A Textbook of Clinical Pharmacology and Therapeutics

PREVENTION OFALLERGICDRUGREACTIONS 67

antibiotics, such as penicillinorneomycin). The mechanism
here is that the drug applied to the skin forms an antigenic
conjugate with dermal proteins, stimulating formation of sen-
sitized T-lymphocytes in the regional lymph nodes, with a
resultant rash if the drug is applied again. Drug photosensitiv-
ity is due to a photochemical combination between the drug
(e.g.amiodarone,chlorpromazine,ciprofloxacin, tetracyc-
lines) and dermal protein. Delayed sensitivity can also result
from the systemic administration of drugs.

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

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.

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).

Central immune

apparatus

Type IV response

Type I, II and III responses

Humoral antibodies

T

Lymphocytes

Sensitized

lymphocytes

Cell

membrane

Drug or its

metabolites

Drug or its

metabolites

Drug

(large molecule)

Protein Antigen

B

Lymphocytes

Macrophages

Figure 12.1:The immune response to drugs.

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