Topics in drug therapy

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Chapter 2 Topics in drug therapy

Practical prescribing

First, on this topic, Professor Sir Peter Rubin, Chair of the General Medical Council, the body that regulates the practice of medicine by doctors in the UK, writes on the prescribing of medicines.

Prescribing is a task carried out many times each day and can seem mundane – a technical process that is far less stimulating and interesting than reaching a diagnosis. However, there is no such thing as a safe drug and prescribing has the potential to cause harm or death as well as good. This section includes some practical advice aimed at identifying common pitfalls and reducing risk.

The case histories are all real. The data given in the text and figures come from a study commissioned by the General Medical Council.1

Prescribing

Getting it right

Good prescribing starts with taking a good history:

Good prescribing means:

Examples of when things went wrong

Top ten prescribing errors in a UK hospital setting1

Error % of errors
Omission on admission 29.8
Wrong dose 19.6
No dose given 11.0
Wrong/no formulation 7.5
Omission on discharge 6.2
Wrong dosing intervals 6.1
Duplication 5.5
Wrong drug 3.1
No signature 1.7
Contraindication 1.1

Why do mistakes happen?

Human error in one form or another – rather than a simple lack of knowledge – is responsible for most prescribing mistakes. Newly qualified doctors are no more likely than their older colleagues to prescribe incorrectly. Many factors associated with prescribing mistakes are common to mistakes in all walks of life and include the following:

There are also factors specific to the medical environment, including:

When lack of knowledge does play a part, it is often the flawed application of knowledge in that particular patient – i.e. the right drug for the presenting condition, but the wrong drug for that patient because of coexisting medical or drug factors.

What all this adds up to is: prescribing is important, must be taken seriously and must be given the time and care that your patient deserves.

The General Medical Council expects that, by the time they graduate, medical students will be able to:2

The therapeutic situation

Mike Schachter

Some background

Alleviating effects of disease and trauma has been a major concern of human beings from the earliest times. Records of the ancient civilisations of Mesopotamia (modern Iraq), India, China, Mexico and Egypt, from about 3000 BC, describe practices of diagnosis and treatment predicated on differing, often complex, concepts of disease: the supernatural, religious theories (sin, punishment of sin, uncleanness), omens, deities and rites. Among many modes of therapy, a reliance on diet and use of herbs figured prominently (the Mexicans knew of 1200 medicinal plants).

From about 500 BC, the Greek system of humoural medicine began to replace the supernatural with thinking that was rational, scientific and naturalistic. Its core concept was that health was an equilibrium, and disease a disequilibrium, of the four constituent fluids or ‘humours’ of the body (yellow bile, phlegm, blood and black bile). It followed that the condition was correctable by evacuation techniques to re-establish the balance, and hence came blooding, leeching, cathartics, sweating and emetics. Here, the focus was on the patient, as the degree of humoural imbalance was specific to that individual.

Remarkably, this system persisted among ‘learned and rational’ (i.e. university-trained) physicians until it was challenged in the 17th century. Thomas Sydenham3 (1624–1689) showed that during epidemics, many people could suffer the same disease, and different epidemics had distinct characteristics. Later, Giovanni Morgagni (1682–1771), by correlating clinical and autopsy findings, demonstrated that diseases related to particular organs. Now the study of disease, rather than the patient, became the centre of attention. Yet it was only in the 19th century that medicine developed as a science, when the microscope revealed the cell as the basic construction unit of the body and specific entities of pathology became recognisable, most notably in the case of infection with microorganisms (‘germ theory’).

The one major dimension of medicine that remained underdeveloped was therapeutics. An abundance of preparations in pharmacopoeias compared with a scarcity of genuinely effective therapies contributed to a state of ‘therapeutic nihilism’, expressed trenchantly by Oliver Wendell Holmes (1809–1894):

The writer was exaggerating to emphasise his point, but the position was to change throughout the 20th century as understanding of human physiology and pathophysiology deepened and agents that could be relied on to interfere with these processes became available. Modern physicians have at their disposal an array of medicines that empowers them to intervene beneficially in disease but also carries new responsibilities.

Treating patients with drugs

A book can provide knowledge and contribute to the formation of judgement, but it can do little to impart skill and wisdom, which are the products of example of teachers and colleagues, of experience and of innate and acquired capacities. But: ‘It is evident that patients are not treated in a vacuum and that they respond to a variety of subtle forces around them in addition to the specific therapeutic agent.’5

When a patient receives a drug, the response can be the result of numerous factors:

The relative importance of these factors varies according to circumstances. An unconscious patient with meningococcal meningitis does not have a personal relationship with the doctor, but patients sleepless with anxiety because they cannot cope with their family responsibilities may respond as much to the interaction of their own personality with that of the doctor as to anxiolytics.

The physician may consciously use all of the factors listed above in therapeutic practice. But it is still not enough that patients get better: it is essential to know why they do so. This is because potent drugs should be given only if their pharmacodynamic effects are needed; many adverse reactions have been shown to be due to drugs that are not needed, including some severe enough to cause hospital admission.

Uses of drugs/medicines

Physician-induced (iatrogenic) disease

It is a salutary thought that each year medical errors kill an estimated 44 000–98 000 Americans (more than die in motor vehicle accidents) and injure 1 000 000.7 Among inpatients in the USA and Australia, about half of the injuries caused by medical mismanagement result from surgery, but therapeutic mishaps and diagnostic errors are the next most common. In one survey of adverse drug events, 1% were fatal, 12% life-threatening, 30% serious and 57% significant.8 About half of the life-threatening and serious events were preventable. Errors of prescribing account for one-half and those of administering drugs for one-quarter of these. Inevitably, a proportion of lapses result in litigation, and in the UK 20–25% of complaints received by the medical defence organisations about general practitioners follow medication errors.

The most shameful act in therapeutics, apart from actually killing a patient, is to injure a patient who is but little disabled or who is suffering from a self-limiting disorder. Such iatrogenic disease,9 induced by misguided treatment, is far from rare.

Doctors who are temperamentally extremist will do less harm by therapeutic nihilism than by optimistically overwhelming patients with well-intentioned polypharmacy. If in doubt whether or not to give a drug to a person who will soon get better without it, don’t.

In 1917 the famous pharmacologist Sollmann felt able to write:

The doctor’s aim must be not merely to give the patient what will do good, but to give only what will do good – or at least more good than harm. The information explosion of recent decades is now under better control such that prescribers can, from their desktop computer terminals, enter the facts about their patient (age, sex, weight, principal and secondary diagnoses) and receive suggestions for which drugs should be considered, with proposed doses and precautions.

Benefits and risks of medicines

Modern technological medicine has been criticised, justly, for following the tradition of centuries by waiting for disease to occur and then trying to cure it rather than seeking to prevent it in the first place. Although many diseases are partly or wholly preventable by economic, social and behavioural means, these are too seldom adopted and are slow to take effect. In the meantime, people continue to fall sick, and to need and deserve treatment.

We all have eventually to die from something and, even after excessive practising of all the advice on how to live a healthy life, the likelihood that the mode of death for most of us will be free from pain, anxiety, cough, diarrhoea, paralysis (the list is endless) seems so small that it can be disregarded. Drugs already provide immeasurable solace in these situations, and the development of better drugs should be encouraged.

Doctors know the sick are thankful for drugs, just as even the most dedicated pedestrians and environmentalists struck down by a passing car are thankful for a motor ambulance to take them to hospital. The reader will find reference to the benefits of drugs in individual diseases throughout this book and further expansion is unnecessary here. But a general discussion of risk of adverse events is appropriate.

Unavoidable risks

Consider, for the sake of argument, the features that a completely risk-free drug would exhibit:

These criteria may be completely fulfilled, for example in a streptococcal infection sensitive to penicillin in patients whose genetic constitution does not render them liable to an allergic reaction to penicillin.

These criteria are partially fulfilled in insulin-deficient diabetes. But the natural modulation of insulin secretion in response to need (food, exercise) does not operate with injected insulin and even sophisticated technology cannot yet exactly mimic the normal physiological responses. The criteria are still further from realisation in, for example, some cancers and schizophrenia.

Some reasons why drugs fail to meet the criteria of being risk-free include the following:

Whenever a drug is taken a risk is taken

The risk comprises the properties of the drug, the prescriber, the patient and the environment; it is often so small that second thoughts are hardly necessary, but sometimes it is substantial. The doctor must weigh the likelihood of gain for the patient against the likelihood of loss. There are often insufficient data for a rational decision to be reached, but a decision must yet be made, and this is one of the greatest difficulties of clinical practice. Its effect on the attitudes of doctors is often not appreciated by those who have never been in this situation. The patient’s protection lies in the doctor’s knowledge of the drug and of the disease, and experience of both, together with knowledge of the patient.

We continue to use drugs that are capable of killing or disabling patients at doses within the therapeutic range where the judgement of overall balance of benefit and risk is favourable. This can be very difficult for the patient who has suffered a rare severe adverse reaction to understand and to accept (see below).

In some chronic diseases that ultimately necessitate suppressive drugs, the patient may not experience benefit in the early stages. Patients with early Parkinson’s disease may experience little inconvenience or hazard from the condition, and premature exposure to drugs can exact such a price in unwanted effects that they prefer the untreated state. What patients will tolerate depends on their personality, their attitude to disease, their occupation, mode of life and relationship with their doctor (see Compliance, p. 21).

Public view of drugs and prescribers

The current public view of modern medicines, ably fuelled by the mass media, is a compound of vague expectation of ‘miracle’ cures and ‘breakthroughs’ (often with the complicity of doctors) with outrage when anything goes wrong. It is also unreasonable to expect the public to trust the medical profession (in collaboration with the pharmaceutical industry) to the extent of leaving to them all drug matters, and of course this is not the case.

The public wants benefits without risks and without having to alter its unhealthy ways of living; a deeply irrational position, but then humans are not perfectly rational. It is easy to understand that a person who has taken into his body a chemical with intent to relieve suffering, whether or not it is self-induced, can feel profound anger when harm ensues.

Expectations have been raised and now, at the beginning of the 21st century, with the manifest achievements of technology all around us, the naive expectation that happiness can be a part of the technological package is increasingly seen to be unrealisable.

Patients are aware that there is justifiable criticism of the standards of medical prescribing – indeed doctors are in the forefront of this – as well as justifiable criticism of promotional practices of the profitably rich, aggressive, transnational pharmaceutical industry.

There are obvious areas where some remedial action is possible:

If restraint by both parties is not forthcoming, and it may not be, then both doctor and industry can expect even more control to be exercised over them by politicians responding to public demand. If doctors do not want their prescribing to be restricted, they should prescribe better.

Criticisms of modern drugs

Extremist critics have attracted public attention for their view that modern drug therapy, indeed modern medicine in general, does more harm than good; others, while admitting some benefits from drugs, insist that this is medically marginal. These opinions rest on the undisputed fact that favourable trends in many diseases preceded the introduction of modern drugs and were due to economic and environmental changes, sanitation, nutrition and housing. They also rest on the claim that drugs have not changed expectation of life or mortality (as measured by national mortality statistics), or at least it is very difficult to show that they have, and that drugs indisputably can cause illness (adverse reactions).

If something is to be measured then the correct criteria must be chosen. Overall mortality figures are an extremely crude and often an irrelevant measure of the effects of drugs whose major benefits are so often on quality of life rather than on its quantity.

Two examples of inappropriate measurements will suffice:

1. In the case of many infections it is not disputed that environmental changes have had a greater beneficial effect on health than the subsequently introduced antimicrobials. But this does not mean that environmental improvements alone are sufficient in the fight against infections. When comparisons of illnesses in the pre- and post-antimicrobial eras are made, like is not compared with like. Environmental changes achieved their results when mortality from infections was high and antimicrobials were not available; antimicrobials were introduced later against a background of low mortality as well as of environmental change; decades separate the two parts of the comparison, and observers, diagnostic criteria and data recording changed during this long period. It is evident that determining the value of antimicrobials is not simply a matter of looking at mortality rates.

2. About 1% of the UK population has diabetes mellitus, a figure which is increasing rapidly, and about 1% of death certificates mention diabetes. This is no surprise because all must die and insulin is no cure15 for this lifelong disease. A standard medical textbook of 1907 stated that juvenile-onset ‘diabetes is in all cases a grave disease, and the subjects are regarded by all assurance companies as uninsurable lives: life seems to hang by a thread, a thread often cut by a very trifling accident’. Most, if not all, life insurance companies now accept young people with diabetes with no or only modest financial penalty, the premium of a person 5–10 years older. Before insulin replacement therapy was available few survived beyond 3 years16 after diagnosis; they died for lack of insulin. It is unjustified to assert that a treatment is worthless just because its mention on death certificates (whether as a prime or as a contributory cause) has not declined. The relevant criteria for juvenile-onset diabetes are change in the age at which the subjects die and the quality of life between diagnosis and death, and both of these have changed enormously.

Drug-induced injury17 (see also Ch. 9)

Responsibility for drug-induced injury raises important issues affecting medical practice and development of needed new drugs, as well as of law and of social justice.

Negligence and strict and no-fault liability

All civilised legal systems provide for compensation to be paid to a person injured as a result of using a product of any kind that is defective due to negligence (fault: failure to exercise reasonable care).18 But there is a growing opinion that special compensation for serious personal injury, beyond the modest sums that general social security systems provide, should be automatic and not dependent on fault and proof of fault of the producer, i.e. there should be ‘liability irrespective of fault’, ‘no-fault liability’ or ‘strict liability’.19 After all, victims need assistance (compensation) regardless of the cause of injury and whether or not the producer and, in the case of drugs, the prescriber deserves censure. The question why a person who has suffered injury due to the biological accident of disease should have to depend on social security payments while an identical injury due to a drug (in the absence of fault) should attract special added compensation receives no persuasive answer except that this is what society seems to want.

Many countries are now revising their laws on liability for personal injury due to manufactured products and are legislating Consumer Protection Acts (Statutes) which include medicines, for ‘drugs represent the class of product in respect of which there has been the greatest pressure for surer compensation in cases of injury’.20

Issues that are central to the debate include:

Nowhere has a scheme that meets all the major difficulties yet been implemented. This is not because there has been too little thought, it is because the subject is so difficult. Nevertheless, no-fault schemes operate in New Zealand, Scandinavia and France.21 The following principles might form the basis of a workable compensation scheme for injury due to drugs:

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