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:

• Rushing.

• Tired.

• Doing several things at once.

• Communication breakdown.

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

• Not familiar with the drug chart (usually on moving to a new hospital).

• Unfamiliar patient – and not taking the time to become familiar with the full medical and drug history.

• Arithmetical errors in calculating dose.

• Omitting drugs for a newly admitted patient because of inadequate information.

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 desire to take medicines is perhaps the greatest feature that distinguishes man from animals’ (Sir William Osler, 1849–1919).

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 Sydenham ³ (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):

Throw out opium …; throw out a few specifics …; throw out wine, which is a food, and the vapours which produce the miracle of anaesthesia, and 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 all the worse for the fishes…⁴

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.

Drug therapy involves a great deal more than matching the name of the drug to the name of a disease; it requires knowledge, judgement, skill and wisdom, but above all a sense of responsibility.

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 pharmacodynamic effect of the drug and interactions with any other drugs the patient may be taking.

• The pharmacokinetics of the drug and its modification in the individual by genetic influences, disease, other drugs.

• The act of medication, including the route of administration and the presence or absence of the doctor.

• What the doctor has told the patient.

• The patient’s past experience of doctors.

• The patient’s estimate of what has been received and of what ought to happen as a result.

• The social environment, e.g. whether it is supportive or dispiriting.

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.

Drugs can do good

Medically, this good may sometimes seem trivial, as in the avoidance of a sleepless night in a noisy hotel or of social embarrassment from a profusely running nose due to seasonal pollen allergy (hay fever). Such benefits are not necessarily trivial to recipients, concerned to be at their best in important matters, whether of business, pleasure or passion, i.e. with quality of life.

Or the good may be literally life-saving, as in serious acute infections (pneumonia, septicaemia) or in the prevention of life-devastating disability from severe asthma, from epilepsy or from blindness due to glaucoma.

Drugs can do harm

This harm may be relatively trivial, as in hangover from a hypnotic or transient headache from glyceryl trinitrate used for angina.

The harm may be life-destroying, as in the rare sudden death following an injection of penicillin, rightly regarded as one of the safest of antibiotics, or the destruction of the quality of life that occasionally attends the use of drugs that are effective in rheumatoid arthritis (adrenocortical steroids, penicillamine) and Parkinson’s disease (levodopa).

There are risks in taking medicines, just as there are risks in food and transport. There are also risks in declining to take medicines when they are needed, just as there are risks in refusing food or transport when they are needed.

Efficacy and safety do not lie solely in the molecular structure of the drug. Doctors must choose which drugs to use and must apply them correctly in relation not only to their properties, but also to those of the patients and their disease. Then patients must use the prescribed medicine correctly (see Compliance p. 21).

Uses of drugs/medicines

Drugs are used in three principal ways:

• To cure disease: primary and auxiliary.

• To suppress disease.

• To prevent disease (prophylaxis): primary and secondary.

Cure

implies primary therapy, as in bacterial and parasitic infections, that eliminates the disease and the drug is withdrawn; or auxiliary therapy, as with anaesthetics and with ergometrine and oxytocin in obstetrics.

Suppression

of diseases or symptoms is used continuously or intermittently to avoid the effects of disease without attaining cure (as in hypertension, diabetes mellitus, epilepsy, asthma), or to control symptoms (such as pain and cough) while awaiting recovery from the causative disease.

Prevention

(prophylaxis). In primary prevention, the person does not have the condition and avoids getting it. For malaria, vaccinations and contraception, the decision to treat healthy people is generally easy.

In secondary prevention, the patient has the disease and the objective is to reduce risk factors, so as to retard progression or avoid repetition of an event, e.g. aspirin and lipid-lowering drugs in atherosclerosis and after myocardial infarction, antihypertensives to prevent recurrence of stroke.

Taking account of the above, a doctor might ask the following questions before treating a patient with drugs:

1. Should I interfere with the patient at all?

2. If so, what alteration in the patient’s condition do I hope to achieve?

3. Which drug is most likely to bring this about?

4. How can I administer the drug to attain the right concentration in the right place at the right time and for the right duration?

5. How will I know when I have achieved the objective?

6. What other effects might the drug produce, and are these harmful?

7. How will I decide to stop the drug?

8. Does the likelihood of benefit, and its importance, outweigh the likelihood of damage, and its importance, i.e. the benefit versus risk, or efficacy against safety?

Physician-induced (iatrogenic) disease

They used to have a more equitable contract in Egypt: for the first three days the doctor took on the patient at the patient’s risk and peril: when the three days were up, the risks and perils were the doctor’s.

But doctors are lucky: the sun shines on their successes and the earth hides their failures.⁶

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:

Pharmacology comprises some broad conceptions and generalisations, and some detailed conclusions, of such great and practical importance that every student and practitioner should be absolutely familiar with them. It comprises also a large mass of minute details, which would constitute too great a tax on human memory, but which cannot safely be neglected.¹⁰

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:

• The physician would know exactly what action is required and use the drug correctly.

• The drug would deliver its desired action and nothing else, either by true biological selectivity or by selective targeted delivery.

• The drug would achieve exactly the right amount of action – neither too little, nor too much.

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:

• Drugs may be insufficiently selective. As the concentration rises, a drug that acts at only one site at low concentrations begins to affect other target sites (receptors, enzymes) and recruit new (unwanted) actions; or a disease process (cancer) is so close to normal cellular mechanisms that perfectly selective cell kill is impossible.

• Drugs may be highly selective for one pathway but the mechanism affected has widespread functions and interference with it cannot be limited to one site only, e.g. atenolol on the β-adrenoceptor, aspirin on cyclo-oxygenase.

• Prolonged modification of cellular mechanisms can lead to permanent change in structure and function, e.g. carcinogenicity.

• Insufficient knowledge of disease processes (some cardiac arrhythmias) and of drug action can lead to interventions that, although undertaken with the best intentions, are harmful.

• Patients are genetically heterogeneous to a high degree and may have unpredicted responses to drugs.

• Dosage adjustment according to need is often unavoidably imprecise, e.g. in depression.

• Prescribing ‘without due care and attention’.¹¹

Reduction of risk

Strategies that can limit risk include those directed at achieving:

• Better knowledge of disease (research) – as much as 40% of useful medical advances derive from basic research that was not funded towards a specific practical outcome.

• Site-specific effect – by molecular manipulation.

• Site-specific delivery – drug targeting:

by topical (local) application

by target-selective carriers.

• Informed, careful and responsible prescribing.

Two broad categories of risk

1. First are those that we accept by deliberate choice. We do so even if we do not exactly know their magnitude, or we know but wish they were smaller, or, especially when the likelihood of harm is sufficiently remote though the consequences may be grave, we do not even think about the matter. Such risks include transport and sports, both of which are inescapably subject to potent physical laws such as gravity and momentum, and surgery to rectify disorders that we could tolerate or treat in other ways, as with much cosmetic surgery.

2. Second are those risks that cannot be significantly altered by individual action. We experience risks imposed by food additives (preservatives, colouring), air pollution and some environmental radioactivity. But there are also risks imposed by nature, such as skin cancer due to excess ultraviolet radiation in sunny climes, as well as some radioactivity.

It seems an obvious course to avoid unnecessary risks, but there is disagreement on what risks are truly unnecessary and, on looking closely at the matter, it is plain that many people habitually take risks in their daily and recreational life that it would be a misuse of words to describe as necessary. Furthermore, some risks, although known to exist, are, in practice, ignored other than by conforming to ordinary prudent conduct. These risks are negligible in the sense that they do not influence behaviour, i.e. they are neglected.¹²

Elements of risk

Risk has two elements:

• The likelihood or probability of an adverse event.

• Its severity.

In medical practice in general, concern ceases when risks fall below about 1 in 100 000 instances, when the procedure then is regarded as ‘safe’. In such cases, when disaster occurs, it can be difficult indeed for individuals to accept that they ‘deliberately’ accepted a risk; they feel ‘it should not have happened to me’ and in their distress they may seek to lay blame on others where there is no fault or negligence, only misfortune (see Warnings and consent).

The benefits of chemicals used to colour food verge on or even attain negligibility, although some cause allergy in humans. Our society permits their use.

There is general agreement that drugs prescribed for disease are themselves the cause of a significant amount of disease (adverse reactions), of death, of permanent disability, of recoverable illness and of minor inconvenience. In one major UK study the prevalence of adverse drug reactions as a cause of admission to hospital was 6.5% (see Chapter 9 for other examples).

Three major grades of risk

These are: unacceptable, acceptable and negligible. Where disease is life-threatening and there is reliable information on both the disease and the drug, then decisions, though they may be painful, present relatively obvious problems. But where the disease risk is remote, e.g. mild hypertension, or where drugs are to be used to increase comfort or to suppress symptoms that are, in fact, bearable, or for convenience rather than for need, then the issues of risk acceptance are less obvious.

Risks should not be weighed without reference to benefits any more than benefits should be weighed without reference to risks.

Risks are among the facts of life. In whatever we do and in whatever we refrain from doing, we are accepting risk. Some risks are obvious, some are unsuspected and some we conceal from ourselves. But risks are universally accepted, whether willingly or unwillingly, whether consciously or not.¹³

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:

• Improvement of prescribing by doctors, including better communication with patients, i.e. doctors must learn to feel that introduction of foreign chemicals into their patients’ bodies is a serious matter, which many or most do not seem to feel at present.¹⁴

• Introduction of no-fault compensation schemes for serious drug injury (some countries already have these).

• Informed public discussion of the issues between the medical profession, industrial drug developers, politicians and other ‘opinion-formers’ in society, and patients (the public).

• Restraint in promotion by the pharmaceutical industry including self-control by both industry and doctors in their necessarily close relationship, which the public is inclined to regard as a conspiracy, especially when the gifts and payments made to doctors get into the news. (This is much less prevalent than it was in the 1990s.)

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 cure ¹⁵ 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 injury ¹⁷ (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: