Chapter 32. Adverse reactions to drugs, testing of drugs and pharmacovigilance
At the end of this chapter, the reader should be able to:
• explain what is meant by type A and type B adverse reactions to drugs and list the four causes of type B reactions
• explain what is meant by an acute anaphylactic reaction and appreciate the possibility of drug interactions in patients on large numbers of drugs
• list the five main sites in the body where drug interactions can occur
• explain how certain types of drugs such as monamine oxidase inhibitors (MAOIs) are strongly associated with drug and food interactions
• list the important drug interactions listed on p. 422
• give an account of the processes involved in the introduction and testing of new drugs and explain what is meant by phases I, II and III in clinical trials and what is meant by a double-blind trial
• describe the pivotal role of the nurse in the running of these trials
• explain what is meant by pharmacovigilance and pharmacoeconomics and how they affect the patient
Types of adverse reactions
During recent years, adverse reactions to drugs have become increasingly common. They are responsible for about 5% of admissions to hospital and occur in 10–20% of hospital inpatients. This is probably due to the enormous increase in the range and number of drugs now in use. It is particularly important for nurses to be aware of the possibility of drug reactions as they may be the first to realize that something is wrong, and so the drug can be stopped before too much damage is done.
Drugs most commonly causing adverse reactions are:
• warfarin
• diuretics
• digoxin
• tranquillizers
• antibacterials
• steroids
• potassium
• antihypertensives
• drugs for treatment of Parkinson’s disease
• antineoplastic drugs.
The classification of adverse reactions to drugs has been simplified by Professors Rawlins and Thompson of the University of Newcastle. They have suggested that reactions can be divided into type A reactions and type B reactions.
Type A reactions are more common and are due to the normal pharmacological actions of the drug, which for various reasons are greater than would normally be expected. They are therefore predictable.
Type B reactions (idiosyncratic) are considerably less common and are unrelated to the drug’s normal pharmacological action. They are therefore unpredictable and not related to the dose of the drug.
In some texts, the terms types C, D and E may be found with reference to adverse effects. These refer not to actual reaction types, but to the characteristic of the reaction. Thus, C refers to Continuous chronic occurrences of the reaction, D refers to Delayed adverse reactions and E refers to End-of-use reactions.
Type A reactions
They can be due to incorrect dose or excessive absorption, which is uncommon, decreased elimination of drugs or undue sensitivity of organs.
Decreased elimination
This is due to slower breakdown or poor excretion by the kidneys. This in turn leads to accumulation of the drug in the body and adverse effects. Examples are the slow breaking down of morphine by the liver in patients with liver damage, causing undue sedation and even coma, and poor elimination of gentamicin by the kidneys in renal failure, causing accumulation of the antibiotic and damage to the ears.
Undue sensitivity
Undue sensitivity to the action of a drug can produce symptoms of overdosage or abnormal responses. Examples include the increased sensitivity of the heart to digoxin, leading to toxicity, in patients with potassium deficiency, and the undue sensitivity of the respiratory centre of the patient with chronic lung disease to opioids, so that normal therapeutic doses cause symptoms of overdose.
This type of reaction is usually related to the dose of the drug and can be relieved if a lower dose is given or the drug is stopped for a time.
Type B reactions
These are bizarre and unexpected reactions, and are not dose related. In many cases the reason for and mechanism of this type of adverse reaction is not known: for example, chloramphenicol causes severe depression of the bone marrow in about 1:30 000 treatment courses. It is very difficult to relate the adverse effect to the drug when it occurs in such a small proportion of patients.
Among the known causes of type B reactions are:
• genetic factors
• host factors
• environmental factors
• allergic reactions.
Genetic factors
A tendency to certain reactions of this type is related to the genetic make-up of the individual. For example, subjects of tissue type HLA-DR3 are more likely to suffer from gold toxicity.
Genetic factors may make the drug act in a completely abnormal way. For example, primaquine, an antimalarial agent, causes breakdown of red blood cells in a number of people of African and Indian descent. This has been shown to be due to a deficiency in the red blood cells of the enzyme glucose-6-phosphate dehydrogenase (G6PD). The same enzyme deficiency is responsible for favism, in which red blood cells break down as a result of eating beans.
Host factors
Host disease may predispose to a certain adverse reaction. For example, patients with infectious mononucleosis (glandular fever) are liable to get a rash if given ampicillin.
Environmental factors
These have been little studied, but it is possible in certain individuals that diet, tobacco or alcohol consumption and other, as yet unknown, factors may influence the response to a drug.
Allergic reactions
Allergy plays an important part in unexpected drug reactions, although here the mechanism is only partially understood.
This type of reaction implies that the patient has been exposed to the drug on some previous occasion. This exposure has resulted in the production of an antibody against the drug. Antibodies are proteins which are formed in the body as the result of the introduction of some foreign substance (antigen). They often serve a useful purpose: for example, antibodies formed against bacteria combine with and destroy the bacteria. Several different types of antibodies are produced in response to drugs. Sometimes these antibodies combine with a drug in such a way as to cause damage to tissue and so produce the symptoms of an allergic reaction. Four types are described:
Type I
The antibody (produced in response to a drug) may become attached to the surface of certain cells called mast cells which are scattered throughout the body. If the drug is given on a second occasion, the drug (antigen) and antibody combine on the surface of the mast cells, which are destroyed, liberating substances such as histamine, which cause an acute anaphylactic reaction (see later).
Type II
The antibody may become attached to the surface of red blood cells. On second exposure to the drug, the combination occurs on the surface of the red blood cells, which are destroyed, producing a haemolytic anaemia.
Type III
Antigens and antibodies may combine in the bloodstream to form immune complexes. They may penetrate various organs, where they are deposited, together with a further substance called complement, which is present in the blood. The antigen/antibody/complement combination stimulates inflammation, which may affect the skin, kidneys and other organs.
Type IV
Drugs acting as antigens may sensitize lymphocytes, which, on further contact with the antigen, will cause tissue damage. This type of reaction usually causes rashes.
Although the exact mechanism of all allergic reactions is not understood, some form of drug/antibody combination is always involved.
Clinical disorders caused by allergic reactions
Allergic reactions cause a number of clinical disorders:
• acute anaphylaxis
• serum sickness
• rashes
• renal disorders
• other allergies.
Acute anaphylaxis
This may be caused by certain foods (especially nuts, eggs and fish), by drugs (notably penicillin), by wasp and bee stings, by injection of foreign serum and by contact with latex rubber. The onset is usually rapid.
Mild cases show urticaria, nausea and coughing. More severe attacks include bronchospasm, facial oedema, hypotension, substernal pain and collapse. Severe anaphylaxis can be fatal.
Treatment
Acute anaphylaxis should be avoidedif at all possible. Patients must always be questioned about previous reactions before they are given a drug or a vaccine, especially one such as a flu vaccine, which is prepared in eggs. Particular care is required with sufferers from certain allergic disorders, notably asthma, hay fever and infantile eczema, as they are more prone to anaphylactic reactions.
The treatment depends on the severity of the reaction; if severe, it consists of:
1. The patient should be recumbent.
2. Ensure a clear airway and give 100% oxygen.
3. Give adrenaline (epinephrine) 1:1000 solution 0.6 ml (600 micrograms) intramuscularly and repeat as required at 10-minute intervals.
4. Give hydrocortisone (as sodium succinate) 100 mg intravenously, and repeat as required, although its effect may be delayed.
5. Give chlorphenamine 10 mg intravenously or intramuscularly.
6. Give an intravenous infusion of 500–1000 ml of colloid, if circulatory collapse occurs.
7. Use a nebulized bronchodilator if bronchospasm is marked.
8. Nurses should never leave the patient alone.
9. Follow up to determine the cause of the reaction and to prevent a recurrence.
Serum sickness
This develops about a week after the serum or drug has been administered. There is usually an urticarial rash with stiffness and swelling of joints, sometimes a mild nephritis and lymph node enlargement. Spontaneous recovery is usual, but calamine lotion applied to the rash and oral chlorphenamine, together with prednisolone for a few days in more severe cases, will relieve the symptoms and speed recovery.
Rashes
Rashes may occur as a result of drugs allergy, but not all rashes which occur when drugs are given are due to allergy. An example of a non-allergic drug rash is the typical erythematosus rash which often occurs when ampicillin is taken.
Renal disorders
Damage to the glomerulus by several drugs, including penicillamine and gold, can cause gross proteinurea. Non-steroidal anti-inflammatory drugs (NSAIDs) and angiotensin-converting enzyme (ACE) inhibitors can cause renal failure and there are a number of other types of drug-induced renal disease.
Other allergies
Other allergies have been implicated as the cause of various other disorders, including depression of the bone marrow leading to leucopenia, thrombocytopenia and anaemia, haemolysis (breakdown) of red blood cells, jaundice and renal damage. These drug reactions are not always caused by allergic mechanisms and in many cases the exact way in which a drug damages the tissues and organs is not known.
Adverse reactions cannot be eliminated entirely, but they can be minimized by:
1. Taking a drug history to discover whether patients are already taking medicines and whether they have had adverse effects from a drug or drugs in the past.
2. Reducing prescribing to a reasonable minimum.
3. Remembering that certain patients (i.e. the elderly, those with liver or renal disease) may not handle drugs in the usual way and dose modifications may be required.
4. Always remembering that some unexpected change in a patient’s condition may be due to an adverse drug reaction.
Drug interactions
If the prescription sheet of a patient in hospital is examined it will probably show that he or she is receiving perhaps half a dozen separate drugs. This treatment with multiple drugs, which has become a feature of medical practice, has brought with it the danger that certain drugs may interact, occasionally with disastrous consequences. Dangerous interactions are particularly liable to occur:
• in seriously ill patients because they will probably be taking several drugs at the same time
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