A Pharmacology Primer

Theory, Application and Methods

Terry P. Kenakin, Terry Kenakin

• Publisher: Academic Press
• Year: 2009
• eBook ISBN: 9780080923338
• Edition: 3
• Topic: Medicine
• Subtopic: Pharmacology

This successful guide assists scientists trained in molecular biology and related fields who now need to know the basic theories, principles and practical applications of pharmacology. This latest edition continues the tradition of better preparing researchers in the basics of pharmacology. With expanded hands-on exercises and the addition of Pharmacokinetics coverage, new human interest material including historical facts in pharmacology and a new section on therapeutics that will help readers identify with diseases and drug treatments.The ideal book for researchers in drug discovery who have seen their role shift from "individual" to "team player" where that team includes chemists, biologists, and others with strong, but varied, science backgrounds who must now work together toward their common pharmacology goal. At GlaxoSmithKline, a pharmaceuticals world-leader, Terry Kenakin regularly teaches a course for their research scientists and has drawn on his experience to create a pharmacology primer.*New - Latest coverage of the chemistry of drugs including expanded coverage of the pharmacokinetic discussion of druglike properties -- Increases reader understanding of necessary ADME (Absorption, Distribution, Metabolism, and Excretion) properties and increases the rate of drug approval and acceptance. *Context - Unique discussions on various drug discovery teams and the role of the chemist on those teams -- Promotes the understanding of these expanding roles and responsibilities and how to maximize the effective contributions of each matrix team member. *Real-world learning - There are hands-on exercises, with extensive answers, utilizing real data on structure activity relationships; utilization of pharmacological principles to make general statements about how changes in structure lead to changes in drug activity. + hands on exercises with extensive answers on Pharmacokinetics -- Stengthens practical application and understanding of core concepts and principles.*Study sections are organized with ASPET (American Society for Pharmacology and Experimental Therapeutics)and other international organizations -- Ensures that learning follows professional industry standards.

Chapter 1

What Is Pharmacology?

Publisher Summary

This chapter focuses on the methods and tools used in pharmacology to quantify drug activity. Pharmacology is a broad discipline describing the use of chemicals to treat and cure disease. It as a separate science is approximately 120 to 140 years old. The relationship between chemical structure and biological activity began to be studied systematically in the 1860s. 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. Rudolf Bucheim founded the first formalized chair of pharmacology, indicating a formal university department, in Estonia in 1847. In North America, John Jacob Abel at Johns Hopkins University founded the first chair in 1890. The pharmacologist Sir William Paton gave a differentiation of physiology and pharmacology. 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. Receptor pharmacology is based on the comparison of experimental data to simple mathematical models with a resulting inference of drug behavior to the molecular properties of drugs. A certain understanding of the mathematics involved in the models is useful but not imperative.

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 (1813–1878)

1.1 About This Book

1.2 What is Pharmacology?

1.3 The Receptor Concept

1.4 Pharmacological Test Systems

1.5 The Nature of Drug Receptors

1.6 Pharmacological Intervention and the Therapeutic Landscape

1.7 System-Independent Drug Parameters: Affinity and Efficacy

1.8 What is Affinity?

1.9 The Langmuir Adsorption Isotherm

1.10 What is Efficacy?

1.11 Dose-Response Curves

1.12 Chapter Summary and Conclusions

1.13 Derivations: Conformational Selections as a Mechanism of Efficacy

References

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 to simple mathematical models with a resulting inference of drug behavior to the molecular properties of drugs. From this standpoint, a certain 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 to 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 to no 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 where 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 disease. 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 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).

Pharmacology as a separate science is approximately 120 to 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 Bucheim 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 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.

The human genome is now widely available for drug discovery research. Far from being a simple blueprint of how drugs should be targeted, it has shown biologists that receptor genotypes (i.e., properties of proteins resulting from genetic transcription to their amino acid sequence) are secondary to receptor phenotypes (how the protein interacts with the myriad of cellular components and how cells tailor the makeup and functions of these proteins to their individual needs). Since the arrival of the human genome, receptor pharmacology as a science is more relevant than ever in drug discovery. Current drug therapy is based on less than 500 molecular targets, yet estimates utilizing the number of genes involved in multifactorial diseases suggest that the number of potential drug targets ranges from 2000 to 5000 [3]. Thus, current therapy is using only 5 to 10% of the potential trove of targets available in the human genome.

A meaningful dialogue between chemists and pharmacologists is the single most important element of the drug discovery process. The necessary link between medicinal chemistry and pharmacology has been elucidated by Paton [2]:

For pharmacology there results a particularly close relationship with chemistry, and the work may lead quite naturally, with no special stress on practicality, to therapeutic application, or (in the case of adverse reactions) to toxicology.

— W. D. M. Paton (1986)

Chemists and biologists reside in different worlds from the standpoint of the type of data they deal with. Chemistry is an exact science with physical scales that are not subject to system variance. Thus, the scales of measurement are transferable. Biology deals with the vagaries of complex systems that are not completely understood. Within this scenario, scales of measurement are much less constant and much more subject to system conditions. Given this, a gap can exist between chemists and biologists in terms of understanding and also in terms of the best method to progress forward. In the worst circumstance, it is a gap of credibility emanating from a failure of the biologist to make the chemist understand the limits of the data. Usually, however, credibility is not the issue, a...

Table of contents

• Cover image
• Title page
• Table of Contents
• Copyright
• Dedication
• Preface
• Preface to the Second Edition
• Preface to the First Edition
• 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 Drug Antagonism
• Chapter 8. The Process of Drug Discovery
• Chapter 9. Pharmacokinetics
• Chapter 10. Target- and System-Based Strategies for Drug Discovery
• Chapter 11. “Hit” to Drug: Lead Optimization
• Chapter 12. Statistics and Experimental Design
• Chapter 13. Selected Pharmacological Methods
• Chapter 14. Exercises in Pharmacodynamics and Pharmacokinetics
• Appendices
• Glossary of Pharmacological Terms
• Index