Ebook: Drug Benefits and Risks

The second edition of this textbook of clinical pharmacology is welcome in a world of evidence-based pharmacotherapy and guidelines. The key concept of the textbook continues to be the emphasis on drug benefit to risk ratio. The book is divided into three sections. Section I contains general principles, such as medicines and society, pharmacoepidemiology and drug evaluation, pharmacoeconomics, drug regulation, sources of drug information, and concepts essential to drug utilization in different populations. Section II incorporates an overview of drug classes discussed under a mechanistic point of view, providing the best possible evidence-based information on pharmacological issues. Section III is an evidence-based approach to the treatment of specific health problems. Benefits and risks of biologicals are also discussed. Finally, critical information is given on drugs that have been withdrawn in western countries, but are freely available in low income countries. Included in this section are chapters on symptomatic treatment and emergency medicine. The textbook provides a practical and useful expert guidance on patient treatment, and by offering a mechanistic description of most important drugs, it presents a basis to individualise dosages.

The textbook will be an excellent tool for optimal drug utilisation, not only by clinical pharmacologists but also by medical practitioners. This is of great importance because evidence-based pharmacotherapy and the profusion of guidelines have contributed to weaken the therapy individualisation approach. As a result, even if the benefits of drugs may have increased, the ratio benefit/risk may be decreasing. For instance, adverse drug events still account for 2.5% of estimated emergency department visits for all unintentional injuries, and for 2.1, 6.7 and 30% of hospitalisations in the paediatric, adult and elderly populations, respectively (BMJ 2004;329:15-9; JAMA 2006;296:1858-66). The incidence of drug-related deaths in university hospitals is around 0.5% (Eur J Clin Pharmacol 2002;58:479-82). It is distressing that 33% of adverse drug effects are still associated to warfarin, insulin and digoxin (Ann Int Med 2007;147:755-65). Approximately half the adverse effects reported are preventable. The cost of adverse drug effects to society is colossal, e.g. close to one billion $/year for a population of 60 000 000 (BMJ 2004;329:15-9).

Evidence-based pharmacotherapy provides a succinct appreciation of the benefits of a drug, but rarely takes into account the patient's quality of life. For instance, intensive statin therapy is recommended because it reduces the incidence of cardiovascular death (odds ratio 0.86), myocardial infarction (odds ratio 0.84), and stroke (odds ratio 0.82); however, the increased risks for any adverse event (odds ratio 1.44), for abnormalities on liver function testing (odds ratio 4.48), for elevations in CK (odds ratio 9.97) and for adverse events requiring discontinuation of therapy (odds ratio 1.28) are less often taken into account by the prescriber. This example emphasises that individualisation is of the utmost importance to keep an acceptable benefit/risk ratio (Clin Ther 2007;29:253-60). The benefits of evidence-based pharmacotherapy may be obtained whenever concordance/compliance of the patient is adequate. However, concordance rate is slightly higher than 30% for chronic conditions, such as hypertension (Curr Hypertens Rep 2007;9:184-9), indicating that the patient has to be educated about the use of drugs, and therapy has to be individualised.

Evidence-based pharmacotherapy and guidelines alone cannot solve the problems highlighted above, since individualisation, the risk of medication, as well as quality of life are insufficiently taken into account. Rational drug individualisation is required and the textbook will be a practical and easy tool to achieve this goal.

Montréal, December 2007

Patrick du Souich, MD, PhD, Chairman, Division of Clinical Pharmacology, International Union of Basic and Clinical Pharmacology

The subject of both sections of this chapter is complex. In the first place because after marketing the spectators in the therapeutic scene have a tendency to see different plays. Healthy people see something different from patients and the perspectives of governments, health insurers and manufacturers are all different. Furthermore we know that with respect to drug use important differences between countries exist and that intercultural and interethnic variations can have a decisive influence on the final outcome of drug use. It might therefore be good to first cite some figures to illustrate that in the modern world pharmaceuticals cannot and should not be considered as trivialities.

In most Western countries 70% to over 90% of visits to a general practitioner result in the writing of a prescription. Also in the Western world the prescription of 9 drugs on medical wards is common procedure and 20% of patients are using more than 4 agents in the period before they are admitted.

And finally, in the Western world total drug costs range between 6 and 10% of the health budget and in developing countries this percentage can even be much higher.

Drugs and vaccines can affect the outcome of disease in individual subjects and in populations. An example of this is shown in Fig. 1 relating to notifications of poliomyelitis in the UK. Poliomyelitis changed in the early 20th Century from a disease that was endemic in young children (infantile paralysis) to a disease that became epidemic in young adults (paralytic poliomyelitis). This change was associated with improvements in hygiene and sanitation which tended to limit the faecal–oral spread of the virus in infants and young children. As a result fewer children grew up with naturally acquired immunity and a pool of susceptible young adults accumulated in the population. Figure 1 shows the dramatic increase in notifications of poliomyelitis in the early years following World War II and the dramatic effect of the Salk killed virus vaccine which was given by injection and the Sabin live attenuated vaccine which was given orally. Many of the small number of cases reported after the vaccines had become available and were widely used had, in fact, been acquired overseas. Figure 1 shows the dramatic effect of the anti-poliomylitis vaccines on the incidence of the illness in the UK community. Figure 2 shows deaths due to all forms of tuberculosis in the UK from 1840 until near the end of the 20th Century. Horton Hinshaw and William Feldman's paper on “Streptomycin in treatment of clinical tuberculosis: A preliminary report” appeared in the Proceedings of the Mayo Clinic in 1945. For his work on antibiotics and the discovery of streptomycin Selman Waksman received the Nobel Prize in 1952. Streptomycin and the later anti-tuberculosis drugs made a very dramatic differerence to the prognosis of individual tuberculous patients in the early post-War years following their introduction into clinical medicine. However, the dramatic decline in the number of deaths due to tuberculosis in the years from 1940 to the end of World War II – as shown in Fig. 2 – was due to continuing improvements in hygiene, housing, sanitation, diet and the rising standards of living. Thus Fig. 2 very nicely demonstrates the dramatic effect of a very serious disease such as tuberculosis in response to improvements in the social environment of the community. The specific anti-tuberculosis drugs, once they became available, made a dramatic difference to the outcome of infection in individual patients and thus to the pool of infection affecting the UK community.

Despite all the good that prescription drugs do, evidence continues to mount that adverse drug events are a common, costly, and often preventable cause of illness, disability, and even death. The challenge is to appreciate this downside of drug therapy, to define it, and to understand how the problems associated with it can be prevented. More and more data are becoming available concerning the frequency, clinical consequences, and cost of adverse drug events. At a time in which measures of quality and expenditures in the healthcare system are being scrutinized with great care, these are particularly important issues. Perhaps most importantly, adverse drug events are preventable in many instances. For healthcare resources to be used as efficiently as possible, preventing drug induced illness is one of the most promising areas for future efforts. This does not require rationing or withholding of care; it just requires better clinical decision making. In order to accomplish this, it is necessary to understand the causes of drug induced illness.

Most drug-induced illness comes about through one of four mechanisms: (a) poor prescribing decisions by physicians, despite the availability of clear evidence; (b) errors in dispensing or administration of a drug; (c) poor compliance by the patient resulting in under use, overuse, misuse, or complete cessation of therapy; and (d) the occurrence of previously unanticipated adverse drug reactions, whose existence was not clearly predicted by pre-marketing clinical trials. For each of these causes one must consider the origin, its consequences, and, perhaps most important, what can be done for each cause to prevent it.

I. History; II. Development of pharmacology; III. Development of clinical pharmacology; IV. The scientific basis of therapeutics; V. Hierarchy of kinds of information; VI.‘Evidence-based medicine’; VII. Conclusion: Therapeutics as a science; Bibliography; Appendix: Newcomers' Guide to the Cochrane Collaboration

Modern drugs are generally evaluated according to three major criteria: efficacy, safety, and cost-effectiveness. Studies to address these criteria begin once a compound is discovered. At any stage of drug development, the process can be terminated if the compound fails to meet these criteria. Even if a drug survives the pre-market testing and is introduced to the market, it can be withdrawn if adverse effects later prove to be unacceptable. Drug evaluation includes 4 phases that – in stepwise manner of number of patients, characteristics of patients and trial design, and complexity of patients and trial design – aim to provide the information for eventual product. With the introduction of more and more modern drugs and the dramatic increase in drug consumption and health care costs, more demand is being placed on the tools and techniques needed for generating data for decision makers at the various stages of drug evaluation. Pharmacoepidemiology, which specifically addresses this need, is an important discipline that has gained recognition and prominence in recent decades.

Pharmacoepidemiology is traditionally defined as the discipline concerned with the study of the use and effects of drugs in large numbers of people. It applies epidemiologic methods, knowledge, and reasoning to the subject of clinical pharmacology and therefore can be considered a subdiscipline of both clinical pharmacology and epidemiology. The epidemiologic methods used by this discipline range from single case reports to the observational or non-experimental population-based approach with several years of follow-up, to large-scale randomized clinical trials. Historically, the field of pharmacoepidemiology began with a focus on safety evaluation or the study of adverse drug reactions, particularly Type B reactions, which tend to be uncommon, dose-unrelated, unpredictable, and potentially more serious than Type A, i.e., dose-related and pharmacologic, reactions. It has evolved to include the study of the effectiveness of new drugs and the use of drugs post-marketing, such as patterns of and variations in prescribing in a particular health care facility or area, and strategies to improve the use of the drug. Recent extended applications that apply the population perspective to improve rational drug therapy have enhanced the impact of the field, and include studies of drug utilization, evaluating and improving physician prescribing, the development of treatment guidelines, drug utilization review, risk management, and the development of national drug policies. Another major area of drug evaluation, economic assessment, is discussed elsewhere in this book.

The field of pharmacoepidemiology has expanded enormously since the publication of the last edition of this book. Numerous research articles have been published and there are now many journals competing to accommodate those works. In addition, interest in further training in this discipline is rapidly increasing, as well as the number of training programs. The essence of the discipline has been incorporated into many postgraduate training programs in the medical sciences, such as clinical epidemiology, public health, clinical pharmacology, etc. Pharmacoepidemiology has contributed significantly to the area of regulatory approval and control, and it will continue to impact this area as long as drugs are permitted to enter the market with potentially unknown adverse side effects. The objective of this chapter is to summarize and describe important methods and applications in the field of pharmacoepidemiology, with a focus on developing countries.

Conventional evaluation of new medical technologies such as pharmaceutical products includes consideration of efficacy, effectiveness, and safety. The methodology for such analyses is well developed, and studies of safety and efficacy often are required prior to drug marketing. Health care researchers from a variety of disciplines have developed new techniques for the evaluation of the economic effects of clinical care and new medical technologies. Clinicians, pharmacists, economists, epidemiologists, operations researchers, and others have contributed to the field of ‘clinical economics’, an evolving discipline dedicated to the study of how different approaches to patient care and treatment influence the resources consumed in clinical medicine.

The growth of clinical economics has proceeded rapidly as health policymakers have faced a series of decisions about funding new clinical therapies in an era of increasingly constrained health care resources. Assessments of new therapies include an accounting of the resources required for the new therapy, the extent of the substitution of the new resources for existing resources, if any, and the health outcomes that result from therapeutic intervention. Thus, clinical economics includes not only an assessment of the cost of a new therapy, but an assessment of its overall economic and clinical effect.

This chapter discusses the need for applying economic concepts to the study of pharmaceuticals, introduces the concepts of clinical economics and the application of these concepts to pharmaceutical research, reviews some of the methodologic issues addressed by investigators studying the economics of pharmaceuticals, and finally offers examples of this type of research.

The discipline of clinical pharmacology brings together clinical and scientific practice to support critical and independent appraisal of data pertaining to drugs and therapeutics, and the rational use of medicines. An understanding and knowledge of clinical pharmacology encourages and makes possible the cost-effective use of medicines and vaccines in prevention and treatment of disease at every level of health care and it assists in the making of policies that govern such use. It is important that there should be an educational infrastructure and career path for health professionals in clinical pharmacology.

In its modern form clinical pharmacology was developed in the 1960s, principally in response to public scares about the safety of medicines. The trigger was thalidomide, an incompletely tested drug administered to pregnant women that caused congenital malformations in more than 10,000 newborn infants. In 1961 it was found to be a cause of phocomelia (seal-like rudimentary upper and lower limbs) and other associated abnormalities in infants at birth. The medical world came to realise that the scientific discipline of pharmacology, until then preoccupied with drug action, receptors and laboratory experiments (as important as these are), needed to address more systematically issues of efficacy, safety and rational use of medicines in humans. It was a crucial development that logically followed the earlier contributions of Bradford Hill and others who had systematically developed a logical basis for the controlled clinical trial. The discipline was born of necessity and it held the promise of bringing together drug action, pathology, toxicology, immunology statistics and epidemiology in the interest of safe and effective use of medicines in the clinic and hospital.

Given the public health importance of clinical pharmacology and its potential to contribute to health policy, it is surprising that over the past 40 years it has not thrived, and that it is weakest in the developing world. This chapter reflects the personal experience of the authors, and their efforts to establish clinical pharmacology in a country with a developing economy. It is intended to serve as an affirmation of the need for science and clinical practice to come together in support of rational and cost-effective use of medicines, especially in resource-limited countries and situations. A large proportion of what is expended on medicines in many countries is lost through inefficient systems of procurement and distribution, irrational use, poor adherence, counterfeit and sub-standard medicines, and corruption. Renewed efforts are needed to stimulate clinical pharmacology and to attract inspired leadership. The public needs to have confidence in the medicines available to them, without which people even come to doubt the soundness and reliability of the health system itself. That is a central issue in national and international health policy.

I. History of medicines regulation; II. Why regulating drugs?; III. What is medicines regulation?; IV. Drug registration; V. Role of WHO in drug regulation; VI. Future of medicines regulation; Bibliography

Major causes of morbidity and mortality in many developing countries such as malaria, tuberculosis, pneumonia, acute diarrheas, maternal diseases can be treated with simple essential medicines (Box 1). But, essential medicines will save lives and improve health, only if they are available, affordable and of good quality, and properly utilized.

In developed countries, the discovery of new medicines and their introduction in the existing health care system during the second part of the last century has dramatically improved health, reducing mortality and morbidity from many common diseases. The society in general have benefited from these advances through the regular access to the needed medicines in their health care system. However, in many developing countries the needed essential medicines are not always available, accessible and affordable to those in need.

The discovery of new medicines and their introduction into the market will not optimally have positive impacts on health if the needed essential medicines are not available and affordable, if they are not of good quality and if they are not properly utilized by the health care providers and consumers. This chapter will highlight the issues related to commonly occurring problems in the area of medicines in developing countries, and relevant policies and programme to deal with them. In particular, the chapter will highlight the problems of access to the needed medicines, the problems irrational use by providers and consumers and the problems of counterfeit medicines. The sections on equitable access to essential medicines and on promoting rational use are taken from WHO Policy Perspectives on Medicines (WHO, 2004; WHO, 2002) reflecting the positions advocated by WHO on these issues.

“We are drowning in information and starving for knowledge” (Rutherford D. Roger).

This famous statement is as true for drug information as it is for many other scientific areas today. With the globalisation of access to computer based sources of drug information, this applies to developing and western countries alike. As for drug treatment, no matter how much information is available, there is still the need to search, sort, critically evaluate and digest the information into useful knowledge or guidance in any given therapeutic situation. This is one of the main goals of clinical pharmacology. In developing countries, just a few years ago, the lack of information concerning drugs, in parallel to the lack of the drugs themselves, was a major challenge. Today, with a growing access to both generic drugs, and information about drugs, the right use of available information is the key to success. The more scarce the economical resources, the more there is to gain from the critical use of drug information, both on a community level and for the benefit of the individual patient.

The task of gathering and critically evaluating drug information can be performed on several levels: by individual physicians or prescribers, by local Drugs and Therapeutics Committees, by national authorities or by large international organisations, like the Cochrane Collaboration. This chapter will more specifically deal with the concept and function of the Drug Information Centre.

In this chapter an overview will be given of the drug development process, which is both exciting and complex. We will focus on the development of new drugs and neglect developments based on existing drugs. Examples of the latter are improvements of the active ingredient (new ester, salt or non-covalent derivative, single enantiomer of a racemic drug, or the active metabolite of a (pro-)drug, new pharmaceutical formulations, new combinations and new indications). Of the drug candidates in development the majority belongs to the category of chemically synthesized small molecules (also referred to as new chemical entities, NCEs). However, in recent years an increasing number of drug candidates have been produced using biotechnological methods, the so-called biotech compounds, biologic(al)s or new biological entities (NBEs). Examples of the latter category are proteins, monoclonal antibodies (which are also proteins) and peptides, but also vaccines. Of the 28 new drugs approved in 2005 by FDA 8 were biologicals (29%). It is expected that over the coming years this percentage will remain between 25–35%.

The aim of drug development is to gather comprehensive information on the optimal use of a new drug in the treatment or prevention of disease, and to document the quality of the drug product. Efficacy, safety and quality are the main criteria for granting marketing authorization. However, it should be realized that clinical studies carried out during the development of a drug are not generating sufficient data to warrant the safety of a new drug. In fact, this aspect can only be appraised when there has been sufficient exposure to the drug in medical practice over longer periods of time.

For reasons of space we will not discuss the development of the production process nor that of the formulation and presentation form. The reader should appreciate, however, that this is a major part of the overall drug development process, subject to the highest quality requirements and a key factor in the regulatory approval and medical and commercial success of the drug.

Students often find pharmacokinetics difficult. Two of the reasons are that a very formal writing style together with many equations make the subject appear much more difficult than it is. In this chapter we have deliberately adopted an informal style and aimed to keep key concepts as simple as possible. We hope we have succeeded and that you will find the chapter helpful as you prepare to become good prescribers.

Why is, amoxycillin administered three times daily, cotrimoxazole twice and phenobarbitone only as a single daily doses? Why was a slow-release theophylline preparation developed and why may it be taken only once a day? Why do we often give analgesics as a single dose but antibiotics as a course of doses, which should be taken regularly for a period of days?

If you could design it, what would an ‘ideal’ drug do, and how would it behave? Perhaps this depends on what it is being used for. If it is to treat a chronic condition such as high systemic blood pressure then it should be easy to take, not require injection, and should reduce the blood pressure to the normal range and maintain it there without causing adverse effects. If it were hardly metabolized in, or lost from, the body in any way it might be possible to give a single dose and maintain the effect for a very long time – weeks or even months – good for the patient but not so good for the manufacturer who wants to sell lots of his drug! What about a drug for headache? It needs to be easy to take, to act quickly, but it does not need to stay around in the body for a long period once the headache is relieved, and indeed, this could be a disadvantage if the drug produces unwanted or adverse effects. So it needs characteristics different from those of a drug to treat hypertension which ideally requires a long duration of effect.

In the past before clinical pharmacokinetics (literally – “movement of drugs” – implying measurement of the rate of movement of drugs into, out of, and around the body compartments) had been established in the 1970s, dosage regimens were decided largely by trial and error, relying on measurement of the therapeutic effect to tell you when a response had occurred and the appearance of toxic effects to tell you when you had given too much. The ability to measure drug concentrations in body fluids meant a more precise way existed for deciding by what route and how frequently drugs needed to be given to get the best outcome for the patient.

In this chapter we will look at the factors that are responsible for differences in the rate of onset, the duration and size, and the rate of offset – or loss – of a drug's effect.

Drugs are molecules that interact with macromolecular structures in the body to produce effects that are intended to be beneficial, most often through modification of pathophysiological processes. Some drugs may also be designed to kill intruders, such as bacteria and parasites, or endogenous cells that have lost their growth control and behave as cancer cells. Because a pharmacological effect requires the association of a drug molecule with a receptor structure, one may assume that the more active drug is available at the effect site (biophase), the more effect will be produced. This is basically correct, but reality is more complex as will be shown below when discussing various relationships between drug concentrations and drug effects. The term pharmacokinetic–pharmacodynamic (PK–PD) analysis has been coined to include both the evaluation of pharmacokinetics, which denotes the systematic description of drug transfer through the body, and pharmacodynamics, which means the study and control of drug effects.

Biopharmaceuticals deserve some attention here. At the moment a considerable part of the drugs newly approved by regulatory agencies belong to the so called biologicals. These medicines have a number of characteristics that set them aside from low molecular weight drugs. Their activity can strongly be influenced by their complicated shape based on secondary, tertiary and (sometimes) quaternary structures. These structures cannot be fully defined with our present set of analytical techniques and approaches. They often are the same as (or closely resemble) endogenous proteins. Those are challenging issues but those challenges need to be met and PK/PD studies with biologicals have been published.

In stark contrast to adults, the use of drugs in infants, children and adolescents embodies a unique element which must be considered to ensure drug safety and efficacy; namely, the impact of development on both drug disposition and action.

Development, per se, represents a continuum of biologic events that enables adaptation, somatic growth, neuro-behavioral maturation and eventually, reproduction. The impact of development on the disposition of a given drug is determined, to a great degree, by age-associated changes in body composition (e.g. body water spaces, circulating plasma protein concentrations) and the acquisition of function of organs and organ systems which are important in determining drug metabolism (e.g. the liver) and excretion (e.g. the kidney). While it is often convenient to classify pediatric patients on the basis of postnatal age for the provision of drug therapy (e.g. neonate≤1 month of age; infant= 1–24 months of age: children=2–12 years of age; and adolescents=12–18 years of age), it is important to recognize that the changes in physiology which characterize development may not correspond to these age defined ‘breakpoints’. In fact, the most dramatic changes in drug disposition occur during the first 18 months of life where the acquisition of organ function is most dynamic. Additionally, it is important to note that the pharmacokinetics of a given drug may be altered in pediatric patients consequent to intrinsic (e.g. gender, genotype, ethnicity, inherited diseases) and/or extrinsic (e.g. acquired disease states, xenobiotic exposure, diet) factors which may occur during the first two decades of life.

In addition to the physiological and psychological development that is quite evident during the first two decades of life, it is apparent that ontogeny can also have a profound impact on drug action. While current information rarely permits one to profile a predictable relationship between age and pharmacodynamics, age-associated differences in the dose versus concentration versus effect relationship are evident for many therapeutic drugs. It is not known, however, whether these differences represent discrete and definable ‘events’ associated with drug receptor interaction (e.g. receptor number/density, affinity, kinetics of association/dissociation) or alternatively, age related differences in the complex milieu of post receptor biochemical events (e.g. the availability and residence of second messengers, the number and types of G-proteins, alterations in transmembrane ion flux capable of altering activity of channel-linked receptors, etc.).

For a practitioner to develop a rational and sound pharmacotherapeutic approach to the pediatric patient, it is essential that he or she considers the developmental ‘factors’ (physiological, psychological and pharmacological) that make infants, children and adolescents different from adults. It is the goal of this chapter to provide the reader not with a drug-specific overview of pediatric clinical pharmacology but rather, a premise upon which to consider the potential impact (both therapeutic and toxicologic) of ontogeny on drug disposition and action.

Drug use in older patients generally is similar to that in younger adults. There are however, unique challenges that make drug use more complicated in the older population. These include altered physiology that can change pharmacokinetics and drug sensitivity with age. In addition, multiple diseases are common in older patients and this leads to multiple drug therapy. In turn the risk of drug–drug interactions and drug–disease interactions increase with age. These problems are discussed in this chapter in addition to discussion of therapeutics of important disorders in the older population.

Adverse drug reactions constitute a major morbidity, causing deaths in some cases. About 6% of all hospital admissions are related to ADRs and about half of these are avoidable. There is also a substantial diagnostic problem since there is a limited way in which the body may respond patho-physiologically. This means that ADRs often masquerade as other diseases. Commonly reported ADRs are given in Table 1.

In some instances ADRs may be more specifically related to drug or chemical exposure: some examples of these are shown in Table 2. From this latter table note that there are some very common problems with a relatively lower drug relatedness at the bottom, but these constitute a numerically higher public health risk.

It follows from this that practising clinicians must always consider adverse drug reactions as part of their clinical diagnosis. The causal relationship of a drug to a clinical event may be far from easy to distinguish from other (disease) candidates in the differential diagnosis.

There are some general points for any doctor to bear in mind before prescribing, related to safety:

• The skill of therapeutics is to anticipate, and then use drugs in a way that minimizes risk.

• Drugs are capable of modifying fundamental biological processes profoundly, and their use is associated with the risk of adverse drug reactions.

• Always consider the risks and benefits of using any drug. Think also about all of the costs of using that drug. Compare it with other treatments for the same indication. Then decide which is best to use for your particular patient.

• Remember that it is the patient stands to gain the benefits, but also runs the risks! The benefit of your specialised knowledge of both the patient and the drug must be shared as completely as possible.

• All drug effects are the result of complex interaction between the drug, the patient and the illness. Extrinsic factors, such as speed of administration intravenously, diet, chemical exposures (including other drugs) and many other factors, can also modify drug response.

• Important general predisposing factors to adverse reactions include an excessive amount of the drug due to non-individualised dosage, altered responsiveness to drugs at extremes of age, previous history of allergy or reaction to drugs.

• Pregnancy and labour are also times of altered drug responsiveness: the fetus has special susceptibility to some adverse drug reactions though may be immune to others, for example due to the drug not passing the placenta.

• The incidence of adverse reactions increases with the number of drugs. A minority of adverse effects of drugs can be attributed to drug interaction, but some important adverse interactions are predictable and can be avoided. In the WHO global database of individual case safety reports (ICSR), only about 0.7% of possible adverse events which might be due to interactions between drugs known to share the same CYP enzyme are recorded as possibly due to interaction by the reporter, therefore missing a possible important signal. It should be noted, however, that many interactions have been reported in the literature without much evidence (see Chapter 15).

• Adverse drug reactions should be avoided, managed by dose reduction or withdrawal of the offending drug, replacement with another if necessary, but not treated by with other drugs unless essential.

• The clinician has a responsibility to recognise the possibility of an adverse drug reaction and include it as part of the differential diagnosis or problem list.

• The clinician must report clinically important adverse drug effects to a committee or registry, which have responsibility for deciding on drug formularies (local or national) and for advice on therapeutics.

Interactions between drugs were first recognised over 100 years ago. A drug interaction is said to occur when the response of a patient to a drug is changed by the presence of another drug, food, drink, herb or by some environmental chemical agent. The net effect of the combination may be:

• synergism or additive effect of one or more drugs

• antagonism or reduction of the effects of one or more drugs

• alteration of effect of one or more drugs or the production of idiosyncratic effects or toxicity.

Although many recognised interactions are deliberately used with therapeutic benefit, drug interactions are an increasingly important cause of adverse drug reactions (ADRs). Contributing factors include a plethora of new therapeutic agents with complex mechanisms of action and multiple effects, and the increasing prevalence of polypharmacy. Despite rigorous attempts to ensure that the safety profile of these new medicines is as fully defined as possible when they are authorised for marketing, the potential for adverse interactions may not be evident. This was illustrated by the worldwide withdrawal of the calcium channel blocker mibefradil, within months of launch, following reports of serious drug interactions. Recent advances in the drug treatment of HIV infection is another pertinent example; the current treatment approach involves the early use of combination antiviral therapy in an attempt to reduce the plasma viral load markedly. The combinations of drugs used are chosen to have synergistic or additive activity, a good example of beneficial drug–drug interactions. However, some of the drugs used, particularly protease inhibitors, inhibit the cytochrome P450 enzyme system and consequently their potential to cause significant drug interactions is great.

The medical literature contains thousands of reports of adverse drug interactions, of which only a relatively small proportion are clinically important. The importance of drug interactions to the clinician primarily involves knowing or predicting those occasions when a potential interaction is likely to have significant consequences for the patient. When these arise, the clinician should take steps to minimize adverse effects, for example by using an alternative treatment to avoid the combination of risk, by making a dosage adjustment, or by monitoring the patient closely. In order to predict the possible consequences of the co-administration of two or more drugs it is essential that the clinician has a practical knowledge of the pharmacological mechanisms involved in drug interactions, an awareness of the drugs associated with greatest risk, and the most susceptible patient groups. Clinicians must also be alert to the possible involvement of non-prescribed medicines and other substances in drug interactions. There is an increasing tendency for patients to self-treat with medications that can be purchased without a prescription, including herbal medicines. In addition, some foodstuffs, most notably grapefruit juice, have attracted attention as a cause of drug interactions.

This chapter reviews the main mechanisms of drug interactions. It gives some clinically important examples of these, and suggests how they can be assessed and managed. It focuses on drug interactions that may have an adverse clinical outcome, rather than those that are used to therapeutic advantage. The issues of pharmaceutical incompatibility and drug interactions with food and alcohol will not be covered here.

I. Background and definitions; II. General clinical guidelines on drug dependence; III. Comments on some abused substances; IV. Treatment of craving; V. Clinical guidelines on the diagnosis of drug dependence arising in therapeutic situations; VI. Reporting of dependence; VII. Prevention; VIII. Conclusion; Acknowledgement; Bibliography

I. Introduction; II. Prevention of poisoning; III. Treatment of poisoning; IV. Continuing critical care; V. Conclusion; Bibliography

I. The autonomic and somatic motor nervous system; II. The parasympathetic system; III. The sympathetic system; Bibliography

The word Autacoids comes from the Greek “Autos” (self) and “Acos” (drug) and the general meaning is self-remedy. They are naturally occurring substances which do not normally circulate and are localized in tissues. Their sites of action are thus restricted to the synthesis area. They have diverse physiological and pharmacological activities with a short duration of action which primarily involve responses to injury. Of general importance are effects on smooth muscle contraction. With respect to vascular smooth muscle, there are both vasoconstrictor and vasodilator autacoids. Vasodilator autacoids can be released during periods of exercise. Their main effect is seen in the skin, allowing for heat loss.

Autacoids are a chemically diverse group of substances which are released in response to various types of stimulation. An imbalance in their synthesis, release or in the transduction system contributes significantly to pathological conditions such as inflammation, allergy, hypersensitivity and ischaemia.

The autacoids comprise histamine, serotonin, angiotensin, neurotensin, NO (nitric oxide), kinins, platelet-activating factor, endothelins and the four families of traditional eicosanoids – the leukotrienes and three types of prostanoids i.e. prostaglandins, prostacyclins, and thromboxanes. Several other natural occurring molecules are sometimes called eicosanoid, including the hepoxilins, resolvins, isofurans, isoprostanes, lipoxins, epoxyeicosatrienoic acids (EETs) and some endocannabinoids. However, not all the substances which can be categorized as autacoids have a direct bearing on our pharmacotherapeutic armamentarium.

I. α-Adrenoceptor antagonists (α-blockers); II. β-Adrenoceptor antagonists (β-blockers); III. Peripheral blockers of the sympathetic nervous system; IV. Centrally acting antihypertensive drugs; V. Vasodilator drugs with a direct action; VI. Organic nitrates (nitro compounds); VII. Calcium antagonists; VIII. Potassium channel openers; IX. Ace-inhibitors; X. Angiotensin II-receptor antagonists (AT₁-blockers); XI. Direct renin inhibitors; XII. Positive inotropic agents; XIII. Antiarrhythmic drugs; XIV. Diuretic agents; XV. Lipid-lowering (hypolipaemic) drugs; Bibliography