History and Role of Pharmacology

Since the beginning of the species, people have treated pain and disease with substances derived from plants, animals, and minerals. However, the science of pharmacology is less than 150 years old, ushered in by the ability to isolate pure compounds and the establishment of the scientific method. Historically, the selection and use of drugs were based on superstition or on experience (empiricism).

In the first or earliest phase of drug usage, noxious plant and animal preparations were administered to a diseased patient to rid the body of the evil spirits believed to cause illness. The Greek word pharmakon, from which the term pharmacology is derived, originally meant a magic charm for treating disease. Later, pharmakon came to mean a remedy or drug.

In the second phase of drug usage, experience enabled people to understand which substances were actually beneficial in relieving particular disease symptoms. The first effective drugs were probably simple external preparations, such as cool mud or a soothing leaf; the earliest known prescriptions, from 2100 BCE, included salves containing thyme. Over many centuries, people learned the therapeutic value of natural products through trial and error. By 1500 BCE, Egyptian prescriptions called for castor oil, opium, and other drugs that are still used today. In China, ancient scrolls from that time listed prescriptions for herbal medicines for more than 50 diseases. Dioscorides, a Greek army surgeon who lived in the 1st century, described more than 600 medicinal plants that he collected and studied as he traveled with the Roman army. Susruta, a Hindu physician, described the principles of Ayurvedic medicine in the 5th century. During the Middle Ages, Islamic physicians (most famously Avicenna) and Christian monks cultivated and studied the use of herbal medicines.

The third phase of drug usage, the rational or scientific phase, gradually evolved with important advances in chemistry and physiology that gave rise to the new science of pharmacology. At the same time, a more rational understanding of disease mechanisms provided a scientific basis for using drugs whose physiologic actions and effects were understood.

The advent of pharmacology was particularly dependent on the isolation of pure drug compounds from natural sources and on the development of experimental physiology methods to study these compounds. The isolation of morphine from opium in 1804 was rapidly followed by the extraction of many other drugs from plant sources, providing a diverse array of pure drugs for pharmacologic experimentation. Advances in physiology allowed pioneers, such as François Magendie and Claude Bernard, to conduct some of the earliest pharmacologic investigations, including studies that localized the site of action of curare to the neuromuscular junction. The first medical school pharmacology laboratory was started by Rudolf Buchheim in Estonia. Buchheim and one of his students, Oswald Schmiedeberg, trained many other pharmacologists, including John Jacob Abel, who established the first pharmacology department at the University of Michigan in 1891 and is considered the father of American pharmacology.

The goal of pharmacology is to understand the mechanisms by which drugs interact with biologic systems to enable the rational use of effective agents in the diagnosis and treatment of disease. The success of pharmacology in this task has led to an explosion of new drug development, particularly in the past 50 years. Twentieth-century developments include the isolation and use of insulin for diabetes, the discovery of antimicrobial and antineoplastic drugs, and the advent of modern psychopharmacology. Recent advances in molecular biology, genetics, and drug design suggest that new drug development and pharmacologic innovations will provide even greater advances in the treatment of medical disorders in this century.

The history of many significant events in pharmacology, as highlighted by selected Nobel Prize recipients, is presented in Table 1-1.

Pharmacology and Its Subdivisions

Pharmacology is the biomedical science concerned with the interaction of chemical substances with living cells, tissues, and organisms. It is particularly concerned with the mechanisms by which drugs counteract the manifestations of disease and affect fertility. Pharmacology is not primarily focused on the methods of synthesis or isolation of drugs or with the preparation of pharmaceutical products. The disciplines that deal with these subjects are described later.

Pharmacology is divided into two main subdivisions, pharmacokinetics and pharmacodynamics. The relationship between these subdivisions is shown in Figure 1-1. Pharmacokinetics is concerned with the processes that determine the concentration of drugs in body fluids and tissues over time, including drug absorption, distribution, biotransformation (metabolism), and excretion. Pharmacodynamics is the study of the actions of drugs on target organs. A shorthand way of thinking about it is that pharmacodynamics is what the drug does to the body, and pharmacokinetics is what the body does to the drug. Modern pharmacology is focused on the biochemical and molecular mechanisms by which drugs produce their physiologic effects and with the dose-response relationship, defined as the relationship between the concentration of a drug in a tissue and the magnitude of the tissue’s response to that drug. Most drugs produce their effects by binding to protein receptors in target tissues, a process that activates a cascade of events known as signal transduction. Pharmacokinetics and pharmacodynamics are discussed in greater detail in Chapters 2 and 3.

Toxicology

Toxicology is the study of poisons and organ toxicity. It focuses on the harmful effects of drugs and other chemicals and on the mechanisms by which these agents produce pathologic changes, disease, and death. As with pharmacology, toxicology is concerned with the relationship between the dose of an agent and the resulting tissue concentration and biologic effects that the agent produces. Most drugs have toxic effects at high enough doses and may have adverse effects related to toxicity at therapeutic doses.

Pharmacotherapeutics

Pharmacotherapeutics is the medical science concerned with the use of drugs in the treatment of disease. Pharmacology provides a rational basis for pharmacotherapeutics by explaining the mechanisms and effects of drugs on the body and the relationship between dose and drug response. Human studies known as clinical trials are then used to determine the efficacy and safety of drug therapy in human subjects. The purpose, design, and evaluation of human drug studies are discussed in Chapter 4.

Pharmacy and Related Sciences

Pharmacy is the science and profession concerned with the preparation, storage, dispensing, and proper use of drug products. Related sciences include pharmacognosy, medicinal chemistry, and pharmaceutical chemistry. Pharmacognosy is the study of drugs isolated from natural sources, including plants, microbes, animal tissues, and minerals. Medicinal chemistry is a branch of organic chemistry that specializes in the design and chemical synthesis of drugs. Pharmaceutical chemistry, or pharmaceutics, is concerned with the formulation and chemical properties of pharmaceutical products, such as tablets, liquid solutions and suspensions, and aerosols.

Natural Sources of Drugs

Drugs have been obtained from plants, microbes, animal tissues, and minerals. Among the various types of drugs derived from plants are alkaloids, which are substances that that contain nitrogen groups and produce an alkaline reaction in aqueous solution. Examples of alkaloids include morphine, cocaine, atropine, and quinine. Antibiotics have been isolated from numerous microorganisms, including Penicillium and Streptomyces species. Hormones are the most common type of drug obtained from animals, whereas minerals have yielded a few useful therapeutic agents, including the lithium compounds used to treat bipolar mental illness.

Synthetic Drugs

Modern chemistry in the 19th century enabled scientists to synthesize new compounds and to modify naturally occurring drugs. Aspirin, barbiturates, and local anesthetics (e.g., procaine) were among the first drugs to be synthesized in the laboratory. Semisynthetic derivatives of naturally occurring compounds have led to new drugs with different properties, such as the morphine derivative oxycodone.

In some cases, new drug uses were discovered by accident when drugs were used for another purpose, or by actively screening a huge number of related molecules for a specific pharmacologic activity. Medicinal chemists now use molecular modeling software to discern the structure-activity relationship, which is the relationship among the drug molecule, its target receptor, and the resulting pharmacologic activity. In this way a virtual model for the receptor of a particular drug is created, and drug molecules that best fit the three-dimensional conformation of the receptor are synthesized. This approach has been used, for example, to design agents that inhibit angiotensin synthesis, treat hypertension, and inhibit the maturation of the human immunodeficiency virus (HIV).