Clinical Pharmacology and Therapeutics. Группа авторов
infections in patients taking immuno‐suppressive drugs for inflammatory disorders
Drug allergy
Drug allergy is a subset of type B adverse drug reaction. Allergy is a reproducible, immune‐mediated adverse reaction. While allergies can be mild, a patient who is allergic to a drug should avoid taking it again as repeated exposure can prompt more severe allergic reactions.
Allergies can be classified based on the Coombs and Gell classification of hypersensitivity reactions.
Type 1 hypersensitivity is relatively common. This is IgE mediated, immediate type allergy which can be recognised by rapid onset (usually within 1 hour) of itchy rash, swelling (particularly airway and tongue swelling), wheeze and if particularly severe anaphylactic shock. Common causes of type 1 drug allergy are penicillins and non‐steroidal anti‐inflammatory drugs.
Type 2 hypersensitivity is caused by antibodies binding to cells or tissues within the body. Such adverse reactions are much less common than type 1. Examples include haemolytic anaemia secondary to the antibiotic rifampicin.
Type 3 hypersensitivity is caused by antibodies binding to soluble factors within the body and generating immune complexes that can inflame small blood vessels and cause an illness known as serum sickness. This is another uncommon mechanism of drug allergy and no drug commonly causes it. Potential drug causes include penicillin or cephalosporin antibiotics and allopurinol.
Type 4 hypersensitivity causes most delayed‐type cutaneous drug reactions. It is mediated by the action of T lymphocytes within the skin rather than antibodies. Such reactions are not usually severe but in unusual cases severe cutaneous or systemic illness can arise. Antibiotics are common causes of delayed‐type rashes. Severe reactions such as Stevens–Johnson syndrome or DRESS (drug reaction with eosinophilia and systemic symptoms) are rare but can be caused by almost any drug.
While drug allergy should be taken seriously, it is also overdiagnosed. It is important to carefully record the circumstances of a possible drug allergy and consider seeking specialist advice if the situation is unclear. This is particularly important if the drug is felt to be particularly useful or important in the patient's management. It is a consistent finding that around 10–15% of any population will report having an allergy to penicillin but only around 10% of these patients will actually have evidence of an allergy on detailed testing.
Drug interactions
When administration of one drug influences the effect of another, the term ‘drug interaction’ is used. Interactions account for approximately one quarter of all adverse drug reactions, and are most commonly seen in elderly people taking a variety of drugs for multiple problems. There are an almost limitless number of drug interactions and while it is important to be aware of some of the most commonly encountered ones, there is no substitute for looking up prescribing resources or consulting a pharmacist. This is particularly important when prescribing an unfamiliar drug.
Drug interactions can result from interference between the pharmacological action of the drug – for example through action on the same receptor or a similar biological process – or it may be due to interference with drug absorption, metabolism or clearance leading to altered drug levels at the site of action. It is important to bear in mind that drug interactions can also occur between non‐prescribed drugs such as over the counter medicines or herbal remedies. St John's Wart can be bought in health food shops and is known to interfere with the metabolism of many drugs. Grapefruit juice is also known to alter the bioavailability of many drugs.
Pharmacodynamic interactions
These tend to involve the administration of two drugs with similar effects. Such interactions may involve two agents acting at one receptor (attenuation of salbutamol's bronchodilatory effect by non‐specific beta‐blockers) or through a less specific effect upon particular tissues (potentiation of the sedative effect of benzodiazepines by alcohol). Pharmacodynamic interactions at one receptor may have therapeutic use, such as the reversal of opiate toxicity by naloxone. The clinical effects are largely predictable and can be prevented by thoughtful prescribing.
Pharmacokinetic interactions
These interactions involve interference with absorption, distribution or metabolism of one drug as a consequence of the administration of another. They tend to be less easy to predict than pharmacodynamic interactions, although the consequences may be no less severe. Some commonly encountered pharmacokinetic interactions are summarised in Table 4.2.
Table 4.2 Examples of pharmacokinetic interactions.
| Absorption interactions |
| Tetracyclines chelate calcium, iron and magnesium salts leading to reduced antibiotic absorption |
| Cholestyramine reduces warfarin absorption by binding to it |
| Distribution interactions |
| Aspirin displaces warfarin from plasma proteins, potentiating the anti‐coagulant effect |
| Meropenem displaces valproate from its protein binding sites leading to greatly increased clearance of valproate and rapid loss of effect |
| Metabolism interactions |
| Induction |
| Carbamazepine induces enzymes which metabolise phenytoin, necessitating larger doses of phenytoin |
| The antibiotic rifampicin is a potent inducer of many enzymes involved in drug metabolism and causes many troublesome pharmacokinetic drug interactions |
| Inhibition |
| Macrolide antibiotics such as clarithromycin inhibit metabolic enzymes in the liver leading to increased drug levels of many drugs including many statins such as simvastatin |
| Allopurinol potentates the cytotoxic effect of azathioprine by inhibiting xanthine oxidase, the enzyme responsible for its enzymatic degradation |
An exhaustive list of all potential interactions lies out with the scope of this text. Appendix 1 of the BNF provides a useful reference, and should be consulted whenever the question of a potential interaction arises.
Adherence
A 74‐year‐old man with high blood pressure is admitted to hospital for a routine operation (transurethral resection of prostate). The admitting doctor writes up his drug chart for the three different blood pressure tablets he is normally prescribed. The day after his operation he is given the three drugs by the nurse doing the drug round. The patient then complains of dizziness on standing and is noted to have a low blood pressure with postural drop. Is there a problem with adherence?
Adherence is the degree to which a patient takes the treatment(s) prescribed for them as directed. The old term for this is