Pharmacology for Chemists

Drug Discovery in Context

Raymond Hill, Terry Kenakin, Tom Blackburn, Raymond Hill, Terry Kenakin, Tom Blackburn

• Publisher: Royal Society of Chemistry
• Year: 2017
• ISBN:
  9781788012454
• Edition: 1
• Topic: Medicine
• Subtopic: Pharmacology

Assuming little previous knowledge of biology, this book aids graduate chemists to close the gap in their knowledge of pharmacology and make the link between medicinal chemistry and the way in which drugs act on the body. The availability of receptor structures has revolutionized drug discovery and development necessitating an up-to-date source of information for chemists entering this new pharmacological world.

Chapters, written by experts with an appreciation of most graduate chemists' knowledge, explain the history of pharmacology, the relationship between receptor structure and function and receptor pharmacology relevant to drug design. Importantly, as drugs are normally discovered in test rather than therapeutic systems, this text describes how pharmacology provides methods to characterize drug activity through scales that allow prediction of drug effect in all systems. Moreover, it outlines the relationship between drug distribution in the body and the action of drugs in particular organ systems relevant to disease. Readers will also find information on pharmacokinetics and drug metabolism, safety pharmacology and toxicology, clinical and regulatory pharmacology and the use of imaging techniques.

Carefully edited for relevance to the modern chemist, this unique textbook will be an essential resource for chemists planning to work in drug discovery, or postgraduate students and practicing chemists interested in expanding their pharmacology knowledge

1 What is Pharmacology?

Humphrey Rang

British Pharmacological Society, London, UK
Email: [email protected]

1.1 Introduction

Pharmacology is the study of the action of drugs on living systems – neatly paraphrased as the chemical control of physiology and pathology. It lies at the interface of chemistry and biology. Drugs, in this context, are chemicals of known structure that are administered as external agents – whether deliberately or accidentally – to the organism, and produce an observable effect on its function. Living organisms are, of course, complex chemical machines, which produce and use many of their own chemicals as a means of controlling their own functions. Not surprisingly, exposure to other chemicals (i.e. drugs) from the outside world is liable to confuse and subvert the internal signals, and that in essence is what pharmacology is all about. An understanding of pharmacology plays an essential role in the discovery and application of drugs as therapeutic agents, where the aim is to provide benefit to individuals by the alleviation of symptoms and disabilities, improved prognosis, prolongation of life, or disease prevention. A drug that does none of these things, even though it has been exquisitely engineered to interrupt what was thought to be a key step in the pathogenesis of the disorder, is of no use as therapy, though it may prove to be a valuable research tool.

Pharmacology comprises two main components, namely pharmacodynamics, which is concerned with the effects that drugs produce on living systems (i.e. what the drug does to the body), and pharmacokinetics, which describes the mechanisms by which the drug is absorbed, distributed, metabolised and excreted (i.e. what the body does to the drug). To explain fully the effects of a drug in an intact organism, both need to be understood.

Given the extreme chemical complexity of living organisms, and the delicately balanced regulatory mechanisms that have evolved over millions of years to allow organisms to survive environmental threats, it is not surprising that the intrusion of a foreign chemical is, in general, more likely to do harm than good.¹ The aim of drug discovery research is to find those few compounds that – against all odds – can deliver benefit to individuals affected by disease. Therapeutic benefit depends not only on choosing the right compound, but delivering it in the right dose, to the right patient, by the best route, at the right time and under the right circumstances. These important aspects are the concern of the subdiscipline of clinical pharmacology.

When developed as therapeutic agents, drugs are incorporated into medicines, which normally include other substances to enable them to be administered as pills, solutions for injection, skin patches, aerosols or other dosage forms (Box 1.1).

Box 1.1 Some definitions

• Pharmacology. The study of the action of drugs on living systems. Clinical pharmacology is a branch of pharmacology concerned with the action of drugs used clinically to treat patients.
• Drug. A substance of known chemical structure that produces a functional effect when added exogenously to a living system. Many endogenous chemical mediators that regulate normal physiological functions in higher animals can also be administered as drugs, but most drugs are synthetic chemicals or natural products not found in higher animals.
• Medicine. A preparation containing one or more drugs, designed for therapeutic use. Medicines usually contain additional materials to improve their suitability for clinical use, for example as an injectable solution, a pill to be swallowed, or an ointment for topical application.
• Therapeutic efficacy. The disease-related benefit to humans that a medicine produces. The benefit may be:
  • relief of symptoms or disabilities associated with disease;
  • improved prognosis, i.e. slowing or reversal of the progress of the disease;
  • prolongation of life;
  • prevention of disease.

1.2 Origins and Antecedents

The word “pharmakon” in ancient Greek, could mean a medicine or a poison; in the ancient world there was little distinction. Attempts to heal the sick by the use of “medicines” – largely herbal and mineral in origin, and based on spiritualist dogma rather than science – was in the hands of spiritual healers, and the tradition survives to the present day, carried on by “medicine men” and “witch doctors”, whose stock-in-trade is not only to heal the sick, but also to inflict harm on enemies. Compilations of such remedies go back thousands of years and it was the task of healers to produce them according to closely guarded recipes. Such traditional practices, based on dogma rather than science, remain popular to this day, despite the fact that evidence that they deliver benefit is generally weak or nonexistent. Prior to the 19th century, even though “medicines” based on traditional dogma had been catalogued and used for thousands of years, the understanding of drug action in terms of scientific principles – in other words, the emergence of pharmacology – was impossible. Chemistry had not yet advanced to the point of defining compounds in terms of their structure; physiology and pathology could not yet describe the functioning and malfunctioning of the body; traditional teaching emphasised the importance of esoteric procedures for concocting herbal preparations as a prerequisite for their clinical use. There were, however, a few earlier breaks with tradition – discoveries that found application in modern medicine. For example, Thomas Sydenham (1624–89) described in 1666 the use of opium (containing morphine) to control pain and “Jesuit’s bark” (containing quinine) to control “intermittent fever” (i.e. malaria); William Withering (1741–99) described the use of foxglove (digitalis) to treat “dropsy” (heart failure) in 1785. But until the nineteenth century these preparations were generally assumed to owe their properties to the vital forces possessed by “organic” substances. Chemistry did not come into it, nor did any understanding of biological mechanism.

Materia medica – the description of natural products and their medicinal uses, based on beliefs passed from generation to generation down the ages – began to be commercialised in the mid-17th century by the apothecary’s trade, the forerunner of the modern pharmaceutical industry, its aim being to satisfy the demand for medicines containing ingredients that were difficult to obtain, and prepared in an approved manner. At the same time, the “Age of Enlightenment”, a gradual shift from dogma to science in the practice of medicine began to grow, when luminaries such as Robert Boyle (in chemistry) and William Harvey (in physiology) started to use evidence based on careful observation and experiment, as opposed to received wisdom, as a basis for understanding the natural world. The idea of living organisms as machines governed by the same physical laws as everything else in the material world, and of chemistry as the underlying basis of every substance and structure, slowly took root over the next two centuries, and dogmatic beliefs began to be challenged by discoveries based on empirical observations, many of which have stood the test of time.

1.3 The Emergence of Pharmacology as a Science

Pharmacology as a distinct biomedical discipline began in 1847, when Buchheim (1820–1879) established the first university department with that name in Dorpat. His was a bold vision, for at that time the medicines in use were mainly plant extracts of unknown composition and a few, mostly poisonous, inorganic compounds, such as salts of mercury and arsenic. Complicated mixtures were recommended, prepared and administered in accordance with elaborate rituals. Vomiting, sweating, diarrhoea and fever commonly resulted, and were regarded as evidence of the treatment’s effectiveness in ridding the body of harmful “toxins”. A famous quotation from an eminent contemporary physician, Oliver Wendell Holmes in 1860 dismissed them thus: “If all the materia medica, as currently used, could be thrown into the sea, it would be the better for mankind, and the worse for the fishes”.¹ It is certainly true that the “remedies” in use at that time were not based on any understanding of how they produced their effects, or of the underlying pathological dysfunction that needed to be corrected (beyond the “toxins” notion mentioned above), and the idea of testing their therapeutic efficacy rarely surfaced. Nevertheless, Buchheim saw that the challenge, then as now, was to understand better the mechanisms by which they produced their effects in order to put their medicinal uses on a rational, and hopefully effective, basis. Even though organic chemistry had hardly come into being, he had the vision to see that physiology, pathology and chemistry were all advancing rapidly in the very fertile scientific environment of the mid-nineteenth century, to a point where a new interdisciplinary science could emerge.

1.3.1 Chemistry Makes its Entry

One of the essential foundations of pharmacology – the use of structural formulae to define chemical compounds – did not exist until the middle of the nineteenth century. A key figure was August Kekule, a German chemist who described both the tetravalent nature of carbon and the aromatic ring structure of benzene, two essential principles that allowed accurate structural formulae of organic molecules to be produced for the first time. The idea that the biological effects of plant extracts was likely to result from their chemical constituents rather than mysterious vital forces was implicit in the work of Buchheim and other pharmacological pioneers in the nineteenth century, but it was not until 1905 that a German pharmacist, Serturner, isolated crystals of morphine from opium poppies, tested it on himself and nearly died – the first irrefutable evidence that opium worked by chemistry, not by magic. Serturner’s achievement was followed quickly by others who similarly extracted and purified chemical compounds from medicinal plants and showed them to possess distinctive pharmacological properties. Studying how such plant-derived substances as nicotine, atropine, curare, strychnine and ergot alkaloids, produce their effects, and relating them to the emerging knowledge of physiology and pathology, gave pharmacology the scientific foundations that it needed. But still, at this time, synthetic compounds, as opposed to natural products, played only a very minor part.

1.3.2 Pathology and Physiology Lay Important Foundations

The other essential foundations of pharmacology, namely physiology and pathology, also flourished in the nineteenth century. Some key milestones are worth noting. The cell theory, proposed by the German pathologist Rudolf Virchow (1821–1902), identified the cell as the fundamental unit of all living organisms, and proposed that cellular dysfunction – cells dying, dividing, migrating, or otherwise functioning incorrectly – was the basic cause of disease. Louis Pasteur (1822–1896), a French chemist, proposed the germ theory of infection in 1878, having famously demonstrated the role of air-borne micro-organisms in fermentation. He showed that cholera could be transferred from chicken to chicken by inoculation with fresh, but not “stale” material. In fact, inoculation with stale material actually protected against future infection, so Pasteur inadvertently discovered the phenomenon of immunisation.

The first physiological studies aimed at pinning down the site of action of poisons were performed by Francois Magendie (1783–1855) in Paris, who showed that the convulsant action of strychnine was due to its action on the spinal cord, rather than elsewhere in the brain, nerves or muscles. His pupil, Claude Bernard (1813–1878) used a similar anatomical approach to pinpoint the paralysing effect of the arrow-poison curare to the junction between motor nerve and muscle fibre.

1.3.3 The Receptor Concept is Established

The realisation that drugs act very specifically at precise anatomical sites led in later years to the search for cellular components and actual molecules involved. A particularly important stage in the development of modern pharmacology was the emergence of the receptor concept, pharmacology’s Big Idea (reviewed by Rang, 2006²) of a “lock and key” mechanism by which drug molecules act on specific cellular molecules to produce their effects. This idea had been expressed, in a philosophical way, centuries earlier: “Did we but know the mechanical affections of the particles of rhubarb, hemlock, opium and a man……we should be able to tell beforehand that rhubarb will purge, hemlock kill and opium make a man sleep…….”³(John Locke, 1690, Essay concerning human understanding). These “mechanical affections”, which we would today call chemical interactions, are what pharmacology is all about. The Cambridge physiologist, J. N. Langley (1852–1925), first used the term “receptive substance” in 1878 to describe the hypothetical endogenous substance in salivary glands with which pilocarpine (which causes salivary secretion) and atropine (which blocks pilocarpine’s action) combine and compete with each other for binding. A. V. Hill (1886–1977), a student in Langley’s laboratory, applied the Law of Mass Action to describe quantitatively the interaction of drug and receptor molecules, and this quantitative approach was further developed by later pharmacologists. We now know that specific receptors exist in all cells and tissues, and are key players in the numerous chemical signalling pathways used by all living organisms to control their physiological functions. The subversion of these signalling pathways by introducing alien chemicals is the basis is modern pharmacology. Understanding pharmacology in this mechanistic way, underpinned now through the application of molecular biological approaches and by detailed knowledge of the structure and function of receptor molecules, has become crucial for the discovery of new therapeutic drugs.

Receptors form one important class of targets for therapeutic drugs. Enzymes, transporter molecules, ion channels, etc. are other types of target, described elsewhere in this book. Identifying such drug targets, and explaining how drugs are able to act on them to influence the function of the cells and tissues that express them, is a central theme in modern pharmacology, and an important starting point for drug discovery and therapeutic innovation.

1.3.4 Many Chemical Mediators are Identified

The idea that internal secretions – chemical substances liberated into the bloodstream by organs such as the thyroid gland, testis and liver – play an important physiological role, emerged in the 17th century, and slowly gained ground over the next 200 years. The term “hormone” was coined in 1905 by Bayliss and Starling, who showed that the duodenum, in response to gastric acid production, produced a substance “secretin” that caused the pancreas to release digestive enzymes. Around the same time, many physiologists described the effects of removing individual glands – adrenal, thyroid, pituitary, pancreas, etc. – and of injecting various gland extracts, on different physiological functions, though chemical techniques for isolating and identifying the mediators involved were not yet available. The realisation that the release of chemical transmitters is the mechanism by which nerve cells communicate with each other, and with other cells and tissues came initially from work by Dale and Loewi, who identified acetylcholine as the transmitter ...