CLINICAL PHARMACOLOGY 2003 (PART 10)

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CLINICAL PHARMACOLOGY 2003 (PART 10)

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Background Definitions Causation: degrees of certainty Pharmacovigilance and pharmacoepidemiology Classification Causes Allergy in response to drugs Effects of prolonged administration: chronic organ toxicity Adverse effects on reproduction Background Cur'd 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 mankind, in its desire to avoid suffering and death, that decides that some of the biological effects of drugs are desirable (therapeutic) and others are undesirable (adverse). In addition to this arbitrary division, which has no fundamental biological basis, 1 From, The remedy worse...

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  1. 8 Unwanted effects and adverse drug reactions SYNOPSIS unwanted effects of drugs are promoted, or even caused, by numerous nondrug factors. Because of Background the variety of these factors, attempts to make a Definitions simple account of the unwanted effects of drugs Causation: degrees of certainty must be imperfect. Pharmacovigilance and There is general agreement that drugs prescribed pharmacoepidemiology for disease are themselves the cause of a serious Classification amount of disease (adverse reactions), ranging from Causes mere inconvenience to permanent disability and Allergy in response to drugs death. Effects of prolonged administration: chronic Since drugs are intended to relieve suffering, organ toxicity patients find it peculiarly offensive that they can also Adverse effects on reproduction cause disease (especially if they are not forewarned). Therefore it is important to know how much dis- ease they do cause and why they cause it, so that preventive measures can be taken. It is not enough to measure the incidence of adverse reactions to drugs, their nature and their Background severity, though accurate data are obviously useful. It is necessary to take, or to try to take, into acc- Cur'd yesterday of my disease ount which effects are avoidable (by skilled choice I died last night of my physician.1 and use) and which are unavoidable (inherent in drug or patient). Also, different adverse effects Nature is neutral, i.e. it has no 'intentions' towards can matter to a different degree to different humans, though it is often unfavourable to them. It is people. mankind, in its desire to avoid suffering and death, Since there can be no hope of eliminating all that decides that some of the biological effects of adverse effects of drugs it is necessary to evaluate drugs are desirable (therapeutic) and others are patterns of adverse reaction against each other. One undesirable (adverse). In addition to this arbitrary drug may frequently cause minor ill-effects but division, which has no fundamental biological basis, pose no threat to life, though patients do not like it and may take it irregularly, to their own detriment. 1 From, The remedy worse than the disease. Matthew Prior Another drug may be pleasant to take, so that (1664-1721). patients take it consistently, with benefit, but it may 135
  2. 8 UNWANTED EFFECTS AND A D V E R S E DRUG REACTIONS rarely kill someone. It is not obvious which drug is altered by antibiotics; diuretic-induced hypokalaemia to be preferred. causing digoxin intolerance. Some patients, e.g. those with a history of allergy or previous reactions to drugs, are up to four times Intolerance means a low threshold to the normal more likely to have another adverse reaction, so pharmacodynamic action of a drug. Individuals that the incidence does not fall evenly. It is also vary greatly in their susceptibility to drugs, those at useful to discover the causes of adverse reactions, one extreme of the normal distribution curve being for such knowledge can be used to render avoid- intolerant of the drugs, those at the other, tolerant. able what are at present unavoidable reactions. Avoidable adverse effects will be reduced by Idiosyncrasy (see Pharmacogenetics) implies an more skilful prescribing and this means that inherent qualitative abnormal reaction to a drug, doctors, amongst all the other claims on their usually due to genetic abnormality, e.g. porphyria. time, must find time better to understand drugs, as well as to understand their patients and their diseases. Causation: degrees of conviction Definitions Reliable attribution of a cause-effect relationship provides the biggest problem in this field. The Many unwanted effects of drugs are medically following degrees of conviction assist in attributing trivial, and in order to avoid inflating the figures adverse events to drugs:2 of drug-induced disease, it is convenient to retain the term side-effects for minor effects of type A • Definite: time sequence from taking the drug is events/effects (p. 139). reasonable; event corresponds to what is known The term adverse reaction should be confined of the drug; event ceases on stopping the drug; to: harmful or seriously unpleasant effects occurr- event returns on restarting the drug (rarely ing at doses intended for therapeutic (including advisable). prophylactic or diagnostic) effect and which call • Probable: time sequence is reasonable; event for reduction of dose or withdrawal of the drug corresponds to what is known of the drug; event and/or forecast hazard from future administration; ceases on stopping the drug; event not it is effects of this order that are of importance in reasonably explained by patient's disease. evaluating drug-induced disease in the community. • Possible: time sequence is reasonable; event corresponds to what is known of the drug; event Toxicity implies a direct action of the drug, often at could readily have been result of the patient's high dose, damaging cells, e.g. liver damage from disease or other therapy. paracetamol overdose, eighth cranial nerve damage • Conditional: time sequence is reasonable; event from gentamicin. All drugs, for practical purposes, does not correspond to what is known of the are toxic in overdose and overdose can be absolute drug; event could not reasonably be explained or relative; in the latter case an ordinary dose may by the patient's disease. be administered but may be toxic due to an under- • Doubtful: event not meeting the above criteria. lying abnormality in the patient, e.g. disease of the kidney. Mutagenicity, carcinogenicity and terato- Recognition of adverse drug reactions. When an genicity (see index) are special cases of toxicity. unexpected event, for which there is no obvious cause, occurs in a patient already taking a drug, the Secondary effects are the indirect consequences possibility that it is drug-caused must always of a primary drug action. Examples are: vitamin deficiency or opportunistic infection which may occur in patients whose normal bowel flora has been Journal of the American Medical Association 1975 234: 1236. 136
  3. PH ARM A C O V I G I L A N C E AND P H A RM A C O E P I D EM I O LO GY 8 be considered. Distinguishing between natural pro- this effect is likely to remain undiscovered before gression of a disease and drug-induced deteriora- the drug is released for general prescribing; the tion is particularly challenging, e.g. sodium in effect should be detected by informal clinical antacid formulations may aggravate cardiac failure, observation or during any special tricyclic antidepressants may provoke epileptic postregistration surveillance and confirmed by a seizures, bronchospasm may be caused by aspirin case-control study (see p. 68), e.g. chloram- in some asthmatics. phenicol and aplastic anaemia; practolol and oculomucocutaneous syndrome. • Drug commonly induces an otherwise common illness: this effect will not be discovered by Pharmacovigilance and informal clinical observation. If very common, it pharmacoepidemiology may be discovered in formal therapeutic trials and in case-control studies, but if only moderately common it may require The principal methods of collecting data on adverse observational cohort studies, e.g. proarrhythmic reactions (pharmacovigilance) are: effects of antiarrhythmic drugs. • Experimental studies, i.e. formal therapeutic trials • Drug adverse effects and illness incidence in of Phases 1-3. These provide reliable data on intermediate range: both case-control and cohort only the commoner events as they involve studies may be needed. relatively small numbers of patients (hundreds); Some impression of the features of drug-induced they detect an incidence of up to about 1:200. illness can be gained from the following statistics: • Observational studies, where the drug is observed epidemiologically under conditions of normal • Adverse reactions cause 2-3% of consultations in use in the community, i.e. pharmaco- general practice. epidemiology. Techniques used for post- • Adverse reactions account for 5% of all hospital marketing (Phase 4) studies include the obser- admissions. vational cohort study and the case-control study. • Overall incidence in hospital inpatients is The systems are described on page 69. 10-20%, with possible prolongation of hospital stay in 2-10% of patients in acute medical wards. DRUG-INDUCED ILLNESS • A review of records of a Coroner's Inquests for a The discovery of drug-induced illness can be district with a population of 1.19 million (UK) analysed thus:3 during the period 1986-91 found that of 3277 inquests on deaths, 10 were due to errors of • Drug commonly induces an otherwise rare prescribing and 36 were caused by adverse drug illness: this effect is likely to be discovered by reactions.4 Nevertheless, 17 doctors in the UK clinical observation in the licensing were charged with manslaughter in the 1990s (premarketing) formal therapeutic trials and the compared with two in each of the preceding drug will almost always be abandoned; but some decades, a reflection of 'a greater readiness to call patients are normally excluded from such trials, the police or to prosecute'.5 e.g. pregnant women, and detection will then • Predisposing factors: age over 60 years or under occur later. one month, female, previous history of adverse • Drug rarely induces an otherwise common reaction, hepatic or renal disease. illness: this effect is likely to remain undiscovered. • Drug rarely induces an otherwise rare illness: 4 Ferner R E, Whittington R M 1994 Journal of the Royal Society of Medicine 87:145-148. 5 Ferner R E 2000 Medication errors that have led to 3 After: Jick H 1977 New England Journal of Medicine 296: manslaughter charges. British Medical Journal 321: 481-485. 1212-1216. 137
  4. 8 UNWANTED E F F E C T S AND A D V E R S E DRUG R E A C T I O N S • Adverse reactions most commonly occur early in This latter is sometimes forgotten and a drug is therapy (days 1-10). condemned as useless when it has been used in a dose or way which absolutely precluded a It is important to avoid alarmist or defeatist successful result; this can be regarded as a negative extremes of attitude. Many treatments are dangerous, adverse effect. e.g. surgery, electroshock, drugs, and it is irrational to accept the risks of surgery for biliary stones or hernia and refuse to accept any risk at all from PRACTICALITIES OF DETECTING drugs for conditions of comparable seriousness. RARE ADVERSE REACTIONS Many patients whose death is deemed to be For reactions with no background incidence the partly or wholly caused by drugs are dangerously number of patients required to give a good (95%) ill already; justified risks may be taken in the hope chance of detecting the effect is given in Table 8.1. of helping them; ill-informed criticism in such cases Assuming that three events are required before can act against the interest of the sick. On the other any regulatory or other action should be taken, it hand there is no doubt that some of these accidents shows the large number of patients that must be are avoidable. Avoidability is often more obvious monitored to detect even a relatively high incidence when reviewing the conduct of treatment after death, adverse effect. The problem can be many orders of i.e. with hindsight, than it was at the time. magnitude worse if the adverse reactions closely Sir Anthony Carlisle,6 in the first half of the 19th resemble spontaneous disease with a background century, said that 'medicine is an art founded on incidence in the population. conjecture and improved by murder'. Although medicine has advanced rapidly, there is still a ring Caution. About 80% of well people not taking any of truth in that statement to anyone who follows the drugs admit on questioning to symptoms (often introduction of new drugs and observes how, after several) such as are commonly experienced as the early enthusiasm, the reports of serious toxic lesser adverse reactions to drugs. These symptoms effects appear. The challenge is to find and avoid are intensified (or diminished) by administration of these, and indeed, the present systems for detecting a placebo. Thus, many (minor) symptoms may be adverse reactions came into being largely in the wake wrongly attributed to drugs. of the thalidomide, practolol and benoxaprofen disasters (see Ch. 5); they are now an increasingly sophisticated and effective part of medicines development. Classification Another cryptic remark of this therapeutic nihilist was 'digitalis kills people' and this is true. It is convenient to classify adverse reactions to William Withering in 1785 laid down rules for the drugs under the following headings: use of digitalis that would serve today. Neglect of these rules resulted in needless suffering for patients with heart failure for more than a century TABLE 8.1 Detecting rare adverse reactions7 until the therapeutic criteria were rediscovered. Expected incidence Required number of Any drug that is really worth using can do harm. of adverse reaction patients for event I event 2 events 3 events It is an absolute obligation on doctors to use only drugs I in 100 300 480 650 I in 200 600 960 1300 about which they have troubled to inform themselves. I in 1000 3000 4800 6500 I in 2000 6000 9600 13 000 I in 10000 30000 48000 65000 Effective therapy depends not only on the correct choice of drugs but also on their correct use. 7 By permission from, Safety requirements for the first use of 6 Noted for his advocacy of the use of 'the simple carpenter's new drugs and diagnostic agents in man. CIOMS (WHO) saw' in surgery. 1983. Geneva. 138
  5. CAUSES 8 Type A (Augmented) reactions will occur in A) reactions. Other drugs, e.g. antimicrobials, everyone if enough of the drug is given because have a tendency to cause allergy and may lead to they are due to excess of normal, predictable, bizarre (type B) reactions. Ingredients of a dose-related, pharmacodynamic effects. They are formulation, e.g. colouring, flavouring, sodium common and skilled management reduces their content, rather than the active drug may also incidence, e.g. postural hypotension, hypoglycaemia, cause adverse reactions. hypokalaemia. • The prescriber. Adverse reactions may occur Type B (Bizarre) reactions will occur only in because a drug is used for an inappropriately some people. They are not part of the normal long time (type C), at a critical phase in pharmacology of the drug, are not dose-related and pregnancy (type D), is abruptly discontinued are due to unusual attributes of the patient interact- (type E) or given with other drugs (interactions). ing with the drug. These effects are predictable Aspects of the two sections above, Classification where the mechanism is known (though predictive and Causes, appear throughout the book. Selected tests may be expensive or impracticable), otherwise topics are discussed below. they are unpredictable for the individual, although the incidence may be known. The class includes unwanted effects due to inherited abnormalities AGE (idiosyncrasy) (see Pharmacogenetics) and immuno- The very old and the very young are liable to be logical processes (see Drug allergy). These account intolerant of many drugs, largely because the for most drug fatalities. mechanisms for disposing of them in the body Type C (Chronic) reactions due to long-term are less efficient. The young, it has been aptly said, exposure, e.g. analgesic nephropathy, dyskinesias are not simply 'small adults' and 'respect for their with levodopa. pharmacokinetic variability should be added to the Type D (Delayed) effects following prolonged list of our senior citizens' rights'.8 The old are also exposure, e.g. carcinogenesis or short-term exposure frequently exposed to multiple drug therapy which at a critical time, e.g. teratogenesis. predisposes to adverse effects (see Prescribing for Type E (Ending of use) reactions, where dis- the elderly, p. 126). continuation of chronic therapy is too abrupt, e.g. of adrenal steroid causing rebound adrenocortical insufficiency, of opioid causing the withdrawal GENETIC CONSTITUTION syndrome. Inherited factors that influence response to drugs are discussed in general under Pharmacogenetics (p. 122). It is convenient here to describe the porphyrias, a specific group of disorders for which Causes careful prescribing is vital. The porphyrias comprise a number of rare, geneti- When an unusual or unexpected event, for which cally determined single enzyme defects in haem there is no evident natural explanation, occurs in a biosynthesis. Acute porphyrias (acute intermittent patient already taking a drug, the possibility that porphyria, variegate porphyria and hereditary the event is drug-caused must always be consi- coproporphyria) are characterised by severe attacks dered, and may be categorised as follows: of neurovisceral dysfunction precipitated principally by a wide variety of drugs (and also by alcohol, fasting, • The patient may be predisposed by age, genetic and infection); nonacute porphyrias (porphyria constitution, tendency to allergy, disease, cutanea tarda, erythropoietic protoporphyria and personality, habits. congenital erythropoietic porphyria) present with • The drug. Anticancer agents are by their nature cutaneous photosensitivity for which alcohol (and cytotoxic. Some drugs, e.g. digoxin, have steep dose-response curves and small increments of 8 dose are more likely to induce augmented (type Fogel B S 1983 New England Journal of Medicine 308:1600. 139
  6. 8 UNWANTED E F F E C T S AND A D V E R S E DRUG REACTIONS prescribed oestrogens in women) is the principle regularly, mostly with additions made as informa- provoking agent. tion becomes available. Updated information can In healthy people, forming haemoglobin for be obtained.9 their erythrocytes and haem-dependent enzymes, Use of a drug about which there is uncertainty the rate of haem synthesis is controlled by negative may be justified. Dr M. Badminton writes: 'Essential feedback according to the amount of haem present. treatment should never be withheld, especially for a When more haem is needed there is increased condition that is serious or life-threatening. The production of the rate-controlling enzyme delta- clinician should assess the severity of the condition aminolaevulinic acid (ALA) synthase which provides and the activity of the porphyria. If no recognised the basis of the formation of porphyrin precursors of safe option is available, a reasonable course is to: haem. But in people with porphyria one or other of 1. Measure urine porphyrin and porphobilinogen the enzymes that convert the various porphyrins before starting treatment. to haem is deficient and so porphyrins accumulate. 2. Repeat the measurement at regular intervals or if A vicious cycle occurs: less haem —> more ALA the patient has symptoms in keeping with an synthase —> more porphyrin precursors, the meta- acute attack. If there is an increase in the precursor bolism of which is blocked, and a clinical attack levels, stop the treatment and consider giving occurs. haem arginate for acute attack (see below). It is of interest that those who inherited acute 3. Contact an expert centre for advice.' intermittent porphyria and variegate porphyria suffered no biological disadvantage from the In the treatment of the acute attack it is rational natural environment and bred as well as the normal to use any safe means of depressing the formation population until the introduction of barbiturates of ALA-synthase. Haem arginate (human haematin) and sulphonamides. They are now at serious dis- infusion, by replenishing haem and so removing advantage, for many other drugs can precipitate the stimulus to ALA-synthase, is effective if given fatal acute attacks. early, and may prevent chronic neuropathy. Addi- The exact precipitating mechanisms are uncertain. tionally, attention to nutrition, particularly the supply Increase in the haem-containing hepatic oxidising of carbohydrate, relief of pain (with an opioid), and enzymes of the cytochrome P450 group causes of hypertension and tachycardia (with a (B-adreno- an increased demand for haem. Therefore drugs ceptor blocker) are important. Hyponatraemia is that induce these enzymes would be expected to a frequent complication, and plasma electrolytes precipitate acute attacks of porphyria and they do should be monitored. so; tobacco smoking may act by this mechanism. In the treatment of the acute attack it would seem Apparently unexplained attacks of porphyria should rational to use any safe means of depressing the be an indication for close enquiry into all possible formation of ALA-synthase. Indeed, haem arginate chemical intake. Guaiphenesin, for example, is (human haematin) infusion, by replenishing haem hazardous; it is included in a multitude of multi- and so removing the stimulus to ALA-synthase, ingredient cough medicines (often nonprescription). appears to be effective if given early, and may Patients must be educated to understand their prevent chronic neuropathy. Additionally, attention condition, to possess a list of safe and unsafe drugs, to nutrition, particularly the supply of carbohydrate, and to protect themselves from themselves and relief of pain (with opioid), and of hypertension from others, including prescribing doctors. and tachycardia (with propranolol) are important. The greatest care in prescribing for these patients is required if serious illness is to be avoided. THE ENVIRONMENT Patients (1 in 10 000 UK population) are so highly vulnerable that lists of drugs known or believed to Significant environmental factors causing adverse be unsafe are available, e.g. in the British National Formulary. Additionally, we provide a table of drugs 9 www.uwcm.ac.uk/study/medicine/medical_biochem/ considered safe for use in the acute porphyrias at porphyria.htm the time of publication (Table 8.2). The list is revised www.utc.ac.za/depts/liver/porphpts.htm 140
  7. CAUSES 8 TABLE 8.2 Drugs that are considered safe for use in acute porphyrias Acetazolamide Dextran Ibuprofen Pirenzepine Acetylcysteine Dextromethorphan Immunisations Prazosin Aciclovir Dextromoramide Immunoglobulins Prednisolone Adrenaline (epinephrine) Dextropropoxyphene Indomethacin Prilocaine Alfentanil Dextrose Insulin Primaquine Allopurinol Diamorphine Iron Probucol Alpha tocopheryl Diazoxide Isoflurane Procainamide Aluminium salts Dicyclomine (dicycloverine) Ispaghula Procaine Amantadine Diflunisal Ketoprofen Prochlorperazine Amethocaine (tetracaine) Digoxin Ketotifen Proguanil Amiloride Dihydrocodeine Lactulose Promazine Aminoglycosides Dimercaprol Leuproelin Promethazine Amitriptyline Dimeticone Levothyroxine Propantheline Amphotericin Diphenhydramine LHRH Propofol Ascorbic acid Diphenoxylate Lignocaine2 (lidocaine) Propylthiouracil Aspirin Dipyridamole Lisinopril3 Proxymetacaine Atropine Distigmine Lithium Pseudoephedrine Azathioprine Dobutamine Lofepramine Pyridoxine Beclomethasone Domperidone Loperamide Pyrimethamine Beta blockers Dopamine Loratadine Quinidine Bezafibrate Doxorubicin Lorazepam Quinine Bismuth Droperidol Magnesium sulphate Resorcinol Bromazepam Enalapril Meclozine Salbutamol Bumetanide Enoxaparin Mefloquine Senna Bupivacaine Epinephrine Melphalan Sodium acid phosph Buprenorphine Ethambutol Mequitazine Sodium bicarbonate Buserelin Ether Mesalazine Sodium fusidate Calcitonin Famciclovir Metformin Sodium valproate4 Calcium carbonate Fenbufen Methadone Sorbitol Carbimazole Fenofibrate Methotrimeprazine (levomepromazine) Streptokinase Chloral hydrate Fentanyl Methylphenidate Streptomycin Chloroquine Flucloxacillin1 Methylprednisolone Sucralfate Chlorothiazide Flucytosine Mianserin Sulindac Chlorpheniramine (chlorphenamine) Flumazenil Midazolam Suxamethonium Chlorpromazine Fluoxetine Morphine Temazepam Colestyramine Fluphenazine Naftidrofuryl Tetracaine Cisplatin Flurbiprofen Nalbuphine Thiamine Clobazam Fructose Naloxone Thyroxine (levothyroxine) Clofibrate FSH Naproxen Tiaprofenic acid Clomifene Gabapentin Neostigmine Tinzaparin Clonazepam Ganciclovir Nitrous oxide Tranexamic acid Co-amoxiclav Gemfibrozil Octreotide Triamterene Co-codamol Glipizide Omeprazole Triazolam Co-dydramol Glucagon Oxybuprocaine Trifluoperazine Codeine phosphate Glucose Oxytocin Trimeprazine Colchicine Glycopyrronium Pancuronium Urokinase Colestipol Gonadorelin Paracetamol Vaccines Corticosteroids Goserelin Paraldehyde Valaciclovir Corticotrophin GTN Penicillamine Valproate4 Cyclizine Guanethidine Penicillins Vancomycin Cyclopenthiazide Haloperidol Pentamidine Vigabatrin Cyclopropane Heparin Pethidine Vitamins Dalteparin Hetastarch Phentolamine Warfarin Danthron Hydrochlorothiazide Phytomenadione Zalcitabine Desferrioxamine Hydrocortisone Pipothiazine Zinc preparations This list is produced jointly by Professor G Elder and Dr M Badminton, the Department of Medical Biochemistry, University Hospital of Wales and the staff of the Welsh Medicines Information Centre (WMIC; fiona.woods@cardiffandvale.wales.nhs.uk). It is based on the best information available at the time of completion. Inclusion of a drug does not guarantee that it will be safe in all circumstances. 1 Large intravenous doses may be associated with acute attacks (unproven as causative agent). 2 Intravenous doses should be avoided. 3 Safety under review; contact WMIC. 4 Sodium valproate should be used only where other antiepilepsy drugs are ineffective or inappropriate. 141
  8. 8 U N W A N T E D E F F E C T S AND A D V E R S E DRUG REACTIONS reactions to drugs include simple pollution, e.g. skin, respiratory tract, gastrointestinal tract, blood penicillin in the air of hospitals or in milk (see and blood vessels. below), causing allergy. Allergic reactions in general may be classified Drug metabolism may also be increased by according to four types of hypersensitivity, and hepatic enzyme induction from insecticide accumu- drugs can elicit reactions of all types, namely: lation, e.g. dicophane (DDT) and from alcohol and the tobacco habit, e.g. smokers require a higher Type I reactions: immediate or anaphylactic type. dose of theophylline. The drug causes formation of tissue-sensitising IgE Antimicrobials used in feeds of animals for antibodies that are fixed to mast cells or leucocytes; human consumption have given rise to concern in on subsequent administration the allergen (conjugate relation to the spread of resistant bacteria that may of drug or metabolite with tissue protein) reacts affect man. with these antibodies, activating but not damaging the cell to which they are fixed and causing release of pharmacologically active substances, e.g. histamine, DRUG INTERACTIONS leukotrienes, prostaglandins, platelet activating factor, and causing effects such as urticaria, anaphy- (see p. 129) lactic shock and asthma. Allergy develops within minutes and lasts 1-2 hours. Type II reactions: antibody-dependent cytotoxic Allergy in response to type. The drug or metabolite combines with a drugs 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 com- Allergic reactions to drugs are the resultant of bine with the antigen and activate complement the interaction of drug or metabolite (or a nondrug which damages cells, e.g. penicillin- or methyldopa- element in the formulation) with patient and induced haemolytic anaemia. disease, and subsequent re-exposure. Lack of previous exposure is not the same as lack Type III reactions: immune complex-mediated of history of previous exposure, and 'first dose type. Antigen and antibody form large complexes reactions' are among the most dramatic. Exposure and activate complement. Small blood vessels is not necessarily medical, e.g. penicillins may occur are damaged or blocked. Leucocytes attracted to in dairy products following treatment of mastitis in the site of reaction engulf the immune complexes cows (despite laws to prevent this), and penicillin and release pharmacologically active substances antibodies are commonly present in those who deny (including lysosomal enzymes), starting an inflam- ever having received the drug. Immune responses matory process. These reactions include serum sick- to drugs may be harmful (allergy) or harmless; the ness, glomerulonephritis, vasculitis and pulmonary fact that antibodies are produced does not mean disease. a patient will necessarily respond to re-exposure with clinical manifestations; most of the UK popula- Type IV reactions: lymphocyte-mediated type. tion has antibodies to penicillins but, fortunately, Antigen-specific receptors develop on T-lympho- comparatively few react clinically to penicillin cytes. Subsequent administration leads to a local or administration. tissue allergic reaction, e.g. contact dermatitis. Whilst macromolecules (proteins, peptides, dex- tran polysaccharides) can act as complete antigens, Cross-allergy within a group of drugs is usual, e.g. most drugs are simple chemicals (mol. wt less than the penicillins. When allergy to a particular drug is 1000) and act as incomplete antigens or haptens, established, a substitute should be selected from a which become complete antigens in combination chemically different group. Patients with allergic with a body protein. diseases, e.g. eczema, are more likely to develop The chief target organs of drug allergy are the allergy to drugs. 142
  9. ALLERGY IN R E S P O N S E TO DRUGS 8 The distinctive features of allergic reactions are characteristic maculopapular, sometimes purpuric, their:10 rash which is probably allergic, when an amino- penicillin (ampicillin, amoxycillin) is taken; patients • Lack of correlation with known pharmacological may not be allergic to other penicillins. Erythromycin properties of the drug may cause a similar reaction. • Lack of linear relation with drug dose (very small doses may cause very severe effects) 3. Anaphylactic shock (type I) occurs with peni- • Rashes, angioedema, serum sickness syndrome, cillin, anaesthetics (i.v.), iodine-containing radio- anaphylaxis or asthma; characteristics of classic contrast media and a huge variety of other drugs. protein allergy A severe fall in blood pressure occurs, with broncho- • Requirement of an induction period on primary constriction, angioedema (including larynx) and exposure, but not on re-exposure sometimes death due to loss of fluid from the intra- • Disappearance on cessation of administration vascular compartment. Anaphylactic shock usually and reappearance on re-exposure occurs suddenly, in less than an hour after the drug, • Occurrence in a minority of patients receiving but within minutes if it has been given i.v. the drug • Temporary nature in some cases Treatment is urgent, as follows: • Possible response to desensitisation. • First, 500 micrograms of adrenaline (epinephrine) injection (0.5 ml of the 1 in 1000 solution) should PRINCIPAL CLINICAL be given i.m. to raise the blood pressure and to MANIFESTATIONS AND TREATMENT dilate the bronchi (vasoconstriction renders the s.c. route less effective). Up to 10% of patients may 1. Urticarial rashes and angioedema (types I, III). need a second injection 10-20 min later and These are probably the commonest type of drug subsequent injections may be given until the allergy. Reactions may be generalised, but frequently patient improves. Noradrenaline are worst in and around the external area of admin- (norepinephrine) lacks any useful bronchodilator istration of the drug. The eyelids, lips and face are action (p-effect) (see adrenaline, Chapter 23). usually most affected. They are usually accompa- • If treatment is delayed and shock has developed, nied by itching. Oedema of the larynx is rare but may adrenaline 500 micrograms should be given i.v. be fatal. They respond to adrenaline (epinephrine) by slow injection at a rate of 100 (i.m. if urgent), ephedrine, H1-receptor antihistamine micrograms/min (1 ml/min of the Dilute 1 in and adrenal steroid. 10 000 solution over 5 min) with continuous ECG monitoring, stopping when a response has been 2a. Nonurticarial rashes (types I, II, IV). These obtained. For greater control and safety, a further occur in great variety; frequently they are weeping x 10 dilution in dextrose may be preferred (i.e. a exudative lesions. It is often difficult to be sure solution of 1 in 100 000). when a rash is due to a drug. Apart from stopping • Note that preventive self-management is feasible the drug, treatment is nonspecific; in severe cases where susceptibility to anaphylaxis is known, an adrenal steroid should be used. Skin sensitisa- e.g. in patients with allergy to bee- or wasp- tion to antimicrobials may be very troublesome, stings. The patient is taught to administer especially amongst those who handle them (see adrenaline i.m. from a prefilled syringe (EpiPen Drugs and the Skin, Ch. 16, for more detail). Auto-injector, delivering adrenaline 300 micrograms per dose). 2b. Diseases of the lymphoid system. Infectious • The adrenaline should be accompanied by an H1- mononucleosis (and lymphoma, leukaemia) is asso- receptor antihistamine [say chlorpheniramine ciated with an increased incidence (> 40%) of (chlorphenamine) 10-20 mg by slow i.v. injection] and hydrocortisone (100-300 mg i.m. 10 Assem E-S K 1992 In: Davies D M (ed) Textbook of adverse or i.v.). The adrenal steroid may act by reducing drug reactions. Oxford University Press, London. vascular permeability and by suppressing 143
  10. 8 UNWANTED EFFECTS AND ADVERSE DRUG REACTIONS further response to the antigen-antibody number of drugs, including: gold, quinine, quini- reaction. Benefit from an adrenal steroid is not dine, rifampicin, heparin, thionamide derivatives, immediate; it is unlikely to begin for 30 minutes thiazide diuretics, sulphonamides, oestrogens, indo- and takes hours to reach its maximum. methacin. Adrenal steroid may help. • In severe anaphylaxis, hypotension is due to vasodilation and loss of circulating volume 6b. Granulocytopenia (type II, but also pseudo- through leaky capillaries. Colloid is more effective allergic) sometimes leading to agranulocytosis, is a at restoring blood volume than crystalloid and very serious allergy which may occur with many 1-21 of plasma substitute should be infused drugs, e.g. clozapine, carbamazepine, carbimazole, rapidly. Oxygen and artificial ventilation may be chloramphenicol, sulphonamides (including diuretic necessary. Advice on the management of and hypoglycaemic derivatives), colchicine, gold. anaphylactic shock may be altered from time to The value of precautionary leucocyte counts for time; check the UK Resuscitation Council website drugs having special risk remains uncertain.12 (www.resus.org.uk) for current information. Weekly counts may detect presymptomatic granulo- cytopenia from antithyroid drugs but onset can be Any hospital ward or other place where ana- sudden and an alternative view is to monitor only phylaxis may be anticipated should have all the with drugs having special risk, e.g. clozapine. The drugs and equipment necessary to deal with it in chief clinical manifestation of agranulocytosis is one convenient kit, for when they are needed there sore throat or mouth ulcers and patients should is little time to think and none to run about from be warned to report such events immediately and place to place (see also Pseudoallergic reactions, to stop taking the drug; but they should not p. 146). be frightened into noncompliance with essential therapy. Treatment of the agranulocytosis involves 4a. Pulmonary reactions: asthma (type I). Aspirin both stopping the drug responsible and giving a and other nonsteroidal anti-inflammatory drugs bactericidal drug, e.g. a penicillin, to prevent or may cause an asthmatic attack. Whether this is an treat infection. allergic or pseudoallergic reaction or a mixture of the two is uncertain. 6c. Aplastic anaemia (type II, but not always 4b. Other types of pulmonary reaction (type III) allergic). Causal agents include chloramphenicol, include syndromes resembling acute and chronic lung sulphonamides and derivatives (diuretics, antidiabe- infections, pneumonitis, fibrosis and eosinophilia. tics), gold, penicillamine, allopurinol, felbamate, phenothiazines and some insecticides, e.g. dicophane 5. The serum-sickness syndrome (type HI). This (DDT). In the case of chloramphenicol, bone marrow occurs about 1-3 weeks after administration. Treat- depression is a normal pharmacodynamic effect (type ment is by an adrenal steroid, and as above if there A reaction), although aplastic anaemia may also be is urticaria. due to idiosyncrasy or allergy (type B reaction). Death occurs in about 50% of cases, and treat- 6. Blood disorders11 ment is as for agranulocytosis, with, obviously, blood transfusion. 6a. Thrombocytopenia (type II, but also pseudo- allergic) may occur after exposure to any of a large 6d. Haemolysis of all kinds is included here for convenience. There are three principal categories: 11 • Allergy (type II) occurs with methyldopa, Where cells are being destroyed in the periphery and production is normal, transfusion is useless or nearly so, as levodopa, penicillins, quinine, quinidine, the transfused cells will be destroyed, though in an 12 emergency even a short cell life (platelets, erythrocytes) may In contrast to the case of a drug causing bone marrow tip the balance usefully. Where the bone marrow is depression as a pharmacodynamic dose-related effect, when depressed, transfusion is useful and the transfused cells will blood counts are part of the essential routine monitoring of survive normally. therapy, e.g. cytotoxics. 144
  11. ALLERGY IN RESPONSE TO DRUGS 8 sulfasalazine and organic antimony. It may be Development of reliable in-vitro predictive tests, that in some of these cases a drug-protein- e.g. employing serum or lymphocytes, is a matter of antigen/antibody interaction involves considerable importance, not merely to remove erythrocytes casually, i.e. a true 'innocent hazard but to avoid depriving patients of a drug bystander' phenomenon. that may be useful. Detection of drug-specific • Dose-related pharmacodynamic action on normal cells circulating IgE antibodies by the radioallergo- e.g. lead, benzene, phenylhydrazine, chlorates sorbent test (RAST) is best developed for penicillins (weed-killer), methyl chloride (refrigerant), some and succinyl choline. snake venoms. Drug allergy, once it has occurred, is not neces- • Idiosyncrasy (see Pharmacogenetics). sarily permanent, e.g. less than 50% of patients Precipitation of a haemolytic crisis may also giving a history of allergy to penicillin have a occur with the above drugs in the rare genetic reaction if it is given again. haemoglobinopathies. Treatment is to withdraw the drug, and an adrenal steroid is useful in DESENSITISATION severe cases if the mechanism is immunological. Blood transfusion may be needed. Once patients become allergic to a drug, it is better that they should never again come into contact 7. Fever is common; a mechanism is the release of with it. Desensitisation (in hospital) may be interleukin-1 by leucocytes into the circulation which considered where a patient has suffered an IgE- acts on receptors in the hypothalamic thermoregu- mediated reaction to penicillin and requires the drug latory centre, releasing prostaglandin E1. for serious infection, e.g. meningitis or endocarditis. Such people can be desensitised by giving very 8. Collagen diseases (type II) and syndromes small amounts of allergen, which are than gradually resembling them, e.g. systemic lupus erythematosus increased (usually every few hours) until a normal are sometimes caused by drugs, e.g. hydralazine, dose is tolerated. The procedure may necessitate procainamide, isoniazid, sulphonamides. Adrenal cover with a corticosteroid and a (B-adrenoceptor steroid is useful. agonist (both of which inhibit mediator synthesis and release), and an H-receptor antihistamine may be 9. Hepatitis and cholestatic jaundice are some- added if an adverse reaction occurs. A full kit for times allergic (type II, see Drugs and the Liver). treating anaphylactic shock should be at hand. Adrenal steroid may be useful. Desensitisation may also be carried out for other antimicrobials, e.g. antituberculosis drugs. 10. Nephropathy of various kinds (types II, III) The mechanism underlying desensitisation may occurs as does damage to other organs, e.g. myo- involve the production by the patient of blocking carditis. Adrenal steroid may be useful. antibodies that compete successfully for the allergen but whose combination with it is innocuous; or the threshold of cells to the triggering antibodies may DIAGNOSIS OF DRUG ALLERGY be raised. Sometimes allergy is to an ingredient This still depends largely on clinical criteria, of the preparation other than the essential drug history, type of reaction, response to withdrawal and merely changing the preparation is sufficient. and systemic rechallenge (if thought safe to do so). Impurities are sometimes responsible and purified Simple patch skin testing is naturally most useful penicillins and insulins reduce the incidence of in diagnosing contact dermatitis, but it is unreliable reactions. for other allergies. Skin prick tests are helpful in specialist hands for diagnosing IgE-dependent drug PREVENTION OF ALLERGIC reactions, notably due to penicillin, cephalosporins, REACTIONS muscle relaxants, thiopental, streptokinase, cis- platin, insulin and latex. They can cause anaphyl- Prevention is important since these reactions are actic shock. False positive results occur. unpleasant and may be fatal; it provides good 145
  12. 8 UNWANTED EFFECTS AND ADVERSE DRUG REACTIONS reason for taking a drug history. Patients should MISCELLANEOUS ADVERSE always be told when they are thought to be allergic REACTIONS to a drug. Transient reactions to intravenous injections are If a patient claims to be allergic to some drug then that fairly common, resulting in hypotension, renal drug should not be given without careful enquiry that may pain, fever or rigors, especially if the injection is include testing (as above); neglect of this had caused very rapid. death When looking for an alternative drug to avoid an Effects of prolonged adverse reaction it is important not to select one from the same chemical group, as may inadver- administration: chronic tently occur because the proprietary name gives no organ toxicity indication of the nature of the drug. This is another good reason for using the nonproprietary (generic) While the majority of adverse events occur within names as a matter of course. days or weeks after a drug is administered, some reactions develop only after months or years of ex- PSEUDOALLERGIC REACTIONS posure. In general, pharmacovigilance programmes reveal such effects; once recognised, they demand These are effects that mimic allergic reactions careful monitoring during chronic drug therapy for but have no immunological basis and are largely their occurrence may carry serious consequences genetically determined. They are due to release of for the patient (and the nonvigilant doctor, medico- endogenous, biologically active substances, e.g. legally). Descriptions of such (types C and D) histamine and leukotrienes, by the drug. A variety of reactions appear with the accounts of relevant mechanisms is probably involved, direct and drugs; some examples are: indirect, including complement activation leading to formation of polypeptides that affect mast cells, as in Eye. Toxic cataract can be due to chloroquine true immunological reactions. Some drugs may and related drugs, adrenal steroids (topical and produce both allergic and pseudoallergic reactions. systemic), phenothiazines and alkylating agents. Pseudoallergic effects mimicking type I reactions Corneal opacities occur with phenothiazines and (above) are called anaphylactoid and they occur with chloroquine. Retinal injury occurs with thioridazine aspirin and other nonsteroidal anti-inflammatory (particularly, of the antipsychotics), chloroquine and drugs (indirect action as above) (see also Pulmonary indomethacin. reactions, above); corticotrophin (direct histamine release); i.v. anaesthetics and a variety of other Nervous system. Tardive dyskinesias occur with drugs i.v. (morphine, tubocurarine, dextran, radio- neuroleptics; polyneuritis with metronidazole; graphic contrast media) and inhaled (cromoglicate). optic neuritis with ethambutol. Severe cases are treated as for true allergic ana- phylactic shock (above) from which, at the time, Lung. Amiodarone may cause pulmonary fibrosis. they are not distinguishable. Sulphasalazine is associated with fibrosing alveolitis. Type II reactions are mimicked by the haemo- Kidney. Gold salts may cause nephropathy; see lysis induced by drugs (some antimalarials, sulpho- also Analgesic nephropathy (p. 284). namides and oxidising agents) and food (broad beans) in subjects with inherited abnormalities of Liver. Methotrexate may cause liver damage and erythrocyte enzymes or haemoglobin (see p. 123). hepatic fibrosis; (see also alcohol p. 184). Type III reactions are mimicked by nitrofuran- toin (pneumonitis) and penicillamine (nephropathy). Carcinogenesis: see also Preclinical testing (p. 45). Lupus erythematosus due to drugs (procainamide, Mechanisms of carcinogenesis are complex; pre- isoniazid, phenytoin) may be pseudoallergic. diction from animal tests is uncertain and causal 146
  13. ADVERSE EFFECTS ON REPRODUCTION 8 attribution in man has finally to be based on epide- on reproduction has been mandatory since the miological studies. The principal mechanisms are: thalidomide disaster, even though the extrapolation of the findings to humans is uncertain (see Pre- • Alteration ofDNA (genotoxicity, mutagenicity). clinical testing, p. 47). The placental transfer of Many chemicals or their metabolites act by drugs from the mother to the fetus is considered on causing mutations, activating oncogenes; those page 98. substances that are used as medicines include griseofulvin and alkylating cytotoxics. Leukaemias and lymphomas are the most Drugs may act on the embryo and fetus: common malignancies. Directly (thalidomide, cytotoxic drugs, anti- • Immunosuppression.The immune system has a thyroid drugs, aromatic retinoids, e.g. isotretinoin): role in suppressing cancers (immune any drug affecting cell division, enzymes, protein surveillance). A wide range of cancers develop in synthesis or DNA synthesis, is a potential terato- immunosuppressed patients, e.g after organ gen, e.g. many antimicrobials. transplantation and cancer chemotherapy. Indirectly: • Hormonal. Long-term use of oestrogen • on the uterus (vasoconstrictors reduce blood replacement in postmenopausal women induces supply and cause fetal anoxia, misoprostol endometrial cancer. causes uterine contraction leading to abortion) Combined oestrogen/progestogen oral contra- • on the mother's hormone balance. ceptives may both suppress and enhance cancers (see pp. 719, 723). Early pregnancy. During the first week after ferti- Diethylstilbestrol caused vaginal adenosis and lisation, exposure to antimetabolites, misoprostol, cancer in the offspring of mothers who took it during ergot alkaloids or stilboesterol can cause abortion pregnancy in the hope of preventing miscarriage. It which may not be recognised as such. The most was used for this purpose for decades after its vulnerable period for major anatomical abnormal- introduction in the 1940s, on purely theoretical ity is that of organogenesis which occurs during grounds. Controlled therapeutic trials were not weeks 2-8 of intrauterine life (4-10 weeks after done and there is no valid evidence of therapeutic the first day of the last menstruation). After the efficacy. Male fetuses developed nonmalignant organs are formed, abnormalities are less anatom- genital abnormalities. ically dramatic. Thus the activity of a teratogen Carcinogenesis due to medicines requires that (teratos: monster) is most devastating soon after drug exposure be prolonged,13 i.e. months or years; implantation, at doses which may not harm the the cancers develop most commonly over 3-5 years mother and at a time when she may not know she and often years after treatment has ceased. is pregnant. Incidence of second cancers in patients treated Drugs known to be teratogenic include cyto- for primary cancer can be as high as 15 times the toxics, warfarin, alcohol, lithium, methotrexate, normal rate. The use of immunosuppression in, e.g. phenytoin, valproate, ACE inhibitors and isotreti- rheumatoid arthritis and organ transplants, also noin. Selective interference can produce character- increases the incidence of cancers. istic anatomical abnormalities, and the phocomelia (flipper-like) limb defect was one factor that caused thalidomide to be so readily recognised. (For an Adverse effects on account of thalidomide see p. 81.) Innumerable drugs have come under suspicion. reproduction Those for which evidence of safety was subsequently found include diazepam, oral contraceptives, Testing of new drugs on animals for their effects spermicides, and salicylates. Naturally the subject is a highly emotional one for prospective parents. A 13 definitive list of unsafe drugs is not practicable. Carcinogens that are effective as a single dose in animals are known, e.g. nitrosamines. Much depends on the dose taken and at what stage 147
  14. 8 UNWANTED EFFECTS AND ADVERSE DRUG REACTIONS of pregnancy. The topic must be followed in the general anaesthetics; they may also cause fetal current literature. distress by reducing uterine blood flow, and prolong labour by depressing uterine muscle. Late pregnancy. Because the important organs are Diazepam (and other depressants) in high doses already formed, drugs will not cause the gross ana- may cause hypotonia in the baby and possibly tomical defects that can occur when they are given interfere with suckling. There remains the possi- in early pregnancy. Administration of hormones, bility of later behavioural effects due to impaired androgens or progestogens, can cause fetal mascu- development of the central nervous system due to linisation; iodide and antithyroid drugs in high psychotropic drugs used during pregnancy; such dose can cause fetal goitre, as can lithium; tetra- effects have been shown in animals, including cyclines can interfere with tooth and bone develop- impaired ability to learn their way around mazes. ment, angiotensin-converting enzyme inhibitors are associated with renal tubular dysgenesis and a Detection of teratogens. Anatomical abnormalities skull ossification defect. Tobacco smoking retards are the easiest to detect. Nonanatomical (functional) fetal growth; it does not cause anatomical abnor- effects can also occur, though it is not appropriate to malities in man as far as is known. use the term teratogenesis (see definition above). Inhibitors of prostaglandin synthase (aspirin, They include effects on brain biochemistry which indomethacin) may delay onset of labour and, in may have late behavioural consequences. the fetus, cause closure of the ductus arteriosus, There is a substantial spontaneous background patency of which is dependent on prostaglandins. incidence of birth defect in the community (up to It is probable that drug allergy in the mother can 2%) so that the detection of a low-grade teratogen also occur in the fetus and it is possible that the that increases the incidence of one of the commoner fetus may be sensitised where the mother shows abnormalities presents an intimidating task. Also, no effect, e.g. neonatal thrombocytopenia from most teratogenic effects are probably multifactorial. thiazide diuretics. In this emotionally charged area it is indeed hard The suggestion that congenital cataract (due for the public and especially for parents of an to denaturation of lens protein) might be due to affected child to grasp that: drugs has some support in man. Chloroquine and chlorpromazine are concentrated in the fetal eye. The concept of absolute safety of drugs needs to Since both can cause retinopathy it would seem be demolished ... In real life it can never be shown wise to avoid them in pregnancy if possible. that a drug (or anything else) has no teratogenic Anticoagulants in pregnancy: see page 571. activity at all, in the sense of never being a Drugs given to the mother just prior to labour contributory factor in anybody under any can cause postnatal effects: CNS depressants circumstances. This concept can neither be tested may persist in and affect the baby for days after nor proved. birth; vasoconstrictors can cause fetal distress Let us suppose for example, that some agent by reducing uterine blood supply; B-adrenoceptor doubles the incidence of a condition that has blockers may impair fetal response to hypoxia; natural incidence of 1 in 10 000 births. If the sulphonamides displace bilirubin from plasma hypothesis is true, then studying 20 000 pregnant protein (risk of kernicterus); anticoagulants can women who have taken the drug and 20 000 who cause haemorrhage. have not may yield respectively two cases and one Babies born to mothers dependent on opioids case of the abnormality. It does not take a may show a physical withdrawal syndrome. statistician to realise that this signifies nothing, and it may need ten times as many pregnant women Drugs given during labour. Any drug that acts (almost half a million) to produce a statistically to depress respiration in the mother can cause significant result. This would involve such an respiratory depression in the newborn; opioid extensive multicentre study that hundreds of analgesics are notorious in this respect, but there doctors and hospitals have to participate. The can also be difficulty with any sedatives and participants then each tend to bend the protocol to 148
  15. ADVERSE EFFECTS ON REPRODUCTION 8 fit in with their clinical customs and in the end it is (reversible), cytotoxic anticancer drugs (reversible difficult to assess the validity of the data. and irreversible) and nitrofurantoin. There has been Alternatively, a limited geographical basis may a global decline in sperm concentration and an be used, with the trial going on for many years. environmental cause, e.g. chemicals that possess During this time other things in the environment oestrogenic activity, seems likely. change, so again the results would not command Causation of birth defects due to abnormal our confidence. If it were to be suggested that there sperm remains uncertain. was something slightly teratogenic in milk, the hypothesis would be virtually untestable. GENERAL DISCUSSION In practice we have to make up our minds which drugs may reasonably be given to pregnant Human toxic effects not predicted from animal women. Do we start from a position of presumed experiments are often reversible, but even the most guilt or from one of presumed innocence? If the optimistic enthusiasts for drugs must shrink from former course is chosen then we cannot give any the thought that their hands wrote prescriptions drugs to pregnant women because we can never resulting in deformed, surviving babies. prove that they are completely free of teratogenic Clinical data are, at present, inevitably open to influence. It therefore seems that we must start doubt, and any list of suspected drugs must become from a position of presumed innocence and then obsolete and misleading very quickly. This topic take all possible steps to find out if the must, therefore, be followed in the periodical press presumption is correct. and manufacturers' up-to-date information. Finally, we must put the matter in perspective by The medical profession clearly has a grave duty considering the benefit/risk ratio. The problem of to refrain from all unessential prescribing of drugs prescription in pregnancy cannot be considered with, say, less than 10-15 years widespread use from the point of view of only one side of the behind them, for all women of childbearing poten- equation. Drugs are primarily designed to do tial. It is not sufficient safeguard merely to ask a good, and if a pregnant woman is ill it is in the best woman if she is or may be pregnant, for it is also interests of her baby and herself that she gets better necessary to consider the possibility of a woman, as quickly as possible. This often means giving her who is not pregnant at the time of prescribing, may drugs. We can argue about the necessity of giving become so whilst taking the drug. drugs to prevent vomiting, but there is no Since morning sickness of pregnancy occurs argument about the need for treatment of women during the time when the fetus is vulnerable, it is with meningitis, septicaemia or venereal disease. specially important to restrict drug therapy of this What we must try to avoid is medication by the symptom to a minimum; but severe vomiting with media or prescription by politicians. A public scare its accompanying biochemical changes may itself about a well-tried drug will lead to wider use of harm the fetus. less-tried alternatives. We do not want to be forced Thus, before a drug is condemned as a cause of to practise the kind of defensive medicine that is fetal damage, it is necessary to consider whether the primarily designed to avoid litigation.14 disease for which it was given, or other intercurrent disease, might perhaps be responsible. Since the only way to be certain that a drug causes fetal MALE REPRODUCTIVE FUNCTION damage in humans is to test it in humans, it is Impotence may occur with drugs affecting autonomic necessary that doctors should (a) suspect a drug- sympathetic function, e.g. some antihypertensives. induced abnormality when it occurs and (b) report Spermatogenesis is reduced by a number of it to a central organisation (e.g. UK Committee on drugs including sulfasalazine and mesalazine Safety of Medicines) or to a national register of all birth defects (such a register ideally should be kept 14 By permission from Smithells R W 1983 In: Hawkins D F plus a full drug history of the mother from prior to (ed) Drugs and pregnancy. Churchill Livingstone, conception). Unfortunately, none of these require- Edinburgh. ments is easily satisfied. Minor congenital abnor- 149
  16. 8 UNWANTED E F F E C T S AND A D V E R S E DRUG REACTIONS malities are common in the absence of drug therapy Herbst A L1984 Diethylstilboestrol exposure—1984 and some may be virtually undetectable, e.g. [effects of exposure during pregnancy on mother reduced intelligence or learning ability. In addition, and daughters]. New England Journal of Medicine the more cautiously a new drug is introduced, the 311:1433-1435 more difficult it is going to be to detect, by Kaufman D W, Shapiro S 2000 Epidemiological epidemiological methods, a capacity to cause fetal assessment of drug-induced disease. Lancet 356: abnormality. This is especially so if the abnormality 1339-1343 produced is already fairly common. Human Knowles S R, Uetrecht J, Shear N H 2000 Idiosyncratic frailty also causes any reporting system based on drug reactions: the reactive metabolite syndromes. voluntary cooperation to be less than perfect. Lancet 356:1587-1591 The possibility of fetal abnormalities resulting Koren D, Pastuszak A, Ito S 1998 Drugs in pregnancy. from drugs taken by the father exists but has only New England Journal of Medicine 338:1128-1137 begun to be explored. (lists drugs that are safe and unsafe to use in pregnancy) Meyer U A 2000 Pharmacogenetics and adverse drug reactions. Lancet 356:1667-1671 GUIDETO FURTHER READING Pirmohammed M et al 2000 Adverse drug reactions. Edwards I R, Aronson J K 2000 Adverse drug British Medical Journal 316:1295-1298 reactions: definitions, diagnosis, and management. Scott J L et al 1965 A controlled double-blind study of Lancet 356:1255-1259 the haematologic toxicity of chloramphenicol. New Ewan P W 1998 Anaphylaxis. British Medical Journal England Journal of Medicine 272:1137 316:1442-1445 Vervolet D, Durham S 1998 ABC of allergies: adverse Gruchalla R S 2000 Clinical assessment of drug- reactions to drugs. British Medical Journal 316: induced disease. Lancet 356:1505-1511 1511-1514 150
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