Unwanted effects and adverse drug reactions SYNOPSIS Background Definitions Causation: degrees of certainty Pharmacovigilance and pharmacoepidemiology Classification Causes Allergy in re
Trang 1Unwanted effects and adverse drug reactions
SYNOPSIS
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 than the disease Matthew Prior
(1664-1721).
unwanted effects of drugs are promoted, or even caused, by numerous nondrug factors 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
Since 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 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 severity, though accurate data are obviously useful
It is necessary to take, or to try to take, into acc-ount which effects are avoidable (by skilled choice and use) and which are unavoidable (inherent
in drug or patient) Also, different adverse effects can matter to a different degree to different people
Since there can be no hope of eliminating all adverse effects of drugs it is necessary to evaluate patterns of adverse reaction against each other 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 detriment Another drug may be pleasant to take, so that patients take it consistently, with benefit, but it may
Trang 2rarely 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,
for such knowledge can be used to render
avoid-able what are at present unavoidavoid-able reactions
Avoidable adverse effects will be reduced by
more skilful prescribing and this means that
doctors, amongst all the other claims on their
time, must find time better to understand drugs,
as well as to understand their 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 term side-effects for minor effects of type A
events/effects (p 139)
The term adverse reaction should be confined
to: harmful or seriously unpleasant effects
occurr-ing at doses intended for therapeutic (includoccurr-ing
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
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 overdose and overdose can be absolute
or relative; in the latter case an ordinary dose may
be administered but may be toxic due to an
under-lying abnormality in the patient, e.g disease of the
kidney Mutagenicity, carcinogenicity and
terato-genicity (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 which may
occur in patients whose normal bowel flora has been
altered by antibiotics; diuretic-induced hypokalaemia causing digoxin intolerance
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 Pharmacogenetics) implies an inherent qualitative abnormal reaction to a drug, usually due to genetic abnormality, e.g porphyria
Causation: degrees of conviction
Reliable attribution of a cause-effect relationship provides the biggest problem in this field The following degrees of conviction assist in attributing adverse events to drugs:2
• Definite: time sequence from taking the drug is
reasonable; event corresponds to what is known
of the drug; 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
• Possible: time sequence is reasonable; event
corresponds to what is known of 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
• Doubtful: event not meeting the above criteria.
Recognition of adverse drug reactions 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-caused must always
Journal of the American Medical Association 1975 234: 1236.
Trang 3PH ARM A C O V I G I L A N C E AND P H A R M A C O E P I D E M I O L O G Y 8
be considered Distinguishing between natural
pro-gression of a disease and drug-induced
deteriora-tion is particularly challenging, e.g sodium in
antacid formulations may aggravate cardiac failure,
tricyclic antidepressants may provoke epileptic
seizures, bronchospasm may be caused by aspirin
in some asthmatics
Pharmacovigilance and
pharmacoepidemiology
The principal methods of collecting data on adverse
reactions (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 1:200
• Observational studies, where the drug is observed
epidemiologically under conditions of normal
use in the community, i.e
pharmaco-epidemiology Techniques used for
post-marketing (Phase 4) studies include the
obser-vational cohort study and the case-control study
The systems are described on page 69
DRUG-INDUCED ILLNESS
The discovery of drug-induced illness can be
analysed thus:3
• Drug commonly induces an otherwise rare
illness: this effect is likely to be discovered by
clinical observation in the licensing
(premarketing) 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
• Drug rarely induces an otherwise common
illness: this effect is likely to remain
undiscovered
• Drug rarely induces an otherwise rare illness:
3 After: Jick H 1977 New England Journal of Medicine 296:
481-485.
this effect is likely to remain undiscovered before the drug is released for general prescribing; the effect should be detected by informal clinical observation or during any special
postregistration surveillance and confirmed by a case-control study (see p 68), e.g chloram-phenicol and aplastic anaemia; practolol and oculomucocutaneous syndrome
• 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 proarrhythmic effects of antiarrhythmic drugs
• Drug adverse effects and illness incidence in 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:
• Adverse reactions cause 2-3% of consultations in general practice
• Adverse reactions account for 5% of all hospital admissions
• Overall incidence in hospital inpatients is 10-20%, with possible prolongation of hospital stay in 2-10% of patients in acute medical wards
• A review of records of a Coroner's Inquests for a district with a population of 1.19 million (UK) during the period 1986-91 found that of 3277 inquests on deaths, 10 were due to errors of prescribing and 36 were caused by adverse drug reactions.4 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'.5
• Predisposing factors: age over 60 years or under one month, female, previous history of adverse reaction, hepatic or renal disease
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 manslaughter charges British Medical Journal 321:
1212-1216.
Trang 4• Adverse reactions most commonly occur early in
therapy (days 1-10)
It is important to avoid alarmist or defeatist
extremes of attitude 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 refuse to accept any risk at all from
drugs for conditions of comparable seriousness
Many patients whose death is deemed to be
partly or wholly caused by drugs are dangerously
ill already; justified 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 Avoidability is often more obvious
when reviewing the conduct of treatment after death,
i.e with hindsight, than it was at the time
Sir Anthony Carlisle,6 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 to anyone who follows the
introduction of new drugs and observes how, after
the early enthusiasm, the reports of serious toxic
effects appear 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 Ch 5); they are now an increasingly
sophisticated and effective part of medicines
development
Another cryptic remark of this therapeutic
nihilist was 'digitalis kills people' and this is true
William Withering in 1785 laid down rules for the
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
until the therapeutic criteria were rediscovered
Any drug that is really worth using can do harm
It is an absolute obligation on doctors to use only drugs
about which they have troubled to inform themselves.
Effective therapy depends not only on the
correct choice of drugs but also on their correct use
6 Noted for his advocacy of the use of 'the simple carpenter's
saw' in surgery.
This latter is sometimes forgotten and a drug is condemned as useless when it has been used in
a dose or way which absolutely precluded a successful result; this can be regarded as a negative adverse effect
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 is given in Table 8.1 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
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 These symptoms are intensified (or diminished) by administration of
a placebo Thus, many (minor) symptoms may be wrongly attributed to drugs
Classification
It is convenient to classify adverse reactions to drugs under the following headings:
TABLE 8.1 Detecting rare adverse reactions7
Expected incidence Required number of
of adverse reaction patients for event
I event 2 events 3 events
I in 100 300 480 650
I in 200 600 960 1300
I in 1000 3000 4800 6500
I in 2000 6000 9600 13 000
I in 10000 30000 48000 65000
7 By permission from, Safety requirements for the first use of new drugs and diagnostic agents in man CIOMS (WHO)
1983 Geneva.
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Type A (Augmented) reactions will occur in
everyone if enough of the drug is given because
they are due to excess of normal, predictable,
dose-related, pharmacodynamic effects They are
common and skilled management reduces their
incidence, e.g postural hypotension, hypoglycaemia,
hypokalaemia
Type B (Bizarre) reactions will occur only in
some people They are not part of the normal
pharmacology of the drug, are not dose-related and
are due to unusual attributes of the patient
interact-ing with the drug These effects are predictable
where the mechanism is known (though predictive
tests may be expensive or impracticable), otherwise
they are unpredictable for the individual, although
the incidence may be known The class includes
unwanted effects due to inherited abnormalities
(idiosyncrasy) (see Pharmacogenetics) and
immuno-logical processes (see Drug allergy) These account
for most drug fatalities
Type C (Chronic) reactions due to long-term
exposure, e.g analgesic nephropathy, dyskinesias
with levodopa
Type D (Delayed) effects following prolonged
exposure, e.g carcinogenesis or short-term exposure
at a critical time, e.g teratogenesis
Type E (Ending of use) reactions, where
dis-continuation of chronic therapy is too abrupt, e.g
of adrenal steroid causing rebound adrenocortical
insufficiency, of opioid causing the withdrawal
syndrome
Causes
When an unusual or unexpected event, for which
there is no evident natural explanation, occurs in a
patient already taking a drug, the possibility that
the event is drug-caused must always be
consi-dered, and may be categorised as follows:
• The patient may be predisposed by age, genetic
constitution, tendency to allergy, disease,
personality, habits
• The drug Anticancer agents are by their nature
cytotoxic Some drugs, e.g digoxin, have steep
dose-response curves and small increments of
dose are more likely to induce augmented (type
A) reactions Other drugs, e.g antimicrobials, have a tendency to cause allergy and may lead to bizarre (type B) reactions Ingredients of a formulation, e.g colouring, flavouring, sodium content, rather than the active drug may also cause adverse reactions
• The prescriber Adverse reactions may occur because a drug is used for an inappropriately long time (type C), at a critical phase in pregnancy (type D), is abruptly discontinued (type E) or given with other drugs (interactions) Aspects of the two sections above, Classification and Causes, appear throughout the book Selected topics are discussed below
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, it has been aptly said, are not simply 'small adults' and 'respect for their pharmacokinetic variability should be added to the list of our senior citizens' rights'.8 The old are also frequently exposed to multiple drug therapy which predisposes to adverse effects (see Prescribing for the elderly, p 126)
GENETIC CONSTITUTION
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 careful prescribing is vital
The porphyrias comprise a number of rare, geneti-cally determined single enzyme defects in haem
biosynthesis Acute porphyrias (acute intermittent porphyria, variegate porphyria and hereditary coproporphyria) are characterised by severe attacks
of neurovisceral dysfunction precipitated principally by
a wide variety of drugs (and also by alcohol, fasting,
and infection); nonacute porphyrias (porphyria cutanea tarda, erythropoietic protoporphyria and congenital erythropoietic porphyria) present with cutaneous photosensitivity for which alcohol (and
8 Fogel B S 1983 New England Journal of Medicine 308:1600.
Trang 6prescribed oestrogens in women) is the principle
provoking agent
In healthy people, forming haemoglobin for
their erythrocytes and haem-dependent enzymes,
the rate of haem synthesis is controlled by negative
feedback according to the amount of haem present
When more haem is needed there is increased
production of the rate-controlling enzyme
delta-aminolaevulinic acid (ALA) synthase which provides
the basis of the formation of porphyrin precursors of
haem But in people with porphyria one or other of
the enzymes that convert the various porphyrins
to haem is deficient and so porphyrins accumulate
A vicious cycle occurs: less haem —> more ALA
synthase —> more porphyrin precursors, the
meta-bolism of which is blocked, and a clinical attack
occurs
It is of interest that those who inherited acute
intermittent porphyria and variegate porphyria
suffered no biological disadvantage from the
natural environment and bred as well as the normal
population until the introduction of barbiturates
and sulphonamides They are now at serious
dis-advantage, for many other drugs can precipitate
fatal acute attacks
The exact precipitating mechanisms are uncertain
Increase in 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 may act by this mechanism
Apparently unexplained attacks of porphyria should
be an indication for close enquiry into all possible
chemical intake Guaiphenesin, for example, is
hazardous; it is included in a multitude of
multi-ingredient cough medicines (often nonprescription)
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 prescribing doctors
The greatest care in prescribing for these patients
is required if serious illness is to be avoided
Patients (1 in 10 000 UK population) are so highly
vulnerable that lists of drugs known or believed to
be unsafe are available, e.g in the British National
Formulary Additionally, we provide a table of drugs
considered safe for use in the acute porphyrias at
the time of publication (Table 8.2) The list is revised
regularly, mostly with additions made as informa-tion becomes available Updated informainforma-tion can
be obtained.9
Use of a drug about which there is uncertainty may be justified Dr M Badminton 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 If no recognised safe option is available, a reasonable course is to:
1 Measure urine 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)
3 Contact an expert centre for advice.'
In the treatment of the acute attack it is rational
to use any safe means of depressing the formation
of ALA-synthase Haem arginate (human haematin)
infusion, by replenishing haem and so removing the stimulus to ALA-synthase, is effective if given early, and may prevent chronic neuropathy Addi-tionally, attention to nutrition, particularly the supply
of carbohydrate, relief of pain (with an opioid), and
of hypertension and tachycardia (with a (B-adreno-ceptor blocker) are important Hyponatraemia is
a frequent complication, and plasma electrolytes should be monitored
In the treatment of the acute attack it would seem rational to use any safe means of depressing the
formation of ALA-synthase Indeed, haem arginate
(human haematin) infusion, by replenishing haem and so removing the stimulus to ALA-synthase, appears to be effective if given early, and may prevent chronic neuropathy Additionally, attention
to nutrition, particularly the supply of carbohydrate, relief of pain (with opioid), and of hypertension and tachycardia (with propranolol) are important
THE ENVIRONMENT
Significant environmental factors causing adverse
9 www.uwcm.ac.uk/study/medicine/medical_biochem/ porphyria.htm
www.utc.ac.za/depts/liver/porphpts.htm
Trang 7C A U S E S 8
TABLE 8.2 Drugs that are considered safe for use in acute porphyrias
Acetazolamide
Acetylcysteine
Aciclovir
Adrenaline (epinephrine)
Alfentanil
Allopurinol
Alpha tocopheryl
Aluminium salts
Amantadine
Amethocaine (tetracaine)
Amiloride
Aminoglycosides
Amitriptyline
Amphotericin
Ascorbic acid
Aspirin
Atropine
Azathioprine
Beclomethasone
Beta blockers
Bezafibrate
Bismuth
Bromazepam
Bumetanide
Bupivacaine
Buprenorphine
Buserelin
Calcitonin
Calcium carbonate
Carbimazole
Chloral hydrate
Chloroquine
Chlorothiazide
Chlorpheniramine (chlorphenamine)
Chlorpromazine
Colestyramine
Cisplatin
Clobazam
Clofibrate
Clomifene
Clonazepam
Co-amoxiclav
Co-codamol
Co-dydramol
Codeine phosphate
Colchicine
Colestipol
Corticosteroids
Corticotrophin
Cyclizine
Cyclopenthiazide
Cyclopropane
Dalteparin
Danthron
Desferrioxamine
Dextran Dextromethorphan Dextromoramide Dextropropoxyphene Dextrose
Diamorphine Diazoxide Dicyclomine (dicycloverine) Diflunisal
Digoxin Dihydrocodeine Dimercaprol Dimeticone Diphenhydramine Diphenoxylate Dipyridamole Distigmine Dobutamine Domperidone Dopamine Doxorubicin Droperidol Enalapril Enoxaparin Epinephrine Ethambutol Ether Famciclovir Fenbufen Fenofibrate Fentanyl Flucloxacillin 1
Flucytosine Flumazenil Fluoxetine Fluphenazine Flurbiprofen Fructose FSH Gabapentin Ganciclovir Gemfibrozil Glipizide Glucagon Glucose Glycopyrronium Gonadorelin Goserelin GTN Guanethidine Haloperidol Heparin Hetastarch Hydrochlorothiazide Hydrocortisone
Ibuprofen Immunisations Immunoglobulins Indomethacin Insulin Iron Isoflurane Ispaghula Ketoprofen Ketotifen Lactulose Leuproelin Levothyroxine LHRH Lignocaine 2 (lidocaine) Lisinopril 3
Lithium Lofepramine Loperamide Loratadine Lorazepam Magnesium sulphate Meclozine Mefloquine Melphalan Mequitazine Mesalazine Metformin Methadone Methotrimeprazine (levomepromazine) Methylphenidate
Methylprednisolone Mianserin Midazolam Morphine Naftidrofuryl Nalbuphine Naloxone Naproxen Neostigmine Nitrous oxide Octreotide Omeprazole Oxybuprocaine Oxytocin Pancuronium Paracetamol Paraldehyde Penicillamine Penicillins Pentamidine Pethidine Phentolamine Phytomenadione Pipothiazine
Pirenzepine Prazosin Prednisolone Prilocaine Primaquine Probucol Procainamide Procaine Prochlorperazine Proguanil Promazine Promethazine Propantheline Propofol Propylthiouracil Proxymetacaine Pseudoephedrine Pyridoxine Pyrimethamine Quinidine Quinine Resorcinol Salbutamol Senna Sodium acid phosph Sodium bicarbonate Sodium fusidate Sodium valproate 4
Sorbitol Streptokinase Streptomycin Sucralfate Sulindac Suxamethonium Temazepam Tetracaine Thiamine Thyroxine (levothyroxine) Tiaprofenic acid Tinzaparin Tranexamic acid Triamterene Triazolam Trifluoperazine Trimeprazine Urokinase Vaccines Valaciclovir Valproate 4
Vancomycin Vigabatrin Vitamins Warfarin Zalcitabine 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.
Trang 8reactions to drugs include simple pollution, e.g.
penicillin in the air of hospitals or in milk (see
below), causing allergy
Drug metabolism may also be increased by
hepatic enzyme induction from insecticide
accumu-lation, e.g dicophane (DDT) and from alcohol 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
DRUG INTERACTIONS
(see p 129)
Allergy in response to
drugs
Allergic reactions to drugs are the resultant of
the interaction of drug or metabolite (or a nondrug
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 (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
popula-tion has antibodies to penicillins but, fortunately,
comparatively few react clinically to penicillin
administration
Whilst macromolecules (proteins, peptides,
dex-tran 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, namely:
Type I reactions: immediate or anaphylactic type.
The drug causes formation of tissue-sensitising IgE 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, anaphy-lactic shock and asthma Allergy develops within minutes and lasts 1-2 hours
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 com-bine 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 inflam-matory process These reactions include serum sick-ness, glomerulonephritis, vasculitis and pulmonary disease
Type IV reactions: lymphocyte-mediated type.
Antigen-specific receptors develop on T-lympho-cytes 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 When allergy to a particular drug is established, a substitute should be selected from a chemically different group Patients with allergic diseases, e.g eczema, are more likely to develop allergy to drugs
Trang 9The distinctive features of allergic reactions are
their:10
• 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
• Occurrence in a minority of patients receiving
the drug
• Temporary nature in some cases
• 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
admin-istration of the drug The eyelids, lips and face are
usually most affected They are usually
accompa-nied by itching Oedema of the larynx is rare but may
be fatal They respond to adrenaline (epinephrine)
(i.m if urgent), ephedrine, H1-receptor antihistamine
and adrenal steroid
2a Nonurticarial 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 nonspecific; in severe cases
an adrenal steroid should be used Skin
sensitisa-tion to antimicrobials may be very troublesome,
especially amongst those who handle them (see
Drugs and the Skin, Ch 16, for more detail)
2b Diseases of the lymphoid system Infectious
mononucleosis (and lymphoma, leukaemia) is
asso-ciated with an increased incidence (> 40%) of
10 Assem E-S K 1992 In: Davies D M (ed) Textbook of adverse
drug reactions Oxford University Press, London.
A L L E R G Y I N R E S P O N S E T O D R U G S
characteristic maculopapular, sometimes purpuric, rash which is probably allergic, when an amino-penicillin (ampicillin, amoxycillin) is taken; patients may not be allergic to other penicillins Erythromycin may cause a similar reaction
3 Anaphylactic shock (type I) occurs with peni-cillin, anaesthetics (i.v.), iodine-containing radio-contrast media and a huge variety of other drugs
A severe fall in blood pressure occurs, with broncho-constriction, angioedema (including larynx) and sometimes death due to loss of fluid from the intra-vascular compartment Anaphylactic shock usually occurs suddenly, in less than an hour after the drug, but within minutes if it has been given i.v
Treatment is urgent, as follows:
• First, 500 micrograms of adrenaline (epinephrine) injection (0.5 ml of the 1 in 1000 solution) should
be given i.m to raise the blood pressure and to dilate the bronchi (vasoconstriction renders the s.c route less effective) Up to 10% of patients may need a second injection 10-20 min later and subsequent injections may be given until the patient improves Noradrenaline
(norepinephrine) lacks any useful bronchodilator action (p-effect) (see adrenaline, Chapter 23)
• If treatment is delayed and shock has developed, adrenaline 500 micrograms should be given i.v
by slow injection at a rate of 100 micrograms/min (1 ml/min of the Dilute 1 in
10 000 solution over 5 min) with continuous ECG monitoring, stopping when a response has been obtained For greater control and safety, a further
x 10 dilution in dextrose may be preferred (i.e a solution of 1 in 100 000)
• Note that preventive self-management is feasible where susceptibility to anaphylaxis is known, e.g in patients with allergy to bee- or wasp-stings The patient is taught to administer adrenaline i.m from a prefilled syringe (EpiPen Auto-injector, delivering adrenaline 300
micrograms per dose)
• The adrenaline should be accompanied by an H1 -receptor antihistamine [say chlorpheniramine (chlorphenamine) 10-20 mg by slow i.v
injection] and hydrocortisone (100-300 mg i.m
or i.v.) The adrenal steroid may act by reducing vascular permeability and by suppressing
Trang 10further response to the antigen-antibody
reaction Benefit from an adrenal steroid is not
immediate; it is unlikely to begin for 30 minutes
and takes hours to reach its maximum
• In severe anaphylaxis, hypotension is due to
vasodilation and loss of circulating volume
through leaky capillaries Colloid is more effective
at restoring blood volume than crystalloid and
1-21 of plasma substitute should be infused
rapidly Oxygen and artificial ventilation may be
necessary Advice on the management of
anaphylactic shock may be altered from time to
time; check the UK Resuscitation Council website
(www.resus.org.uk) for current information
Any hospital ward or other place where
ana-phylaxis 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 Pseudoallergic reactions,
p 146)
4a Pulmonary reactions: asthma (type I) Aspirin
and other nonsteroidal anti-inflammatory drugs
may cause an asthmatic attack Whether this is an
allergic or pseudoallergic reaction or a mixture of
the two is uncertain
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 HI) This
occurs about 1-3 weeks after administration
Treat-ment is by an adrenal steroid, and as above if there
is urticaria
6 Blood disorders 11
6a Thrombocytopenia (type II, but also
pseudo-allergic) may occur after exposure to any of a large
11 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.
number of drugs, including: gold, quinine, quini-dine, rifampicin, heparin, thionamide derivatives, thiazide diuretics, sulphonamides, oestrogens, indo-methacin Adrenal steroid may help
6b Granulocytopenia (type II, but also pseudo-allergic) sometimes leading to agranulocytosis, is a very serious allergy 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.12
Weekly counts may detect presymptomatic granulo-cytopenia from antithyroid drugs but onset can be sudden and an alternative view is to monitor only with drugs having special risk, e.g clozapine 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 noncompliance 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, antidiabe-tics), 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 (type
A reaction), although aplastic anaemia may also be due to idiosyncrasy or allergy (type B reaction) Death occurs in about 50% of cases, and treat-ment 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 methyldopa,
levodopa, penicillins, quinine, quinidine,
12 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.