A Pharmacology Primer

Techniques for More Effective and Strategic Drug Discovery

Terry P. Kenakin, Terry Kenakin

• Publisher: Academic Press
• Year: 2018
• eBook ISBN: 9780128139585
• Edition: 5
• Topic: Medicine
• Subtopic: Pharmacology

A Pharmacology Primer: Techniques for More Effective and Strategic Drug Discovery, Fifth Edition features the latest ideas and research regarding the application of pharmacology to the process of drug discovery. Written by well-respected pharmacologist, Terry P. Kenakin, this primer is an indispensable resource for all those involved in drug discovery. This updated edition has been thoroughly revised to include material on quantifying drug efficacy through bias and cluster analysis, the impact of molecular dynamics and protein structural analysis, the real time kinetic analysis of drug effect, virtual screening for new drug chemical scaffolds, and much more.With full color illustrations and new examples throughout, this book remains a top reference for all industry and academic scientists that is also ideal for students directly involved in drug discovery or pharmacologic research.- Highlights changes surrounding strategies for drug discovery, providing a comprehensive reference and featuring advances in the methods involved- Includes multiple new sections, such as development and utilization of models in pharmacology, de-orphanization of new drug targets, predicting impact of disease on drug pharmacokinetics, and the impact of enzyme kinetics on drug-drug interactions- Illustrates the application of rapid inexpensive assays to predict activity in the therapeutic setting, showing data outcomes and the limitations inherent in interpreting this data

Chapter 1

What is Pharmacology?

Abstract

In this chapter, the relevance of pharmacology to new drug discovery is presented as well as the two most important properties of drugs used to quantify drug activity; affinity and efficacy. The groundwork for the rest of the volume is completed with discussions of the receptor concepts, different biological drug targets and the major tool used in pharmacological experimentation (dose–response curves).

Keywords

Pharmacology; drug receptors; affinity; efficacy and dose–response curves

I would in particular draw the attention to physiologists to this type of physiological analysis of organic systems which can be done with the aid of toxic agents ….

—Claude Bernard (1813–78).

Outline

• 1.1 About This Book 1
• 1.2 What is Pharmacology? 1
• 1.3 The Receptor Concept 3
• 1.4 Pharmacological Test Systems 4
• 1.5 The Nature of Drug Receptors 7
• 1.6 Pharmacological Intervention and the Therapeutic Landscape 7
• 1.7 System-Independent Drug Parameters: Affinity and Efficacy 10
• 1.8 What is Affinity? 13
• 1.9 The Langmuir Adsorption Isotherm 13
• 1.10 What is Efficacy? 15
• 1.11 Dose–Response Curves 16
• 1.12 Chapter Summary and Conclusions 19
• 1.13 Derivations: Conformational Selection as a Mechanism of Efficacy 20
• References 21

1.1 About This Book

Essentially this is a book about the methods and tools used in pharmacology to quantify drug activity. Receptor pharmacology is based on the comparison of experimental data and simple mathematical models, with a resulting inference of drug behavior to the molecular properties of drugs. From this standpoint, a certain level of understanding of the mathematics involved in the models is useful but not imperative. This book is structured such that each chapter begins with the basic concepts and then moves on to the techniques used to estimate drug parameters, and, finally, for those so inclined, the mathematical derivations of the models used. Understanding the derivation is not a prerequisite for understanding the application of the methods or the resulting conclusion; these are included for completeness and are for readers who wish to pursue exploration of the models. In general, facility with mathematical equations is definitely not required for pharmacology; the derivations can be ignored without any detriment to the use of this book.

Second, the symbols used in the models and derivations, on occasion, duplicate each other (i.e., α is an extremely popular symbol). However, the use of these multiple symbols has been retained, since this preserves the context of where these models were first described and utilized. Also, changing these to make them unique would cause confusion if these methods were to be used beyond the framework of this book. Therefore, care should be taken to consider the actual nomenclature of each chapter.

Third, an effort has been made to minimize the need to cross-reference different parts of the book (i.e., when a particular model is described, the basics are reiterated somewhat to minimize the need to read the relevant but different part of the book in which the model is initially described). While this leads to a small amount of repeated description, it is felt that this will allow for a more uninterrupted flow of reading and use of the book.

1.2 What is Pharmacology?

Pharmacology (an amalgam of the Greek pharmakos, medicine or drug, and logos, study) is a broad discipline describing the use of chemicals to treat and cure diseases. The Latin term pharmacologia was used in the late 1600s, but the term pharmacum was used as early as the fourth century to denote the term drug or medicine. There are subdisciplines within pharmacology representing specialty areas. Pharmacokinetics deals with the disposition of drugs in the human body. To be useful, drugs must be absorbed and transported to their site of therapeutic action. Drugs will be ineffective in therapy if they do not reach the organs(s) to exert their activity; this will be discussed specifically in Chapter 9, Pharmacokinetics, of this book. Pharmaceutics is the study of the chemical formulation of drugs to optimize absorption and distribution within the body. Pharmacognosy is the study of plant natural products and their use in the treatment of disease. A very important discipline in the drug-discovery process is medicinal chemistry, the study of the production of molecules for therapeutic use. This couples synthetic organic chemistry with an understanding of how biological information can be quantified and used to guide the synthetic chemistry to enhance therapeutic activity. Pharmacodynamics is the study of the interaction of the drug molecule with the biological target (referred to generically as the “receptor,” vide infra). This discipline lays the foundation of pharmacology since all therapeutic application of drugs has a common root in pharmacodynamics (i.e., as a prerequisite to exerting an effect, all drug molecules must bind to and interact with receptors).

The history of pharmacology is tied to the history of drug discovery—see Chapter 8, The Optimal Design of Pharmacological Experiments. As put by the great Canadian physician Sir William Osler (1849–1919; the “father of modern medicine”), “… the desire to take medicine is perhaps the greatest feature which distinguishes man from animals ….” Pharmacology as a separate science is approximately 120–140 years old. The relationship between chemical structure and biological activity began to be studied systematically in the 1860s [1]. It began when physiologists, using chemicals to probe physiological systems, became more interested in the chemical probes than the systems they were probing. By the early 1800s, physiologists were performing physiological studies with chemicals that became pharmacological studies more aimed at the definition of the biological activity of chemicals. The first formalized chair of pharmacology, indicating a formal university department, was founded in Estonia by Rudolf Bucchiem in 1847. In North America, the first chair was founded by John Jacob Abel at Johns Hopkins University in 1890. A differentiation of physiology and pharmacology was given by the pharmacologist Sir William Paton [2]:

If physiology is concerned with the function, anatomy with the structure, and biochemistry with the chemistry of the living body, then pharmacology is concerned with the changes in function, structure, and chemical properties of the body brought about by chemical substances

—W. D. M. Paton (1986)

Many works about pharmacology essentially deal in therapeutics associated with different organ systems in the body. Thus, in many pharmacology texts, chapters are entitled drugs in the cardiovascular system, the effect of drugs on the gastrointestinal (GI) system, the central nervous system (CNS), and so on. However, the underlying principles for all of these is the same, namely, the pharmacodynamic interaction between the drug and the biological recognition system for that drug. Therefore, a prerequisite to all of pharmacology is an understanding of the basic concepts of dose–response and how living cells process pharmacological information. This generally is given the term pharmacodynamics or receptor pharmacology, where receptor is a term referring to any biological recognition unit for drugs (membrane receptors, enzymes, DNA, and so on). With such knowledge in hand, readers will be able to apply these principles to any branch of therapeutics effectively. This book treats dose–response data generically and demonstrates methods by which drug activity can be quantified across all biological systems irrespective of the nature of the biological target.

A great strength of pharmacology as a discipline is that it contains the tools and methods to convert “descriptive data,” i.e., data that serves to characterize the activity of a given drug in a particular system, to “predictive data.” This latter information can be used to predict that drug's activity in all organ systems, incl...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Preface
• Chapter 1. What is Pharmacology?
• Chapter 2. How Different Tissues Process Drug Response
• Chapter 3. Drug–Receptor Theory
• Chapter 4. Pharmacological Assay Formats: Binding
• Chapter 5. Agonists: The Measurement of Affinity and Efficacy in Functional Assays
• Chapter 6. Orthosteric Drug Antagonism
• Chapter 7. Allosteric Modulation
• Chapter 8. The Optimal Design of Pharmacological Experiments
• Chapter 9. Pharmacokinetics
• Chapter 10. Safety Pharmacology
• Chapter 11. The Drug Discovery Process
• Chapter 12. Statistics and Experimental Design
• Chapter 13. Selected Pharmacological Methods
• Chapter 14. Exercises in Pharmacodynamics and Pharmacokinetics
• Index