General and Molecular Pharmacology. Principles of Drug Action

Description

With a focus on functional relationships between drugs and their targets, this book covers basic and general pharmacology, from a cellular and molecular perspective, with particular attention to the mechanisms of drug action – the fundamental basis for proper clinical use- without neglecting clinical application, toxicology and pharmacokinetics.

• Covers cell and molecular pharmacology, bringing together current research on regulation of drug targets, at a level appropriate for advanced undergrad and graduate students
• Discusses the relevance of pharmacokinetics and drug development for the clinical application of drugs
• Presents material from the perspective of drug targets and interaction, the theoretical basis of drug action analysis, and drug properties
• Focuses on structure-function relationships of drug targets – informing about their biochemical and physiologic functions and experimental and clinical pathways for drug discovery and development
• Has a companion website that offers a host of resources: short additional chapters about methodology, topics at the forefront of research, all figures and tables from the book, and Power Point slides
  

Table of Contents

SECTION 1-INTRODUCTION TO PHARMACOLOGY

1 Essential lexicon of pharmacology
F. Clementi and G. Fumagallli
The social impact of pharmacology
Essential lexicon
1.1 Alternative or non-conventional therapies
1.2 The placebo

2 A short history of pharmacology
V. Sironi
Birth and historical developments of pharmacology
Modern pharmacology
The biotechnology era and the pharmacology in the third millennium
2.1 The drugs of the ancients
2.2 Ehrlich’s chemotherapy: receptor theory and clinical experimentation
2.3 The thalidomide case

SECTION 2 GETTING THE DRUG TO ITS SITE OF ACTION

3 Cellular basis of pharmacokinetics
R. Fesce and G. Fumagalli
A quick journey with a drug in the body
Crossing cell membranes
Drug diffusion across membranes and the Fick’s law
Drug diffusion to organs and tissues
Properties of the most important cell barriers
3.1 Pharmacokinetics

4 Drug absorption and administration routes
R. Fesc and, G. Fumagalli
General rules about drug absorption rate
Enteral routes of administration
Systemic parenteral routes of administration
Other routes of drug administration
Absorption kinetics
Drug delivery: formulations to control absorption and release site

5 Drug distribution and elimination
R. Fesce and G. Fumagalli
Distribution
Elimination
Renal excretion of drugs
Hepatic excretion and entero-hepatic cycle

6 Drug metabolism
E. Chiesara, L. Marabini and S.Radice
Metabolic modification of drug activity
Two phases of drug metabolism
Phase I reactions
Phase II enzymatic reaction
Extrahepatic biotransformations
Pharmaco-metabolic induction and inhibition
6.1 Factors that modify drug metabolism
6.2 Induction of drug metabolism
6.3 Modulations of efficacy due to interactions between synthetic and herbal drugs

7 Control of drug plasma concentration
R. Fesce and G. Fumagalli
Time course of plasma drug concentration following a single administration
Drugs distribute to organs and tissues and then are eliminated
Drug plasma concentration time course during ripetitive administration
Multi compartmental kinetics
Corrections of the therapeutic regimen
7.1 Therapeutic drug monitoring
7.2 The distribution of drugs administered by inhalation

SECTION 3 RECEPTORS AND SIGNAL TRANSDUCTION

8 Drug-receptor interactions: quantitative and qualitative aspects
G. Rovati and V. Capra
General properties of drug receptors
Chraracteristics of drug-receptor interactions
Quantitative aspects of drug effects: dose-response curves
From drug-receptor interaction to drug response
8.1 Methods for receptor investigations
8.2 Receptor binding assays

9 Receptors and modulation of their response
F. Clementi and G. Fumagalli
Classes of receptor and strategies of signal transduction
Control of receptor localisation in the cell membrane
Intracellular traffic of cell receptors
Modulation of receptor responses
Receptor modulation by drugs
9.1 Birth and evolution of receptor’s theories
9.2 Regulation of the receptor response
9.3 Intracellular trafficking of receptors

10 Adaptation to drug response and drug dependence
C. Chiamulera
Molecular, cellular and systemic adaptation
Drug addiction as a paradigm of allostatic adaptation
Therapy for drug dependence
10.1 Types of memory
10.2 A modern definition of memory
10.3 Conditioning as the core od addictive behavior
10.4 Visualization techniques

11 Pharmacological modulation of post-translational modifications
M. Di Luca, F. Valtorta and F. Gardoni
Protein phosphorilation
SUMOylation
Ubiquitination
Glycosylation
Acetylation
Hydroxylation
Carboxylation
Methylation
S-nitrosylation
Disulfide bonds
Lipids modifications
Pharmacological control of post-translational modifications

12 Calcium homeostasis within the cells
J. Meldolesi and G.Fumagalli
The cytosol, a crossroad of Ca2+ fluxes
The plasma membrane: channels, pumps and transporters
Ca2+ in the intracellular organelles
Ca2+ in cell pathology
12.1 Cytosolic proteins that bind Ca2+ with high affinity
12.2 Surface Ca2+ channels: TRP, ORAI, SOCC channels and their functions
12.3 Ca2+ pumps of plasma membrane and intracellular rapidly exchanging Ca2+ stores
12.4 Ca2+ binding proteins of the ER lumen
12.5 ER channels: Ip3 and Ryanodine receptors
12.6 Local Ca2+ spikes can evolve into oscillations and waves
12.7 Mitochondria: semiautonomous organelles that need ER to operate
12.8 The nucleus is also operative in Ca2+ homeostasis

13 Pharmacology of MAP Kinases
L. Vicentini and M. G. Cattaneo
The MAPK family and the activation mechanism
MAPK specificity
Pharmacological inhibition of MAPK
13.1 Phosphatases with dual specificity as regulators of MAPK activity
13.2 Role of MAPKs in memory and learning
13.3 ERK activation by G protein-coupled receptors

14 Small G Proteins
E. Ligeti and T. Wieland
Structure and funtion of SMGs
Physiological role of major SGG families
Posttranslational modifications and subcellular localizationsì of SMGs
Regulatory proteins
Modulation of small G-protein signaling by bacterial toxins and drugs
Future perspectives

15 Integration in intracellular transduction of receptor signals
Jacopo Meldolesi
Dualism of receptors in the nucleus and in the cytoplasm
Heterogeneity of receptor assembly
Transduction cascades depend on cross-talk and complementarity among receptors
Development of new drugs and therapies
15.1 Neurotrophins
15.2 Wnt and Hedgehog signaling pathways: two future drug targets?

SECTION 4 RECEPTOR CLASSES

16 Ligand gated ion channels
C. Gotti and F. Clementi
Tissue distribution and subcellular localization of LGICs
Molecular organisation of LGICs
Topology of LGICs
Modulation of LGICs
Cross talk with other receptor systems
Mechanisms of action of drugs that modulate LGICs
16.1 Evolution of ligand gated ion channels
16.2 How to identify the amino acids that make up the inner wall of LGICs

17 G-protein coupled receptors
L. Vallar, M.P. Abbracchio and L. Vicentini,
Molecular organisation of GPCRs
Molecular organization and function of G protein
Effectors pathways of GPCRs
Interactions of GPCRs with other proteins
17.1 Orphan receptors
17.2 Structure and conformation modifications of GPCRs
17.3 Drugs active on phosphodiesterases

18 Growth factor receptors
S. Giordano, C. Boccaccio and P. M. Comoglio
Molecular structure of growth factors receptors
Receptor activation and signal transduction
Pharmacological approaches to the control of growth factor activity

19 Cytokines receptors
M. Locati
Classification of cytokines and their receptors
Cytokines in their biological settings
Pharmacology of cytokines and of their receptors

20 Adhesion molecules receptors
G. Berton and C. Laudanna
Adhesion receptors
Signal transduction by adhesion receptors
Adhesion receptors as drug targets
20.1 Adhesion and platelets activation
20.2 Adhesion and leukocyte recruitment

21 Soluble Cytochines receptors and monoclonal antibodies in pathophysiology and therapy
A. Mantovani and A. Vecchi
Soluble receptors
Monoclonal antibodies

SECTION 5 MODULATION OF GENE ESPRESSION

22 Pharmacology of transcription
R. Benfante and D.Fornasari
Introduction to the mechanisms of transcriptional regulation
Transcriptional regulation by extracellular stimuli
From the pharmacology of transcription to pharmacoepigenomics
22.1 Pharmacoepigenomics

23 Pharmacogenetics and personalized therapy
D. Fornasari
Variations of drug responses and the definition of pharmacogenetics
Genetic basis of variability in drug response
Genetic polymorphisms and drug metabolism
Genetc polymorphisms in encoding phase l enzymes
Polymorphisms in genes encoding phase II enzymes
Genetic polymorphisms in genes encoding transporters involved in drug absorption, distribution and excretion
Genetic polymorphisms in genes encoding transporters involved in drug absorption, distribution and excretion
Genetic polymorphisms in genes encoding molecular targets of drug action
Methods of pharmacogenetic studies
The future of pharmacogenetic
23.1 Genetic polymorphisms

24 Intracellular receptors
A. Maggi and E. Vegeto
Structural features of intracellular receptors
Intracellular receptors as ligand-regulated transcription factors
Extra-nuclear activity of intracellular receptors
Physiological activities and pharmacological control of intracellular receptors
24.1 Ligands of intracellular receptors

25 RNA molecule as a drug: from RNA interference to aptamers
V. Fulci and G. Macino
Mechanisms of action of RNA drugs
Delivery
General chemical structure
Pharmaco-toxicology
Present use and future perspectives

SECTION 6 REGENERATIVE MEDICINE

26 Regenerative medicine and gene therapy
L. Conti and E. Cattaneo
Principles of regenerative medicine
Definition, classification and features of stem cells
Stem Cells-based drugs
Cell therapy and regenerative medicine
Gene therapy
Future perspectives
26.1 History and development of iPS cell research
26.2 Use of blood stem cells in haematology
26.3 Viral vectors for gene therapy in somatic cells
26.4 Gene therapy for cystic fibrosis and tumors

SECTION 7 PHARMACOLOGICAL CONTROL OF MEMBRANE TRANSPORT

27 Ion channels
M. Taglialatel and E. Wanke
Ion channels and transporters
Characterization and function of ion channels
Structural organization of ion channels
Drugs and ion channels
Sodium channels
Calcium channels
Potassium channels
Non selective channels, anionic channel and others
27.1 How to observe ion channel current in real time
27.2 How to study interactions between drugs and ion channels
27.3 Natural peptide toxins
27.4 Physiopathology and pharmacology of muscular contraction
27.5 Physiopathology of VGCCs: genetic studies in animal models and humans
27.6 Drug induced long QT syndrome
27.7 TRP Channels
27.8 Non-voltage–dependent Na+ channels and their role as mechano-sensitive and acid-sensitive transducers
27.9 Anion channels
27.10 Water channels: Aquaporins
27.11 Voltage-independent Ca2+ channels activated by store depletion
27.12 Pharmacological modulation of gap junctions channels and electric synapses

28 Membrane transporters
L. Annunziato, G. Pignataro and G. Di Renzo
Transporter classification
ATP dependent transporters
ATP independent transporters
Na/K ATPases
H/K ATPases
Plasma membranes Ca2+ ATPases
Sarcoplasmic/endoplasmic reticulum Ca2+ATPase (SERCA)
Sodium/calcium exchanger
Sodium/ proton exchanger
Na+/K+/Cl- co-transporter (NKCC)
28.1 Systems for drug extrusion
28.2 Cardiac glycosides
28.3 Diuretic drugs
28.4 The Na*/Ca 2+exchanger as a new molecular target for the development of drugs to treat cerebral ischemia

29 Neurotransmitter transporters
G. Di Chiara
Neurotransmitter transporters and synaptic function
Neurotransmitter transporter families
Na+/K+ -dependent transporters for excitatory aminoacids
Na+/Cl– -dependent plasma membrane transporters
H+-dependent vesicular transporters
29.1 Therapeutic properties of GABA transporter inhibitors
29.2 Mechanism of action of amphetamines
29.3 Inhibitors of amine transporters and antidepressant drugs

SECTION 8 CONTROL OF PROTEOLYSIS

30 Intracellular proteolysis
F. Di Lisa and E. Melloni
General characteristics of proteases
Characteristics and regulation of intracellular proteolysis
Lysosomal proteases
Compartmentalized proteases with specific functions
Cytoplasmic proteases
Proteasome inhibitors as anti-inflammatory and anti-tumoral drugs
Exogenous intracellular proteases
30.1 Protease classification and nomenclature
30.2 Autophagy
30.3 ACE inhibitors and their effects on cardiovascular system
30.4 Ubiquitin and proteasome

31 Extracellular proteolysis
F. Blasi
The extracellular matrix proteolytic degradation systems
Plasminogen system and its activators
Matrix metalloproteases
31.1 Plasminogen activators and cardiovascular diseases
31.2 Plasminogen activators and tumor malignancy
31.3 uPAR, cancer and stem cells.

SECTION 9 CONTROL OF CELL CYCLE AND CELLULAR PROLIFERATION

32 Cell cycle and cell death
M. Corazzari and M.Piacentini
Cell cycle
Cell death
Programmed cell death or apotosis
Necrosis
Drugs and apoptosis
32.1 P53: regulator of mitotic cycle progression and apoptosis inducer
32.2 Mitotic catastrophe
32.3 Intrinsic apototic pathway induced by endoplasmic reticulum

33 Mechanisms of action of antitumor drugs
G. L. Beretta, L. Gatti and G.Perego
Conventional antitumor drugs
Target specific antitumor drugs
Monoclonal antibodies in clinical use
33.1 Mechanisms of drug resistance in cancer chemotherapy

SECTION 10 CONTROL OF CELLULAR METABOLISM

34 Mitochondria, oxidative stress and cell damage: Pharmacological perspectives
Cl. De Palma, O. Cantoni and F. Di Lisa
Reactive Oxygen Species (ROS)
The mitochondrial permeability transition pore
Drug and mitochondria
34.1 Structure, organization and dynamics of mitochondria

35 Pharmacological control of lipid synthesis
L. Arnaboldi, A. Corsini and N. Ferri
Cholesterol Biosynthesis
Biosynthesis of fatty acids
Triglycerides biosynthesis
Transcriptional control of genes involved in lipid metabolism
Lipid transfer proteins
35.1 Pharmacology of the mevalovate pathway
35.2 Pharmacology of the biosynthesis of fatty acids
35.3 Pharmacology of biosynthesis of triglycerides
35.4 Role of LXR receptors in lipid metabolism and their pharmacological role
35.5 The lipoproteins
34.6 Lipid Transfer proteins

36 Glucose transport and pharmacological control of glucose metabolism
P. Moghetti and G Zoppini
Mechanisms of glycemic control
Pharmacology of glycemic control
Insulin resistance and new therapeutic perspectives
36.1 The controinsular hormones

SECTION 11 INTERCELLULAR COMUNICATION

37 Pharmacological regulation of synaptic function
M. Matteoli, E. Menna, C. Capuano and Cl. Verderio
The Synapse
Synaptic organization complexity and synaptopathies
The presynaptic compartment: Neurotransmitter release
The post-synaptic compartment: Signal reception
Synapse formation, maintenance and plasticity
The pharmacology of neurosecretion
37.1 Role of astrocytes in synaptic transmission
37.2 Dynamic organization of synaptic vesicle pools
37.3 Endocytic process of synaptic vesicles
37.4 Neupeptide secretion
37.5 Role of lipids in exo-endo cytotic cycle of synaptic vesicles

38 Catecholaminergic transmission
S Sigala, M. Memo, M. C. Missale, M. Pizzi and P. F. Spano
The catecholaminergic system in the autonomic nervous system
The catecholaminergic system in the central nervous system
Synthesis of catecholamines
Vesicular storage anmd release of catecholamines and drugs acting on them
Catabolism and reuptake of catecholamines.
Catecholamines receptors
Principles of drug actions on catecholaminergic receptors
38.1 Dopamine and Parkinson’s disease
38.2 Brain reward circuits
38.3 Modulation of the functional properties of dopamine receptors by interactions with other proteins

39 Cholinergic transmission
G. Pepeu
Distribution and function of the cholinergic systems
Acetylcholine synthesis and metabolism
Acetylcholine intracellular storage and release
Cholinergic receptors
Drugs acting on cholinergic receptors
39.1 Methods for investigating the role of brain cholinergic system in learning and memory
39.2 Cholinesterases and cholinesterase inhibitors
39.3 Neuromuscular blocking agents

40 The serotonergic transmission
M. Popoli, L. Musazzi and G. Racagni
Functions and distribution and of serotonergic system in the body
Synthesis and metabolism of serotonin
Vesicular storage, release and extracellular clearance of serotonin
Classification of serotonin receptors
Drugs acting on serotonin receptors
40.1 Drugs active on the serotonergic system
40.2 Serotonergic system and modulation of pain perception
40.3 Pineal gland, melatonin, serotonin and regulation of circadian rhytms

41 Histaminergic Transmission
E. Masini and L. Lucarini
Distribution and function of histaminergic system
Synthesis and metabolism of histamine
Histamine receptors and their pharmacological modulation
41.1 Histamine receptors and signal transmission pathways

42 GABAergic Transmission
M. Serra, E. Sanna and G.Biggio
GABA distribution, synthesis and metabolism
GABA release and uptake
GABAA receptor classification
Pharmacology of GABA A receptors
42.1 Antiepileptic drugs with GABAergic mechanism of action
42.2 Physiological and pharmacological modulation of GABA A receptor gene expression

43 Glutamate mediated neurotransmission
F. Moroni
Glutamate synthesis and metabolism
Glutamate transporters and signal inactivation
Glutamate receptors
Glutamate neurotransmission in physiology and pathgology
43.1 Long-term potentiation (LTP) and long term depression (LTD) of excitatory synaptic transmission

44 Purinergic transmission
S. Ceruti, F. Cattabeni and M. P. Abbracchio
Purines as intercellular transmitters
Receptors for purine
Biological roles of purines
44.1 Purines and ischemia
44.2 Drugs active on purinergic system

45 Neuropeptides
L. Negri and R. Lattanzi
Neuropeptide synthesis
Storage and secretion of neuropeptides
Peptidergic transmission
Neuropeptide functions and therapeutic potential
45.1 Characteristics of some neuropeptides
45.2 Hypothalamus and neuropeptides
45.3 Neuropeptides and nociception

46 The opioid system
P. Romualdi and S. Candeletti
Endogenous opioid peptides
Opioid receptors
Opioid receptor distribution and effects
Tolerance and physical dependence to opiates
Addiction to opioids
46.1 Opiate drugs
46.2 Nociceptin
46.3 Opioid receptor distribution
46.4 Neurobiological basis of acute and chronic pain
46.5 OIpiate addiction

47 The endocannabinoid system
D. Parolaro and T.Rubino
Cannabinoids receptors
Endocannabinoids
Biological functions of endocannabinoids
Drugs affecting the cannabinoid system
47.1 Drugs acting on the endocannabinoid system
47.2 Cannabinoids and drug dependence

48 Pharmacology of nitric oxide
E. Clementi
Chemistry and biosynthesis of nitric oxide
Biosynthesis of nitric oxide
Biochemistry of nitric oxide
Systemic and organ effects of nitric oxide
Pharmacology of nitric oxide
48.1 Chemistry of nitric oxide
48.2 Catalitic activity, molecular features and regulation of NO snthase
48.3 Nitric oxide and control of cell death
48.4 Role of NO in inflammation and in tumor pathology

49 Arachidonic acid metabolism
G. Patrono and P.Patrignani
Arachidonic acid release from membrane lipids
Enzymatic metabolism of arachidonic acid
Non enzymatic metabolism of arachidonic acid
Eicosanoid receptors
49.1 Mechanism of action of glucocorticoids as antiinflammatory drugs
49.2 Mechanism of action aspirin as antithrombotic drug

SECTION 12 PHARMACOLOGY OF DEFENCE PROCESSES

50 Pharmacological modulation of the immune system
C. Riccardi and G. Migliorati
The immune response
Immunosuppressive drugs
Immunostimulant drugs

51 Mechanisms of action of anti-infective drugs
F. Scaglione
Antibacterial drugs and their mechanisms of action
Antifungal drugs
Antiviral drugs
51.1 Mechanisms of antibiotic resistance in bacteria

SECTION 13 TOXICOLOGY AND DRUG INTERACTIONS

52 Introduction to Toxicology
H. Greim
Components of risk assessment
Toxicological evaluation of new and existing chemicals
Tests guidelines
General approach for hazard identification and risk assessment
Toxicological issues related to specific chemical classes
Classification and labelling of chemicals
The Threshold of Toxicological Concept
The precautionary principle
Conclusion

53 Drug interactions
A. Caputi, G. Fava and A. De Sarro
Pharmacokinetic drug interactions
Pharmacodynamic drug interactions
Chemical antagonism
Interactions between herbal remedies and drugs
Interactions between dietary supplements/components and drugs
53.1 Interactions between drugs and grapefruit juice

SECTION 14- DRUG DEVELOPMENT

54 Preclinical Research and development of new drugs
E. Ongini
Technological innovation and scientific knowledge in today pharmaceutical research
The research strategies
The research stages
The development stages
The drugs in 2020
54.1 The significant contribution given by small research groups (start-ups and spin-offs)
54.2 High-throughput screening
54.3 The beginning of a project on a new drug
54.4 The patent
54.5 Biotech drugs
54.6 Toxicology tests
54.7 Safety pharmacology: how to evaluate whether a new molecule will cause side effects on vital functions

55 Role of drug metabolism and pharmacokinetics in drug development
S. Braggio and M. Pellegatti
Pharmacokinetics in drug discovery
Pharmacokinetics in the regulatory phase of drug development
Pharmacokinetics in clinical trials
Pharmacokinetiscs in drug formulation of generic equivalent drugs
New perspectives

56 Clinical testing development of a new drug and methodology of drug trials
C. Patrono
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 points
Sample size calculation
A look at the future

Author Information

Francesco Clementi is a Professor Emeritus of Pharmacology at the University of Milan. He has been President of several national and international societies and is member of the Accademia dei Lincei, the prestigious Academy of Italian Sciences. He authored over 200 publications dealing with neurotransmitter receptors and co-edited several books on neuropharmacology and cell biology including all four editions of the Italian language version of this book,Farmacologia Generale e Molecolare.

Guido Fumagalli has been the Dean of Faculty Director of the PhD School of Translational Medicine, Vice-Provost for Research, and Vice-Provost for International Affairs at the University of Verona. He has over 80 publications in international journals to his credit along with numerous books on pharmacology and sports science