What Is Pharmacology?

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; dose-response curves

Outline

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 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).

The history of pharmacology is tied to the history of drug discovery – see Chapter 8. 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 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]:

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, 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, including the therapeutic one. This defines the drug discovery process which is the testing of new potential drug molecules in surrogate systems (where a potentially toxic chemical can do no lasting harm) before progression to the next step, namely testing in human therapeutic systems. The models and tools contained in pharmacology to convert drug behaviors in particular organs to molecular properties (see Chapter 2) are the main subject of this book and the step-by-step design of pharmacologic experiments to do this are described in detail in Chapter 8 (after the meaning of the particular parameters and terms is described in previous chapters).

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...