Mike Schachter
Synopsis
As drugs are intended to relieve suffering, patients find it peculiarly offensive that they can also cause disease (especially if they are not forewarned). Therefore, it is important to know how much disease drugs do cause and why they cause it, so that preventive measures can be taken. The chapter will examine:
• Background.
• Definitions.
• Attribution and degrees of certainty.
• Pharmacovigilance and pharmacoepidemiology.
• Sources of adverse drug reactions.
• Allergy in response to drugs.
• Effects of prolonged administration: chronic organ toxicity.
• Adverse effects on reproduction.
Background
Cured yesterday of my disease, I died last night of my physician.1
Nature is neutral, i.e. it has no ‘intentions’ towards humans, though it is often unfavourable to them. It is humans, in their desire to avoid suffering and death, who decide that some of the biological effects of drugs are desirable (therapeutic) and others undesirable (adverse). In addition to this arbitrary division, which has no fundamental biological basis, numerous non-drug factors promote or even cause unwanted effects. Because of the variety of these factors, attempts to make a simple account of the unwanted effects of drugs must be imperfect.
There is general agreement that drugs prescribed for disease are themselves the cause of a serious amount of disease (adverse reactions), ranging from mere inconvenience to permanent disability and death.
It is not enough to measure the incidence of adverse reactions to drugs, their nature and their severity, although accurate data are obviously useful. It is necessary to take, or to try to take, into account which effects are avoidable (by skilled choice and use) and which unavoidable (inherent in drug or patient).
As there can be no hope of eliminating all adverse effects of drugs, it is necessary to evaluate patterns of adverse reaction against one another. One drug may frequently cause minor ill-effects but pose no threat to life, though patients do not like it and may take it irregularly, to their own long-term harm. Another drug may be pleasant to take, so that patients take it consistently, with benefit, but on rare occasions it may kill someone. It is not obvious which drug is to be preferred.
Some patients, e.g. those with a history of allergy or previous reactions to drugs, are up to four times more likely to have another adverse reaction, so that the incidence does not fall evenly. It is also useful to discover the causes of adverse reactions (e.g. individuals who lack certain enzymes), for use of such knowledge can render avoidable what are at present unavoidable reactions.
More skilful prescribing will reduce avoidable adverse effects and this means that doctors, among all the other claims on their time, must find time better to understand drugs, as well as understanding patients and their diseases.
Definitions
Many unwanted effects of drugs are medically trivial and, in order to avoid inflating the figures of drug-induced disease, it is convenient to retain the widely-used term side-effects for minor reactions that occur at normal therapeutic doses, and that are predictable and usually dose related.
The term adverse drug reaction (ADR) should be confined to harmful or seriously unpleasant effects occurring at doses intended for therapeutic (including prophylactic or diagnostic) effect and which call for reduction of dose or withdrawal of the drug and/or forecast hazard from future administration; it is effects of this order that are of importance in evaluating drug-induced disease in the community. The term adverse ‘reaction’ is almost synonymous with adverse ‘effect’, except that an ‘effect’ relates to the drug and a ‘reaction’ to the patient. Both terms should be distinguished from an adverse ‘event’, which is an adverse happening that occurs during exposure to a drug without any assumption being made about its cause (see Prescription event monitoring, p. 52).
Toxicity
implies a direct action of the drug, often at high dose, damaging cells, e.g. liver damage from paracetamol overdose, eighth cranial nerve damage from gentamicin. All drugs, for practical purposes, are toxic in overdose2 and overdose can be absolute or relative; in the latter case an ordinary dose may be administered but may be toxic due to an underlying abnormality in the patient, e.g. disease of the kidney. Mutagenicity, carcinogenicity and teratogenicity (see Index) are special cases of toxicity.
Secondary effects
are the indirect consequences of a primary drug action. Examples are: vitamin deficiency or opportunistic infection in patients whose normal bowel flora has been altered by antimicrobials; diuretic-induced hypokalaemia causing digoxin toxicity.
Intolerance
means a low threshold to the normal pharmacodynamic action of a drug. Individuals vary greatly in their susceptibility to drugs, those at one extreme of the normal distribution curve being intolerant of the drugs, those at the other, tolerant.
Idiosyncrasy
(see also Pharmacogenomics, p. 101) implies an inherent qualitative abnormal reaction to a drug, usually due to genetic abnormality, e.g. porphyria.
Attribution and degrees of certainty
When an unexpected event, for which there is no obvious cause, occurs in a patient already taking a drug, the possibility that it is drug attributable must always be considered. Distinguishing between natural progression of a disease and drug-induced deterioration is particularly challenging, e.g. sodium in antacid formulations may aggravate cardiac failure, tricyclic antidepressants may provoke epileptic seizures, and aspirin may cause bronchospasm in some asthmatics.
The following elements are useful in attributing the cause of an adverse event to a drug:
1. The time sequence in relation to taking the drug. The majority of reactions develop soon after exposure. Anaphylactic reactions (within minutes or hours) and hypersensitivity reactions (within weeks) may readily suggest an association, but delayed effects such as carcinogenesis or tardive dyskinesia (after years or even decades) present more difficulty.
2. The effects of withdrawing or reintroducing the drug. Most reactions subside when the drug is discontinued, unless an autoimmune reaction is established, when effects persist. Planned re-exposing a patient to a drug is rarely indicated unless treatment with it is essential and there is no reliable alternative.
3. The relationship to what is already known about the drug. This of course invites questions about consistency with the established pharmacology and toxicology of the drug or related substances.
Degrees of conviction for attributing adverse reactions to drugs may be ascribed as3:
• Definite: time sequence from taking the drug is reasonable; event corresponds to what is known of the drug and is not explicable by concurrent disease or drugs; event ceases on stopping the drug; event returns on restarting the drug (rarely advisable).
• Probable: time sequence is reasonable; event corresponds to what is known of the drug; event ceases on stopping the drug; event not reasonably explained by patient's disease or other drugs.
• Possible: time sequence is reasonable; event corresponds to what is known of the drug; uncertain relationship to effect of stopping the drug; event could readily have been result of the patient's disease or other therapy.
• Conditional: time sequence is reasonable; event does not correspond to what is known of the drug; event could not reasonably be explained by the patient's disease or other drugs.
• Doubtful: event not meeting the above criteria.
Caution
About 80% of well people not taking any drugs admit on questioning to symptoms (often several) such as are commonly experienced as lesser adverse reactions to drugs. Administration of a placebo intensifies (or diminishes) these symptoms. Thus, many (minor) symptoms may be wrongly attributed to drugs. Similarly, minor and possibly transient abnormalities in laboratory results, e.g. liver function tests, occur in apparently healthy people.
Practicalities of detecting rare adverse reactions
For reactions with no background incidence, the number of patients required to give a good (95%) chance of detecting the effect appears in Table 9.1. Assuming that three events are required before any regulatory or other action should be taken, it shows the large number of patients that must be monitored to detect even a relatively high-incidence adverse effect. The problem can be many orders of magnitude worse if the adverse reactions closely resemble spontaneous disease with a background incidence in the population.
Table 9.1 Detecting rare adverse drug reactions.
Pharmacovigilance and pharmacoepidemiology
The principal methods of collecting data on ADRs (pharmacovigilance) are:
• Experimental studies, i.e. formal therapeutic trials of Phases 1–3. These provide reliable data on only the commoner events as they involve relatively small numbers of patients (hundreds); they detect an incidence of up to about 1 in 200.
• Observational studies, where the drug is observed epidemiologically under conditions of normal use in the community, i.e. pharmacoepidemiology and pharmacovigilance. Techniques used for post-marketing (Phase 4) studies include the observational cohort study and the case–control study. The surveillance systems are described on pages 52–53.
Drug-induced illness
The discovery of drug-induced illness can be analysed as follows4:
• A drug commonly induces an otherwise rare illness: this effect is likely to be discovered by clinical observation in the licensing (pre-marketing) formal therapeutic trials and the drug will almost always be abandoned; but some patients are normally excluded from such trials, e.g. pregnant women, and detection will then occur later.
• A drug rarely or uncommonly induces an otherwise common illness: this effect is likely to remain undiscovered. Cardiovascular risk from coxibs (e.g. rofecoxib, Vioxx) approximates as an example, but the degree of increased risk did become apparent after meta-analysis of several clinical trials and observational studies.
• A drug rarely induces an otherwise rare illness: this effect is likely to remain undiscovered before the drug is released for general prescribing. The effect could be detected by informal clinical observation or during any special post-registration surveillance and confirmed by a case–control study (see p. 52); aplastic anaemia with chloramphenicol5 and the oculomucocutaneous syndrome with practolol were uncovered in this way.
• A drug commonly induces an otherwise common illness: this effect will not be discovered by informal clinical observation. If very common, it may be discovered in formal therapeutic trials and in case–control studies, but if only moderately common it may require observational cohort studies, e.g. pro-arrhythmic effects of anti-arrhythmic drugs.
• Drug adverse effects and illness incidence in an intermediate range: both case–control and cohort studies may be needed.
Some impression of the features of drug-induced illness can be gained from the following statistics:
• In a large UK study, the prevalence of ADRs as a cause of admission to hospital was 6.5%, with a median bed stay of 8 days (4% of hospital bed capacity); most reactions were definitely or possibly avoidable; the commonest drugs were: low-dose aspirin, diuretics, warfarin, non-steroidal anti-inflammatory drugs (other than aspirin); the commonest adverse reaction was gastrointestinal bleeding.6
• Overall incidence in hospital inpatients is 10–20%, with possible prolongation of hospital stay in 2–10% of patients in acute medical wards.
• ADRs cause 2–3% of consultations in general practice.
• A study of 661 ambulatory patients found that 25% experienced adverse events, of which 13% were serious and 11% were preventable.7
• Predisposing factors for ADRs are: age over 60 years or under 1 month, female sex, previous history of adverse reaction, hepatic or renal disease, number of medications taken.
• A review of records of coroner's inquests for a (UK) district with a population of 1.19 million during the period 1986–1991 found that, of 3277 inquests on deaths, 10 were due to errors of prescribing and 36 were caused by adverse drug reactions.8 Nevertheless, 17 doctors in the UK were charged with manslaughter in the 1990s, compared with two in each of the preceding decades, a reflection of ‘a greater readiness to call the police or to prosecute’.9
It is important to avoid alarmist or defeatist reactions. Many treatments are dangerous, e.g. surgery, electroshock, drugs, and it is irrational to accept the risks of surgery for biliary stones or hernia and to refuse to accept any risk at all from drugs for conditions of comparable severity.
Many patients whose death is deemed to be partly or wholly caused by drugs, are dangerously ill already; justifiable risks may be taken in the hope of helping them; ill-informed criticism in such cases can act against the interest of the sick. On the other hand, there is no doubt that some of these accidents are avoidable. This is often more obvious when reviewing the conduct of treatment after the event, i.e. with the benefit of hindsight.
Sir Anthony Carlisle,10 in the first half of the 19th century, said that ‘medicine is an art founded on conjecture and improved by murder’. Although medicine has advanced rapidly, there is still a ring of truth in that statement, as witness anyone who follows the introduction of new drugs and observes how, after the early enthusiasm, there follow reports of serious toxic effects, and withdrawal of the drug may then follow. The challenge is to find and avoid these, and, indeed, the present systems for detecting adverse reactions came into being largely in the wake of the thalidomide, practolol and benoxaprofen disasters (see p. 63); they are now an increasingly sophisticated and effective part of medicines development.
It is an absolute obligation on doctors to use only drugs about which they have troubled to inform themselves.
Drugs and skilled tasks
Many medicines affect performance, and it is relevant to review here some examples with their mechanisms of action. As might be expected, centrally acting and psychotropic drugs are prominent, e.g. the sedative antidepressants, benzodiazepines, non-benzodiazepine and other hypnotics, and antipsychotics (the ‘classical’ type more so than the ‘atypicals’; see p. 322). Many drugs possess anticholinergic activity either directly (atropine, oxybutynin) or indirectly (tricyclic antidepressants, antipsychotics), the central effects of which cause confusion and impaired ability to process information. The first-generation H1-receptor antihistamines (chlorphenamine, diphenhydramine) are notably sedating and impair alertness and concentration, which features the recipient may not recognise. Drugs may also affect performance through cerebral depression (antiepileptics, opioids), hypoglycaemia (antidiabetics) and hypotension (antihypertensives). For alcohol and cannabis, see pp. 142 and 155.
Car driving is a complex multifunction task that includes: visual search and recognition, vigilance, information processing under variable demand, decision-making and risk-taking, and sensorimotor control. It is plain that prescribers have a major responsibility here, both to warn patients and, in the case of those who need to drive for their work, to choose medicines with a minimal liability to cause impairment.11 Patients who must drive when taking a drug of known risk, e.g. benzodiazepine, should be specially warned of times of peak impairment.12
A patient who has an accident and was not warned of drug hazard, whether orally or by labelling, may successfully sue the doctor. It is also essential that patients be advised of the additive effect of alcohol with prescribed medicines.
How the patient feels is not a reliable guide to recovery of skills, and drivers may be more than usually accident prone without any subjective feeling of sedation or dysphoria. The criteria for safety in aircrew are much more stringent than are those for car drivers.
Resumption of car driving or other skilled activity after anaesthesia is a special case, and an extremely variable one, but where a sedative, e.g. intravenous benzodiazepine, opioid or neuroleptic, or any general anaesthetic, has been used it seems reasonable not to drive for 24 h at least.
The emphasis on psychomotor and physical aspects (injury) should not distract from the possibility that those who live by their intellect and imagination (politicians and even journalists may be included here) may suffer cognitive disability from thoughtless prescribing.
Sources of adverse drug reactions
The reasons why patients experience ADRs are varied and numerous, but reflection on the following may help a prescriber to anticipate and avoid unwelcome events:
• The patient may be predisposed to an ADR by age, sex, genetic constitution, known tendency to allergy, disease of drug eliminating organs (see Ch. 8), or social habits, e.g. use of tobacco, alcohol, other recreational drugs (see Ch. 11).
• The known nature of the drug may forewarn. Some drugs, e.g. digoxin, have steep dose–response curves and small increments of dose are more likely to induce adverse or toxic reactions (see p. 92). The capacity of the body to eliminate certain drugs, e.g. phenytoin, may saturate within the therapeutic dose range so that standard increases cause a disproportionate rise in plasma concentration, risking toxic effects (see p. 356). Some drugs, e.g. antimicrobials and particularly penicillins, have a tendency to cause allergy. Anticancer agents warrant special care as they are by their nature cytotoxic (see Ch. 31). Use of these and other drugs may raise longer-term issues of mutagenicity, carcinogenicity and teratogenicity. Ingredients of a formulation, rather than the active drug, may also cause adverse reactions. Examples include the high sodium content of some antacids, and colouring and flavouring agents. The latter are designated in the list of contents by E numbers; tartrazine (E102) may cause allergic reactions.
• The prescriber needs to be aware that adverse reactions may occur after a drug has been used for a long time, at a critical phase in pregnancy, is abruptly discontinued (see p. 99) or given with other drugs (see Drug interactions, Ch. 8).
Aspects of the above appear throughout the book as is indicated. Selected topics are:
Age
The very old and the very young are liable to be intolerant of many drugs, largely because the mechanisms for disposing of them in the body are less efficient. The young are not simply ‘small adults’ and ‘respect for their pharmacokinetic variability should be added to the list of our senior citizens’ rights’.13 Multiple drug therapy is commonly found in the old, which further predisposes to adverse effects (see Prescribing for the elderly, p. 105).
Sex
Females are more likely to experience adverse reactions to certain drugs, e.g. mefloquine (neuropsychiatric effects).
Genetic constitution
Inherited factors that influence response to drugs appear in general under Pharmacogenomics (see p. 101). For convenience, we describe here the porphyrias,14 a specific group of disorders for which careful prescribing in a subgroup, the acute porphyrias, is vital.
Healthy people need to produce haem, e.g. for erythrocytes and haem-dependent enzymes. Haem is synthesised by a sequence of enzymes and in nonerythroid cells (including the liver) the rate of the synthetic process is controlled by the first of these, D-aminolaevulinic acid (ALA) synthase, on which haem provides a negative feedback.
The porphyrias comprise a number of rare, genetically determined, single-enzyme defects in haem biosynthesis and give rise to two main clinical manifestations: acute neurovisceral attacks and/or skin lesions. Non-acute porphyrias (porphyria cutanea tarda, erythropoietic protoporphyria and congenital erythropoietic porphyria) present with cutaneous photosensitivity that results from the overproduction of porphyrins, which are photosensitising. In porphyria cutanea tarda, a mainly acquired disorder of hepatic enzyme function, one of the main provoking agents is alcohol (and prescribed oestrogens in women).
The acute hepatic porphyrias (acute intermittent porphyria, variegate porphyria and hereditary co-proporphyria) are characterised by severe attacks of neurovisceral dysfunction precipitated principally by a wide variety of drugs (also by alcohol, fasting and infection). Clinical effects arise from the accumulation of the precursors of haem synthesis, D-ALA, porphobilinogen, though the exact mechanism remains obscure.
The exact precipitating mechanisms are uncertain. Induction of the haem-containing hepatic oxidising enzymes of the cytochrome P450 group causes an increased demand for haem. Therefore drugs that induce these enzymes would be expected to precipitate acute attacks of porphyria, and they do so: tobacco smoking and alcohol excess may also act via this mechanism. Apparently unexplained attacks of porphyria should be an indication for close enquiry into all possible chemical intake, including recreational substances such as marijuana, cocaine, amfetamines and ecstasy. Patients must be educated to understand their condition, to possess a list of safe and unsafe drugs, and to protect themselves from themselves and from others, including, especially, prescribing doctors.
Great care in prescribing for these patients is required if serious illness is to be avoided and it is therefore essential that patients and their clinicians have access to information concerning the safe use of prescription medication. Drug lists should be reviewed regularly, and a recent initiative in Europe has made a consensus-based list of safe drugs (available at http://www.porphyria-europe.org) as well as details of common prescribing problems and a link to a searchable drug safety database (http://www.drugs-porphyria.org).
If no recognised safe option is available, use of a drug about which there is uncertainty may be justified. Dr M. Badminton15 writes: ‘Essential treatment should never be withheld, especially for a condition that is serious or life threatening. The clinician should assess the severity of the condition and the activity of the porphyria and make a risk versus benefit assessment.’ In these circumstances the clinician may wish to contact an expert centre for advice (see the list at http://www.porphyria-europe.com), which is likely to recommend that the patient be monitored as follows:
1. Measure porphyrin and porphobilinogen before starting treatment.
2. Repeat the measurement at regular intervals or if the patient has symptoms in keeping with an acute attack. If there is an increase in the precursor levels, stop the treatment and consider giving haem arginate for acute attack (see below).
In treatment of the acute attack the rationale is to use means of reducing D-ALA synthase activity. Haem arginate (human haematin) infusion, by replenishing haem and so removing the stimulus to D-ALA synthase, is effective if given early, and may prevent chronic neuropathy. Additionally, attention to nutrition, particularly the supply of carbohydrate, relief of pain (with an opioid), and of hypertension and tachycardia (with a β-adrenoceptor blocker) are important. Hyponatraemia is a frequent complication, and plasma electrolytes should be monitored.
The environment and social habits
Drug metabolism may be increased by hepatic enzyme induction from insecticide accumulation, e.g. dicophane (DDT), and from alcohol use and the tobacco habit, e.g. smokers require a higher dose of theophylline. Antimicrobials used in feeds of animals for human consumption have given rise to concern in relation to the spread of resistant bacteria that may affect man. Penicillin in the air of hospitals or in milk (see below) may cause allergy.
Allergy in response to drugs
Allergic reactions to drugs are the result of the interaction of drug or metabolite (or a non-drug element in the formulation) with patient and disease, and subsequent re-exposure.
Lack of previous exposure is not the same as lack of history of previous exposure, and ‘first dose reactions’ are among the most dramatic. Exposure is not necessarily medical, e.g. penicillins may occur in dairy products following treatment of mastitis in cows (despite laws to prevent this), and penicillin antibodies are commonly present in those who deny ever having received the drug. Immune responses to drugs may be harmful in varying degrees (allergy) or harmless; the fact that antibodies are produced does not mean a patient will necessarily respond to re-exposure with clinical manifestations; most of the UK population has antibodies to penicillins but, fortunately, comparatively few react clinically to penicillin administration.
While macromolecules (proteins, peptides, dextran polysaccharides) can act as complete antigens, most drugs are simple chemicals (mol. wt. less than 1000) and act as incomplete antigens or haptens, which become complete antigens in combination with a body protein.
The chief target organs of drug allergy are the skin, respiratory tract, gastrointestinal tract, blood and blood vessels.
Allergic reactions in general may be classified according to four types of hypersensitivity, and drugs can elicit reactions of all types.
Type I reactions: immediate or anaphylactic type
The drug causes formation of tissue-sensitising immunoglobulin (Ig) E antibodies that are fixed to mast cells or leucocytes. On subsequent administration the allergen (conjugate of drug or metabolite with tissue protein) reacts with these antibodies, activating but not damaging the cell to which they are fixed and causing release of pharmacologically active substances, e.g. histamine, leukotrienes, prostaglandins, platelet activating factor, and causing effects such as urticaria, anaphylactic shock and asthma. Allergy develops within minutes and lasts for 1–2 h: it may of course be fatal.
Type II reactions: antibody-dependent cytotoxic type
The drug or metabolite combines with a protein in the body so that the body no longer recognises the protein as self, treats it as a foreign protein and forms antibodies (IgG, IgM) that combine with the antigen and activate complement which damages cells, e.g. penicillin- or methyldopa-induced haemolytic anaemia.
Type III reactions: immune complex-mediated type
Antigen and antibody form large complexes and activate complement. Small blood vessels are damaged or blocked. Leucocytes attracted to the site of reaction engulf the immune complexes and release pharmacologically active substances (including lysosomal enzymes), starting an inflammatory process.
These reactions include serum sickness, glomerulonephritis, vasculitis and pulmonary disease.
Type IV reactions: lymphocyte-mediated type
Antigen-specific receptors develop on T lymphocytes. Subsequent administration leads to a local or tissue allergic reaction, e.g. contact dermatitis.
Cross-allergy
within a group of drugs is usual, e.g. the penicillins. (The extent of cross-reaction with cephalosporins is highly controversial). When allergy to a particular drug is established, select a substitute from a chemically different group. Patients with allergic diseases (atopy), e.g. eczema, are more likely to develop allergy to drugs.
The distinctive features of allergic reactions are16:
• Lack of correlation with known pharmacological properties of the drug.
• Lack of linear relation with drug dose (very small doses may cause very severe effects).
• Rashes, angioedema, serum sickness syndrome, anaphylaxis or asthma; characteristics of classic protein allergy.
• Requirement of an induction period on primary exposure, but not on re-exposure.
• Disappearance on cessation of administration and reappearance on re-exposure to a small dose.
• Occurrence in a minority of patients receiving the drug.
• Possible response to desensitisation.
Principal clinical manifestations and treatment
1. Urticarial rashes and angioedema (types I, III)
These are probably the commonest type of drug allergy. Reactions may be generalised, but frequently are worst in and around the external area of administration of the drug. The eyelids, lips and face are usually most affected and itching is usual; oedema of the larynx is rare but may be fatal. They respond to adrenaline/epinephrine, ephedrine, H1-receptor antihistamine and adrenal steroid (see below).
2a. Non-urticarial rashes (types I, II, IV)
These occur in great variety; frequently they are weeping exudative lesions. It is often difficult to be sure when a rash is due to a drug. Apart from stopping the drug, treatment is non-specific; in severe cases an adrenal steroid should be used. Skin sensitisation to antimicrobials may be very troublesome, especially among those who handle them (see Ch. 17 for more detail).
2b. Diseases of the lymphoid system
Infectious mononucleosis (and lymphoma, leukaemia) is associated with an increased incidence (> 40%) of a characteristic maculopapular, sometimes purpuric, rash which is probably allergic, when an aminopenicillin (ampicillin, amoxicillin) is taken; patients may not be allergic to other penicillins. Erythromycin may cause a similar reaction.
3. Anaphylactic shock (type I)
occurs with penicillin, anaesthetics (intravenous), iodine-containing radio-contrast media and a huge variety of other drugs. A severe fall in blood pressure occurs, with bronchoconstriction, angioedema (including larynx) and sometimes death due to loss of fluid from the intravascular compartment and respiratory obstruction. Anaphylactic shock usually occurs suddenly, in less than an hour after the drug, but within minutes if it has been given intravenously.
Treatment is urgent. The following account combines advice from the UK Resuscitation Council with comment on the action of the drugs used. Advice on the management of anaphylactic shock is altered periodically and the reader should check the relevant website (http://www.resus.org.uk) for the latest information.
• In adults, 500 micrograms of adrenaline/epinephrine injection (0.5 mL of the 1 in 1000 solution) should be given intramuscularly to raise the blood pressure and dilate the bronchi (vasoconstriction renders the subcutaneous route less effective). If there is no clinical improvement, further intramuscular injections of adrenaline/epinephrine 500 micrograms should be given at 5-min intervals according to blood pressure, pulse and respiration. (See website for doses in those <12 years.)
• If shock is profound, cardiopulmonary resuscitation/advanced life support are necessary. Consider also giving adrenaline/epinephrine 1: 10 000 by slow intravenous infusion, at a rate of 100 micrograms/min (1 mL/min of the dilute 1 in 10 000 solution over 5 min), preferably with continuous ECG monitoring, stopping when a response has been obtained. This procedure is hazardous and should be undertaken only by an experienced practitioner who can obtain immediate intravenous access and where other resuscitation facilities are available.
• The adrenaline/epinephrine should be accompanied by an H1-receptor antihistamine, e.g. chlorphenamine 10–20 mg intramuscularly or by slow intravenous injection, and by hydrocortisone 200–500 mg intramuscularly or by slow intravenous injection. The adrenal steroid acts by reducing vascular permeability and by suppressing further response to the antigen–antibody reaction. Benefit from an adrenal steroid is not immediate; it is unlikely to begin for 30 min and takes hours to reach its maximum.
• In severe anaphylaxis, hypotension is due to vasodilatation and loss of circulating volume through leaky capillaries. Thus, when there is no response to drug treatment, 1–2 L of plasma substitute should be infused rapidly. Crystalloid may be safer than colloid, which causes more allergic reactions.
• Where bronchospasm is severe and does not respond rapidly to other treatment, a β2-adrenoceptor agonist is a useful adjunctive measure. Noradrenaline/norepinephrine lacks any useful bronchodilator action (β effect) (see Adrenaline, Ch. 24).
• Where susceptibility to anaphylaxis is known, e.g. in patients with allergy to bee or wasp stings, preventive self-management is feasible. The patient is taught to administer adrenaline/epinephrine intramuscularly from a pre-filled syringe (EpiPen Auto-injector, delivering adrenaline/epinephrine 300 micrograms per dose).
• Half of the above doses of adrenaline/epinephrine may be safer for patients who are receiving amitriptyline or imipramine (increased effect; see p. 318).
Any hospital ward or other place where anaphylaxis may be anticipated should have all the drugs and equipment necessary to deal with it in one convenient kit, for when they are needed there is little time to think and none to run about from place to place (see also Pseudo-allergic reactions, p. 118).
4a. Pulmonary reactions: asthma (type I)
Aspirin and other non-steroidal anti-inflammatory drugs may cause bronchoconstriction, and not only in asthmatic patients. Abnormal levels of leukotrienes synthesis following blockade of cyclo-oxygenase may be causal; this is a pseudo-allergic reaction (see below). Another such reaction is the well-known occurrence of cough due to angiotensin-converting enzyme inhibitors: in this case, pro-inflammatory peptides such as bradykinin accumulate and trigger cough.
4b. Other types of pulmonary reaction (type III)
include syndromes resembling acute and chronic lung infections, pneumonitis, fibrosis and eosinophilia.
5. The serum sickness syndrome (type III)
This occurs about 1–3 weeks after administration. Treatment is by an adrenal steroid, and as above if there is urticaria.
6. Blood disorders17
6a. Thrombocytopenia (type II, but also pseudo-allergic)
may occur after exposure to any of a large number of drugs, including: gold, quinine, quinidine, rifampicin, heparin, thionamide derivatives, thiazide diuretics, sulphonamides, oestrogens, indometacin. Adrenal steroid may help.
6b. Granulocytopenia (type II, but also pseudo-allergic),
sometimes leading to agranulocytosis, is a very serious reaction which may occur with many drugs, e.g. clozapine, carbamazepine, carbimazole, chloramphenicol, sulphonamides (including diuretic and hypoglycaemic derivatives), colchicine, gold.
The value of precautionary leucocyte counts for drugs having special risk remains uncertain.18 Weekly counts may detect presymptomatic granulocytopenia from antithyroid drugs, but onset can be sudden and an alternative view is to monitor only with drugs having special risk, e.g. clozapine, where it is mandatory. The chief clinical manifestation of agranulocytosis is sore throat or mouth ulcers, and patients should be warned to report such events immediately and to stop taking the drug, but they should not be frightened into non-compliance with essential therapy. Treatment of the agranulocytosis involves both stopping the drug responsible and giving a bactericidal drug, e.g. a penicillin, to prevent or treat infection.
6c. Aplastic anaemia (type II, but not always allergic)
Causal agents include chloramphenicol, sulphonamides and derivatives (diuretics, antidiabetics), gold, penicillamine, allopurinol, felbamate, phenothiazines and some insecticides, e.g. dicophane (DDT). In the case of chloramphenicol, bone marrow depression is a normal pharmacodynamic effect, although aplastic anaemia may also be due to idiosyncrasy or allergy.
Death occurs in about 50% of cases, and treatment is as for agranulocytosis, with, obviously, blood transfusion.
6d. Haemolysis of all kinds
is included here for convenience. There are three principal categories:
• Allergy (type II) occurs with penicillins, methyldopa, levodopa, quinine, quinidine, sulfasalazine and organic antimony. In some of these cases a drug–protein–antigen/antibody interaction may involve erythrocytes only casually, i.e. a true ‘innocent bystander’ phenomenon.
• Dose-related pharmacodynamic action on normal cells, e.g. lead, benzene, phenylhydrazine, chlorates (weed-killer), methyl chloride (refrigerant), some snake venoms.
• Idiosyncrasy (see Pharmacogenetics). Precipitation of a haemolytic crisis may also occur with the above drugs in the rare genetic haemoglobinopathies. Treatment is to withdraw the drug, and an adrenal steroid is useful in severe cases if the mechanism is immunological. Blood transfusion may be needed.
7 Fever
is common; a mechanism is the release of interleukin-1 by leucocytes into the circulation; this acts on receptors in the hypothalamic thermoregulatory centre, releasing prostaglandin E1.
8 Collagen diseases (type II)
and syndromes resembling them. Systemic lupus erythematosus is sometimes caused by drugs, e.g. hydralazine, procainamide, isoniazid, sulphonamides. Adrenal steroid is useful.
9 Hepatitis and cholestatic jaundice
are sometimes allergic (see Drugs and the liver, Ch. 34). Adrenal steroid may be useful.
10 Nephropathy
of various kinds (types II, III) occurs, as does damage to other organs, e.g. myocarditis. Adrenal steroid may be useful.
Diagnosis of drug allergy
This still depends largely on clinical criteria, history, type of reaction, response to withdrawal and systemic re-challenge (if thought safe to do so).
Simple patch skin testing is naturally most useful in diagnosing contact dermatitis, but it is unreliable for other allergies. Skin prick tests are helpful in specialist hands for diagnosing IgE-dependent drug reactions, notably due to penicillin, cephalosporins, muscle relaxants, thiopental, streptokinase, cisplatin, insulin and latex. They can cause anaphylactic shock. False-positive results occur.
Development of reliable in vitro predictive tests, e.g. employing serum or lymphocytes, is a matter of considerable importance, not merely to remove hazard but also to avoid depriving patients of a drug that may be useful. Detection of drug-specific circulating IgE antibodies by the radioallergosorbent test (RAST) is best developed for many drugs and other allergens.
Drug allergy, once it has occurred, is not necessarily permanent, e.g. less than 50% of patients giving a history of allergy to penicillin have a reaction if it is given again, but re-challenging is best avoided if possible!
Desensitisation
Once patients become allergic to a drug, it is better that they should never again receive it. Desensitisation may be considered (in hospital) where a patient has suffered an IgE-mediated reaction to penicillin and requires the drug for serious infection, e.g. meningitis or endocarditis. Such people can be desensitised by giving very small amounts of allergen, which are than gradually increased (usually every few hours) until a normal dose is tolerated.
The procedure may necessitate cover with a corticosteroid and a β-adrenoceptor agonist (both of which inhibit mediator synthesis and release), and an H1-receptor antihistamine may be added if an adverse reaction occurs. A full kit for treating anaphylactic shock should be at hand. Desensitisation may also be carried out for other antimicrobials, e.g. antituberculous drugs.
The mechanism underlying desensitisation may involve the production by the patient of blocking antibodies that compete successfully for the allergen but whose combination with it is innocuous; or the threshold of cells to the triggering antibodies may be raised. Sometimes allergy is to an ingredient of the preparation other than the essential drug, and merely changing the preparation is sufficient. Impurities are sometimes responsible, and purified penicillins and insulins reduce the incidence of reactions.
Prevention of allergic reactions
Prevention is important because these reactions are unpleasant and may be fatal; it provides good reason for taking a drug history. Patients should always be told if there is reason to believe they are allergic to a drug.
When looking for an alternative drug to avoid an adverse reaction, it is important not to select one from the same chemical group, as may inadvertently occur because the proprietary name gives no indication of the nature of the drug. This is another good reason for using the non-proprietary (generic) names as a matter of course.
If a patient claims to be allergic to a drug then that drug should not be given without careful enquiry that may include testing (above). Neglect of this has caused death.
Pseudo-allergic reactions
These are effects that mimic allergic reactions but have no immunological basis and are largely genetically determined. They are due to release of endogenous, biologically active substances, e.g. histamine and leukotrienes, by the drug. A variety of mechanisms is probably involved, direct and indirect, including complement activation leading to formation of polypeptides that affect mast cells, as in true immunological reactions. Some drugs may produce both allergic and pseudo-allergic reactions.
Pseudo-allergic effects mimicking type I reactions (above) are called anaphylactoid; they occur with aspirin and other non-steroidal anti-inflammatory drugs and with N-acetylcysteine(indirect action as above) (see also Pulmonary reactions, above); corticotropin (direct histamine release); intravenous anaesthetics and a variety of other drugs given intravenously (morphine, tubocurarine, dextran, radiographic contrast media) and inhaled (cromoglicate). Severe cases are treated as for true allergic anaphylactic shock (above), from which, at the time, they are not distinguishable.
Type II reactions are mimicked by the haemolysis induced by drugs (some antimalarials, sulphonamides and oxidising agents) and food (broad beans) in subjects with inherited abnormalities of erythrocyte enzymes or haemoglobin.
Type III reactions are mimicked by nitrofurantoin (pneumonitis) and penicillamine (nephropathy). Lupus erythematosus due to drugs (procainamide, isoniazid, phenytoin) may be pseudo-allergic.
Miscellaneous adverse reactions
Transient reactions to intravenous injections are fairly common, resulting in hypotension, renal pain, fever or rigors, especially if the injection is very rapid.
Effects of prolonged administration: chronic organ toxicity
Although the majority of adverse events occur within days or weeks after a drug is administered, some reactions develop only after months or years of exposure. In general, pharmacovigilance programmes reveal such effects; once recognised, they demand careful monitoring during chronic drug therapy for their occurrence may carry serious consequences for the patient (and the non-vigilant doctor, medicolegally). Descriptions of such reactions appear with the accounts of relevant drugs; some examples are given.
Eye
Toxic cataract can be due to chloroquine and related drugs, adrenal steroids (topical and systemic), phenothiazines and alkylating agents. Corneal opacities occur with phenothiazines and chloroquine. Retinal injury develops with thioridazine (particularly, of the antipsychotics), chloroquine and indometacin, and visual field defects with vigabatrin.
Nervous system
Tardive dyskinesias occur with neuroleptics; polyneuritis with metronidazole; optic neuritis with ethambutol.
Lung
Amiodarone may cause pulmonary fibrosis. Sulfasalazine is associated with fibrosing alveolitis.
Kidney
Gold salts may cause nephropathy; see also analgesic nephropathy (p. 461).
Liver
Methotrexate may cause liver damage and hepatic fibrosis; amiodarone may induce steatohepatitis (fatty liver) (see also alcohol, p. 142).
Carcinogenesis:
see also Preclinical testing (Ch. 3). Mechanisms of carcinogenesis are complex; prediction from animal tests is uncertain and causal attribution in humans has finally to be based on epidemiological studies. The principal mechanisms are:
• Alteration of DNA (genotoxicity, mutagenicity). Many chemicals or their metabolites act by causing mutations, activating oncogenes; those substances that are used as medicines include griseofulvin and alkylating cytotoxics. Leukaemias and lymphomas are the most common malignancies.
• Immunosuppression. Malignancies develop in immunosuppressed patients, e.g. after organ transplantation and cancer chemotherapy. There is a high incidence of lymphoid neoplasm. Chlorambucil, melphalan and thiotepa present particular high relative risks. The use of immunosuppression in, e.g., rheumatoid arthritis, also increases the incidence of neoplasms.
• Hormonal. Long-term use of oestrogen replacement in postmenopausal women induces endometrial cancer. Combined oestrogen/progestogen oral contraceptives may both suppress and enhance cancers (see Ch. 38). Diethylstilbestrol caused vaginal adenosis and cancer in the offspring of mothers who took it during pregnancy in the hope of preventing miscarriage. It was used for this purpose for decades after its introduction in the 1940s, on purely theoretical grounds. Controlled therapeutic trials were not done and there was no valid evidence of therapeutic efficacy. Male fetuses developed non-malignant genital abnormalities.19
Carcinogenesis due to medicines follows prolonged drug exposure,20 i.e. months or years; the cancers develop most commonly over 3–5 years, but sometimes years after treatment has ceased. There is a higher incidence of secondary cancers in patients treated for a primary cancer.
Adverse effects on reproduction
The medical profession has a grave duty to refrain from all unessential prescribing for women of child-bearing potential of drugs with, say, less than 10–15 years of widespread use behind them. It is not sufficient safeguard merely to ask a woman if she is, or may be, pregnant, for it is also necessary to consider the possibility that a woman who is not pregnant at the time of prescribing may become so while taking the drug.
Testing of new drugs on animals for reproductive effects has been mandatory since the thalidomide disaster, even though the extrapolation of the findings to humans is uncertain (see Preclinical testing, Ch. 3). The placental transfer of drugs from the mother to the fetus is considered on page 86.
Drugs may act on the embryo and fetus:
• Directly (thalidomide, cytotoxic drugs, antithyroid drugs, aromatic retinoids, e.g. isotretinoin): any drug affecting cell division, enzymes, protein synthesis or DNA synthesis is a potential teratogen, e.g. many antimicrobials.
• Indirectly:
on the uterus (vasoconstrictors reduce blood supply and cause fetal anoxia, misoprostol causes uterine contraction leading to abortion)
on the mother's hormone balance.
Early pregnancy
During the first week after fertilisation, exposure to antimetabolites, misoprostol, ergot alkaloids or diethylstilbestrol can cause abortion, which may not be recognised as such. The most vulnerable period for major anatomical abnormality is that of organogenesis which occurs during weeks 2–8 of intrauterine life (4–10 weeks after the first day of the last menstruation). After the organs are formed, abnormalities are less anatomically dramatic. Thus, the activity of a teratogen (teratos, monster) is most devastating soon after implantation, at doses that may not harm the mother and at a time when she may not know she is pregnant.
Drugs known to be teratogenic include cytotoxics, warfarin, alcohol, lithium, methotrexate, phenytoin, sodium valproate, angiotensin-converting enzyme (ACE) inhibitors and isotretinoin. Selective interference can produce characteristic anatomical abnormalities; the phocomelia (flipper-like) limb defect was one factor that caused the effects of thalidomide to be recognised so readily (see p. 63).
Innumerable drugs have come under suspicion. Those subsequently found to be safe include diazepam (but see below), oral contraceptives, spermicides and salicylates. Naturally, the subject is a highly emotional one for prospective parents. A definitive list of unsafe drugs is not practicable. Much depends on the dose taken and at what stage of pregnancy. The best advice is to follow current literature.
Late pregnancy
Because the important organs are well formed, drugs will not cause the gross anatomical defects that can occur following exposure in early pregnancy. Administration of hormones, androgens or progestogens can cause fetal masculinisation; iodide and antithyroid drugs in high dose can cause fetal goitre, as can lithium; tetracyclines can interfere with tooth and bone development, ACE inhibitors are associated with renal tubular dysgenesis and a skull ossification defect. Tobacco smoking retards fetal growth; it does not cause anatomical abnormalities in humans as far as is known.
Inhibitors of prostaglandin synthesis (aspirin, indometacin) may delay onset of labour and, in the fetus, cause closure of the ductus arteriosus, patency of which is dependent on prostaglandins.
The suggestion that congenital cataract (due to denaturation of lens protein) might be due to drugs has some support in humans. Chloroquine and chlorpromazine are concentrated in the fetal eye. As both can cause retinopathy, it would seem wise to avoid them in pregnancy if possible.
For a discussion of anticoagulants in pregnancy, see Chapter 29.
Drugs given to the mother just prior to labour can cause postnatal effects. CNS depressants may persist in and affect the baby for days after birth; vasoconstrictors can cause fetal distress by reducing uterine blood supply; β-adrenoceptor blockers may impair fetal response to hypoxia; sulphonamides displace bilirubin from plasma protein (risk of kernicterus).
Babies born to mothers dependent on opioids may show a physical withdrawal syndrome.
Drugs given during labour
Any drug that acts to depress respiration in the mother can cause respiratory depression in the newborn; opioid analgesics are notorious in this respect, but there can also be difficulty with any sedatives and general anaesthetics; they may also cause fetal distress by reducing uterine blood flow, and prolong labour by depressing uterine muscle.
Diazepam (and other depressants) in high doses may cause hypotonia in the baby and possibly interfere with suckling. There remains the possibility of later behavioural effects due to impaired development of the central nervous system from psychotropic drugs use during pregnancy; such effects are known in animals.
Detection of teratogens
Anatomical abnormalities are the easiest to detect. Non-anatomical (functional) effects can also occur; they include effects on brain biochemistry that may have late behavioural consequences.
There is a substantial spontaneous background incidence of birth defect in the community (up to 2%), so the detection of a low-grade teratogen that increases the incidence of one of the commoner abnormalities presents an intimidating task. In addition, most teratogenic effects are probably multifactorial. In this emotionally charged area it is indeed hard for the public, and especially for parents of an affected child, to grasp that:
The concept of absolute safety of drugs needs to be demolished … In real life it can never be shown that a drug (or anything else) has no teratogenic activity at all, in the sense of never being a contributory factor in anybody under any circumstances. This concept can neither be tested nor proved.
Let us suppose for example, that some agent doubles the incidence of a condition that has natural incidence of 1 in 10 000 births. If the hypothesis is true, then studying 20 000 pregnant women who have taken the drug and 20 000 who have not may yield respectively two cases and one case of the abnormality. It does not take a statistician to realise that this signifies nothing, and it may need ten times as many pregnant women (almost half a million) to produce a statistically significant result. This would involve such an extensive multicentre study that hundreds of doctors and hospitals have to participate. The participants then each tend to bend the protocol to fit in with their clinical customs and in the end it is difficult to assess the validity of the data.
Alternatively, a limited geographical basis may be used, with the trial going on for many years. During this time other things in the environment change, so again the results would not command our confidence. If it were to be suggested that there was something slightly teratogenic in milk, the hypothesis would be virtually untestable.
In practice we have to make up our minds which drugs may reasonably be given to pregnant women. Do we start from a position of presumed guilt or from one of presumed innocence? If the former course is chosen then we cannot give any drugs to pregnant women because we can never prove that they are completely free of teratogenic influence. It therefore seems that we must start from a position of presumed innocence and then take all possible steps to find out if the presumption is correct.
Finally, we must put things in perspective by considering the benefit/risk ratio. The problem of prescription in pregnancy cannot be considered from the point of view of only one side of the equation. Drugs are primarily designed to do good, and if a pregnant woman is ill it is in the best interests of her baby and herself that she gets better as quickly as possible. This often means giving her drugs. We can argue about the necessity of giving drugs to prevent vomiting, but there is no argument about the need for treatment of women with meningitis, septicaemia or HIV.
What we must try to avoid is medication by the media or prescription by politicians. A public scare about a well-tried drug will lead to wider use of less-tried alternatives. We do not want to be forced to practise the kind of defensive medicine that is primarily designed to avoid litigation.21
Male reproductive function
Impotence may occur with drugs affecting autonomic sympathetic function, e.g. many antihypertensives.
Spermatogenesis is reduced by a number of drugs including sulfasalazine and mesalazine (reversible), cytotoxic anticancer drugs (reversible and irreversible) and nitrofurantoin. There has been a global decline in sperm concentration and an environmental cause, e.g. chemicals that possess oestrogenic activity, seems likely.
Causation of birth defects due to abnormal sperm remains uncertain.
Guide to further reading
Aronson J.K. Routes of drug administration: uses and adverse effects. Part 1: intramuscular and subcutaneous injection. Drug Ther. Bull. 2008;253:971–974. (also Part 2: sublingual, buccal, rectal, and some other routes. 254, 975–978)
Aronson J.K., Ferner R.E. Joining the DoTS: new approach to classifying adverse drug reactions. Br. Med. J.. 2003;327:1222–1225.
Baxter K., Sharp J.M. Adverse drug interactions. Drug Ther. Bull.. 2008;248:952–954.
Eigenmann P.A., Haenggeli C.A. Food colourings and preservatives – allergy and hyperactivity. Lancet. 2004;364:823–824.
Ferner R.E., McDowell S.E. Doctors charged with manslaughter in the course of medical practice, 1795–2005: a literature review. J. R. Soc. Med.. 2006;99:309–314.
Gray J. Why can't a woman be more like a man? Clin. Pharmacol. Ther.. 2007;82:15–17.
Greenhalgh T., Kostopoulou O., Harries C. Making decisions about benefits and harms of medicines. Br. Med. J.. 2004;329:47–50.
Peters T.J., Sarkany R. Porphyria for the general physician. Clin. Med. (Northfield Il). 2005;5:275–281.
Strickler B.H.C., Psaty B.M. Detection, verification, and quantification of adverse drug reactions. Br. Med. J.. 2004;329:44–47.
Trontell A. Expecting the unexpected – drug safety, pharmacovigilance and the prepared mind. N. Engl. J. Med.. 2004;351:1385–1387.
Woosley R.L. Discovering adverse reactions: why does it take so long? Clin. Pharmacol. Ther.. 2004;76:287–289.
1 From: The remedy worse than the disease. Matthew Prior (1664–1721).
2 A principle appreciated by Paracelsus 500 years ago, who stated that ‘All things are poisons and there is nothing that is harmless; the dose alone decides that something is no poison’. The physician, alchemist and philosopher is regarded as the founder of chemical therapeutics; he was the first to use carefully measured doses of mercury to treat syphilis.
3 Journal of the American Medical Association 1975 234:1236.
4 After Jick H 1977 The discovery of drug-induced illness. New England Journal of Medicine 296:481–485.
5 Scott J L, Finegold S M, Belkin G A, Lawrence J S 1965 A controlled double-blind study of the hematologic toxicity of chloramphenicol. New England Journal of Medicine 272:1137–1142.
6 Pirmohamed M, James S, Meakin S et al 2004 Adverse drug reactions as a cause of admission to hospital: prospective analysis of 18 820 patients. British Medical Journal 329:15–19.
7 Gandhi T K, Weingart S N, Borus J et al 2003 Adverse events in ambulatory care. New England Journal of Medicine 348:1556–1564.
8 Ferner R E, Whittington R M 1994 Coroner's cases of death due to errors in prescribing or giving medicines or to adverse drug reactions: Birmingham 1986–1991. Journal of the Royal Society of Medicine 87:145–148.
9 Ferner R E 2000 Medication errors that have led to manslaughter charges. British Medical Journal 321:1212–1216.
10 Noted for his advocacy of the use of ‘the simple carpenter's saw’ in surgery.
11 Gull D G, Langford N J 2006 Drugs and driving. Adverse Drug Reactions Bulletin 238:911–914.
12 Nordic countries require that medicines liable to impair ability to drive or to operate machinery be labelled with a red triangle on a white background. The scheme covers antidepressants, benzodiazepines, hypnotics, drugs for motion sickness and allergy, cerebral stimulants, antiepileptics and antihypertensive agents. In the UK there are some standard labels that pharmacists are recommended to apply, e.g. ‘Warning. May cause drowsiness. If affected do not drive or operate machinery. Avoid alcoholic drink’.
13 Fogel B S 1983 New England Journal of Medicine 308:1600.
14 The view that King George III suffered from acute porphyria is widely expressed but erroneous: his illness was probably bipolar disorder (Peters T 2011 King George III, bipolar disorder, porphyria and lessons for historians. Clinical Medicine 11:261–264).
15 Department of Medical Biochemistry, University Hospital of Wales, Cardiff, UK. We are grateful to Dr Badminton for contributing the section on porphyria.
16 Assem E-S K 1998 Drug allergy and tests for its detection. In: Davies D M (ed) Davies's textbook of adverse drug reactions. Chapman and Hall, London, p. 790.
17 Where cells are being destroyed in the periphery and production is normal, transfusion is useless or nearly so, as the transfused cells will be destroyed, though in an emergency even a short cell life (platelets, erythrocytes) may tip the balance usefully. Where the bone marrow is depressed, transfusion is useful and the transfused cells will survive normally.
18 In contrast to the case of a drug causing bone marrow depression as a pharmacodynamic dose-related effect, when blood counts are part of the essential routine monitoring of therapy, e.g. cytotoxics.
19 Herbst A L 1984 Diethylstilboestrol exposure – 1984 [effects of exposure during pregnancy on mother and daughters]. New England Journal of Medicine 311:1433–1435.
20 Carcinogens that are effective as a single dose in animals are known, e.g. nitrosamines.
21 By permission from Smithells R W 1983 In: Hawkins D F (ed) Drugs and pregnancy. Churchill Livingstone, Edinburgh.