PHARMACOLOGY IN THE 20TH AND 21 ST CENTURIES

Beginning in the 20th century, the fresh wind of synthetic chemistry began to revolutionise the pharmaceutical industry, and with it the science of pharmacology. New synthetic drugs, such as barbiturates and local anaesthetics, began to appear, and the era of antimicrobial chemotherapy began with the discovery by Paul Ehrlich in 1909 of arsenical compounds for treating syphilis. Further breakthroughs came when the sulfonamides, the first antibacterial drugs, were discovered by Gerhard Domagk in 1935, and with the development of penicillin by Chain and Florey during the Second World War, based on the earlier work of Fleming .

These few well-known examples show how the growth of synthetic chemistry, and the resurgence of natural product chemistry, caused a dramatic revitalisation of therapeutics in the first half of the 20th century. Each new drug class that emerged gave pharmacologists a new challenge, and it was then that pharmacology really established its identity and its status among the biomedical sciences.

In parallel with the exuberant proliferation of therapeutic molecules-driven mainly by chemistry-which gave pharmacologists so much to think about, physiology was also making rapid progress, particularly in relation to chemical mediators, which are discussed in depth elsewhere in this book. Many hormones, neurotransmitters and inflammatory mediators were discovered in this period, and the realisation that chemical communication plays a central role in almost every regulatory mechanism that our bodies possess immediately established a large area of common ground between physiology and pharmacology, for interactions between chemical substances and living systems were exactly what pharmacologists had been preoccupied with from the outset. The concept of 'receptors' for chemical mediators, first proposed by Langley in 1905, was quickly taken up by pharmacologists such as Clark, Gaddum, Schild and others and is a constant theme in present day pharmacology (as you will soon discover as you plough through the next two chapters). The receptor concept, and the technologies developed from it, have had a massive impact on drug discovery and therapeutics. Biochemistry also emerged as a distinct science early in the 20th century, and the discovery of enzymes and the delineation of biochemical pathways provided yet another framework for understanding drug effects. The picture of pharmacology that emerges from this brief glance at history is of a subject evolved from ancient prescientific therapeutics, involved in commerce from the 17th century onwards, and which gained respectability by donning the trappings of science as soon as this became possible in the mid-19th century. Signs of its carpetbagger past still cling to pharmacology, for the pharmaceutical industry has become very big business and much pharmacological research nowadays takes place in a commercial environment, a rougher and more pragmatic place than the glades of academia.3 No other biomedical 'ology' is so close to Mammon.

ALTERNATIVE THERAPEUTIC PRINCIPLES

Modern medicine relies heavily on drugs as the main tool of therapeutics. Other therapeutic procedures such as surgery, diet, exercise, etc. are also important, of course, as is deliberate non-intervention, but none is so widely applied as drug-based therapeutics.

Before the advent of science-based approaches, repeated attempts were made to construct systems of therapeutics, many of which produced even worse results than pure empiricism. One of these was allopathy, espoused by James Gregory (1735-1821). The favoured remedies included blood letting, emetics and purgatives, which were used until the dominant symptoms of the disease were suppressed. Many patients died from such treatment, and it was in reaction against it that Hahnemann introduced the practice of hom[oelig ]opathy in the early 19th century. The guiding principles of homæopathy are:

like cures like activity can be enhanced by dilution.

The system rapidly drifted into absurdity: for example, Hahnemann recommended the use of drugs at dilutions of 1:1060, equivalent to one molecule in a sphere the size of the orbit of Neptune.

Many other systems of therapeutics have come and gone, and the variety of dogmatic principles that they embodied have tended to hinder rather than advance scientific progress. Currently, therapeutic systems that have a basis which lies outside the domain of science are actually gaining ground under the general banner of 'alternative' or 'complementary' medicine. Mostly, they reject the 'medical model', which attributes disease to an underlying derangement of normal function that can be defined in biochemical or structural terms, detected by objective means, and influenced beneficially by appropriate chemical or physical interventions. They focus instead mainly on subjective malaise, which may be disease-associated or not. Abandoning objectivity in defining and measuring disease goes along with a similar departure from scientific principles in assessing therapeutic efficacy and risk, with the result that principles and practices can gain acceptance without satisfying any of the criteria of validity that would convince a critical scientist, and that are required by law to be satisfied before a new drug can be introduced into therapy. Public acceptance, alas, has little to do with demonstrable efficacy.

THE EMERGENCE OF BIOTECHNOLOGY

Since the 1980s, biotechnology has emerged as a major source of new therapeutic agents in the form of antibodies, enzymes and various regulatory proteins, including hormones, growth factors and cytokines. Although such products (known as biopharmaceuticals) are generally produced by genetic engineering rather than by synthetic chemistry, the pharmacological principles are essentially the same as for conventional drugs. Looking further ahead, gene- and cell-based therapies, although still in their infancy, will take therapeutics into a new domain. The principles governing the design, delivery and control of functioning artificial genes introduced into cells, or of engineered cells introduced into the body, are very different from those of drug-based therapeutics and will require a different conceptual framework, which texts such as this will increasingly need to embrace if they are to stay abreast of modern medical treatment.

PHARMACOLOGY TODAY

As with other biomedical disciplines, the boundaries of pharmacology are not sharply defined, nor are they constant. Its exponents are, as befits pragmatists, ever ready to poach on the territory and techniques of other disciplines. If it ever had a conceptual and technical core that it could really call its own, this has now dwindled almost to the point of extinction, and the subject is defined by its purpose-to understand what drugs do to living organisms, and more particularly how their effects can be applied to therapeutics-rather than by its scientific coherence.

shows the structure of pharmacology as it appears today. Within the main subject fall a number of compartments (neuropharmacology, immunopharmacology, pharmacokinetics, etc.), which are convenient, if not watertight, subdivisions. These topics form the main subject matter of this book. Around the edges are several interface disciplines, not covered in this book, which form important two-way bridges between pharmacology and other fields of biomedicine. Pharmacology tends to have more of these than other disciplines. Recent arrivals on the fringe are subjects such as pharmacogenomics, pharmacoepidemiology and pharmacoeconomics.

Biotechnology. Originally, this was the production of drugs or other useful products by biological means (e.g. antibiotic production from microorganisms or production of monoclonal antibodies). Currently in the biomedical sphere, biotechnology refers mainly to the use of recombinant DNA technology for a wide variety of purposes, including the manufacture of therapeutic proteins, diagnostics, genotyping, production of transgenic animals, etc. The many non-medical applications include agriculture, forensics, environmental sciences, etc.

Pharmacogenetics. This is the study of genetic influences on responses to drugs. Originally, pharmacogenetics focused on familial idiosyncratic drug reactions, where affected individuals show an abnormal-usually adverse-response to a class of drug. It now covers broader variations in drug response, where the genetic basis is more complex.

Pharmacology today with its various subdivisions. Interface disciplines (brown boxes) link pharmacology to other mainstream biomedical disciplines (green boxes).

Pharmacogenomics. This recent term overlaps with pharmacogenetics, describing the use of genetic information to guide the choice of drug therapy on an individual basis. The underlying principle is that differences between individuals in their response to therapeutic drugs can be predicted from their genetic make-up. Examples that confirm this are steadily accumulating. So far, they mainly involve genetic polymorphism of drug-metabolising enzymes or receptors. Ultimately, linking specific gene variations with variations in therapeutic or unwanted effects of a particular drug should enable the tailoring of therapeutic choices on the basis of an individual's genotype. The consequences for therapeutics will be far-reaching.

Pharmacoepidemiology. This is the study of drug effects at the population level . It is concerned with the variability of drug effects between individuals in a population, and between populations. It is an increasingly important topic in the eyes of the regulatory authorities who decide whether or not new drugs can be licensed for therapeutic use. Variability between individuals or populations has an adverse effect on the utility of a drug, even though its mean effect level may be satisfactory. Pharmacoepidemiological studies also take into account patient compliance and other factors that apply when the drug is used under real-life conditions.

Pharmacoeconomics. This branch of health economics aims to quantify in economic terms the cost and benefit of drugs used therapeutically. It arose from the concern of many governments to provide for healthcare from tax revenues, raising questions of what therapeutic procedures represent the best value for money. This, of course, raises fierce controversy, because it ultimately comes down to putting monetary value on health and longevity. As with pharmacoepidemiology, regulatory authorities are increasingly requiring economic analysis, as well as evidence of individual benefit, when making decisions on licensing.