In delayed hypersensitivity, antibody formation is not in-volved and the reaction solely results from the combina-tion of antigens or haptens with T lymphocytes. The anti-gen or hapten is introduced by contact or injection, forms a complex with macrophages and then combines covalently with receptors on the lymphocyte membrane. This pro-cess results in lymphocyte mitosis and the local release of lymphokines (e.g. tumour necrosis factor, interferon ).
A local inflammatory reaction usually occurs within 24–
48 hours, resulting in erythema, induration, blistering and exfoliation, due to the accumulation of macrophages and lymphocytes at the site of injection.
Delayed hypersensitivity is responsible for the positive response to the Mantoux reaction and occurs in most forms of contact dermatitis, whether produced by metals or drugs. It is also a factor in many drug rashes, erythema multiforme (the Stevens–Johnson syndrome) and in the morbilliform rashes that are sometimes induced by ampi-cillin and amoxiampi-cillin in patients with glandular fever or chronic lymphatic leukaemia.
Hypersensitivity responses associated with anaesthesia
Hypersensitivity responses to anaesthetic drugs are not in-frequent and can occasionally be life-threatening. In many instances, commonly used drugs such as thiopental or
suxamethonium are involved, and colloid infusions may have been administered. It may be particularly difficult to detect patients who are at risk from such responses, al-though those with a history of atopy (asthma, hay fever or eczema) or with a previous or family history of ad-verse reactions must be considered as vulnerable. It has been suggested that some drugs are relatively safe (eto-midate, vecuronium, fentanyl, local anaesthetic amides).
Pretreatment with both H1- and H2-receptor antagonists (e.g. chlorphenamine and ranitidine) may confer some protection in susceptible patients.
Although ‘halothane hepatitis’ is an extremely rare hy-persensitivity response, it is usually unpredictable and can only be prevented by avoiding the clinical use of the drug.
Not all the adverse responses to drugs in ‘normal’ in-dividuals can be related to immunological mechanisms or to underlying genetic disorders. In some cases, adverse responses can be considered as an extension of the phar-macological effects of the agent, or may reflect intrinsic toxicity that is primarily dependent on the chemical prop-erties of the drug or its metabolites. These Type A adverse effects are usually dose-dependent and can usually be re-produced in animals. Adverse responses of this type have become less frequent because of increased understand-ing of the structural features of drugs that contribute to their intrinsic toxicity. In addition, these toxic effects are frequently disclosed in preclinical and clinical trials.
Adverse reactions to drugs during foetal life Drugs that are administered during pregnancy may cross the placental barrier and adversely affect the foetus. The placenta consists of a vascular syncytial membrane, with the functional properties of a typical lipid barrier. Lipid-soluble, low molecular weight drugs are readily transferred across the placental membrane, and their rate of removal from maternal blood is predominantly affected by
rPlacental blood flow
rDiffusional area
rConcentration gradient
In practice, all lipid-soluble drugs that cross the blood–
brain barrier also cross the placenta, and their elimination by foetal tissues may be prolonged. In contrast, polar (ion-ized) or large molecular weight compounds do not readily cross the placenta.
Anaesthetic agents
Inhalational anaesthetics, thiopental, propofol and most opioid analgesics can diffuse from maternal plasma to the
foetus, and when used in labour may produce respira-tory depression in the newborn. Similar effects may be produced by some sedative and hypnotic drugs. When diazepam is used in late pregnancy in pre-eclampsia and eclampsia, it readily crosses the placenta, but is only slowly metabolized by the foetus. Its active metabolites desme-thyldiazepam and oxazepam accumulate in foetal tissues and can cause neonatal hypotonia and hypothermia.
Other drugs
Lipid-soluble-adrenoceptor antagonists (propranolol, oxprenolol) can cross the placenta and may cause foetal bradycardia. In addition, foetal hypoglycaemia may be induced by insulin, oral hypoglycaemic agents or some
-adrenoceptor antagonists.
Teratogenic effects
More serious effects are produced by drugs taken dur-ing pregnancy that produce foetal damage or malforma-tion (teratogenic changes). In early pregnancy (0–18 days), drugs that affect cell division (cytotoxic agents, folate an-tagonists) may affect formation of the blastocyst and cause foetal death. Nevertheless, foetal abnormalities are more commonly produced by drugs that are administered dur-ing organogenesis (2 weeks–2 months), includdur-ing pheny-toin and antithyroid drugs (Table 1.4). In some instances, the effects of drugs may be delayed for many years. When stilboestrol was used in late pregnancy, alteration in the maternal hormonal environment produced vaginal dys-plasia and malignancy in female offspring after a latent period of 10–20 years.
Suggested reading
Axon, A.D. & Hunter, J.M. (2004) Anaphylaxis and anaesthesia – all clear now? British Journal of Anaesthesia 93, 501–503.
Dean, G. (1971) The Porphyrias: A Story of Inheritance and Environment, 2nd edn. London: Pitman, pp. 1–118.
Ellis, F.R. & Halsall, P.J. (2002) Malignant hyperthermia. Anaes-thesia and Intensive Care Medicine 3, 222–225.
Ewan, P.W. (1998) Anaphylaxis. British Medical Journal 316, 1442–1445.
Fisher, M. (1995) Treatment of acute anaphylaxis. British Med-ical Journal 311, 731–733.
Iohom, G., Fitzgerald, D. & Cunningham, A.J. (2004) Principles of pharmacogenetics – implications for the anaesthetist.
British Journal of Anaesthesia 93, 440–450.
James, M.F.M. & Hift, R.M. (2000) Porphyrias. British Journal of Anaesthesia 85, 143–153.
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Kalow, W. (1993) Pharmacogenetics: its biological roots and the medical challenge. Clinical Pharmacology and Therapeutics 54, 235–241.
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La Du, B.N. (1995) Butyrylcholinesterase variants and the new methods of molecular biology. Acta Anaesthesiologica Scan-dinavica 39, 139–141.
Laroche, D., Vergnaud, M.C., Sillard, B., et al. (1991) Biochem-ical markers of anaphylactoid reactions to drugs: compar-ison of plasma histamine and tryptase. Anesthesiology 75, 945–949.
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Stewart, A.G. & Ewan, P.W. (1996) The incidence, aetiology and management of anaphylaxis presenting to an accident and emergency department. Quarterly Journal of Medicine 89, 859–864.