Drug allergy is often a common term used to depict any unexpected and unwanted event
or affect that occurs when an individual is taking a specific drug or therapeutic
agent. A better, overall term to describe these circumstances would be an adverse
reaction to a drug.
Overview of Adverse Drug Reactions
- Most reactions do not involve the immune system
- A skin rash is the most common type of drug reaction,
Most drug reaction occurs in adult females and those individuals who are frequently
exposed to multiple medications
Most allergic drug reactions occur to beta-lactam (e.g. penicillin) antibiotics
than to other antibiotics.
Reactions to radio contrast media (RCM) and aspirin/nonsteroidal anti-inflammatory
agents are frequent causes of allergic-like or nonimmunologic reactions
Classification of Adverse drug reactions
- Toxic: overdose or side effects, delayed expression (e.g. teratogenicity, malignancy)
- Allergy-like side effects
Impaired degradation, excretion of drugs, or both due to organ system failure (increased
- Conditions mimicking allergic reactions
- Ampicillin reactions with infectious mononucleosis and other viral illnesses
- Exanthematous infectious disease
- Controversial: Stevens-Johnson Syndrome
Risk of susceptible population
Definition of Terms used to Describe Adverse Reactions to Drugs:
Intolerance: That condition in which a drug produces its expected
toxic side effects at an unusually low dose. About 90% of adverse reactions to drugs
fall into the intolerance group.
Drug overdose: toxic reaction owing to excess drug dose or impaired
Drug interaction: actions of two or more drugs on the toxicity
or effects of each individual agent.
Idiosyncrasy: That condition in which the adverse reaction is strange
and pharmacologically unexpected (i.e., different from the usual toxic reactions).
Reactions of intolerance and idiosyncrasy may be related to the presence of enzyme
defects in some patients.
Allergy: An acquired potential for developing an adverse reaction
that is immunologically mediated. Allergy and hypersensitivity are often used interchangeably.
In practise, of course, many reactions that are generally considered to be allergic
could in fact be idiosyncratic, since no immune mechanism has been identified.
Anaphylactoid: An adverse reaction that mimics an allergic reaction
but is produced by toxic rather than immune release of potent vasoactive and smooth
muscle reactive mediators.
Carrier: A substance with immunogenic potential that, when coupled
with a low molecular- weight drug or metabolite, renders that chemical (the hapten)
Cross-reaction: The reaction of an antibody or antigen-specific
lymphocyte with an antigen other than the one that induced its formation. For example
penicillin cross-reacts with cephalosporin antibiotics.
Hapten: A substance that can react with a specific antibody but
is of a molecular weight too low for it to be immunogenic by itself. Penicillin
is an example of a hapten.
Immunologically-mediated (true allergy) to drugs account for 6-10% of all adverse
drug effects. There are a number of specific characteristics that are generally
helpful in distinguishing drug allergy from other adverse drug reactions, such as:
- Previous treatment without adverse event
- Occurs in only a small fraction of patients
- Symptoms can be reproduced by a very small dose of drugs
Onset is usually after several days but within several months of initial administration
of the drug
- Subsides within several days to weeks following discontinuation of the drug.
- Differs from any known pharmacologic manifestation
- Can mimic other known allergic reaction including anaphylaxis and serum sickness
Immunologic Drug Reactions
Type I IgE-antibody-mediated (e.g., Penicillin, insulin
urticaria or anaphylaxis)
Type II anti-tissue cytotoxic antibodies (e.g., drug-induced
haemolytic anaemia or thrombocytopenia [reduced platelets])
Type III antigen-antibody immune complex involving complement
reactions (e.g., serum sickness-like drug reactions)
Type IV cell-mediated or delayed hypersensitivity (e.g.,
neomycin contact dermatitis)
Risk Factors for Allergic Reactivity
- Allergic drug reaction more common in adults than children
- Genetic factors that control drug metabolism may influence the risk of drug hypersensitivity
- Atopy is not a risk factor, but being atopic predisposes to a more severe reaction
Immunosuppression may enhance the sensitising potential of some drugs. An immunosupressed
patient may become deficient in those suppressor T cells that regulate IgE antibody
In recent years, immunosuppression associated with HIV infections has become a major
risk factor for adverse drug reactions. Over half of the patients with AIDS develop
adverse reactions when treated with trimethoprim-sulfamethoxazole. The incidence
of reactions to Ampicillin is inversely proportional to CD4+ cell counts. Several
other drugs have been found to have a higher than expected tendency to produce adverse
reactions in HIV-infected patients. Most are mild-to-moderate skin eruptions, but
the risk of anaphylaxis and even toxic epidermal necrolysis may also be enhanced
in HIV infection
Topical medication to the skin (apparently not to the mucous membrane) is the most
likely to sensitise and oral administration the least likely. Intravenous administration
of a drug is less likely to sensitise than other parenteral routes.
The chemical nature of the drug also determines its allergenicity. Whether it is
able to form stable conjugates with carrier proteins either directly or via a reactive
Allergic-like side effects can be produced directly by certain drugs in the absence
of any evidence of hypersensitivity. In contrast to true allergic reactions, these
occurs promptly the first time the drug is taken, if the dose is sufficiently high,
appear only when the dose is increased. There are drugs that directly release histamine
from mast cells. These histamine releasers produce reactions that are similar to
anaphylaxis. Since they are not immunologically mediated they are referred to as
anaphylactoid reactions. Examples of histamine releasing drugs:
- Radiograph contrast Media
Clinical Features of an Allergic Reaction
Only a small percentage of patients exposed to a drug will develop a true allergic
reaction. In part, this depends on the chemical nature of the drug. Drugs that commonly
induce allergic reactions include:
- Sulpha antibiotics
- Allopurinol (prescribed for gout)
- Anti-seizure drugs
- Anti-arrhythmia (heart medication)
When a true allergy develops, the signs and symptoms depend on the part of the immune
system that is reacting. The potentially most severe reaction occurs when an allergic
persons immune system produces the allergic antibody IgE in response to a
drug. When the persons body encounters the drug again, IgE allergic antibodies
bound to the mast cells result in release of histamine and other chemicals. This
triggers symptoms of an allergic reaction, which may range from scattered hives
The chances of developing an allergic reaction may be increased if the drug is given
frequently, in large doses, or by injection rather than by a pill. The most important
factor may be an inherited genetic tendency of the immune system to develop allergies.
Contrary to popular myth, however a family history of allergy to a specific drug
does not mean that a patient has an increased chance of reacting to the same drug.
The most common allergic reaction to a drug is a measles-like rash (without hives),
which typically occurs after several days to two weeks of treatment. This is most
likely caused by specific immune cells in the skin, which react to the drug. In
most cases, only the skin is affected and the rash usually clears once the drug
is discontinued. If there is itching an antihistamine may be helpful.
Urticaria (hives) and Drug Reactions:
- Severe urticaria may be a manifestation of mild anaphylaxis or anaphylactoid reactions
- Urticaria is suggestive, but not diagnostic of an allergic aetiology
- Urticaria may be affected by other factors, such as viral infections.
A drug-induced rash that does not include urticaria does not rule out immunologic
Rarely, blisters develop in association with a drug rash. This is a sign of a serious
complication, called erythema multiforme major (Stevens-Johnson syndrome), and should
be treated as an emergency.
Anaphylaxis is the most severe allergic reaction. Symptoms
suggestive of anaphylaxis include:
- Sense of warmth, flushing, hives
- Swelling of the throat
- Asthma or wheezing
- Nausea or vomiting
- Light headedness from low blood pressure or shock
- Abdominal cramping
These symptoms require emergency attention including an immediate injection of adrenaline.
Rarely, if the reaction is not immediately treated with adrenaline, anaphylaxis
can result in death.
All patients with drug anaphylaxis should be given a Medic-Alert bracelet, naming
the drug that caused the reaction.
Most anaphylactic reaction occurs within one hour after the patient takes the drug.
In 5-20% of cases, a recurrence of the anaphylactic reaction may occur up to several
hours later. This is more common in patients who had a severe initial reaction.
In patients at risk of anaphylaxis, the culprit, IgE antibody, was produced by the
immune system in response to a prior exposure to the drug. As initial IgE production
is gradual, many patients show no symptoms; others may develop itchy hives while
taking the drug.
Clinical Manifestations of Penicillin Allergy
Immediate Type I – <1hour: Anaphylactic shock, urticaria
(hives), angioedema (swelling of lips, tongue etc.)
Accelerated – 1-72 hours: Mainly urticaria
Skin: Measles-like rash, pruritus, Erythema Multiforme, Bullous
Erythema, Erythroderma (generalised redness of the whole body)
Serum Sickness (Type III Reaction): Skin rash, joint pains, fever
Blood Disorders (Type II Reaction): Low white blood cell count,
low platelets, anaemia
Late [Type IV Reaction] – >72 hours): Measles-like rash,
Diagnosis of Drug Allergy
Any reaction to a drug, even over the counter medication should be reported to your
doctor. It is important to know that you could develop an allergy to a drug that
you have previously taken without ill effects.
Skin Prick Test
Currently, only limited tests are available to diagnose specific medication allergy.
Allergy skin testing to determine the presence of IgE antibody is available for
penicillin and insulin. Skin testing is sometimes done for other medication.
General anaphylaxis is unlikely because of the small amount of allergen (drug) introduced,
but a physician should always be available for such occurrences.
This is more sensitive than the skin prick test for drug allergy.
0.05 0.1ml of the drug is injected intradermally in the upper arm and read
at 30 minutes, 24 hours and 48 hours.
A positive reaction at 30 min is suggestive of immediate type (type 1) allergy and
positive reaction at 48 h indicates delayed-type hypersensitivity (type 1V), for
example allergic contact allergy (same information as patch gives).
The risk of general anaphylaxis is higher than in prick test because of the larger
amount of allergen injected.
This test can be useful in patients who have a delayed reaction to drugs. Drugs
that can be tested by patch test include:
- Acyclovir (Zovirax)
- Macrolide Antibiotics
Skin Tests and Patch Tests
are only useful in a minority of patients with drug allergy, for the majority of
patients if the diagnosis needs to be confirmed, it has to be done by oral challenges
in a clinical or hospital setting
One study done, investigating children with suspected Antibiotics Allergy by Oral
challenges, showed that the majority of suspected drug reactions were actually due
to infectious disease or interaction of an infectious agent and the antibiotics.
Can drug Allergy be "outgrown"?
Yes, 70% of patients with penicillin allergy will lose their allergy over 5 to 10
years. Skin tests or RAST can be done to see if you are
still allergic. There is no test to predict the chance of developing recurrent rashes.
In the case of rashes caused by the antibiotic ampicillin, many patients can tolerate
re-administration if the drug is necessary, but this might have to be done under
If you have had a blistering rash related to a drug, you should never be prescribed
that drug again.
Remember to inform the doctor of all your drug reactions every time you are prescribed
Treatment of Drug Allergy
Avoidance & use of Alternative drug is best option
All patients should be given a
Drug desensitisation can be a useful procedure in some carefully selected patients
who have had an allergic or an allergic-like reaction to an agent but require the
drug because their illness is serious and no substitute is available. Most information
exists on desensitisation procedures involving immunological IgE reactions, especially
those involving penicillin and insulin. Desensitisation has also proved helpful
in the cases of some non-immunological anaphylactoid reactions, such as aspirin
and sulphonamide-containing antibiotics. Drug desensitisation has been proved unsuccessful
and dangerous when attempted for reactions of the febrile mucocutaneous type (e.g.
Drugs for which desensitisation has been used successfully include: