Category Archives: Adverse drug reactions and poisoning

POISONING

In most hospitals in the Western World the commonest reason for acute admission of young people to a medical ward is acute poisoning. Such poisoning is usually by selfadministration of prescribed or over-the-counter medicines. Occasionally, however, toxic agents are accidentally ingested or inhaled at home or work or are administered with criminal intent. The types of poisoning.
Self-poisoning is usually a cry for help and some 30% of patients admitted with overdose state that they are unaware of the toxic effects of the drug. The patient often takes whatever drug is easily available at home. Doctors should therefore always prescribe limited amounts of drugs, and it is advisable to keep only small amounts of tablets, preferably foil-wrapped, in the home. Patients should be advised about the potential danger of drugs that should be kept out of reach of children.

Self-poisoning refers to the deliberate ingestion of an overdose of a drug or some other substance not meant for consumption Suicide is the term applied to all patients who die whether it was their intention to kill themselves or not Accidental poisoning occurs mostly in children below 5 years of age, but can occur in adults, e.g. from the accidental inhalation of a gas, ingestion of fluid from a wrongly labelled bottled, stings and bites, or eating poisonous foods (such as mushrooms) Non-accidental poisoning is the deliberate administration of a poison to a child.

Homicidal poisoning

The majority of cases (80%) of self-poisoning do not require intensive medical management but all require a sympathetic and caring approach to their problems. Both the patient and the family may require psychiatric help  and the social services should be contacted to help with social and domestic problems. In England and Wales there are over 100000 hospital admissions each year for self-poisoning, the commonest being with benzodiazepines and anti-depressants, followed by paracetamol and then aspirin. In 1992 there were 3947 deaths from poisoning with medicinal agents and non-medicinal substances. Most deaths occur outside hospital where the commonest causes are from carbon monoxide poisoning from vehicle exhaust fumes and faulty appliances using natural gas. Information from other continents is difficult to compare, but in Asia and Africa it seems that poisoning is a significant medical problem, with children being a particularly vulnerable group. In Cairo, over half of the enquiries at the poisons reference centre involve the poisoning of children. The proportion of accidental poisoning in Asia and Africa is higher than in Europe and North America. Snake bite is an important cause of mortality in Asia and Africa. The number of admissions from self-poisoning is increasing. However, as a result of good supportive care and the reduced availability of coal gas and barbiturates, the mortality of patients has declined and is now well under 1%. Studies of the drugs involved reveal that:
ACUTE OVERDOSES usually involve more than one drug. ALCOHOL is the most commonly implicated second ‘drug’ in mixed self-poisonings; 60% of men and 45% of women consume some alcohol at the same time as the drug.
THERE IS A POOR CORRELATION BETWEEN THE DRUG HISTORY AND THE TOXICOLOGICAL FINDINGS.
Therefore, patients’ statements about the type and amount of drug ingested should not be relied on.
THE USE OF MINOR TRANQUILLIZERS AND ANTIDEPRESSANTS IS INCREASING; barbiturates are now virtually unavailable in the UK.

HISTORY

Eighty per cent of adults are conscious on arrival at hospital and the diagnosis of self-poisoning can usually be made easily from the history. In the unconscious patient a history from friends or relatives is helpful, and the diagnosis can often be inferred from tablet bottles or a suicide note brought by the ambulance attendants. It should be emphasized that in any patient with an altered conscious level, drug overdose must always be considered in the differential diagnosis.

EXAMINATION

On arrival at hospital the patient must be assessed urgently in the accident and emergency department. The following should be evaluated:
1 Level of consciousness-a useful practical grading is:
(I) Drowsy but responds to commands
(II) Unconscious but responds to mild stimulation
(III) Unconscious but responds only to maximal painful stimuli (sternal rubbing)
(IV) Unconscious and no response

Alternatively the Glasgow Coma Scale should be used
2 Respiratory effort and cyanosis
3 Blood pressure and pulse rate
4 Pupil size and reaction to light (NB opiates constrict)
5 Evidence of head injury or drug addiction
If the patient is unconscious the following should also be checked:
• Presence or absence of cough and gag reflex
• Temperature-measured with a low-reading rectal thermometer
The physical signs that may aid identification of the agents responsible for poisoning.

Reduction of Adverse Drug Reactions

The incidence of adverse drug reactions can be reduced by:
• The development and marketing of safer drugs by the pharmaceutical industry
• Tighter control by drug-regulatory authorities within government on the licensing, promotion and marketing of drugs
In addition, the doctor must think carefully about every drug he or she prescribes.
The hazards of adverse drug reaction can be substantially reduced by:
• Understanding the mechanisms underlying the reactions
• Excluding a history of adverse reaction
• Individualizing drug dosage
Prescribing manuals and therapeutic textbooks give recommended ranges of drug doses. The choice of dose for an individual patient, however, depends on a large variety of factors, including genetic and environmental factors, most of which are still only poorly understood. The prescribing doctor must, therefore, determine the optimum drug dose for the patient from the advised range given by considering the factors already discussed and on the basis of his or her own experience. In some cases the dose can be decided by monitoring its therapeutic effect; for example, prothrombin time can be measured when using an oral anticoagulant drug, or blood sugar when using insulin or an oral hypoglycaemic drug. In addition, for drugs with a narrow therapeutic ratio (i.e. the ratio of the dose necessary to produce a therapeutic effect to that necessary to produce a toxic effect), or whose kinetics are not linear, titration of the dose to obtain a desirable blood level may be of value. Such control is called ‘therapeutic drug monitoring’, and is particularly helpful with digoxin, gentamicin, lithium and phenytoin, whose potentially toxic concentrations are relatively close to the therapeutic range.

Drugs for which plasma concentration monitoring may be helpful.

Drugs for which plasma concentration monitoring may be helpful.

Maintaining a low threshold of suspicion

Most important of aU is that aU prescribing doctors should be continually aware of the possibility that any clinical or life event (e.g. an accident) may be associated in some way with a patient’s treatment. The lower the threshold of suspicion on the part of the doctor, the lower the risk of serious long-term adverse drug reactions in the patient.

Monitoring adverse drug reactions

Clinical trials of new drugs are conveniently classified into:
PHASE 1: in which the drug is given to a small number of normal volunteers in closely controlled and supervised conditions to study its kinetics and pharmacological effects.
PHASE 2: in which the drug is given to a relatively small number of patients with the disease for which its use is proposed. The therapeutic efficacy, correct dosage and pharmacokinetics of the drug are determined by comparing the data with those for normal subjects to obtain some evidence of its safety.
PHASE 3: in which the clinical evaluation of the drug is extended to large numbers of patients (perhaps hundreds). Trials include comparisons with placebos and with established treatments.
PH ASE 4: (postmarketing surveillance, PM S): in which long-term assessment of the safety and efficacy of the drug is made in thousands of patients, following the licensing of the drug for marketing. Experience has shown that careful observation of patients in phase 2 and phase 3 clinical trials is only likely to detect those adverse reactions that occur in 1% or more of patients exposed to a drug. Adverse reactions with an incidence of less than 1% require detection in phase 4 (PMS) studies.
Several countries have developed systems for collecting information about suspected adverse drug reactions. In the UK two systems are of particular interest-the prescription event monitoring and yellow card system.

Some examples of drug toxicity associated with disease states, the nature of which is not yet understood.

Some examples of drug toxicity associated with disease states, the nature of which is not yet understood.

Prescription event monitoring (PEM)

The PEM scheme involves identifying doctors and their patients as the prescriptions for a particular drug pass through the central Prescription Pricing Authority office. Relevant prescriptions are photocopied and the copies are sent in confidence to the Drug Surveillance Research Unit in Southampton. Each ‘test’ drug under investigation is matched with a ‘control’ drug that is chemically or pharmacologically similar and already marketed for the same indications. Similar numbers of patients receiving each drug are selected and a simple questionnaire is sent to their general medical practitioners, requesting information on age, new diagnoses or events that have come to the doctor’s attention, and reasons for any referral to a consultant or admission to hospital. PEM should be able to identify adverse drug reactions that have an incidence of 1 in 3000 or greater.

Yellow card system

The voluntary yellow card system has been the most productive to date in the UK for identifying important adverse drug reactions. Yellow reply-paid cards are supplied to doctors and dentists, who are encouraged to use them to report any suspected adverse drug reactions to the government’s advisory Committee on Safety of Medicines. Although the rate of reporting is low, this system has drawn attention to the association of oral contraceptives and thromboembolism, hepatitis and methyldopa, jaundice and halothane, and extrapyramidal effects and metoclopramide. At present, only this system is potentially capable of detecting risk at all levels of incidence. When suspicion has been aroused through the yellow card system, the existence or otherwise of a true association between a reported event and the implicated drug must be demonstrated epidemiologically by case control  or cohort studies, and by clinical pharmacological and toxicological studies of the possible mechanisms involved. The problems associated with long-term surveillance of many thousands of patients must not be underestimated. Such studies are costly in both time and money, and it is difficult to maintain the integrity of the study cohort, the interest and commitment of the doctors, and the compliance of the patients.

Influence of disease on adverse drug reactions

Disease processes may increase the risk and severity of adverse drug reactions in three ways.

1 Disease may lead to changes in the pharmacokinetics of a drug. A reduction in protein binding or reduced renal or hepatic clearance will potentiate the effects of certain drugs.
2 Changes in receptor density and function may occur.
For example, there is evidence that the enhanced bronchoconstrictor effects of J3-adrenoceptor antagonists in asthmatic patients may be due to a reduction (‘downregulation’) in J3-receptor number produced by longterm treatment with J3-agonists such as salbutamol.
The sensitivity of patients with myasthenia gravis to the neuromuscular blocking effects of streptomycin, neomycin or kanamycin may be due to drug-induced changes in cholinergic receptors.
3 Some inherited diseases are associated with enhanced drug toxicity.
There are also several examples of disease-related enhanced drug toxicity the nature of which is not yet understood

Some clinically important drug interactions leading to adverse effects.

Some clinically important drug interactions leading to adverse effects.

Some examples of enhanced drug toxicity associated with inherited diseases.

Some examples of enhanced drug toxicity associated with inherited diseases.

Protein binding

Many drugs are loosely bound to plasma and tissue proteins.
The free unbound fraction is pharmacologically active. This fraction is increased in conditions in which hypoproteinaemia occurs. Competition between drugs for common binding sites can lead to a transient increase in free levels of one following its displacement by another, but the clinical importance of this is uncertain because increased clearance of the free fraction occurs, which tends to re-establish the original equilibrium between free and bound drug levels.

Route and kinetics of metabolism

Adverse reactions are particularly likely to occur where the relationship between drug dose and blood level is non-linear, so that relatively small increments in the dose given may lead to unexpectecl1y large increases in the blood level. Such a relationship is typical of saturation kinetics, in which hepatic metabolizing pathways become saturated or exhausted at a certain dose. Above this dose, proportionately more unchanged drug enters the systemic circulation. An important example of this phenomenon is seen with phenytoin.
Some adverse effects are due not to the parent compound but to highly reactive metabolites. For example, when paracetamol is taken in overdose the capacity of hepatic conjugating mechanisms is exceeded and a hepatotoxic metabolite is formed and accumulates.

Influence of disease on drug toxicity through changes in pharmacokinetics. Local

Influence of disease on drug toxicity through changes in pharmacokinetics.

Saturation kinetics as exhibited by phenytoin.

Saturation kinetics as exhibited by phenytoin.

Excretion

Many drugs are excreted by the kidney, while others are reabsorbed. Changes in urinary pH affect elimination; for example, the excretion of the acidic drug aspirin is increased, whereas that of the basic drug mexiletine is reduced, by alkalinization of the urine. This may be important clinically in patients who have a persistently high urine pH from renal disease or a vegetarian diet. Competition for renal tubular excretion also occurs, e.g. penicillin competes with probenecid.

Local factors

The therapeutic action of some drugs is markedly dependent on the local physiological environment at its site of action. A good example is the effect of myocardial potassium concentration on the cardiac actions of digitalis glycosides, hypokalaemia leading to enhancement of their action, with the risk of toxicity. Another example is the influence of changes in sodium and potassium status on the response to lithium.

Drug interactions

Drugs can interact within the body in many ways that may lead to adverse effects. Some important examples are given.
Cardiac failure Reduced gastrointestinal perfusion and drug absorption Patient compliance Patient compliance is also a factor in adverse reactions. Compliance is influenced by the drug formulation, frequency of dosage, number of drugs prescribed, and by the patient’s age and ability to comprehend instructions.

Neonates

In the neonatal period, drug-metabolizing enzymes may be deficient for at least a month after birth, particularly in the premature neonate. Neonates have problems in effectively metabolizing vitamin K analogues, sulphonami des, barbiturates, morphine and curare. One of the most dramatic examples is the production of the ‘grey baby’ syndrome by chloramphenicol in premature infants. This consists of circulatory collapse and muscular hypotonia and is thought to be due to a combination of defective hepatic conjugation of chloramphenicol and accumulation of unconjugated drug because of immature renal excretion.
In addition to hepatic immaturity, newborn infants have a relatively lower glomerular fi.ltration rate and renal plasma flow than adults, which results in reduced excretion of drugs such as aminoglycosides and digoxin.

The elderly

Adverse drug reactions occur commonly in the elderly. They receive more drugs on average because of their increased incidence of disease conditions, and are therefore more likely to experience drug interactions. They are also more susceptible to most dose-related adverse drug reactions. Reduced hepatic drug extraction and metabolism occurs with increasing age. This contributes to the increased incidence of adverse effects in older patients following the administration of central depressant drugs such as sedatives, tranquillizers and hypnotics. Agerelated changes in the sensitivity of the central nervous system to the effects of these compounds may also be involved.

Drugs that may have unwanted

Drugs that may have unwanted

Some factors which influence drug response in elderly patients.

Some factors which influence drug response in
elderly patients.

Glomerular filtration rate falls with age, leading to the accumulation of drugs principally excreted unchanged by the kidney. In view of this, doses of digoxin, lithium and aminoglycosides have to be reduced in elderly patients. Increasing age is also associated with changes in body composition, as well as with a general tendency to a decrease in body weight. Both of these may influence the distribution and tissue levels of administered drugs.

Differences in enzyme activity

Differences in enzyme activity between individuals may be either inherited or acquired.

Inherited

There are marked differences in the rates of drug metabolism between individuals. Some of these are known to be due to polymorphic genetic control of the metabolic pathways involved. Other examples include the exacerbation of acute intermittent porphyria by barbiturates and the occurrence of a rare familial resistance to coumarin anticoagulants.

Acquired enzyme inhibition

Many adverse drug reactions occur due to the administration of drugs which cause inhibition of enzymes.
MONOAMINE OXIDASE. This is a widely distributed enzyme that is responsible for the intercellular degradation of, amongst other monoamines, adrenaline, noradrenaline, dopamine and 5-hydroxytryptamine (serotonin). Its inhibition by monoamine oxidase inhibitors (MAOIs) may, therefore, give rise to serious adverse effects from the following agents if taken concurrently:
INDIRECTLY ACTING SYMPATHOMIMETIC AMINES such as ephedrine and phenylpropanolamine, whose pressor and cardiac actions are due to the release of noradrenaline from adrenergic nerve terminals, are potentiated by monoamine oxidase inhibition.

Adverse drug reactions associated with inherited enzyme deficiencies.

Adverse drug reactions associated with inherited enzyme deficiencies.

FOODS THAT CONTAIN TYRAMINE, such as cheeses, wines, meat and yeast products. Tyramine is an indirectly acting amine with similar actions to phenylpropanolamine.
MONOAMINE-REUPTAKE INHIBITING (TRICYCLIC) ANTIDEPRESSANTS can cause serious central nervous stimulation, convulsions and circulatory collapse if given together with an MAOI.
ANTIHYPERTENSIVE DRUGS such as reserpine, guanethidine and bethanidine release noradrenaline from its neuronal stores and so can produce serious hypertension if given with an MAOI.
PETHIDINE may produce severe narcotic effects with coma and hyperthermia in patients receiving MAOIs, possibly owing to raised levels of cerebral 5-hydroxytryptamine. Reversible inhibition of monooxidase type A (RIMA) drugs are now available causing less adverse effects.
XANTHINE OXIDASE. Inhibition of xanthine oxidase by allopurinol can lead to reduced breakdown of purines such as 6-mercaptopurine and azathioprine, with an increased risk of their dose-dependent adverse effects, for example on the bone marrow.
ALDEHYDE DEHYDROGENASE. This is inhibited by disulfiram, resulting in an accumulation of acetaldehyde after ingestion of alcohol, with the resulting ‘antabuse’ reaction of flushing, hypotension, headache, sweating, nausea, vomiting and even cardiovascular collapse. This forms the basis of one approach to the management of alcohol dependence. A similar reaction may occur with the antimicrobial drug metronidazole. Competition by drugs for hepatic drug-metabolizing pathways is not uncommon and is recognized as a basis for adverse drug interactions. For example, cimetidine increases the anticoagulant effect of warfarin, the sedative effect of diazepam and the f3-adrenoreceptor blocking action of propranolol by inhibiting their hepatic metabolism. Sulphonamides decrease phenytoin metabolism so that toxic levels may be reached.

Mechanism by which monoamine

Mechanism by which
monoamine

Acquired enzyme induction

The activity of hepatic drug-metabolizing enzymes may be increased by a large number of common substances, including insecticides, pesticides, polycyclic aromatic hydrocarbons, and some drugs such as barbiturates, phenytoin, carbamazepine and rifampicin. Such enzyme induction results in increased drug metabolism and breakdown, reducing the therapeutic activity of certain drugs. Examples include oral anticoagulants, corticosteroids and the contraceptive pill. The importance of enzyme induction lies in the exaggerated effects that can occur if the inducing drug is discontinued and the drug whose metabolism was being induced, e.g. warfarin, continues to be given in an increased dosage.

Factors influencing dosedependent adverse drug reactions

Formulation

The active agent represents only a small proportion of the total weight of a tablet or capsule .. Similarly, drugs for injection require solubilization or suspension in a fluid vehicle of varying complexity. Other constituents of dosage forms, called excipients, are not necessarily inert, and may play an important part in facilitating or hindering  the absorption of a drug. The proportion of an administered drug dose that reaches its site of action in the systemic circulation is known as its bioavaiIability. If the drug is given intravenously its bioavailability is 100%. The dose-dependent adverse effects of many drugs are related to higher blood levels than those necessary for  their therapeutic action. A formulation that results in such high blood levels may, therefore, produce unacceptable effects. In the case of a poorly soluble drug, its physical form may be important in determining its dissolution rate and, therefore, its rate of absorption. For example, when the particle size of digoxin was reduced by a manufacturer, many patients experienced digitalis toxicity because the rate and extent of absorption was increased. Similarly, the influence of a change of the excipient on a drug’s bioavailability was seen in Australia when a manufacturer of phenytoin capsules changed  from using the relatively water-insoluble calcium sulphate to the much more soluble lactose. This led to an increase in the bioavailability of phenytoin, which was even more marked because of the ‘saturation kinetics’ that phenytoin exhibits.
Modification of the physical form of a drug, and changes in other constituents, permits the development of ‘controlled release’ formulations. These produce sustained levels within the therapeutic range and prevent early peak blood levels that enter the toxic range. This effect is particularly useful in drugs with a short half-life.

Relationships between blood drug concentration

Relationships between blood drug concentration

Route of administration

Parenteral administration of a drug may produce higher peak levels than are produced by oral administration, and may therefore produce more marked concentrationrelated adverse effects. For example, the intravenous administration of many drugs, particularly as bolus injections, may cause unwanted cardiac or central nervous effects. Intrathecal penicillin can produce encephalopathy and convulsions due to the toxic effects of high concentrations on the central nervous system; this route is nowadays seldom used.
Adverse reactions may occur owing to accidents during administration; for example, arterial rather than venous injectio  of thiopentone results in vascular spasm, arterial thrombosis and gangrene.

Pregnancy

Some drugs given in the first 3 months of pregnancy may cause congenital abnormalities and are said to be teratogenic. The best known example of a teratogenic drug is thalidomide, which resulted in bizarre and therefore easily recognizable abnormalities such as absent or grossly abnormal limbs (amelia, phocomelia). Stilboestrol administration during pregnancy produced adenosis and adenocarcinoma of the vagina in the female offspring when they reached their late teens or early twenties. This was recognized because of the normally relatively low incidence of this carcinoma in this age group. Low-grade teratogens that cause only minor deformities infrequently are likely to be unrecognized or demonstrated only with difficulty. Other drugs that are known or suspected to be teratogenic are given.
Drugs given after the period of organogenesis may affect the growth or function of normally formed fetal tissues or organs. The more important of these drugs.

Age

Some drugs produce specific adverse effects at the extremes of life.

Agents known or suspected to be teratogenic in humans.

Agents known or suspected to be teratogenic in humans.

Pseudoallergic reactions

In some susceptible patients, substances mimic the allergic reactions described under dose-independent reactions but without the same immunological mechanisms occurring. Unlike allergic reactions they occur on first contact with a drug rather than after previous sensitizing exposure. Susceptibility to such a reaction appears to be determined by genetic and environmental factors. These reactions are produced by compounds that are able to release histamine and other mediators directly from mast cells without involving an antigen-antibody reaction. Examples are:
• Itching, bronchospasm and vasodilatation due to histamine release by morphine
• The flushing, urticaria, angie-oedema, conjunctivitis, rhinitis, bronchial asthma, hypotension and even fatal shock produced by aspirin.
It is probable that reactions to many other drugs are also due to this mechanism. An interesting example is the anaphylactic response produced by aspirin in one patient with urticaria pigmentosa and generalized mastocytosis.
If use of the particular drug to which the pseudoallergic reaction occurs cannot be avoided, its dose should be kept as low as possible, or, in the case of intravenous administration, it should be given by slow infusion rather than rapid injection. Sometimes it is possible to desensitize a patient by starting with a small dose of the drug and gradually increasing it under supervision.

Agents that are believed to be capable

Agents that are believed to be capable

Classification

Adverse drug reactions can be classified in several ways.
They may be divided into reactions due to:
• Overdosage
• Intolerance
• Side-effects
• Secondary effects
• Idiosyncrasy
• Hypersensitivity
Another system of classification divides them into two types:
1 Type A: the results of an exaggerated but otherwise normal pharmacological action of a drug 2 Type B: totally aberrant effects not expected from the known pharmacological actions of a drug.
In this chapter adverse drug reactions are divided into three types:
1 Dose-dependent
2 Dose-independent
3 Pseudoallergic
The mechanisms underlying many drug reactions, however, are unclear and these reactions cannot at present be classified easily, e.g. hepatotoxicity and analgesic nephropathy.

Dose-dependent reactions

These occur in all patients given sufficiently large doses of any drug. The effects produced may be subdivided into two further groups:
1 Reactions that are predictable, being exaggerated therapeutic actions, e.g. depression of cardiac contractility by lignocaine or quinidine, or central nervous depression by barbiturates or narcotics
2 Reactions that appear to be unrelated to their therapeutic effects, e.g. the ototoxicity produced by streptomycin The first group, being predictable, can be anticipated and looked for without much difficulty. The second unpredictable group poses serious problems of recognition and quantification, particularly with a new drug.
Factors that influence the dose at which these dosedependent effects appear.

Dose-independent reactions

These occur in only a small proportion of patients and tend to be limited to certain well-defined manifestations. The possibility, however, of new syndromes occurring must never be overlooked. These reactions usually occur in patients who have previously been exposed and sensitized to the drug itself, to another drug of the same chemical class, or to one of another class of drugs that shares similar antigenic properties. For example, exposure to one form of penicillin usually produces a state of hypersensitivity to other penicillin derivatives, and, in a small proportion of patients, also to cephalosporin derivatives which share cross-antigenicity with the 6-amino-penicillanic acid nucleus.
Most drugs are of relatively low molecular weight and only become antigenic when they are combined covalently and irreversibly with other substances of high molecular weight, usually proteins. The drug is then said to be a hapten. Sometimes it is a metabolite of the drug or an impurity produced during manufacture that acts as the hapten. The most common of these dose-independent reactions are acute hypersensitivity reactions. These are due to the release of histamine and other mediators following the interaction of antigen with antibody (IgE) produced by B lymphocytes and bound to the cell membranes of mast cells or circulating basophils. The released substances cause rashes, oedema and the more serious effects of bronchospasm, peripheral vasodilatation and cardiovascular collapse-the anaphylactic reaction.

Circulating antigen-antibody complexes (immune complexes) cause the serum sickness syndrome. They are deposited for example in the basement membrane of the renal glomerulus.
Delayed hypersensitivity reactions, such as contact dermatitis, are due to the formation of sensitized T lymphocytes, which activate a cell-mediated immune response. Other forms of dose-independent reactions include various blood dyscrasias. These may involve the production of antibodies to circulating blood elements, leading to:

THROMBOCYTOPENIC PURPURA (e.g. with quinine) HAEMOLYTIC ANAEMIA (e.g. with methyldopa) DEPRESSION OF BONE MARROW FUNCTION, either selective (e.g. agranulocytosis) or total (aplastic anaemia). For example, chloramphenicol is a very effective antibiotic, but about one person in every 20000 develops a fatal aplastic anaemia that is unrelated to the dose administered and which cannot at present be predicted by any pre-dose screening test. The exact mechanism of this aplasia is unknown.

Anaphylaxis.

Anaphylaxis.

Comparison between dose-dependent, dose-independent and pseudoallergic reactions.

Comparison between dose-dependent, dose-independent and pseudoallergic reactions.

Adverse drug reactions and poisoning

ADVERSE DRUG REACTIONS

The size of the problem

Any substance that possesses useful therapeutic effects may also produce unwanted, toxic or adverse effects. The incidence of adverse drug reactions in the population is not really known. A survey of 1160 patients given a variety of drugs showed that the incidence of adverse reactions increased with age from about 3% in patients 10- 20 years of age to about 20% in patients 80-89 years of age. It has been estimated that about 0.5% of patients who die in hospital do so as a result of their treatment rather than the condition for which they were admitted.