Clinical Pharmacology and Therapeutics

PREVENTION OF ALLERGIC DRUG REACTIONS 67
Central immune
apparatus
Type IV response
Drug or its
metabolites
Cell
membrane
T
Lymphocytes
Sensitized
lymphocytes
Drug or its
metabolites
Protein
Antigen
Macrophages
Type I, II and III responses
Drug
(large molecule)
B
Lymphocytes
Humoral antibodies
Figure 12.1: The immune response to drugs.
antibiotics, such as penicillin or neomycin). The mechanism
here is that the drug applied to the skin forms an antigenic
conjugate with dermal proteins, stimulating formation of sensitized
T-lymphocytes in the regional lymph nodes, with a
resultant rash if the drug is applied again. Drug photosensitivity
is due to a photochemical combination between the drug
(e.g. amiodarone, chlorpromazine, ciprofloxacin, tetracyclines)
and dermal protein. Delayed sensitivity can also result
from the systemic administration of drugs.
Key points
How to attempt to define the drug causing the adverse
drug reaction:
• Attempt to define the likely causality of the effect to
the drug, thinking through the following: Did the
reaction and its time-course fit with the duration of
suspected drug treatment and known adverse drug
effects? Did the adverse effect disappear on drug
withdrawal and, if rechallenged with the drug,
reappear? Were other possible causes excluded?
• Provocation testing with skin testing – intradermal tests
are neither very sensitive nor specific.
• Test the patient’s serum for anti-drug antibodies, or test
the reaction of the patient’s lymphocytes in vitro to the
drug and/or drug metabolite if appropriate.
• Consider stopping all drugs and reintroducing essential
ones sequentially.
• Carefully document and highlight the adverse drug
reaction and the most likely culprit in the case notes.
PREVENTION OF ALLERGIC DRUG
REACTIONS
Although it is probably not possible to avoid all allergic drug
reactions, the following measures can decrease their incidence:
1. Taking a detailed drug history (prescription and
over-the-counter drugs, drugs of abuse, nutritional and
vitamin supplements and alternative remedies) is essential.
A history of atopy, although not excluding the use of
drugs, should make one wary.
2. Drugs given orally are less likely to cause severe allergic
reactions than those given by injection.
3. Desensitization (hyposensitization) should only be used
when continued use of the drug is essential. It involves
giving a very small dose of the drug and increasing the
dose at regular intervals, sometimes under cover of a
glucocorticosteroid and β 2 -adrenoceptor agonist. An
antihistamine may be added if a drug reaction occurs, and
equipment for resuscitation and therapy of anaphylactic
shock must be close at hand. It is often successful,
although the mechanism by which it is achieved is not
fully understood.
4. Prophylactic skin testing is not usually practicable, and a
negative test does not exclude the possibility of an allergic
reaction.
Key points
Classification of immune-mediated adverse drug reactions:
• Type I – urticaria or anaphylaxis due to the production
of IgE against drug bound to mast cells, leading to
massive release of mast cell mediators locally or
systemically (e.g. ampicillin skin allergy or anaphylaxis).
• Type II – IgG and IgM antibodies to drug which, on
contact with antibodies on the cell surface, cause cell
lysis by complement fixation (e.g. penicillin, haemolytic
anaemia; quinidine, thrombocytopenia).
• Type III – circulating immune complexes produced by
drug and antibody to drug deposit in organs, causing
drug fever, urticaria, rash, lymphadenopathy,
glomerulonephritis, often with eosinophilia (e.g.
co-trimoxazole, β-lactams).
• Type IV – delayed-type hypersensitivity due to drug
forming an antigenic conjugate with dermal proteins
and sensitized T cells reacting to drug, causing a rash
(e.g. topical antibiotics).