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Rang and Dale’s Pharmacology Ninth Edition Preface
In this edition, as in its predecessors, we set out to explain what drugs do in terms of the mechanisms by which they act. This entails analysis not only at the cellular and molecular level, where knowledge and techniques are advancing rapidly, but also at the level of physiological mechanisms and pathological disturbances. Pharmacology has its roots in therapeutics, where the aim is to ameliorate the effects of disease, so we have attempted to make the link between effects at the molecular and cellular level and the range of beneficial and adverse effects that humans experience when drugs are used for therapeutic or other reasons. Therapeutic agents have a high rate of obsolescence. In the decade 2008 to 2017, 301 new drugs gained regulatory approval for use as therapeutic agents. The majority exploit the same molecular targets as drugs already in use. Knowledge of the mechanisms of action of the class of drugs to which a new agent belongs provides a good starting point for understanding and using a new compound intelligently.
Significantly, however, one-third of these new arrivals are ‘first-in-class’ drugs. That is, they act on novel molecular targets not previously exploited for therapeutic purposes, and are therefore likely to produce effects not previously described. Not all will succeed clinically, but some will stimulate the development of improved follow-up compounds of the same type. Furthermore, about a quarter of the new compounds are ‘biopharmaceuticals’ – mainly proteins produced by bioengineering rather than synthetic chemistry. These are growing in importance as therapeutic agents, and generally have characteristics somewhat different from conventional drugs and are covered in a revised chapter. The very high rate of innovation in drug discovery is a recent – and very welcome – change, due in large part to the rapid advances in molecular and cell biology that have stemmed from the sequencing of the human genome in 2003. We have tried to strike a balance between the need to keep up with these modern developments and the danger of information overload. Our emphasis is on explaining the general principles underlying drug action, which apply to old and new alike, and to describe in more detail the actions and mechanisms of familiar, established drugs, while including references that cover modern and future developments.
Pharmacology is a lively scientific discipline in its own right, with an importance beyond that of providing a basis for the use of drugs in therapy, and we aim to provide a good background, not only for future doctors but also for scientists in other disciplines who need to understand how drugs act. We have, therefore, where appropriate, described how drugs are used as probes for elucidating cellular and physiological functions, to improve our understanding of how the human body functions normally and what goes wrong with it in disease, even when the compounds have no clinical use. Besides therapeutic applications, drugs have other impacts on society, which we cover in chapters on psychoactive drugs, drug abuse, and the use of drugs in sport.
Names of drugs and related chemicals are established through usage and sometimes there is more than one name in common use. For prescribing purposes, it is important to use standard names, and we follow, as far as possible,
the World Health Organization’s list of recommended international non-proprietary names (rINN). Sometimes these conflict with the familiar names of drugs (e.g. the endogenous mediator prostaglandin I2 – the standard name in the scientific literature – becomes ‘epoprostenol’ – a name unfamiliar to most scientists – in the rINN list). In these cases, we generally adopt conventional scientific nomenclature. Sometimes English and American usage varies (as with adrenaline/epinephrine and noradrenaline/norepinephrine). Adrenaline and noradrenaline are the official names in EU member states and are used in this book.
Drug action can be understood only in the context of what else is happening in the body. So, at the beginning of most chapters, we briefly discuss the physiological and biochemical processes relevant to the action of the drugs described in that chapter. We have included the chemical structures of drugs only where this information helps in understanding their pharmacological and pharmacokinetic characteristics, since chemical structures are readily available for reference online.
The overall organisation of the book has been retained, with sections covering: (1) the general principles of drug action; (2) the chemical mediators and cellular mechanisms with which drugs interact in producing their therapeutic effects; (3) the action of drugs on specific organ systems; (4) the action of drugs on the nervous system; (5) the action of drugs used to treat infectious diseases and cancer; and (6) a range of special topics such as adverse effects, non-medical uses of drugs, etc. This organisation reflects our belief that drug action needs to be understood, not just as a description of the effects of individual drugs and their uses, but as a chemical intervention that perturbs the network of chemical and cellular signalling that underlies the function of any living organism. In addition to updating each chapter, we have added new material on biopharmaceuticals, and on personalised medicine, topics of particular current interest. Additional current material on cognition-enhancing drugs has been included in Chapter 48.
Despite the fact that pharmacology, like other branches of biomedical science, advances steadily, with the acquisition of new information, the development of new concepts and the introduction of new drugs for clinical use, we have avoided making the ninth edition any longer than its predecessor by cutting out dated and obsolete material, and have made extensive use of small print text to cover more specialised and speculative information that is not essential to understanding the key message, but will, we hope, be helpful to students seeking to go into greater depth. In selecting new material for inclusion, we have taken into account not only new agents but also recent extensions of basic knowledge that presage further drug development. And, where possible, we have given a brief outline of new treatments in the pipeline. Reference lists are largely restricted to guidance on further reading, together with review articles that list key original papers.
Finally, we hope that we have conveyed something of our own enthusiasm for the science and importance of pharmacology in the modern world.
ACKNOWLEDGEMENTS
We are grateful to many colleagues who have helped us with comments and suggestions, and would particularly like to thank the following for their help and advice in the preparation of this edition: Dr Steve Alexander, Professor Emma Baker, Dr Barbara Jennings, Professor Eamonn Kelly, Professor Munir Pirmohamed and Professor Emma Robinson. We would also like to thank Dr Christine Edmead for her work on the self-assessment questions which are available as additional material on the online edition of this book.
We would like to put on record our appreciation of the team at Elsevier who worked on this edition: Alexandra Mortimer (content strategist), Trinity Hutton (content development specialist), Joanna Souch (project manager), Nichole Beard (illustration manager).
London, 2018
Humphrey P. Rang
James M. Ritter
Rod Flower
Graeme Henderson
David MacEwan
Yoon Kong Loke
What is pharmacology? 1
OVERVIEW
In this introductory chapter we explain how pharmacology came into being and evolved as a scientific discipline, and describe the present-day structure of the subject and its links to other biomedical sciences. The structure that has emerged forms the basis of the organisation of the rest of the book. Readers in a hurry to get to the here-and-now of pharmacology can safely skip this chapter.
WHAT IS A DRUG?
For the purposes of this book, a drug can be defined as a chemical substance of known structure, other than a nutrient or an essential dietary ingredient,1 which, when administered to a living organism, produces a biological effect.
A few points are worth noting. Drugs may be synthetic chemicals, chemicals obtained from plants or animals, or products of biotechnology (biopharmaceuticals). A medicine is a chemical preparation, which usually, but not necessarily, contains one or more drugs, administered with the intention of producing a therapeutic effect. Medicines usually contain other substances (excipients, stabilisers, solvents, etc.) besides the active drug, to make them more convenient to use. To count as a drug, the substance must be administered as such, rather than released by physiological mechanisms. Many substances, such as insulin or thyroxine, are endogenous hormones but are also drugs when they are administered intentionally. Many drugs are not used commonly in medicine but are nevertheless useful research tools. The definition of drug also covers toxins, which again are not usually administered in the clinic but nonetheless are critical pharmacological tools. In everyday parlance, the word drug is often associated with psychoactive substances and addiction – unfortunate negative connotations that tend to bias uninformed opinion against any form of chemical therapy. In this book we focus mainly on drugs used for therapeutic purposes but also describe psychoactive drugs and provide important examples of drugs used as experimental tools. Poisons fall strictly within the definition of drugs, and indeed ‘all drugs are poisons… it is only the dose which makes a thing poison’ (an aphorism credited to Paracelsus, a 16th century Swiss physician); conversely, poisons may be effective therapeutic agents when administered in sub-toxic
1Like most definitions, this one has its limits. For example, there are a number of essential dietary constituents, such as iron and various vitamins, that are used as medicines. Furthermore, some biological products (e.g. epoietin) show batch-to-batch variation in their chemical constitution that significantly affects their properties. There is also the study of pharmaceutical-grade nutrients or ‘nutraceuticals’.
doses. Botulinum toxin (Ch. 14) provides a striking example: it is the most potent poison known in terms of its lethal dose, but is widely used both medically and cosmetically. General aspects of harmful effects of drugs are considered in Chapter 58. Toxicology is the study of toxic effects of chemical substances (including drugs), and toxicological testing is undertaken on new chemical entities during their development as potential medicinal products (Ch. 60), but the subject is not otherwise covered in this book.
ORIGINS AND ANTECEDENTS
Pharmacology can be defined as the study of the effects of drugs on the function of living systems. As a science, it was born in the mid-19th century, one of a host of new biomedical sciences based on principles of experimentation rather than dogma that came into being in that remarkable period. Long before that – indeed from the dawn of civilisation – herbal remedies were widely used, pharmacopoeias were written, and the apothecaries’ trade flourished. However, nothing resembling scientific principles was applied to therapeutics, which was known at that time as materia medica.2 Even Robert Boyle, who laid the scientific foundations of chemistry in the middle of the 17th century, was content, when dealing with therapeutics (A Collection of Choice Remedies, 1692), to recommend concoctions of worms, dung, urine and the moss from a dead man’s skull. The impetus for pharmacology came from the need to improve the outcome of therapeutic intervention by doctors, who were at that time skilled at clinical observation and diagnosis but broadly ineffectual when it came to treatment.3 Until the late 19th century, knowledge of the normal and abnormal functioning of the body was too rudimentary to provide even a rough basis for understanding drug effects; at the same time, disease and death were regarded as semi-sacred subjects, appropriately dealt with by authoritarian, rather than scientific, doctrines. Clinical practice often displayed an obedience to authority and ignored what appear to be easily ascertainable facts. For example, cinchona bark was recognised as a specific and effective treatment for malaria, and a sound protocol for its use was laid down by Lind in 1765. In 1804, however, Johnson declared it to be unsafe until the fever had subsided, and he recommended instead the use of large doses of calomel (mercurous chloride) in the early stages – a murderous piece of advice that was slavishly followed for the next 40 years.
2The name persists today in some ancient universities, being attached to chairs of what we would call clinical pharmacology.
3Oliver Wendell Holmes, an eminent physician, wrote in 1860: ‘[I] firmly believe that if the whole materia medica, as now used, could be sunk to the bottom of the sea, it would be all the better for mankind and the worse for the fishes’ (see Porter, 1997).
The motivation for understanding what drugs can and cannot do came from clinical practice, but the science could be built only on the basis of secure foundations in physiology, pathology and chemistry. It was not until 1858 that Virchow proposed the cell theory. The first use of a structural formula to describe a chemical compound was in 1868. Bacteria as a cause of disease were discovered by Pasteur in 1878. Previously, pharmacology hardly had the legs to stand on, and we may wonder at the bold vision of Rudolf Buchheim, who created the first pharmacology institute (in his own house) in Estonia in 1847.
In its beginnings, before the advent of synthetic organic chemistry, pharmacology concerned itself exclusively with understanding the effects of natural substances, mainly plant extracts – and a few (mainly toxic) chemicals such as mercury and arsenic. An early development in chemistry was the purification of active compounds from plants. Friedrich Sertürner, a young German apothecary, purified morphine from opium in 1805. Other substances quickly followed, and, even though their structures were unknown, these compounds showed that chemicals, not magic or vital forces, were responsible for the effects that plant extracts produced on living organisms. Early pharmacologists focused most of their attention on such plant-derived drugs as quinine, digitalis, atropine, ephedrine, strychnine and others (many of which are still used today and will have become old friends by the time you have finished reading this book).4
PHARMACOLOGY IN THE 20TH AND 21ST 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. Around the same time, William Blair-Bell was world renowned for his pioneering work at Liverpool in the treatment of breast cancers with another relatively poisonous agent, lead colloid mixtures. The thinking was that yes, drugs were toxic, but they were slightly more toxic to a microbe or cancer cell. This early chemotherapy has laid the foundations for much of the antimicrobial and anticancer therapies still used today. 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 throughout 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. Indeed, these fields have developed hand-in-hand as wherever there is either a physiological or pathological mechanism, pharmacology could be there to exploit it with a drug. 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 (Fig. 1.1) 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. Pharmacology grew rapidly in partnership with the evolution of organic chemistry and other biomedical sciences, and was quick to assimilate the dramatic advances in molecular and cell biology in the late 20th 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 academia.5 No other biomedical ‘ology’ is so close to Mammon.
ALTERNATIVE THERAPEUTIC PRINCIPLES
4A handful of synthetic substances achieved pharmacological prominence long before the era of synthetic chemistry began. Diethyl ether, first prepared as ‘sweet oil of vitriol’ in the 16th century, and nitrous oxide, prepared by Humphrey Davy in 1799, were used to liven up parties before being introduced as anaesthetic agents in the mid-19th century (see Ch. 42). Amyl nitrite (see Ch. 21) was made in 1859 and can claim to be the first ‘rational’ therapeutic drug; its therapeutic effect in angina was predicted on the basis of its physiological effects – a true ‘pharmacologist’s drug’ and the smelly forerunner of the nitrovasodilators that are widely used today. Aspirin (Ch. 27), the most widely used therapeutic drug in history, was first synthesised in 1853, with no therapeutic application in mind. It was rediscovered in 1897 in the laboratories of the German company Bayer, who were seeking a less toxic derivative of salicylic acid. Bayer commercialised aspirin in 1899 and made a fortune.
Modern medicine relies heavily on drugs as the main tool of therapeutics. Other therapeutic procedures, such
5Some of our most distinguished pharmacological pioneers made their careers in industry: for example, Henry Dale, who laid the foundations of our knowledge of chemical transmission and the autonomic nervous system (Ch. 13); George Hitchings and Gertrude Elion, who described the antimetabolite principle and produced the first effective anticancer drugs (Ch. 57); and James Black, who introduced the first β-adrenoceptor and histamine H2-receptor antagonists (Chs 15 and 31). It is no accident that in this book, where we focus on the scientific principles of pharmacology, most of our examples are products of industry, not of nature.
as surgery, diet, exercise, psychological treatments 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 bloodletting, 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 homeopathy in the early 19th century. The implausible guiding principles of homeopathy 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 that lies outside the domain of science remain popular 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 physiological 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. Demand for ‘alternative’ therapies by the general public, alas, has little to do with demonstrable efficacy.6
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 (see Clark & Pazdernik, 2015). Although such products (known as biopharmaceuticals, biologicals or biologics) are generally produced by genetic engineering rather than by synthetic chemistry, the pharmacological principles are essentially the same as for conventional drugs, although the details of absorption,
6The UK Medicines and Healthcare Regulatory Agency (MHRA) requires detailed evidence of therapeutic efficacy based on controlled clinical trials before a new drug is registered, but no clinical trials data for homeopathic products or for the many herbal medicines that were on sale before the Medicines Act of 1968.
Fig. 1.1 The development of pharmacology.
distribution and elimination, specificity, harmful effects and clinical effectiveness all differ markedly between high molecular-weight biopharmaceuticals and low molecularweight drugs – as does their cost! Looking further ahead, gene- and cell-based therapies (Ch. 5), although still in their infancy, are beginning to take therapeutics into a new domain. The principles governing gene suppression, 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.
Fig. 1.2 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.
Pharmacogenomics. Pharmacogenetics, the study of genetic influences on responses to drugs, initially focused on familial idiosyncratic drug reactions, where affected individuals show an abnormal – usually adverse – response to a class of drug (see Nebert & Weber, 1990). Rebranded as pharmacogenomics, it now covers broader genetically based variations in drug response, where the genetic basis is more complex, the aim being to use genetic information to guide the choice of drug therapy on an individual basis – so-called personalised medicine (Ch. 12). 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 (see Ch. 12). 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. Steady improvements in the cost and feasibility of individual genotyping will
Fig. 1.2 Pharmacology today with its various subdivisions. The grey box contains the general areas of pharmacology covered in this book. Interface disciplines (brown boxes) link pharmacology to other mainstream biomedical disciplines (green boxes)
increase its applicability, potentially with far-reaching consequences for therapeutics (see Ch. 12).
Pharmacoepidemiology. This is the study of drug effects at the population level (see Strom et al., 2013). 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 detracts from the utility of a drug, even though its overall 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.
REFERENCES AND FURTHER READING
Clark, D.P., Pazderink, N.J., 2015. Biotechnology. Elsevier, New York. (General account of biotechnology and its potential applications)
Nebert, D.W., Weber, W.W., 1990. Pharmacogenetics. In: Pratt, W.B., Taylor, P. (Eds.), Principles of Drug Action, third ed. Churchill Livingstone, New York. (A detailed account of genetic factors that affect responses to drugs, with many examples from the pregenomic literature) Porter, R., 1997. The Greatest Benefit to Mankind. Harper-Collins, London. (An excellent and readable account of the history of medicine, with good coverage of the early development of pharmacology and the pharmaceutical industry)
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. For more information on this complex subject, see Rascati (2013).
Rascati, K.L., 2013. Essentials of Pharmacoeconomics, second ed. Lippincott Williams & Wilkins, Philadelphia. (Introduction to a complex and fraught subject)
Strom, B.L., Kimmel, S.E., Hennessy, S., 2013. Textbook of Pharmacoepidemiology, second ed. Wiley, Chichester. (A multiauthor book covering all aspects of a newly emerged discipline, including aspects of pharmacoeconomics)
How drugs act: general principles 2
OVERVIEW
The emergence of pharmacology as a science came when the emphasis shifted from describing what drugs do to explaining how they work. In this chapter we set out some general principles underlying the interaction of drugs with living systems (Ch. 3 goes into the molecular aspects in more detail). The interaction between drugs and cells is described, followed by a more detailed examination of different types of drug–receptor interaction. The receptor concept has been described as the ‘big idea’ of pharmacology (Rang, 2006) and will be a recurring theme throughout this book.
INTRODUCTION
To begin with, we should gratefully acknowledge Paul Ehrlich for insisting that drug action must be explicable in terms of conventional chemical interactions between drugs and tissues, and for dispelling the idea that the remarkable potency and specificity of action of some drugs put them somehow out of reach of chemistry and physics and required the intervention of magical ‘vital forces’. Although many drugs produce effects in extraordinarily low doses and concentrations, low concentrations still involve very large numbers of molecules. One drop of a solution of a drug at only 10 10 mol/L still contains about 3 × 109 drug molecules, so there is no mystery in the fact that it may produce an obvious pharmacological response. Some bacterial toxins (e.g. diphtheria toxin) act with such precision that a single molecule taken up by a target cell is sufficient to kill it.
One of the basic tenets of pharmacology is that drug molecules must exert some chemical influence on one or more cell constituents in order to produce a pharmacological response. In other words, drug molecules must get so close to these constituent cellular molecules that the two interact chemically in such a way that the function of the latter is altered. Of course, the molecules in the organism vastly outnumber the drug molecules, and if the drug molecules were merely distributed at random, the chance of interaction with any particular class of cellular molecule would be negligible. Therefore pharmacological effects require, in general, the non-uniform distribution of the drug molecule within the body or tissue, which is the same as saying that drug molecules must be ‘bound’ to particular constituents of cells and tissues in order to produce an effect. Ehrlich summed it up thus: ‘Corpora non agunt nisi fixata’ (in this context, ‘A drug will not work unless it is bound’).1
1There are, if one looks hard enough, exceptions to Ehrlich’s dictum –drugs that act without being bound to any tissue constituent (e.g. osmotic diuretics, osmotic purgatives, antacids and heavy metal chelating agents). Nonetheless, the principle remains true for the great majority.
These critical binding sites are often referred to as ‘drug targets’ (an obvious allusion to Ehrlich’s famous phrase ‘magic bullets’, describing the potential of antimicrobial drugs). The mechanisms by which the association of a drug molecule with its target leads to a physiological response constitute the major thrust of pharmacological research. Most drug targets are protein molecules. Even general anaesthetics (see Ch. 42), which were long thought to produce their effects by an interaction with membrane lipid, now appear to interact mainly with membrane proteins (see Franks, 2008).
All rules need exceptions, and many antimicrobial and antitumour drugs (Chs 52 and 57), as well as mutagenic and carcinogenic agents (Ch. 58), interact directly with DNA rather than protein; bisphosphonates, used to treat osteoporosis (Ch. 37), bind to calcium salts in the bone matrix, rendering them toxic to osteoclasts, much like rat poison. There are also exceptions among the new generation of biopharmaceutical drugs that include nucleic acids, proteins and antibodies (see Ch. 5).
PROTEIN TARGETS FOR DRUG BINDING
Four main kinds of regulatory protein are commonly involved as primary drug targets, namely:
• receptors
• enzymes
• carrier molecules (transporters)
• ion channels
Furthermore, many drugs bind (in addition to their primary targets) to plasma proteins (see Ch. 9) and other tissue proteins, without producing any obvious physiological effect. Nevertheless, the generalisation that most drugs act on one or other of the four types of protein listed above serves as a good starting point.
Further discussion of the mechanisms by which such binding leads to cellular responses is given in Chapters 3–4.
DRUG RECEPTORS
WHAT DO WE MEAN BY RECEPTORS?
▼ As emphasised in Chapter 1, the concept of receptors is central to pharmacology, and the term is most often used to describe the target molecules through which soluble physiological mediators –hormones, neurotransmitters, inflammatory mediators, etc. – produce their effects. Examples such as acetylcholine receptors, cytokine receptors, steroid receptors and growth hormone receptors abound in this book, and generally the term receptor indicates a recognition molecule for a chemical mediator through which a response is transduced.
‘Receptor’ is sometimes used to denote any target molecule with which a drug molecule (i.e. a foreign compound rather than an endogenous mediator) has to combine in order to elicit its specific
Targets for drug action
• A drug is a chemical applied to a physiological system that affects its function in a specific way.
• With some exceptions, drugs act on target proteins, namely: – receptors – enzymes – carriers – ion channels.
• The term receptor is used in different ways. In pharmacology, it describes protein molecules whose function is to recognise and respond to endogenous chemical signals. Other macromolecules with which drugs interact to produce their effects are known as drug targets
• Specificity is reciprocal: individual classes of drug bind only to certain targets, and individual targets recognise only certain classes of drug.
• No drugs are completely specific in their actions. In many cases, increasing the dose of a drug will cause it to affect targets other than the principal one, and this can lead to side effects.
influence even when no chemical mediator is present (see p. 14).
There is an important distinction between agonists, which ‘activate’ the receptors, and antagonists, which combine at the same site without causing activation, and block the effect of agonists on that receptor. The distinction between agonists and antagonists only exists for pharmacological receptors; we cannot usefully speak of ‘agonists’ for the other classes of drug target described above.
The characteristics and accepted nomenclature of pharmacological receptors are described by Neubig et al. (2003). The origins of the receptor concept and its pharmacological significance are discussed by Rang (2006).
DRUG SPECIFICITY
For a drug to be useful as either a therapeutic or a scientific tool, it must act selectively on particular cells and tissues. In other words, it must show a high degree of binding site specificity. Conversely, proteins that function as drug targets generally show a high degree of ligand specificity; they bind only molecules of a certain precise type.
effect. For example, the voltage-sensitive sodium channel is sometimes referred to as the ‘receptor’ for local anaesthetics (see Ch. 44), or the enzyme dihydrofolate reductase as the ‘receptor’ for methotrexate (Ch. 51). The term drug target, of which receptors are one type, is preferable in this context.
In the more general context of cell biology, the term receptor is used to describe various cell surface molecules (such as T-cell receptors, integrins, Toll receptors, etc; see Ch. 7) involved in the cell-to-cell interactions that are important in immunology, cell growth, migration and differentiation, some of which are also emerging as drug targets. These receptors differ from conventional pharmacological receptors in that they respond to proteins attached to cell surfaces or extracellular structures, rather than to soluble mediators.
Various carrier proteins are often referred to as receptors, such as the low-density lipoprotein receptor that plays a key role in lipid metabolism (Ch. 24) and the transferrin receptor involved in iron absorption (Ch. 26). These entities have little in common with pharmacological receptors. Though quite distinct from pharmacological receptors, these proteins play an important role in the action of drugs such as statins (Ch. 24).
RECEPTORS IN PHYSIOLOGICAL SYSTEMS
Receptors form a key part of the system of chemical communication that all multicellular organisms use to coordinate the activities of their cells and organs. Without them, we would be unable to function.
Some fundamental properties of receptors are illustrated by the action of adrenaline (epinephrine) on the heart. Adrenaline first binds to a receptor protein (the β1 adrenoceptor, see Ch. 15) that serves as a recognition site for adrenaline and other catecholamines. When it binds to the receptor, a train of reactions is initiated (see Ch. 3), leading to an increase in force and rate of the heartbeat. In the absence of adrenaline, the receptor is normally functionally silent. This is true of most receptors for endogenous mediators (hormones, neurotransmitters, cytokines, etc.), although there are examples (see Ch. 3) of receptors that are ‘constitutively active’ – that is, they exert a controlling
These principles of binding site and ligand specificity can be clearly recognised in the actions of a mediator such as angiotensin (Ch. 23). This peptide acts strongly on vascular smooth muscle, and on the kidney tubule, but has very little effect on other kinds of smooth muscle or on the intestinal epithelium. Other mediators affect a quite different spectrum of cells and tissues, the pattern in each case reflecting the specific pattern of expression of the protein receptors for the various mediators. A small chemical change, such as conversion of one of the amino acids in angiotensin from L to D form, or removal of one amino acid from the chain, can inactivate the molecule altogether, because the receptor fails to bind the altered form. The complementary specificity of ligands and binding sites, which gives rise to the very exact molecular recognition properties of proteins, is central to explaining many of the phenomena of pharmacology. It is no exaggeration to say that the ability of proteins to interact in a highly selective way with other molecules – including other proteins – is the basis of living machines. Its relevance to the understanding of drug action will be a recurring theme in this book. Finally, it must be emphasised that no drug acts with complete specificity. Thus tricyclic antidepressant drugs (Ch. 48) act by blocking monoamine transporters but are notorious for producing side effects (e.g. dry mouth) related to their ability to block various other receptors. In general, the lower the potency of a drug and the higher the dose needed, the more likely it is that sites of action other than the primary one will assume significance. In clinical terms, this is often associated with the appearance of unwanted ‘off-target’ side effects,2 of which no drug is free.
Since the 1970s, pharmacological research has succeeded in identifying the protein targets of many different types of drug. Drugs such as opioid analgesics (Ch. 43), cannabinoids (Ch. 20) and benzodiazepine tranquillisers (Ch. 45), whose actions had been described in exhaustive detail for many years, are now known to target well-defined receptors, many of which have been fully characterised by
2‘On-target’ side effects are unwanted effects mediated through the same receptor as the clinically desired effect, for example constipation and respiratory depression by opioid analgesic drugs (see Ch. 43), whereas ‘off target’ side effects are mediated by a different mechanism.
gene-cloning and protein crystallography techniques (see Ch. 3).
RECEPTOR CLASSIFICATION
▼ Where the action of a drug can be associated with a particular receptor, this provides a valuable means for classification and refinement in drug design. For example, pharmacological analysis of the actions of histamine (see Ch. 18) showed that some of its effects (the H1 effects, such as smooth muscle contraction) were strongly antagonised by the competitive histamine antagonists then known. Black and his colleagues suggested in 1970 that the remaining actions of histamine, which included its stimulant effect on gastric secretion, might represent a second class of histamine receptor (H2). Testing a number of histamine analogues, they found that some were selective in producing H2 effects, with little H1 activity. By analysing which parts of the histamine molecule conferred this type of specificity, they were able to develop selective H2 antagonists, which proved to be potent in blocking gastric acid secretion, a development of major therapeutic significance (Ch. 31).3 Two further types of histamine receptor (H3 and H4) were recognised later.
Receptor classification based on pharmacological responses continues to be a valuable and widely used approach. Subsequently, newer experimental approaches produced other criteria on which to base receptor classification. The direct measurement of ligand binding to receptors (see later) allowed many new receptor subtypes to be defined that could not easily be distinguished by studies of drug effects.
Molecular sequencing of the amino acid structure (see Ch. 3) provided a completely new basis for classification at a much finer level of detail than can be reached through pharmacological analysis. Finally, analysis of the biochemical pathways that are linked to receptor activation (see Ch. 3) provides yet another basis for classification.
The result of this data explosion was that receptor classification suddenly became much more detailed, with a proliferation of receptor subtypes for all the main types of ligand. As alternative molecular and biochemical classifications began to spring up that were incompatible with the accepted pharmacologically defined receptor classes, the International Union of Basic and Clinical Pharmacology (IUPHAR) convened expert working groups to produce agreed receptor classifications for the major types, taking into account the pharmacological, molecular and biochemical information available. These wise people have a hard task; their conclusions will be neither perfect nor final but are essential to ensure a consistent terminology. To the student, this may seem an arcane exercise in taxonomy, generating much detail but little illumination. There is a danger that the tedious lists of drug names, actions and side effects that used to burden the subject will be replaced by exhaustive tables of receptors, ligands and transduction pathways. In this book, we have tried to avoid detail for its own sake and include only such information on receptor classification as seems interesting in its own right or is helpful in explaining the actions of important drugs. A comprehensive database of known receptor classes is available (see <www.guidetopharmacology.org/>), as well as a regularly updated summary (Alexander et al., 2015).
DRUG–RECEPTOR INTERACTIONS
Occupation governed by affinity Activation governed by efficacy
Occupation of a receptor by a drug molecule may or may not result in activation of the receptor. By activation, we mean that the receptor is affected by the bound molecule in such a way as to alter the function of the cell and elicit a tissue response. The molecular mechanisms associated with receptor activation are discussed in Chapter 3. Binding and activation represent two distinct steps in the generation of the receptor-mediated response by an agonist ( Fig. 2.1). If a drug binds to the receptor without causing activation and thereby prevents the agonist from binding, it is termed a receptor antagonist. The tendency of a drug to bind to the
3For this work, and the development of β-adrenoceptor antagonists by a similar experimental approach, Sir James Black was awarded the 1984 Nobel Prize in Physiology or Medicine.
Fig. 2.1 The distinction between drug binding and receptor activation. Ligand A is an agonist, because when it is bound, the receptor (R) tends to become activated, whereas ligand B is an antagonist, because binding does not lead to activation. It is important to realise that for most drugs, binding and activation are reversible, dynamic processes. The rate constants k+1, k 1, α and β for the binding, unbinding and activation steps vary between drugs. For an antagonist, which does not activate the receptor, β = 0.
receptors is governed by its affinity, whereas the tendency for it, once bound, to activate the receptor is denoted by its efficacy. These terms are defined more precisely later (pp. 9 and 11). Drugs of high potency generally have a high affinity for the receptors and thus occupy a significant proportion of the receptors even at low concentrations. Agonists also possess significant efficacy, whereas antagonists, in the simplest case, have zero efficacy. Drugs with intermediate levels of efficacy, such that even when 100% of the receptors are occupied the tissue response is submaximal, are known as partial agonists, to distinguish them from full agonists, the efficacy of which is sufficient that they can elicit a maximal tissue response. These concepts, though clearly an oversimplified description of events at the molecular level (see Ch. 3), provide a useful basis for characterising drug effects.
We now discuss certain aspects in more detail, namely drug binding, agonist concentration–effect curves, competitive antagonism, partial agonists and the nature of efficacy. Understanding these concepts at a qualitative level is sufficient for many purposes, but for more detailed analysis a quantitative formulation is needed (see pp. 19–20).
THE BINDING OF DRUGS TO RECEPTORS
▼ The binding of drugs to receptors can often be measured directly by the use of drug molecules (agonists or antagonists) labelled with one or more radioactive atoms (usually 3H, 14C or 125I). The usual procedure is to incubate samples of the tissue (or membrane fragments) with various concentrations of radioactive drug until equilibrium is reached (i.e. when the rate of association [binding] and dissociation [unbinding] of the radioactive drug are equal). The bound radioactivity is measured after removal of the supernatant.
In such experiments, the radiolabelled drug will exhibit both specific binding (i.e. binding to receptors, which is saturable as there are a finite number of receptors in the tissue) and a certain amount of ‘non-specific binding’ (i.e. drug taken up by structures other than receptors, which, at the concentrations used in such studies, is normally non-saturable), which obscures the specific component and needs to be kept to a minimum (Fig. 2.2A–B). The amount of non-specific
(i) Radioactive drug binds to specific and non-specific sites
Specific binding to receptor
R R R
(ii) Increasing concentration of radioactive drug saturates specific sites (iii) Excess non-radioactive drug displaces radioactive drug from specific sites
K
Concentration (nmol/L)
Concentration (nmol/L)
Concentration (nmol/L, log scale)
Fig. 2.2 Measurement of receptor binding. (A) (i) Cartoon depicting radioligand (shown in red) binding to its receptor (R) in the membrane as well as to non-specific sites on other proteins and lipid. In (ii) when the concentration of radioligand is increased all the specific sites become saturated but non-specific binding continues to increase. In (iii) addition of a high concentration of a non-radioactive drug (shown in green) that also binds to R displaces the radioactive drug from its receptors but not from the non-specific sites. (B–D) Illustrate actual experimental results for radioligand binding to β adrenoceptors in cardiac cell membranes. The ligand was [3H]-cyanopindolol, a derivative of pindolol (see Ch. 15). (B) Measurements of total and non-specific binding at equilibrium. Non-specific binding is measured in the presence of a saturating concentration of a non-radioactive β-adrenoceptor agonist, which prevents the radioactive ligand from binding to β adrenoceptors. The difference between the two lines represents specific binding. (C) Specific binding plotted against concentration. The curve is a rectangular hyperbola (Eq. 2.5). (D) Specific binding as in (C) plotted against the concentration on a log scale. The sigmoid curve is a logistic curve representing the logarithmic scaling of the rectangular hyperbola plotted in panel (C) from which the binding parameters K (the equilibrium dissociation constant) and Bmax (the binding capacity) can be determined.
binding is estimated by measuring the radioactivity taken up in the presence of a saturating concentration of a (non-radioactive) ligand that inhibits completely the binding of the radioactive drug to the receptors, leaving behind the non-specific component. This is then subtracted from the total binding to give an estimate of specific binding (Fig. 2.2C). The binding curve (Fig. 2.2C–D) defines the relationship between concentration and the amount of drug bound (B), and in most cases it fits well to the relationship predicted theoretically (see Fig. 2.14), allowing the affinity of the drug for the receptors to be estimated, as well as the binding capacity (Bmax), representing the density of receptors in the tissue. When combined with functional studies, binding measurements have proved very valuable. It has, for example, been confirmed that the spare receptor hypothesis (p. 10) for muscarinic receptors in smooth muscle is correct; agonists are found to bind, in general, with rather low affinity, and a maximal biological effect occurs at low receptor occupancy. It has also been shown, in skeletal muscle and other tissues, that denervation leads to an increase in the number of receptors in the target cell, a finding that accounts, at least in part, for the phenomenon of denervation supersensitivity. More generally, it appears that receptors tend to increase in number, usually over the course of a few days, if the relevant hormone or transmitter is absent or scarce, and to decrease in number if the receptors are activated for a prolonged period, a process of adaptation to continued administration of drugs or hormones (see p. 18).
Non-invasive imaging techniques, such as positron emission tomography (PET), using drugs labelled with an isotope of short half-life (such as 11C or 18Fl), can also be used to investigate the distribution of receptors in structures such as the living human brain. This technique has been used, for example, to measure the degree of dopaminereceptor blockade produced by antipsychotic drugs in the brains of schizophrenic patients (see Ch. 47).
Binding curves with agonists often reveal an apparent heterogeneity among receptors. For example, agonist binding to muscarinic receptors (Ch. 14) and also to β adrenoceptors (Ch. 15) suggests at least two populations of binding sites with different affinities. This may be because the receptors can exist either unattached or coupled within the membrane to another macromolecule, the G protein (see Ch. 3), which constitutes part of the transduction system through which the receptor exerts its regulatory effect. Antagonist binding does not show this complexity, probably because antagonists, by their nature, do not lead to the secondary event of G protein coupling. Because agonist binding results in activation, agonist affinity has proved to be a surprisingly elusive concept, about which aficionados love to argue.
THE RELATION BETWEEN DRUG CONCENTRATION AND EFFECT
Although binding can be measured directly, it is usually a biological response, such as a rise in blood pressure,
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Title: The mutual influence of Christianity and the Stoic school
Author: James Henry Bryant
Release date: May 8, 2024 [eBook #73570]
Language: English
Original publication: London: Macmillan and Co, 1866
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*** START OF THE PROJECT GUTENBERG EBOOK THE MUTUAL INFLUENCE OF CHRISTIANITY AND THE STOIC SCHOOL ***
The Mutual Influence of Christianity and the Stoic School
THE MUTUAL INFLUENCE OF CHRISTIANITY AND THE STOIC SCHOOL.
BY JAMES HENRY BRYANT, B.D.
ST JOHN’S COLLEGE, CAMBRIDGE, INCUMBENT OF ASTLEY, WARWICKSHIRE.
SOPH. Œd.Col.1080.
London and Cambridge: MACMILLAN AND CO. 1866.
Cambridge:
PRINTED BY C. J. CLAY M.A. AT THE UNIVERSITY PRESS.
TO HIS GRACE,
WILLIAM, DUKE OF DEVONSHIRE, K.G., LL.D. CHANCELLOR OF THE UNIVERSITY OF CAMBRIDGE, THE FOLLOWING ESSAY, BEING THE HULSEAN DISSERTATION IN THE UNIVERSITY OF CAMBRIDGE, FOR THE YEAR 1865, IS BY HIS GRACE’S KIND PERMISSION, RESPECTFULLY DEDICATED.
Introduction . . . 1
CHAPTER I.
The Stoic School of Philosophy . . . 13
CHAPTER II.
Stoicism in comparison with Christianity . . . 27
CHAPTER III.
The Influence of Christianity on Stoicism . . . 48
CHAPTER IV.
The Influence of Stoicism on the Christian Church . . . 74
Conclusion . . . 91
CLAUSES directedby the FOUNDER to be alwaysprefixed to the HULSEAN D
ISSERTATION.
CLAUSES from the WILL of the Rev. JOHN HULSE, late of Elworth, in the County of Chester, clerk, deceased: dated the twenty-first day of July, in the year of our Lord one thousand seven hundred and seventy-seven; expressed in the words of the Testator, as he, in order to prevent mistakes, thought proper to draw and write the same himself, and directed that such clauses should every year be printed, to the intent that the several persons, whom it might concern and be of service to, might know that there were such special donations or endowments left for the encouragement of Piety and Learning, in an age so unfortunately addicted to Infidelity and Luxury, and that others might be invited to the like charitable, and, as he humbly hoped, seasonable and useful Benefactions.
He directs that certain rents and profits (now amounting to about a hundred pounds yearly) be paid to such learned and ingenious person, in the University of Cambridge, under the degree of Master of Arts, as shall compose, for that year, the best Dissertation, in the English language, on the Evidences in general, or on the Prophecies or Miracles in particular, or any other particular Argument, whether the same be direct or collateral proofs of the Christian Religion, in order to evince its truth and excellence; the subject of which Dissertation shall be given out by the Vice-Chancellor, and the Masters of Trinity and Saint John’s, his Trustees, or by some of them, on New Year’s Day annually; and that such Dissertation as shall be by them[1] , or any two of them, on Christmas Day annually, the best approved, be also printed, and the expense defrayed out of the
Author’s income under his Will, and the remainder given to him on Saint John the Evangelist’s Day following; and he who shall be so rewarded, shall not be admitted at any future time as a Candidate again in the same way, to the intent that others may be invited and encouraged to write on so sacred and sublime a subject.
He also desires, that immediately following the last of the clauses relating to the prize Dissertation, this invocation may be added: “May the Divine Blessing for ever go along with all my benefactions; and may the Greatest and the Best of Beings, by his all-wise Providence and gracious influence, make the same effectual to His own glory, and the good of my fellow-creatures!”
Subject proposed by the TRUSTEES for the Year 1865: ThemutualInfluenceofChristianityandtheStoicSchool.
INTRODUCTION.
It was at Athens, “the school of the world,” that the first and only contact of Christianity with Gentile Philosophy, recorded in the New Testament, took place. In “the learned city” the mightiest efforts of the human mind had been made to grasp eternal truth. But the contradictions in the teachings of the master-minds of Greece and the consequent doubt and unbelief so prevalent, at the same time, with the most abject superstition, proved that the effort had been vain to arrive at a full comprehension of the Infinite from a consideration of the finite—to rise from man to GOD. In this same city, about half a century after the birth of the Redeemer, there was unveiled to human souls which had been longing for the knowledge of the unseen, “the mystery of Godliness,” that “GOD” had been “manifest in the flesh.” The eyes which had been long looking for the day might now behold the day-star from on high who had visited and blessed the world with light and salvation. Now there could be found repose of soul and certainty of belief, because the Truth had come down from heaven, from GOD to man, that He might raise man to GOD. Heavenly wisdom at length encountered human wisdom and pride of intellect in their stronghold.
By this I do not mean that before St Paul came to Athens there had been no contest of the religion of Christ with mere human conceits. Philosophy is only the endeavor to reduce the thoughts of men to a system, to find a grammar for the language of the mind, or rather, perhaps, to find a language as well as a grammar. Wherever there is mind there will be thought, either with, or without a system. So that Christianity, in winning its way, had met with opposition of human thought before the great Apostle of Jesus reached the metropolis of
thought. Indeed the very sects of philosophy, which sneered at the revelation of heavenly truth on its introduction into Athens, had their counterparts in Judæa, and especially at Jerusalem. We have the testimony of a Pharisee, that the “sect of the Pharisees bore a strong affinity to that called Stoic among the Greeks[2].” We are led to perceive, also, from the accounts we have of the free-living Sadducees, who claimed absolute freedom for the human will, that the Epicureans were represented in some degree by them. They were sceptics as to the providence of GOD, “believed in neither angel, nor spirit[3];” “they took away all fate, and would not allow it to be anything at all, nor to have any power over human affairs, but put all things entirely into the power of our own free will[4].” Both Pharisees and Sadducees, though disagreeing in other respects, yet were united in their efforts against the spread of the truth. From the earliest preaching of the doctrines of the Gospel, the same spirit of self-seeking and pride of human nature which animated the Epicureans and Stoics, showed themselves adverse to the humbling views which Jesus set forth. And we cannot forget that St Paul, immediately after his conversion, having been in great danger at Damascus and at Jerusalem from the rage of the Jews because of his becoming a Christian, dwelt some time in quiet at Tarsus, his native city. We have no record of how he spent his time there on that occasion. But doubtless, as at other places so there, he would proclaim the conviction which he so strongly felt of the excellence and truth of the Gospel. If so, it is probable that he met with the same kind of coldness and contempt for his message from the philosophers of Tarsus, as afterwards from those of Athens. The native city of St Paul was noted for the eagerness for learning displayed by its people. Strabo tells us “the men of this place are so zealous in the study of philosophy and all other subjects of education that they surpass the inhabitants of Athens and Alexandria, and every place that one could mention where schools of philosophy are found. The difference is in this respect. Here they are all natives who are eager after learning, and strangers do not choose a residence here. They themselves (the Tarsians) do not stay, but finish their course of training abroad. Few return home again.
Whereas, in the other cities which I have named, except Alexandria, there is a contrary practice; for many come to them and live willingly there: but you will see few of those born there either going to other places for the sake of philosophy, or caring to study it at home. The Alexandrians combine both descriptions, for they receive many strangers, and send abroad not a few of their own people.” We learn also from other sources that from Cilicia, and especially from Tarsus, a great many of the most celebrated Stoics came, and it appears therefore extremely probable that St Paul would meet with such in his visit to that city. If he met with them, they would hear the truth from his lips. His heart would prompt him, as it did afterwards at Athens, to proclaim glad tidings of salvation to all; and to those who professed to seek the knowledge of deeper mysteries than the ignorant mass cared to inquire about, he would declare “the mystery which” had “been hid for ages,” but was now “revealed to the sons of men by Jesus Christ.”
Of these meetings between the Apostle and the philosophers of his native city, if they took place, we have no record. The first account we have of the contact of the religion of Christ and the wisdom of men is given us by the writer of the Acts of the Apostles, in the seventeenth chapter of the history. We are told that, while St Paul waited at Athens for Silas and Timotheus, “his spirit was stirred within him when he saw the city wholly given to idolatry. Therefore disputed he in the synagogue with the Jews and with the devout persons; and in the market (τῇ ἀγορᾷ) daily with them that met him. Then certain of the Epicureans and of the Stoics encountered him. And some said, ‘What will this babbler say?’ Other some, ‘He seemeth to be a setter forth of strange gods;’ because he preached unto them Jesus and the resurrection.” It seems necessary in passing, to notice here the two sects of philosophers who encountered the Apostle. They were then the two most prominent in Greece; one might say they divided between them the adherence of all thoughtful minds. The Epicureans were advocates of the doctrine of the absolute freedom of the human will to choose what is agreeable to it. They denied the providence of GOD, or that he
concerns himself at all about human affairs. According to them, the universe was neither formed, nor created, by an intelligent being; but was merely the fortuitous concourse of infinite atoms. They taught that happiness consisted in the pursuit of pleasure, and, as all wish to be happy, all should seek after the greatest amount of pleasure to be obtained. Although Epicurus was fiercely assailed by the disciples of the opposite school, and “the garden,” where he taught, was held to be a hot-bed of sensuality, there was probably much exaggeration in the reports that were spread. Epicurus meant by his teaching, perhaps, not that men should seek after every momentary gratification, but for the greatest enjoyment of a whole life. Yet as this doctrine left man to be his own judge, it is not to be wondered at if the moderation of the founder of the sect was little imitated by his disciples. Men took pleasures as they came, not knowing what pleasure might be in the future, and not caring for the morrow; so vice and profligacy were the result, instead of virtue and contentment and true enjoyment.
The Stoics, on the other hand, were absolute fatalists, and taught that virtue consists in following the decrees of nature and acting according to the dictates which ruled all things. We shall not now enter fully into their doctrines, as these will require careful attention and full development in accordance with the purpose of this essay. We shall see, bye and bye, that the principles of their school were of such a nature as to produce in some respects the strongest, in others, the weakest of men. Stoicism and Epicureanism both left man practically to himself. They agreed in looking at self-cultivation and self-interest as the chief good. The controversy between the two systems was what it has continued to be since among ethical philosophers, a controversy as to the sources of moral rules. Epicurus was an advocate of what has been called “the selfish system of morals.” Zeno and the Stoics advocated the contrary system. It seems, however, that though the conflict between them has been so long, and often so fierce, the two systems are not incompatible one with the other. Indeed in the word of GOD both motives are set before us to urge us to right conduct, the loveliness
of virtue in itself, and the combined happiness and blessedness to be gained from a certain course of life. This view has been put in a few forcible words by an eminent writer of the present day, who says, “Some moralists employ themselves mainly in deducing the rules of action from considering the tendencies of actions to produce pleasure or pain, as Paley and Bentham. Others take pains to show that man has a faculty by which he apprehends a higher Rule of action than the mere tendency to produce pleasure, as Butler. But though these two sources of morality are thus separate, they are not really independent; and it is, as I conceive, important to present them in a mode which shows their connexion and relation[5].” One of these springs of action does not necessarily counteract the other. Doubtless, there is in man an innate appreciation of the beauty of virtue. Though the temple of the human soul has been laid in ruins by the touch of sin, yet does it still retain marks of its primeval glory. It was not created for anything but the abode of purity. Hence we perceive naturally the excellence of virtue. When I say naturally, I mean as man is at all times enabled to see by GOD’s help. We must remember that, by virtue of the Redeemer’s merits, all men are blessed with a certain degree of enlightenment. Speaking of the Eternal Logos, St John says[6] , “That was the true light which lighteth every man that cometh into the world.” Only because men in their obstinacy close their eyes, the light which is given them often becomes darkness. So St Paul, speaking of those without Revelation, says[7] , “They are a law to themselves, which show the work of the law written in their hearts, their conscience also bearing witness, and their thoughts between themselves accusing, or else excusing one another.” In order to this they must appreciate the beauty and excellence of virtue. So Justin Martyr declares[8] , “Every race of men participated in the Logos.” When we speak of man by nature then, we mean man with the aid of this light given to him by Christ. And we must perceive great force in the statement of Berkeley, that “There is an idea of beauty natural to the mind of man. This all men desire. This they are pleased and delighted with for its own sake, purely from an instinct of nature. A man needs no argument to make him discern and approve what is beautiful; it strikes at first sight and
attracts without a reason. And as this beauty is found in the shape and form of corporeal things, so also is there analogous to it a beauty of another kind, an order, a symmetry and comeliness in the moral world. And as the eye perceives the one, so the mind doth by a certain interior sense perceive the other: which sense, talent, or faculty, is even quickest and purest in the noblest minds. Thus, as by sight I discern the beauty of a plant, or an animal, even so the mind approves moral excellence, the beauty and decorum of justice and temperance. And as we readily pronounce a dress becoming, or an attitude graceful, we can, with the same free, untutored judgment, at once declare whether this or that conduct or action, be comely or beautiful.”
We cannot deny, on the other hand, that men act from a feeling of self-interest. To obtain pleasure or escape pain is motive enough to make men pursue a certain course instinctively, without weighing accurately, or even caring at all for the motives which prompt them. When men see that virtue brings in its train present blessing and eternal hopes, shall we deny that this is a strong reason why they should pursue it? Doubtless such a reason weighs with many and draws them to a right course, without a question arising in their minds as to the motives by which they are actuated.
Then the enquiry naturally occurs, since virtue commends itself to us as both lovely and beneficial, shall we reject the loveliness as a motive, because our self-interest moves us also? On the other hand, shall we reject hope of benefit, because the innate loveliness of the object commends itself to us? May we not be moved by the double influence? Certainly the word of GOD seems to sanction such a double motive to religion and virtue.
Yet here we are brought to the humbling conviction of the weakness of man without Christianity. Men had this combined motive for ages. What was the result on the heart and the life? What effect had even the teaching of the wisest? The masses were still sunk in superstition and sin. The farthest advanced were only looking at a height which they could not hope to reach. The most acute thinkers
were often in doubt. We see the extremes meeting. Superstition, in its most debased and enthralling forms, stands boldly in the front of the most exalted teachings of philosophy. What could mere philosophy do? She could perhaps find employment for the minds of a few of the most gifted. But what had she to give as food for the hungry souls of the multitude? The starving spirits asked for bread, and she gave them the stone of an unattainable moral excellence. They asked for fish, and she gave them the stinging serpent of pleasure and self-enjoyment[9] . In Athens the human mind reached its zenith, yet could not rise to happiness or peace. How unspeakably was the world blessed, therefore, when the cross of Christ was raised as the means whereby man might reach heaven. Never before was such life-giving truth offered to the Athenians, as the good news which was now brought by the Apostle who “preached unto them Jesus and the resurrection.” This was the subject of St Paul’s daily discourses in the Agora. Instead of blind theories and abstract ideas, he placed before them a person;—a divine person, who had left an example of how to act and how to suffer;—a Saviour, who had died to open the way to happiness for others; who had risen again to show that his sacrifice was complete and sufficient. The Epicureans wondered and yet were unbelieving, while they heard of one who was Lord of all, that he thought of men’s lives and cared for their needs. It was strange and unwelcome to them, who held that happiness was enjoyment and freedom from pain, to hear one proclaimed as worthy of their admiration and trust, who was “a man of sorrows and acquainted with grief,” who even gloried in His sufferings and death; and who had bid those that would be his disciples, take up their cross and follow him, by resisting and subduing self and pride. The Stoics heard the tidings (for “the porch” was in the Agora), and they, stern and self-reliant, were surprised, yet not pleased, to hear of one who led a life of selfsacrifice for others’ sake; who was meek and lowly; and who had sent his messenger to declare to those very self-satisfied philosophers, that the only way to real virtue for them, as for the rest of mankind, was by trusting in the merits of another, and by a change of heart through His divine power. “The resurrection” was
also equally strange and equally contrary to the ideas of the one sect, who regarded death as annihilation; and of the other, who looked on it as the absorption of men into universal nature of which they were component parts. To some the preacher seemed a mere babbler, a picker up of trifles, and therefore contemptible. To others, he was a setter forth of strange gods. But because they are all desirous of hearing anything newer than what they already are acquainted with, they bring the Apostle to Mars’ Hill, and desire him more fully to expound to them the strange things which he had brought to their ears. The locality chosen was more suitable than the busy market-place. The associations of the place were solemn and deeply interesting. The subject then brought before the people in the Areopagus was worthy of those associations,—far more important and of more momentous consequences than had ever been deliberated on there in times that were gone by. The place, the speaker, the hearers, the subject, all appeal to our sympathies and interest us most deeply. The discourse of the Apostle was admirably suited to the place and the hearers. He appealed to their deepest convictions, while at the same time the message which he brought thwarted many of their cherished ideas, St Luke has given us a report of this speech, so eloquent, so worthy of the admiration of all time, so well calculated to show how far Christianity coincided with Gentile, and especially Stoic, philosophy, and how it excelled. This was what St Paul said, “Ye men of Athens, I perceive that in all respects you are extremely devout[10] . For as I passed through your city and beheld the objects of your worship, I found among them an altar on which was this inscription, ‘To the unknown GOD.’ Him, therefore, whom you worship though you know him not, I set before you. GOD, who made the world and all things therein, being Lord of heaven and earth, dwelleth not in temples made with hands; neither is he served by men’s hands as being in need of any, seeing he giveth to all life and breath and all things. And hath made of one blood every nation of men to dwell on the face of the whole earth; having ordained (to all) their appointed seasons and the bounds of their habitations, that they might seek GOD, if haply they would feel after him and find him, though he be not far from every one of us.
For in Him we live and move and have our being; as certain also of your own poets have said, ‘For we are also his offspring.’ We, therefore, being the offspring of GOD, ought not to think the Godhead to be like gold, or silver, or stone graven by art or man’s device. Howbeit those (past) times of ignorance GOD hath overlooked; but now he commandeth all men everywhere to repent. Because he hath appointed a day in which he will judge the world in righteousness by that man whom he hath ordained, whereof he hath given assurance unto all, in that he raised him from the dead[11] . ”
There is much, in connexion with the purpose of our essay, that requires careful consideration in this discourse. If we want to understand the influence which Christianity and Stoicism exercised, one on the other, and on the souls of men, we must notice them side by side at this their first public encounter. When we have observed how far the Christian teacher agreed with the Stoic philosopher, and in what he differed and excelled, we shall have a fair starting-place for investigating the mutual consequences which resulted. In order properly to grasp our subject, it will be necessary to place before our minds what Stoicism was as it came from its founder, and how far it was modified at this time. I purpose therefore in another chapter to give a sketch of the life and teaching of Zeno of Cittium, and of the modifications of his system by Cleanthes and Chrysippus. The way will then be clear to compare the Apostle’s teaching with theirs, and to appreciate the peculiar excellence of the good news preached by St Paul on Mars’ Hill.
CHAPTER I. THE STOIC SCHOOL OF PHILOSOPHY.
Diog. Laert. vit.Phil.Lib. VII. 6, 7.
Zeno was born at Cittium, a small city in the island of Cyprus, founded by Phœnicians, but inhabited by Greeks. His father, who was a merchant, finding his son attracted to the study of philosophy, allowed him to follow his bent. From Athens, whither he had often occasion to go for commercial purposes, the father frequently brought home for his son many writings of the Socratic school of philosophers. Zeno read these with great eagerness and was enchanted with the views which they unfolded. When he was about thirty years of age he made a voyage, probably of business and pleasure combined, to the city which was at once the home of the philosophers who had so delighted him by their works, and a great centre of trade. The story goes that he was shipwrecked on the coast and lost a valuable cargo of Phœnician purple which he had brought with him. Others say he did not lose his property when he first came to Athens, but was, on the contrary, abounding with wealth. The former version of the story would account to those who questioned the disinterestedness of his conduct, for his having attached himself to a sect that professed to despise riches. On his
first arrival, having read, at a bookseller’s stall, a few pages of Xenophon’s Memorabilia, he formed a high opinion of the author of a work which so pleased him, and asked the bookseller where such men were to be found. Crates, the Cynic, happened to pass at the time, and the bookseller replied, “Follow that man.” Zeno acted on the advice, placed himself under the Cynic philosopher’s instruction, and enrolled himself among his disciples; but he did not long remain so. He became disgusted with the manner of the sect, which he found too gross and unrefined for his taste; though at the same time he highly admired their general principles and spirit. Besides, the activity of his mind forbad him to abstain from all scientific enquiry, and indifference to science was a marked characteristic of the Cynics. He became a disciple of the Megaric doctrine, and thought to learn the nature and causes of things. He attended the school of Stilpo, the chief teacher of practical philosophy among the Megaric succession, who declared that the sovereign good was impassivity (ἀπάθεια). Zeno was pleased with the teaching of this school. To Crates, his former master, who, being angry at his desertion, endeavoured to draw him by force from his new teacher, he exclaimed, “You may seize my body, but Stilpo has laid hold of my soul.” Becoming tired of this teacher after some years, he turned to Diodorus Cronus, who taught him Dialectics, and to Philo; both of these being contemporary Megarics with Stilpo. He also studied under Xenocrates and Polemo, who were expositors of Platonic philosophy; and from the Academics he learnt much, for we can perceive a germ of Stoicism in the Platonic philosophy. But he found much in their teaching also contradictory to his own theories. When he came to Polemo, that teacher, with an insight into his disposition, said to him, “I am no stranger to your Phœnician arts, Zeno; I see that you intend slily to creep into my garden and steal my fruit.”
Being now, after twenty years’ study, well informed as to what others could teach him, as he was either dissatisfied with all, or moved by ambition, he determined to found a new school. The place chosen for his teaching was a public portico, adorned with the paintings of Polygnotus and other masters. Hence it was called
ποικίλη στοά (the painted porch); more commonly, as it was the most famous in Athens, it was simply called στοά. From this arose the name of the Stoics. As a teacher, Zeno was celebrated for subtle reasoning and for enjoining strict morality of conduct. As a man, his conduct corresponded with his teaching. His doctrines and manner of life teach us that he gathered much from various systems. He gathered from Pythagoras and Plato and Aristotle by the teaching of Xenocrates and Polemo, from the Megaric school by the teaching of Stilpo, Diodorus Cronus, and Philo. Cicero, in his Academic Questions, tells us that the doctrines of the old Academy were changed by Zeno only in name. He adhered too to the Cynic doctrines, slightly tinged by subsequent training perhaps, especially by Stilpo’s teaching that the perfection of wisdom consisted in impassivity. But he did not share in Cynic grossness, insolence, and affectation. He obtained the applause and love of numerous disciples, among whom was Antigonus Gonatas, king of Macedon, Cleanthes, and perhaps Chrysippus; though the last may have been the disciple of Cleanthes only. To these two we must refer again. The Athenians are said so to have respected Zeno that they trusted to his keeping the keys of the citadel. This may be questioned; but there is no reason to doubt that they honoured him with a golden crown, that they gave him a public burial in the Ceramicus when he died, and erected to his memory a statue of brass. By Cyprians and Sidonians, to whom he was allied by descent, he was also held in reverence. He is described as having been a thin withered man, of dark complexion, and with his neck bent. He preserved his health, though naturally feeble, by abstemious living. His diet, even when honoured by noble guests, as he often was, consisted only of figs, bread, and honey. His brow, furrowed with thought, and his look stern and hard, showed his Cynic education; but, in contrast to his first teachers, he was neat and careful in his dress and person. Frugal in his expenses, he was without avarice. He conversed freely, with poor as with rich. He had only one servant; Seneca says, none at all.
Though he was proverbially sober and chaste, he was assailed by various enemies in his lifetime. Arcesilaus and Carneades of the New Academy, and in his latter years, Epicurus, who disliked the philosophy and pride of Zeno, were his powerful antagonists. Little credit is due, however, to the abuse which passed on both sides. He lived to old age. When he died is matter of doubt. He is said to have been alive in the 130th Olympiad. In his 98th year, as he was leaving his school, he stumbled and fell, and broke one of his fingers in the fall. Pain so affected him that he exclaimed, striking the earth, Ἔρχομαι, τί μ’ ἀΰεις; “I come, why dost thou call me?” He went home and strangled himself, about the year B.C. 260.
In trying, at the present day, to estimate the teaching of Zeno, it is necessary for us to consider the circumstances of the age in which he lived and taught, and to remember also that it is difficult to find out how much of the later Stoic philosophy really came from him. His writings were numerous[12] , but they are lost. His teaching seems to have been modified, and sometimes even changed altogether, by Chrysippus. Indeed the later professed disciples of the school seldom went back to the works of the first Stoic. Let us, as well as we can, however, lay hold of the circumstances in which he was placed as a philosopher, and the alterations he introduced.
He began his course at a time of decay in Greece, and when the mind of men was become sceptical as to all things in heaven and earth. Philosophers had so quarrelled with one another’s dogmas, and proved one another wrong so often, that men began to doubt if there were any foundation on which to rest. GOD was educating the world for the reception of the great truths of revelation. He did this by showing men how helpless they were in divine things by their own unaided nature, how contradictory their speculations, how far short of the truth the highest attainments of human intellects, how uncertain it was which was truth of the various theories proposed, so that men doubted about all truth. Zeno under these circumstances did a great work in educating the world still further, and preparing it for the great Truth. He was to the people of his day in some degree what Socrates was to the men of his age. He brought back the
influence of reason and common sense, rescuing them from the Pyrrhonists, as Socrates did from the Sophists. Like the son of Sophroniscus, also, the founder of the Stoics turned men from mere speculation to action. Socrates taught men to look within themselves, and created a desire to live as became them. He was an ethical reformer, and so turned men away from the guesses of a socalled philosophy, and from the scepticism consequent on failure. Victor Cousin has well said, “La philosophie Grecque avait été d’abord une philosophie de la nature; arrivée à sa maturité elle change de caractère et de direction et elle devient une philosophie morale, sociale, humaine. C’est Socrate qui ouvre cette nouvelle ère et qui en représente le caractère en sa personne.” Plato followed him in this. His fundamental problem was how man might live like GOD. Aristotle turned men’s thoughts back again to physics and metaphysics; and then came a period of systematic scepticism, by which the vanity of the guesses of philosophy was exposed and derided. Zeno and Epicurus, so different in other respects, yet both brought men back to a better mind by teaching them that philosophy was the art of living aright rather than merely thinking aright; the former, because living aright was in accordance with nature,—the latter, because it made men happy, and happiness was the great end to be sought by all[13] . Zeno and Epicurus both had thus their share in training men to receive the great Truth of GOD; for they both proved that man of himself can do nothing but conceive of perfections that human nature alone cannot reach: while the believer in divine love and mercy learns to say with St Paul, “I can do all things through Christ which strengtheneth me.”
I have before intimated that Zeno has been said to have borrowed much of his philosophy from former masters, giving the truths new names. The various schools which at different times prevailed in Greece, amidst much contradiction, yet contained some germs of truth, and therefore so far had some agreement one with the other. But the truth was cumbered with so much rubbish that it was overpowered and hidden. These various schools of thought endeavoured to grasp the same object from different standpoints,
and opposed all others. The Ionics looked around them, and from external objects tried to make one natural law for all subjects and combinations. They wished to reduce all things to accord with a settled physical law. They aimed at discovering a principle, a substance, of which every thing that exists is a combination. The Mathematical school reasoned from within themselves. As Thales looked on the external universe and thence turned within, so Pythagoras reasoned on external objects from within himself, from mental harmonies to physical. Then came the Eleatics, contradicting even reason itself. Zeno, the Eleatic, argued against motion and sensible unity. Parmenides declared that “thought and being are the same;” that “thought and that for which thought exists are one.” Indeed the great maxim of the school was τὰ πάντα ἕν. They taught that the sensible universe was purely phenomenal and accidental: that it was apparent, not real. The Megaric school, which Zeno Citticus attended soon after he came to Athens, taught somewhat similar doctrines, but in a dialectic form. Their tenets, Pliny tells us, produced in daily life, “rigorem quendam torvitatemque naturæ duram et inflexibilem.” I have already said that Stilpo placed the height of wisdom in impassivity. These doctrines, so various, so contradictory to reason oftentimes, made many men professedly sceptics. Pyrrho and his followers, having proved the impossibility of a science superhuman in its height being reached by unaided man, supposed they had destroyed all knowledge and certainty whatever. The state of Athens then was particularly unsatisfactory. Old creeds were tottering. The spiritual life of Greece was decaying, as was its national. Men wanted some refuge from the distractions of their minds. Their spiritual nature, their soul, began to exert its power, to speak in tones that would be heard. The mind had been trying to still its craving with the noble but unsatisfying theories of Plato, or the subtleties of Aristotle. But the soul, the inner life, had been uncared for. Now it claimed its share of attention and new schools arose to satisfy, as far as they could, the newly felt longings. At such a time, Zeno founded his system. When Greece was tottering and falling into ruin, out of materials which I have shown to
be so contradictory, he built up a structure which outlasted Greece, and was removed (altered a little, but in the main the same), to the new centre of the civilization and power of the world. His system lasted from his day to the time of Marcus Aurelius. It was embraced by the Romans with eagerness, as being congenial with their nature, before they became corrupted by their unrivalled prosperity. When at length it had done its destined work in the world, it yielded to a mightier and holier influence; leaving, however, its impress on the souls of men, even as, before its own decay, it received some of the rays of divine light which came from heaven with the Son of GOD, though it did not acknowledge the boon. It would be beside the purpose of the present essay to enter into all the specialities of the Zenonic doctrines; or to enquire at large, how far Zeno differed from Plato, or how nearly he agreed with Aristotle, in defining the manner of perception by the mind. We need not discuss
which Sextus Empiricus alleges to have been held by Zeno and his successors as the one means of judging true from false; respecting which even Cleanthes and Chrysippus differed[14] . An outline of the main features of the system will be sufficient. As I have before said, the first Stoic fixed his thoughts chiefly on moral conduct. His philosophy was eminently practical. It referred to the daily life. In order to stem the torrent of scepticism and sensuality, he taught men the value, the absolute necessity, of virtue. They were to apply his dogmas to their daily experience. They were not to speculate, but to act; not to doubt, but to dare. He taught them also that what Socrates had said was true, that the knowledge and practice of good was virtue and wisdom, that vice was therefore error in its worst form. In order to induce men to conform to this knowledge in their way of life, he unfolded to them how they were related to the universe.
Every rational theory respecting the universe admits of an Absolute Being of some sort. The difference begins, when the relation of the universe with the Absolute Infinite is explained and unfolded. One theory would distinguish the Infinite from the universe, but make him act from a kind of necessity. A second theory would allow him to
act with perfect freedom of will. A third theory would make the universe itself to be the Absolute Infinite; and a fourth would insist that the Infinite Being is matter, of which the universe is only a modification. Zeno seems to have taught the third of these theories; though in after writers we see traces of the first. According to him, there existed from all eternity a chaos, a confused mass, ὕλη πρώτη, which contained the germ of all future things. Gradually, order supervened and creation assumed forms of various kinds, resulting in the universe as it is now. The universe is one whole, which comprises all things; yet contains a passive principle, matter, τὸ πάσχον, and an active principle, τὸ ποιοῦν, which is reason, or GOD. The soul of man is part of this divine nature, and will be reabsorbed into it and lose its individual existence. The Deity in action, if we may so speak, is a certain active æther, or fire, possessed of intelligence. This first gave form to the original chaos, and, being an essential part of the universe, sustains it in order. The overruling power, which seems sometimes in idea to have been separated from the Absolute Being, was εἱμαρμένη, fate, or absolute necessity. To this the universe is subject, both in its material and divine nature. Men return to life totally oblivious of the past, and by the decrees of fate are possessed of a renovated existence, but still in imperfection and subject to sorrow as before. The tenets of the later Stoics may have been tinged with Christian truth on this point, as on others; but they had none of the noble hope of the Christian ἀνάστασις. Indeed, respecting their dogma, Seneca said, “This renewal of life many would reject, were it not that their restored existence is accompanied with utter forgetfulness of the past.”
On their physical principles, the moral principles of the Stoics depended. Conceiving themselves to be part of universal nature, that their souls were part of the divinity which actuated matter, they held themselves in some measure to be gods. In human life therefore they must follow nature, of which they formed part. But then this nature was not this or that man’s natural leaning, but the laws of fate and the universal course of things, from which resulted the unsuitableness of certain courses, and the excellence of others.
To be conformed to the laws of the universe, of which they formed an essential part, was the ultimate end of life. Every man conforming to these laws is happy, notwithstanding external evils. Every man’s happiness, then, is in his own power; he is a god to himself in some measure. To live according to his true nature is to live godly; godly life is virtue. This is itself true happiness, independently of pleasure in the common acceptation of the term; because the supreme good is to follow what the law of nature points out as being good. Virtue having its seat in the soul, outward circumstances cannot reach the good man. As he can distinguish good from evil, he is wise; and this suffices for him. External things, forasmuch as they cannot reach him, can neither increase his happiness or cause him misery. Even torture cannot move him, because it cannot reach his inner, true nature. There is no distinction between different virtues as to degree, because they owe their existence to their accordance with nature. All vices are equal in degree, because they run counter to the one law of virtue. These seem to have been the principal features of Zeno’s teaching. His morality partook of the evil of its origin. It was essentially artificial. Little regard was paid to real nature in the pursuit of what was called natural law: there was little common sense, oftentimes, in the ideas set forth under pretence of philosophy.
We cannot lose sight of the fact, however, that Stoicism, as it came in contact with Christianity, was a system that owed much to Cleanthes, and still more to Chrysippus. Indeed, regarding the latter, we are told[15] that it was said,
στοά. The former was the earnest Stoic; the latter the philosophical and dialectic setter forth of the system. Under his hands, in his various and most copious writings, the system was probably not merely developed, but materially modified in some respects, and systematized. Cleanthes has left few records of his opinions behind him: but his Hymn to Jupiter will ever stand as a marvellous memorial of his worth and intellect. It bears strong evidence to the Monotheism of the system which he espoused. It has been a matter of controversy whether the Stoics were monotheists, or polytheists.
The hymn to which I have just referred, and to which I shall refer again in another chapter, bears strong evidence, on the face of it, to the belief in one absolute supreme being. Yet other passages in many Stoic writers would seem to convey a different idea. But it will be well for us not to forget that the system was founded on a notion of the divine nature totally different from our conception of a divine being. The monotheism of some of the Stoic writers may have been the result of previous education. The fact may be that one, or two, rose to higher conceptions of the Eternal, than others were privileged with. This may have resulted from their having come of a different stock[16] , and having had a different early bent a deeper intuition, as it were, by nature—a purer speculation as to the unseen —than those with which others of the sect were endowed. Those who were of a stock which deified almost all things, might carry their phantasies into the system itself. And indeed it is possible that the same persons, under different influences, may have had rather varied views of the hidden world. The system was one of ethics and not of speculative philosophy. And if Christianity, with all its divine testimonials and influences, does not bring all minds into one accord about all things—even those who are of one school of theology varying in opinion on certain points—how very probable it is that men of the same school of philosophy, with merely the authority of one man, neither possessing, nor claiming a divine mission as founder, should have somewhat different shades of thought. How possible it is that they should, while viewing things from different points of view, be almost inconsistent with themselves. This kind of inconsistency was urged again and again against Chrysippus, the most voluminous writer and chief dialectician of the Stoics. Cleanthes has left few memorials behind him, but his earnest pursuit of knowledge, his struggles to obtain the time and means of study, show the pre-eminent zeal of the man. This zeal was the great motive of his life. Possessed of a strong frame, of great powers of endurance, we are told that he earned by night what enabled him to live in study by day. His determination was so strong that he even made use of potsherds and bones as his note-tablets. Such a man would impress his earnestness on the system he espoused. His
