DRUG ALLERGY

Definition of drug allergy

It

is defined as an adverse reaction to a

drug by a specific immune response
either directly to the drug or one or more
of its metabolites alone, or to a drug
bound to a body protein such as
albumin, (Hapten).
Such binding alters the structure of the
drug/protein complex, rendering it
antigenic.
2

Adverse Drug Reactions

Adverse drug reactions majority of iatrogenic illnesses
- 1% to 15% of drug courses
1. Non-immunologic (90-95%): side
effects, toxic reactions, drug
interactions, secondary or indirect
effects (eg. bacterial overgrowth)
pseudoallergic drug rx (e.g. opiate
reactions, ASA/NSAID reactions)
2. Immunologic (5-10%)

Drugs as immunogens
Complete

antigens - insulin, ACTH,

PTH
- enzymes: chymopapain,
streptokinase
- foreign antisera e.g. tetanus
antitoxin
Incomplete antigens
- drugs with MW < 1000 - drugs acting
as haptens bind to
macromolecules (e.g. proteins,
polysaccharides, cell membranes)

Factors that influence the

development of drug allergy
Route

of administration:
- parenteral route more likely than oral
route to
cause sensitization and anaphylaxis
- inhalational route: respiratory or
conjunctival
manifestations only
- topical: high incidence of sensitization
Scheduling of administration:
- intermittent courses: predispose to
sensitization

Factors that influence the

development of drug allergy
Nature

of the drug:
80% of allergic drug reactions
due to:
- penicillin cephalosporins
sulphonamides (sulpha drugs)
- ASA/NSAIDs

Gell and Coombs reactions

Type

1 : Immediate Hypersensitivity
- IgEmediated
- occurs within minutes to 4-6 hours of drug
exposure
Type 2 : Cytotoxic reactions
- antibody-drug interaction on the cell surface
results in destruction of the cell eg.
hemolytic
anemia due to penicillin, quinidine, quinine,
cephalosporins

Gell and Coombs reactions

Type

3 : Serum sickness
- fever, rash (urticaria, angioedema, palpable

purpura), lymphadenopathy, splenomegaly,

arthralgias
- onset : 2 days up to 4 weeks
- penicillin commonest cause
Type 4 : Delayed type hypersensitivity
- sensitized to drug, the vehicle, or
preservative
(e.g. PABA, parabens, thimerosal)

Classification of hypersensitivity
The

criteria of the classification

1) Based on the time required for the
symptoms or skin test reactions to
appear after exposure--- immediate and
delayed hypersensitivity.
2) Based on the nature of organ
involvement.

Hypersensitivity Reactions
I (immediate)

II (cytotoxic)

III (immune
complex)

IV (delayed)

V
(stimulating/blocki
ng)#

Antigens

Pollens, moulds,
mites, drugs,
food and
parasites

Cell surface or
tissue bound

Exogenous
(viruses,
bacteria,
fungi,
parasites)
Autoantigen
s

Cell/tissue
bound

Cell surface
receptors

Mediators

IgE and mast

cells

IgG, IgM and

complement

IgG, IgM,
IgA and
complement

TD, Tc
activated
macrophages
and
lymphokines

IgG

Diagnostic
tests

Skin-prick tests:
wheal and flare
Specific IgE in
serum

Coombs test
Indirect
immunofluorescen
ce (antibodies)
Red cell
agglutination
Precipitating
antibodies
ELISA

Immune
complexes

Skin test:
erythema
induration
(e.g.
tuberculin
test)

Indirect
Immunofluorescenc
e

Time taken
for reaction
to develop

5-10min

6-36 hours

4-12 hours

48-72 hours

Variable

#Type V hypersensitivity may also be classified with type II reactions

10

I (immediate)

II (cytotoxic)

III (immune
complex)

IV (delayed)

V
(stimulating/blocki
ng)

Immunopathology

Oedema,
vasodilation, mast
cell degranulation,
eosiniophils

Antibody-mediated
damage to target
cells

Acute
inflammatory
reaction,
neutrophils,
vasculitis

Perivascular
inflammation,
mononuclear cells,
fibrin
Granulomas
Caseation and
necrosis in TB

Hypertrophy or
normal

Diseases and
conditions
produced

Asthma (extrinsic)
Urticaria/oedema
Allergic rhinitis
Anaphylaxis

Autoimmune
Haemolytic
anaemia
Transfusion
reactions
Haemolytic
disease of
newborn
Goodpastures
syndrome
Addisonian
pernicious
anaemia
Myasthenia gravis

Autoimmune (e.g.
SLE,
glomerulonephritis
, rheumatoid
arthritis)
Low-grade
persistent
infections (e.g.
viral hepa
hepatitis)
Disease caused by
environmental
antigens (e.g.
far
farmers lung)

Pulmonary TB
Contact dermatitis
Graft-versus-host
disease
Insect
Insect bites
Leprosy

Neonatal
hyperthyroidism
Graves disease
Myasthenia gravis

Exchange
transfusion
Plasmapheresis
Immunosuppressiv
es/cytotoxics

Corticosteroids
Immunosuppressiv
es
Plasmapheresis

Immunosuppressiv
es
Corticosteroids
Removal of
antigen

Treatment of
individual disease

Treatment

Antigen avoidance
Antihistamines
Corticosteroids
(usually topical)
Sodium
cromoglicate
Epinephrine for
life-threatening
RAST, radioallergosorbent
test; SLE,
conditions

systemic lupus erythematosus; TB, tuberculosis;

Tc, T cytotoxic; TD, T delayed hypersensitivity

11

Overview of Drug Allergy

Drug

allergy is an uncommon and

unwanted effect of medication.
Reactions to drugs range from a mild
localized rash to serious effects on vital
systems.
The bodys response can affect many
organ systems, but the skin is the most
frequently involved.

12

The most common drug to cause allergy

Analgesics,

such as codeine,
morphine, nonsteroidal antiinflammatory drugs (NSAIDs, such
as ibuprofen or indomethacin), and
aspirin
Antibiotics such as penicillin, sulfa
drugs, and tetracycline
13

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
andasthma.

14

Drug Allergy Symptoms

Drug

allergies may cause many

different types of symptoms
It depends on the drug and how
often you have taken it.

15

Most common allergic reactions

Rash
Fever
Muscle

and joint aches

Lymph node swelling
Inflammation of the kidney
Anaphylactic shock
16

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

17

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

18

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
19

Allergic reactions on skin

Stevens-Johnson

Syndrome (SJS)
and Toxic Epidermal Necrolysis
(TEN)
-A manifestation of acute graft
versus host disease
-Medications with longer half-lives
are more likely than those with
shorter half-lives to pose a risk for
SJS and TEN
20

Stevens Johnsons syndrome

21

Toxic epidermal necrosis

22

SJS & TEN

SJS

& TEN develop 1-3 weeks after

the culprit medication is initiated
Sulphonamides, other antibiotics,
NSAIDs, anticonvulsant and
antiretroviral agents are the most
common causative medications.

23

Signs and Symptoms of SJS & TEN

Mucosal

erosions
Asymmetric skin
involvement with
blisters
Widespread of
skin distribution
<10% total body
surface area
affected

Mucosal

erosions
Flaccid blisters
and denuded skin
Widespread

of
skin distribution
> 30% total body
surface area
affected
24

Signs and Symptoms of SJS & TEN

Fluid and electrolyte imbalance

Compromised cutaneous integrity promotes
bacterial colonization and infection of the skin
with the risk for sepsis.
Debilitated, bedridden patients are susceptible
to aspiration pneumonia, deep vein thrombosis
and pulmonary embolism
Ocular involvement may manifest to blindness

25

Guideline for Treatment of SJS & TEN

Admit

to intensive care or burn unit

Discontinue culprit medication and
all unnecessary medications
Sterile technique in handling patient
Place intravenous or central line in
area of uninvolved skin if possible

26

Guideline for Treatment of SJS & TEN

Culture

skin, blood, urine daily

Avoid prophylactic systemic
antibiotics and silver sulfadiazine to
skin
Fluid and electrolyte monitoring
and replacement
Initiate total parenteral nutrition or
nasogastric feedings if unable to
take po
27

Guideline for Treatment of SJS & TEN

Debride

necrotic skin and avoid shearing

nonnecrotic skin; local wound care may
vary from Vaseline gauze to silver nitrate
dressings to porcine xenografts to
cutaneous allografts
Air-fluidized bed
Pain control

28

Urticaria
What

is urticaria?
It is local wheals and erythema in
the superficial dermis
Urticaria induced by drug is
generally acute and is limited to the
skin and subcutaneous tissues.

29

Urticaria

30

Urticaria
Signs and symptoms
Pruritus (generally the first symptom)
Crops of hives
Lesion (if lesion persists more than 24
hours, the possibility of vasculitis should
be considered)
Diagnostic tests are seldom required

31

Urticaria
Treatment

for acute urticaria

Symptoms subside in 1 to 7 days,
treatment is chiefly palliative.
All nonessential drugs should be
stopped until the reaction has
subsided.
Symptoms can be relieved by oral
antihistamine and glucocorticoid.

Drugs for Acute Urticaria

Oral

antihistamine:
diphenhydramine 50-100mg q4h,
hydroxyzine 25-100mg bid or
cyproheptadine 4-8mg q4h
Glucocorticoid for more severe
reactions, especially when
associated with angioedema
(prednisone 30-40 mg/ day po)
33

Management for Chronic Urticaria

Chronic

urticaria caused by chronic

ingestion of an unsuspected drug, e.g.
from penicillin in milk, the use of
nonprescription drugs
Spontaneous remissions occur within 2
yr in about cases.
Control of stress often helps reduce the
frequency and severity of episodes

34

 Certain

drugs e.g. aspirin may aggravate

symptoms and should be avoided.
Oral antihistamines with a tranquilizing
effect are usually beneficial
H2 blockers (such as ranitidine 150mg
bid) are often added

35

Angioedema

36

Management for Angioedema

Glucocorticoid

(e.g. prednisone 30-

40mg/day po)
Adrenaline 1:1000, 0.3ml subcutaneously
should be the 1st line treatment for acute
pharyngeal or laryngeal angioedema
IV antihistamine (e.g. diphenhydramine
50-100mg) to prevent airway obstruction
Intubations or tracheotomy and oxygen
administration may be necessary
37

Penicillin Allergy
Skin

tests : Penicillin G, Prepen

(benzyl-penicilloyl-polylysine): false
negative rate of up to 7%

Resolution

of penicillin allergy
- 50% lose penicillin allergy in 5 yr
- 80-90% lose penicillin allergy in 10
yr

Penicillin Allergy
beta

lactam antibiotic
Type 1 reactions : 2% of penicillin courses
Penicillin metabolites:
- 95% : benzylpenicilloyl moiety (the
major
determinant)
- 5% : benzyl penicillin G, penilloates,
penicilloates (the minor
determinants)

Ampicillin rash
non-immunologic

rash
maculopapular, non-pruritic rash
onsets 3 to 8 days into the antibiotic
course
incidence: 5% to 9% of ampicillin or
amoxicillin courses; 69% to 100% in those
with infectious mononucleosis or acute
lymphocytic leukemia
must be distinguished from hives
secondary to ampicillin or amoxicillin

Cephalosporin allergy
beta-lactam

ring and amide side

chain similar to penicillin
degree of cross-reactivity in those
with penicillin allergy: 5% to 16%
skin testing with penicillin
determinants detects most but not
all patients with cephalsporin
allergy

Sulphonamide hypersensitivity
sulpha

drugs more antigenic than beta

lactam antibiotics
common reactions: drug eruptions (e.g.
maculopapular or morbilliform rashes,
erythema multiforme, etc.)
Type 1 reactions: urticaria, anaphylaxis,
etc.
no reliable skin tests for sulpha drugs
re-exposure: may cause exfoliative
dermatitis, Stevens-Johnson syndrome

ASA and NSAID sensitivity

Pseudoallergic

reactions urticaria/angioedema
- asthma
- anaphylactoid reaction
prevalence: 0.2% general population
8-19% asthmatics
30-40%
polyps & sinusitis
ASA quatrad: Asthma, Sinusitis, ASA
sensitivity, nasal Polyps (ASAP
syndrome)

ASA & NSAID sensitivity

ASA

sensitivity: cross-reactive with

all NSAIDs that inhibit cyclooxygenase

ASA & NSAID sensitivity

no

skin test or in vitro test to detect

ASA or NSAID sensitivity
to prove or disprove ASA sensitivity:
oral challenge to ASA (in hospital
setting)
ASA desensitization: highly
successful with ASA-induced
asthma; less successful with ASAinduced urticaria

Allergy skin testing

Skin

tests to detect IgE-mediated drug

reactions is limited to:
Complete antigens - insulin, ACTH, PTH
- chymopapain, streptokinase
- foreign antisera
Incomplete antigens (drugs acting as
haptens)
- penicillins - local
anesthetics
- general anesthetics

Management of drug allergy

Identify

most likely drugs (based on

history).
Perform allergy skin tests (if
available).
Avoidance of identified drug or
suspected drug(s) is essential.
Avoid potential cross-reacting drugs
(e.g. avoid cephalosporins in
penicillin-allergic individuals).

Management of drug allergy

A

Medic-Alert bracelet is
recommended.
Use alternative medications, if at
all possible.
Desensitize to implicated drug, if
this drug is deemed essential.

Desensitization to medications
Basic

approach: administer
gradually increasing doses of the
drug over a period of hours to days,
typically beginning with one tenthousandth of a conventional dose

THANK YOU