization Complexity and Synaptopathies
THE PRESYNAPTIC COMPARTMENT: NEUROTRANSMITTER RELEASE
Chemical Messengers: Neurotransmitters and Neuropeptides
Secretory Granules and SVs
Neurotransmitter Fate
THE POSTSYNAPTIC COMPARTMENT: SIGNAL RECEPTION
SYNAPSE FORMATION, MAINTENANCE, AND PLASTICITY
THE PHARMACOLOGY OF NEUROSECRETION
Drugs Interfering with Secretory Vesicle Transport
Drugs Interfering with Neurotransmitter Loading into Vesicles
Drugs and Toxins Interfering with Late Steps of Neuroexocytosis
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 38 CATECHOLAMINERGIC TRANSMISSION
THE CATECHOLAMINERGIC SYSTEM IN THE AUTONOMIC NERVOUS SYSTEM
Anatomical Organization of the Sympathetic System
Cardiovascular Effects of the Sympathetic System
Other Noncardiovascular Effects of Catecholamines
THE CATECHOLAMINERGIC SYSTEMS IN THE CNS
Distribution and Functions of the Adrenergic and Noradrenergic Systems
Distribution of the Dopaminergic System
Functions of the Dopaminergic Systems in the CNS
SYNTHESIS OF CATECHOLAMINES
VESICULAR STORAGE AND RELEASE OF CATECHOLAMINES
CATABOLISM AND REUPTAKE OF CATECHOLAMINES
Catecholamine Reuptake
CATECHOLAMINE RECEPTORS
Adrenergic Receptors
DA Receptors
PRINCIPLES OF DRUG ACTION ON CATECHOLAMINERGIC RECEPTORS
Drugs Acting on a-Adrenergic Receptors
Drugs Acting on ß-Adrenergic Receptors
Drugs Acting on DA Receptors
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 39 CHOLINERGIC TRANSMISSION
DISTRIBUTION AND FUNCTION OF THE CHOLINERGIC SYSTEMS
Cholinergic Transmission in the Peripheral Nervous System
The Cholinergic Transmission in the Central Nervous System
Role of Brain Cholinergic System in Learning, Memory, and Movement
ACh SYNTHESIS AND METABOLISM
ACh Precursors
ACh Hydrolysis by ChEs
ACh INTRACELLULAR STORAGE AND RELEASE
ACh Release
CHOLINERGIC RECEPTORS
Nicotinic Receptors
Muscarinic Receptors
DRUGS ACTING ON CHOLINERGIC RECEPTORS
Drugs Active on Nicotinic Receptors
Drugs Active on Muscarinic Receptors
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 40 THE SEROTONERGIC TRANSMISSION
FUNCTIONS AND DISTRIBUTION OF THE SEROTONERGIC SYSTEM IN THE BODY
5-HT in the Nervous System
5-HT and the Cardiovascular System
5-HT in Gastrointestinal and Genitourinary Systems
5-HT in Metabolism and Endocrine System
SYNTHESIS AND METABOLISM OF SEROTONIN
VESICULAR STORAGE, RELEASE, AND EXTRACELLULAR CLEARANCE OF SEROTONIN
The 5-HT Reuptake System
CLASSIFICATION OF SEROTONIN RECEPTORS
DRUGS ACTING ON SEROTONIN RECEPTORS
Pharmacology of the 5-HT1 Receptors
Pharmacology of the 5-HT2 Receptors
Pharmacology of the 5-HT3 Receptor
Pharmacology of the 5-HT4 Receptors
Pharmacology of the 5-HT6
Pharmacology of the 5-HT7 Receptors
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 41 HISTAMINERGIC TRANSMISSION
DISTRIBUTION AND FUNCTION OF THE HISTAMINERGIC SYSTEM
Histaminergic Neurons in the CNS
Functions of the Histaminergic System
Histamine in the CNS
Histamine in the Cardiovascular System
Histaminergic System in the Stomach
Histamine Effects on Smooth Muscles
Histamine and the Immune Response
SYNTHESIS AND METABOLISM OF HISTAMINE
Histamine Metabolism
STORAGE AND RELEASE OF HISTAMINE
Pharmacological Modulation of Histamine Metabolism and Release
HISTAMINE RECEPTORS AND THEIR PHARMACOLOGICAL MODULATION
Drugs Active on Histamine Receptors
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 42 GABAergic TRANSMISSION
GABA DISTRIBUTION, SYNTHESIS, AND METABOLISM
GABA RELEASE AND REUPTAKE
GABA RECEPTOR CLASSIFICATION
GABAA RECEPTORS
Drug Binding Sites on GABAA Receptors
Subunit Composition of Native Receptors
Extrasynaptic GABAA Receptors: Phasic and Tonic Inhibition
Pharmacology of GABAA Receptors
GABAB RECEPTORS
Pharmacology of GABAB Receptors
SCHEMATIC OVERVIEW OF THE MAIN PHARMACOLOGICAL INTERVENTIONS ON GABAergic SYNAPSES
TAKE-HOME MESSAGE
REFERENCE
FURTHER READING
CHAPTER 43 GLUTAMATE-MEDIATED NEUROTRANSMISSION
GLUTAMATE SYNTHESIS AND METABOLISM
GLUTAMATE TRANSPORTERS, VESICULAR ACCUMULATION, AND SIGNAL INACTIVATION
Membrane Transporters
Vesicular Transporters
The Cystine-Glutamate Exchanger
GLUTAMATE RECEPTORS
Glutamate Ionotropic Receptors
Metabotropic Receptors
GLUTAMATE NEUROTRANSMISSION IN PHYSIOLOGY AND PATHOLOGY
Glutamate and Excitotoxicity
Glutamate and Depression
DRUGS AND EXCITATORY NEUROTRANSMISSION
GLUTAMATE-MEDIATED NEUROTRANSMISSION IN BRIEF
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 44 PURINERGIC TRANSMISSION
PURINES AS INTERCELLULAR TRANSMITTERS
Source, Metabolism, and Release of Purines
Generation of Active Metabolites by ATP Hydrolysis
RECEPTORS FOR PURINES
P1 Adenosine Receptors
P2 Receptors for ATP
P2X Ion Channel Receptors
P2Y GPCRs
BIOLOGICAL ROLES OF PURINES
Effects on the Cardiovascular System
Effects on the CNS and Peripheral Nervous System
Effects on the Respiratory System
Effects on Other Systems
Adenosine Effects Independent of Receptor Activation
Purines and Antitumor Therapy
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 45 NEUROPEPTIDES
NEUROPEPTIDE SYNTHESIS
Propeptide Processing
STORAGE AND SECRETION OF NEUROPEPTIDES
PEPTIDERGIC TRANSMISSION
Neuropeptide Receptors
NEUROPEPTIDE FUNCTIONS AND THERAPEUTIC POTENTIAL
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 46 THE OPIOID SYSTEM
ENDOGENOUS OPIOID PEPTIDES
Opioid System Distribution
OPIOID RECEPTORS
Signal Transduction
OPIOID RECEPTOR DISTRIBUTION AND EFFECTS
Modulation of Nociceptive Transmission
Respiratory Depression
Cardiovascular Effects
Effects on the GI Tract and Other Smooth Muscles
Effects on Food Intake and Body Temperature
Effects on the Immune System
TOLERANCE AND PHYSICAL DEPENDENCE TO OPIATES
Molecular Mechanisms of Cellular Adaptation to Chronic Exposure to Opiates
Molecular Mechanisms of Withdrawal
Regulation of Gene Transcription by Opioids
ADDICTION TO OPIOIDS
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 47 THE ENDOCANNABINOID SYSTEM
CANNABINOID RECEPTORS
CB1R
CB2 Receptors
GPR55 Receptors
TRPV1 Receptors
PPARs
ENDOCANNABINOIDS
Anandamide
2-Arachidonoylglycerol
The Transporter
BIOLOGICAL FUNCTIONS OF ENDOCANNABINOID SYSTEM
EC-Mediated Synaptic Plasticity
Other Biological Functions
DRUGS AFFECTING THE ECS
Direct Agonists
Antagonists
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 48 PHARMACOLOGY OF NITRIC OXIDE
CHEMISTRY AND BIOSYNTHESIS OF NO
BIOSYNTHESIS OF NO
NO Synthases
BIOCHEMISTRY OF NO
NO and Activation of Guanylate Cyclase
NO and Inhibition of Cytochrome c Oxidase
Nitrosylation of Thiols
NO and MicroRNAs
SYSTEMIC AND ORGAN EFFECTS OF NO
Effects in the Cardiovascular System
NO and the Respiratory System
NO and Metabolic Diseases
NO in Central and Peripheral Nervous Systems
NO and Skeletal Muscle
NO and the Immune System
PHARMACOLOGY OF NO
Nitrate Vasodilators
Nitric Esters of Known Drugs
Stimulators of cGMP Action
NOS Inhibitors
TAKE-HOME MESSAGE
FURTHER READING
Historical Readings
Reviews
CHAPTER 49 ARACHIDONIC ACID METABOLISM
ARACHIDONIC ACID RELEASE FROM MEMBRANE LIPIDS
ENZYMATIC METABOLISM OF ARACHIDONIC ACID
PGH-Synthase Pathway
Cyclic Endoperoxide Metabolism
The Lipoxygenase Pathway
LTA4 Metabolism
Transcellular Metabolism of PGH2 and LTA4
NONENZYMATIC METABOLISM OF ARACHIDONIC ACID
EICOSANOID RECEPTORS
Prostanoid Receptors
Leukotriene Receptors
TAKE-HOME MESSAGE
FURTHER READING
SECTION 12 PHARMACOLOGY OF DEFENCE PROCESSES
CHAPTER 50 PHARMACOLOGICAL MODULATION OF THE IMMUNE SYSTEM
THE IMMUNE RESPONSE
The Concept of Autoimmunity
IMMUNOSUPPRESSIVE DRUGS
Anticancer Chemotherapeutic Agents
Immunosuppressive Drugs with Higher Specificity
Thalidomide
Calcineurin Inhibitors
Antibodies as Selective Immunosuppresants
Other Biological Drugs with Immunomodulatory Activity
Issues Associated with the Use of Antibodies as Pharmacological Agents
IMMUNOSTIMULANT DRUGS
Cytokines
Cytokines as Immunoadjuvants
New Molecular Targets: Phosphodiesterase 4 and p38 MAP Kinases Inhibitors
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 51 MECHANISM OF ACTION OF ANTI-INFECTIVE DRUGS
ANTIBACTERIAL DRUGS AND THEIR MECHANISMS OF ACTION
Inhibitors of Peptidoglycan Synthesis
Inhibitors of Peptidoglycan Polymerization
Transcription Inhibitors
Translation Inhibitors
Inhibitors of DNA Synthesis and Replication
Inhibitors of Cytoplasmic Membrane Functions
Mechanisms of Resistance to Antibacterial Drugs
ANTIFUNGAL DRUGS
Drugs Acting on the Cell Wall
Drugs Acting on the Cytoplasmic Membrane
Inhibitors of DNA and Protein Synthesis
Inhibitors of Enzymatic Metabolic Pathways
Mitotic Inhibitors
Mechanisms of Resistance to Antifungal Drugs
ANTIVIRAL DRUGS
Mechanisms of Action of Antiviral Drugs
Inhibitors of Viral DNA Replication
Drugs Active against Influenza Virus
Drugs Mainly Active on Hepatitis C Viruses (HCV)
New HCV drugs
Other Drugs Active on HCV
Drugs Active against Hepatitis B virus (HBV)
Drugs Active against Immunodeficiency virus (HIV)
Reverse Transcriptase Inhibitors
HIV Protease Inhibitors
Inhibitors of Virus Entry into the Host Cells
Integrase Inhibitors
TAKE-HOME MESSAGE
FURTHER READING
SECTION 13 TOXICOLOGY AND DRUG INTERACTIONS
CHAPTER 52 INTRODUCTION TO TOXICOLOGY
COMPONENTS OF RISK ASSESSMENT
Hazard Identification
Dose-Response and Toxic Potency
Exposure Assessment
Risk Characterization
TOXICOLOGICAL EVALUATION OF NEW AND EXISTING CHEMICALS
General Requirements for Hazard Identification and Risk Assessment
Acute Toxicity, Subchronic Toxicity, and Chronic Toxicity
Irritation and Phototoxicity
Sensitization and Photosensitization
Genotoxicity
Carcinogenicity
Toxicity for Reproduction
Toxicokinetics
Mode and/or Mechanism of Action
TEST GUIDELINES
Alternatives to Animal Experiments
GENERAL APPROACH FOR HAZARD IDENTIFICATION AND RISK ASSESSMENT
Evaluation of Mixtures
Evaluation of Uncertainties
TOXICOLOGICAL ISSUES RELATED TO SPECIFIC CHEMICAL CLASSES
CLASSIFICATION AND LABELLING (C&L) OF CHEMICALS
THE THRESHOLD OF TOXICOLOGICAL CONCERN CONCEPT
THE PRECAUTIONARY PRINCIPLE
CONCLUSIONS
TAKE-HOME MESSAGE
REFERENCES
FURTHER READING
CHAPTER 53 DRUG INTERACTIONS
PHARMACOKINETIC DRUG INTERACTIONS
Interactions during Drug Oral Absorption
Interactions during Drug Distribution
Interactions during Drug Biotransformation
Interaction during Drug Excretion
PHARMACODYNAMIC DRUG INTERACTIONS
CHEMICAL ANTAGONISM
Antidotes
Pharmaceutical Interactions and Incompatibility
INTERACTIONS BETWEEN HERBAL REMEDIES AND DRUGS
INTERACTIONS BETWEEN DIETARY SUPPLEMENTS AND DRUGS
TAKE-HOME MESSAGE
FURTHER READING
SECTION 14 DRUG DEVELOPMENT
CHAPTER 54 PRECLINICAL RESEARCH AND DEVELOPMENT OF NEW DRUGS
TECHNOLOGICAL INNOVATION AND SCIENTIFIC KNOWLEDGE IN CURRENT PHARMACEUTICAL RESEARCH
THE RESEARCH STRATEGIES
Patent as a Driving Force for Innovation
THE RESEARCH STAGES
Start-Up of a New Project and Identification of the Lead Compound
Pharmaceutical Chemistry: From the Mainstream Approach to the Molecular Modeling
Drug Selection: In Vitro Assays and Experimental Models
Biological Drugs
Impact of Genomics Studies on Drug Research
Pharmacokinetic Studies
THE DEVELOPMENTAL STAGES
The Role of National and Supranational Legislation
Scaling Up from Laboratory to Industrial Drug Preparation
Choice of the Pharmaceutical Form
Toxicology Studies
THE DRUGS IN 2020
TAKE-HOME MESSAGE
FURTHER READING
WEB SITES
CHAPTER 55 ROLE OF DRUG METABOLISM AND PHARMACOKINETICS IN DRUG DEVELOPMENT
DMPK IN DRUG DISCOVERY
Evolution of DMPK in Drug Discovery
DMPK IN THE REGULATORY PHASE OF DRUG DEVELOPMENT
Safety of Metabolites
PK IN CLINICAL TRIALS
Interindividual Variability
DDI
PK IN DRUG FORMULATION OF GENERIC EQUIVALENT DRUGS
NEW PERSPECTIVES
TAKE-HOME MESSAGE
FURTHER READING
CHAPTER 56 CLINICAL DEVELOPMENT OF A NEW DRUG AND METHODOLOGY OF DRUG TRIALS
CLINICAL DEVELOPMENT OF A NEW DRUG
Principles and Rules of Clinical Investigation
The Path of Clinical Development of a New Drug
OBSERVATIONAL STUDIES AND RANDOMIZED CLINICAL TRIALS
THE KEY ROLE OF THE PRIMARY HYPOTHESIS
THE CHOICE OF THE PRIMARY END POINT
SAMPLE SIZE CALCULATION
A LOOK AT THE FUTURE
TAKE-HOME MESSAGE
FURTHER READING
Index
EULA

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