Benefits of drugs are manifest to doctor and patient and also, it might be thought, obvious to even the most unimaginative healthy people who find themselves dismayed by some aspects of modern technology.
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 from occurring in the first place.
Although many diseases are partly or wholly preventable by economic, social and behavioural
6 Iatrogenic means 'physician-caused', i.e. disease consequent on following medical advice or intervention (from the Greek iatros, physician).
7 Sollman T A1917 Manual of pharmacology. Saunders, Philadelphia.
The information explosion of recent decades is now being brought under better control such that prescribers can, from their desktop computer terminals, enter the facts about their patient (e.g. age, sex, weight, principal and secondary diagnoses) and receive suggestions for which drugs should be considered, with proposed doses and precautions.
means, these are too seldom adopted and also are slow to take effect. In the meantime people continue to fall sick and to need and to deserve treatment.
In any case we all have eventually to die of 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, but better drugs are needed and their development 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.
Benefits of drugs in individual diseases are discussed throughout this book and will not be further expanded here. But a general discussion of risk of adverse events is appropriate.
A risk-free drug would be one for which:
• The physician knew exactly what action was required and used the drug correctly
• The drug did that and nothing else, either by true biological selectivity or by selective targeted delivery
• Exactly the right amount of action—not too little, not too much—was easily achieved.
These criteria may be completely fulfilled, e.g. 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.
The reasons why criteria for a risk-free drug are not met are as follows:
• Drugs may be insufficiently selective. As the concentration rises, a drug that is highly selective at low concentrations will begin to affect other target sites (receptors, enzymes); a disease process (cancer) is so close to normal cellular mechanisms that perfectly selective cell kill is impossible.
• Drugs may be highly selective, but the mechanism affected has widespread functions and interference with it cannot be limited to one site only, e.g. atenolol, aspirin.
• Prolonged modification of cellular mechanisms can lead to permanent change in structure and function, e.g. carcinogenicity.
• Insufficient knozvledge of disease processes (some cardiac arrhythmias) and of drug action can lead to interventions that, though undertaken with the best intentions, are harmful.
• Patients are genetically heterogeneous to an enormous degree and may have unpredicted responses to drugs.
• Dosage adjustment according to need is often unavoidably imprecise, e.g. in depression.
• Ignorant and casual prescribing.
Reduction of drug risk
This can be achieved by:
• Better knowledge of disease (research); as much as 40% of useful medical advances derive from basic research that was not funded with a practical outcome in view.
• Site-specific effect: by molecular manipulation.
• Site-specific delivery: drug targeting
— by topical (local) application
— by target-selective carriers.
• Informed, careful and responsible prescribing.
First are those that we accept by deliberate choice, even if we do not exactly know their magnitude, or we know but wish they were smaller, or, especially where 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 could either be tolerated or treated in other ways, e.g. hernia, much cosmetic surgery.
Second are those risks that are imposed on us in the sense that they cannot be significantly altered by individual action. Risks such as those of food additives (e.g. preservatives, colouring), air pollution and some environmental radioactivity are imposed by man. 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 truth that unnecessary risks should be avoided, 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.
It is also the case that some risks, though 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.8
• The likelihood or probability of an adverse event
In general it has been suggested that, in medical cases, concern ceases when risks fall below about 1 in 100 000 so that the procedure then becomes 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).
The benefits of chemicals used to colour food verge on or even attain negligibility, although some are known to cause allergy in man. Yet 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
8 Sometimes the term minimal risk is used to mean risk about equal to going about our ordinary daily lives; it includes travel on public transport, but not motor bicycling on a motorway.
minor inconvenience, e.g. in one study (USA) 3% of hospital emergency room visits were attributable to adverse drug reactions.
These are: unacceptable, acceptable and negligible. In the presence of life-threatening disease and with sufficient 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 considered without reference to benefits any more than benefits should be considered 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.9
The risk is made up of the properties of the drug, of the prescriber, of the patient and of 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 patients' protection lies in the doctors' knowledge of the drug and of the disease, and experience of both, together with knowledge of the patient.
Drugs that are capable of killing or disabling patients at doses within the therapeutic range
9 Pochin E E 1975 British Medical Bulletin 31:184.
continue to be used where the overall balance of benefit and risk is judged 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 in which suppressive drugs will ultimately be needed they may not benefit the patient in the early stages. For example, victims of early parkinsonism or hypertension may be little inconvenienced or hazarded by the disease, as yet, and the premature use of drugs can exact such a price in side-effects that patients 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).
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