DRUG ALLERGY

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 Drug allergy
• Epidemiology
• Adverse drug reactions are a major cause of morbidity
and mortality worldwide. It has been estimated that 5–
15% of patients develop adverse reactions to
medications during treatment.
• This number increases to 30% for hospitalized patients.
Of all hospital admissions, approximately 0.3% are due
to adverse medication reactions.
• Fatal drug reactions occur in 0.1% of medical
inpatients.
Reactions to drugs can be divided into two main categories:

– predictable (type A) - Predictable drug reactions

account for approximately 80% of all drug
reactions and are due to the pharmacologic
effects of the drug. These reactions are typically
dose dependent and include reactions due to
overdosage, adverse effects, secondary effects
and drug–drug interactions
– unpredictable (type B) drug reactions-drug
intolerance, idiosyncratic reactions, and immune-
mediated (including hypersensitivity) reactions.
 Hypersensitivity Reactions
 Hypersensitivity (hypersensitivity reaction) refers to undesirable
immune reactions produced by the normal immune system.

Hypersensitivity reactions: four types; based on the mechanisms

involved and time taken for the reaction.
 The classification of the
hypersensitivity
 Type I
 Antigens combine with specific IgE antibodies that
are bound to membrane receptors on tissue mast cells
and blood basophils
 It causes the rapid release of potent vasoactive and
inflammatory mediators
 It produces vasodilatation, increased capillary
permeability, glandular hypersecretion, smooth
muscle spasm and tissue infiltration with eosinophils.

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 The classification of the
hypersensitivity
 Type II
Cytotoxic reactions ( activation of killer T
cells or macrophages to produce
cytotoxicity )resulting when antibody
reacts with antigenic components of a
cell or tissue elements or with antigen or
hapten that is coupled to a cell or tissue.

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 The classification of the hypersensitiity

 Type III
Immune complex (IC) reactions resulting
from deposition of soluble circulating antigen-
antibody ICs in vessels or tissue.

It causes polymorphonuclear cell migration

and release of lysosomal proteolytic enzymes
and permeability factors in tissues, resulting
in acute inflammation.

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 The classification of the hypersensitivity

 Type IV
Cell mediated, delayed hypersensitivity
reactions caused by sensitized T
lymphocytes after contact with a
specific antigen.

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 Types of hypersensitivity reactions caused
by drugs

Type I Immediate, IgE- Anaphylaxis,

mediated urticaria/angioedem
a,
bronchospasm,
hypotension
Type II IgG and IgM- Leukopenia,
dependent vasculitis, rashes,
complement-mediated interstitial nephritis
cytolysis

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 Types of hypersensitivity reactions caused
by drugs
Type III Immune Serum
complexes with sickness,
IgG and IgM vasculitis,
rashes, fever

Type IV T cell- Contact

mediated sensitivity,
reactions delayed rashes

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 Overview of Drug Allergy
• Drug allergy is an uncommon and unwanted
side effect of medication.

• Reactions to drugs range from a mild localized

rash to serious effects on vital systems.

• The body’s response can affect many organ systems,

but the skin is the most frequently involved.

To develop a drug allergy, it is usually necessary to have

received the drug or a closely related one on a previous
occasion. Therefore, a previous good tolerance of a drug
does not rule out an allergy. 11
 The most common drug to cause allergy

• Analgesics, such as codeine, morphine, nonsteroidal anti

inflammatory drugs (NSAIDs, such as ibuprofen or
indomethacin), and aspirin
• Antibiotics such as penicillin, sulfa drugs, and tetracycline

There are some people who say they are

“allergic to all drugs”. This is
scientifically impossible. If the patient
has reactions to various drugs, it should
be assessed if these are related and
whether it is a true allergic reaction or
side effects.

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 Risk factors for Drug Allergy

• Frequent exposure to the drug

• Large doses of the drug
• Drug given by injection rather than pill
• Family tendency to develop allergies and asthma.

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 Most common allergic reactions

• Drug allergies may cause many different types

of symptoms

• It depends on the drug and how often you have

taken it.

• Rash
• Fever
• Muscle and joint aches
• Lymph node swelling
• Inflammation of the kidney
• Anaphylactic shock

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 Morphological types of drug rashes
and some common causes
Maculopapular Penicillin
Urticaria Penicillin, aspirin
Vasculitis Gold, hydralazine
Fixed drug rash Phenolphthalein in laxatives,
tetracyclines, paracetamol
Pigmentation Minocycline (black), amiodarone
(slate grey)
Lupus erythematosus Penicillamine, isoniazid
Photosensitivity Thiazides, chlorpromazine,
sulphonamide, amiodarone
Pustular Carbamazepine
Erythema nodosum Sulphonamides, oral
contraceptive 15
 Morphological types of drug rashes
and some common causes
Erythema multiforme Anticonvulsants
Acneiform Corticosteroids
Lichenoid Chloroquine, thiazides, gold,
allopurinol
Psoriasiform Methyldopa, gold, lithium, beta-
blockers
Toxic epidermal necrolysis Penicillin, co-trimoxazole,
carbamazepine, NSAIDs
Pemphigus Penicillamine, ACE inhibitors
Erythroderma Gold, sulphonylureas,
allopurinol

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 Allergic reactions on skin
• Measles-like rash

• Hives - Slightly red and raised

swellings on the
skin, irregular in shape, itchy

• Photoallergy - Sensitivity to sunlight,

an itchy
and scaly rash when you go out in the sun

• Erythema multiforme - Red, raised and

itchy,
sometimes look like bull's-eye targets,
sometimes with swelling of the face or
tongue

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 Allergic reactions on skin
• Stevens-Johnson Syndrome
(SJS) and Toxic
• Epidermal Necrolysis (TEN)

Anaphylactic Reaction

Life threatening
• Almost all anaphylactic
reactions occur within 4 hours
of the first dose of the drug. Most
occur within 1 hour of
taking the drug, and many occur
within minutes or even
seconds.
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 Symptoms of anaphylactic shock

• Skin reaction - Hives, redness/flushing,

sense of warmth, itching

• Difficulty breathing - Chest tightness, wheezing, throat

• tightness

• Fainting - Light-headness or loss of consciousness due to

• drastic decrease in blood pressure ("shock")

• Rapid or irregular heart beat

• Swelling of face, tongue, lips, throat, joints, hands, or feet

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Urticaria

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Angioedema

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 Diagnosis
The first step is to take a precise clinical history.
 it is very important to know exactly which symptoms the
patient had and when they started and exactly when the
patient had taken the drug.
 Other questions the doctor will address is, whether the
patinet were taking other drugs at that time (eg pain killer,
antibiotics, blood pressure medicine, but also vitamin pills
or complementary medicine) and whether this was the first
time the patient took this particular drug or if the patient
has taken this drug or a similar drug in the past.
 Other preexisting diseases or concomitant factors may be
important.
 Diagnosis
Drug allergy testing is one of the most difficult and tedious subjects in allergy
diagnosis. There are, with the exception of penicillins, no comercial test
solutions in the right dilutions available. That means all test substances need to
be prepared by the doctor or the hospital pharmacy. 
• Skin prick testing (SPT) is normally possible for every drug
whether it is injected or taken in the form of a tablet or
suppository. The drug is disolved in an adequate diluent –a
drop is placed on the forearm and punctured with a lancet. If
after 20 minutes redness and a swelling (like a mosquito bite)
develop, it is possible that the patient is sensitised to the drug.
In patients with non-immediate reactions, readings may be
done after several hours and after one to several days.
• However, depending on the drug and dilution, this reaction can
sometimes also be seen in people who are not allergic to the
drug and has therefore to be interpreted by a doctor
experienced in drug allergy!
 Diagnosis

• When intradermal testing is performed, an extremely small amount of

the soluble drug is injected into the skin. This can only be done with
drugs that are available for injection and not with tablets, syrups etc.
• This test, just like the SPT, is also read after 20 minutes and/or after
hours to days. Intradermal testing is more sensitive, but less specific as
compared to the SPT.
• Unlike pollen, house dust mite and animals, very little in vitro tests are
available for drug allergy. The most validated test is the determination of
specific immunoglobulin E (IgE) antibodies, which is quite reliable against
penicillins and a few other drugs. Other tests, such as the lymphocyte
transformation test, basophil activation test or the lymphocyte activation
test may be helpful in individual patients, but should be done and
interpreted by doctors experienced with drug hypersensitivity.
 Diagnosis

• The most precise way to test if you are drug allergic (also
called the golden standard) is to let you take the drug and
see what happens. This is called a controlled challenge test,
or drug provocation test.
A disadvantage of this test is that the patient can develop
symptoms.Therefore, in this test, we should always start with
a small amount and slow increments of the drug and this is
normally done only in hospital under strict supervision.
It can be very important to clarify the hypersensitivity
reaction, if the drug the patients may have reacted to, is
necessary for maintaining their health.
 Management

• Most of the times, when the patient is allergic to a drug, an

alternative drug is available. If not, the doctor may attempt to
desensitise (make tolerant to the drug again).
• In the desensitization procedure, the patient start with a minute
amount of the drug and take a little more every 30 to 60 minutes
until the patient can tolerate the amount it need to take. This
may take one or two days or even more. This desensitisation
procedure is, just like the drug provocation test. Therefore, this is
normally done in hospital under strict supervision.
Furthermore, the state of tolerance stays as long as the patient
take the drug daily. If the patient stop taking the drug or forget to
take it a few days, he/she does lose its tolerance to the drug!
 Penicillin Allergy
• Symptoms
Fever
Rash
Urticaria
Angioedema
Nephritis
Lymphadenopathy
Arthralgias

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 Cross-reactivity
• The structure of cephalosporin contains a β-
lactam ring with a six-membered dihydrothiazine ring.

• Side chain antigens may be more significant and

probably dominate in cephalosporin (patients with
positive penicillin skin test results who were given
cephalosporin had a cross reaction rate of 10%-20%)

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 Prophylaxis of Penicillin Allergy

Skin tests for immediate-type (IgE-mediated)

hypersensitivity are very useful in diagnosis of
reactions to penicillin, enzymes, and some vaccines.

• Skin test

It should be performed in patients

With a history of penicillin allergy and
β-lactam antibiotic is indicated drug of choice.

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Intradermal Test

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 Prophylaxis of Penicillin Allergy

• Intradermal test

A skin test is considered positive if it produces a wheal

and flare reaction in 15 min with a wheal diameter at
least 5 mm larger than the control.

• If skin tests are positive, the patient risks an anaphylactic reaction if

treated with penicillin

• Negative skin tests minimize but do not exclude the risk of a serious
reaction.

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 Hypersensitivity to Local Anesthetics

• Local anesthetics (LAs) have been used to provide

anesthesia since the discovery of cocaine in 1884.
They may be administered by topical, infiltrative,
nerve block, epidural, or spinal routes. With their
ability to block pain signals to the brain, local
anesthetics have made possible many surgical
procedures once thought impossible. Adverse
reactions to LAs are not uncommon and most are
nonallergic in etiology. LAs are generally safe and
well tolerated
Classification of LAs
Local anesthetics (LAs) have been divided into two groups based upon their chemical structure.

Group I. Para-Amino Benzoic Acid Esters

Group II. Amides

Benzocaine (Americaine, Lanocaine) Articaine (Septocaine, Zorcaine)

Butamben picrate (Butesin) Bupivacaine (Marcaine, Sensorcaine)

Chloroprocaine (Nesacaine) Dibucaine (Nupercainal)

Cocaine Etidocaine (Duranest)

Procaine (Novocaine) Levobupivacaine

Proparacaine (Alcaine, Ophthetic, ) Lidocaine (Xylocaine)

Tetracaine (Pontocaine) Mepivacaine (Carbocaine)

Prilocaine (Citanest)

Ropivacaine (Naropin)
 Incidence

• The true incidence of allergic reactions to LAs

is unknown, but exceedingly rare, less than 1%
of all anesthetic-induced reactions.
• The incidence of systemic toxicity has
significantly decreased in the past 30 years,
from 0.3% to 0.01%.
• Information about cross-reactivity among LAs
is limited, although there is evidence for cross-
reactivity within each group of agents and
minimal evidence for cross-reactivity between
the two groups.
• Most safe are Amides, especially Articaine.
 COPING
If the patient has been diagnosed with the drug allergy,
they should carry with them a detailed report of the
physician which states the diagnosis:
• which drug/s they are allergic to,
• The drugs they should avoid
• the alternative drugs they may use.
In some cases, when a patient is allergic to a very
frequently used drug or has experienced a severe
reaction, a medical alert should be considered
(bracelet, pendant, etc.).
Thank You

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