Transcript Drug hypersensitivity reactions

AIM
 To clarify which reactions reported by patients are
likely to be the result of true drug allergy in the
context of all adverse drug reactions
 To understand the immunological basis for drug
allergy
 To be able to make recommendations to optimise
patient care based on this knowledge
A response to a medication that is noxious,
unintended or undesired occurring at doses
normally used for the prevention, diagnosis
or treatment of disease
WHO
Most ADR’s (85-90%) are predictable, dosedependent and related to the pharmacology
of the drug
Clin Pharmacol Therap 2011; 90(3): 455-60
Toxicity – e.g. digoxin
Intolerance – e.g. colchicine
Secondary effects – e.g. oral steroids
Special situations – e.g. renal impairment in the
elderly
 Drug interaction – e.g. SSRI and tramadol
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Unpredictable, unrelated to the known
pharmacology of the drug, with no clear dose
dependency (10-15%). Drug hypersensitivity
reactions and Drug Hypersensitivity Syndrome
constitute a major part of type B reactions
Clin Pharmacol Therap 2011; 90(3)
TYPE
MEDIATOR
PATHOGENESIS
CLINICAL
PICTURE
CHRONOLOGY
1
IgE
Degranulation
of mast cells
and basophils
Urticaria;
anaphylaxis;
allergic rhinitis;
bronchospasm;
angioedema
Immediate (<
1hr)
2
IgG/M
FcR-dependent
cell lysis
Blood cell
dyscrasia
Intermediate (514 days)
3
IgG/M
FcR-dependent
immune
complexes
deposition
Serum sickness;
vasculitis
Intermediate (78 days)
4
Th1 (IFNγ,
TNFα), Th2 (IL4.
5, 13), Cytotoxic
T cells
Monocyte/macr
ophage eosino
neutrophil
inflamm
Eczema,
maculopapular,
bullous
exanthem
Delayed (weeks)
Refers to reactions characterised by a delayed onset
constellation of symptoms including fever, rash, and
multiple organ involvement
 Classes of drugs most often associated with DHS
include beta lactam antibiotics, sulfonamides,
minocycline, terbinafine, azathioprine, allopurinol
and NSAID’s
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Clin Pharmacol Therap 2011; 90(3): 455-60
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high fever
sore throat / pharyngitis
gritty eyes, photophobia
mouth or genital ulcers
swollen tender lymph glands, and/or head and neck
swelling or puffy eyes
malaise, myalgia, arthralgia and/or arthritis
headache, neck stiffness
dyspnoea, cough, rhinorrhoea and/or ear pain
skin tenderness
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allopurinol
antiepileptics (phenytoin, carbamazepine,
phenobarbitone, lamotrigine)
nonsteroidal anti-inflammatory drugs
(NSAIDs)
sulfonamide antibacterials
antiretrovirals (nevirapine, abacavir)
penicillins, cephalosporins
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Simple exanthematic eruptions are the most common type of drug eruption.
They mimic the full spectrum of infective exanthems. Typically the rash begins on
the trunk and upper limbs. It is usually polymorphous with morbilliform or
urticarial lesions on the limbs, confluent lesions on the upper chest, and purpuric
lesions on the ankles and feet.
Onset: Typically 5 to 14 days after starting a new medication, or hours to days on
rechallenge. Reactions can also occur after drug withdrawal.
Implicated drugs: Almost all medications have been associated with exanthems,
but most frequent reports are with antibacterials (beta lactams, macrolides,
quinolones and sulfonamides), many antiepileptics, allopurinol, antiretrovirals,
nonsteroidal anti-inflammatory drugs, gold, blood products and cytotoxic drugs.
Clinical course: Exanthematic eruptions often progressively worsen for several
days after the drug is stopped, before resolving over 7 to 14 days with minor
desquamation.
Management: Stopping the offending drug is usually all that is required, but if
necessary consider treating symptoms while the rash resolves.
Mast cells and basophils are granulocytes produced
in the bone marrow. Mast cells are found
throughout the body in connective tissues close to
blood vessels and particularly in the respiratory,
genitourinary and gastrointestinal tracts. They both
release their granules as a result of the binding of
allergen to IgE, which sits on their cell surface
through its Fc receptor. Also as the (direct)result of
some drugs (e.g. opioids, radiocontrast agents)
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Asthma
Rhinitis
Urticaria
Allergic dermatitis (e.g. atopic*)
Food hypersensitivity
Anaphylaxis
Stinging insect allergies
* Atopy is a condition of secreting IgE in response to
common environmental allergens
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Allergen binds to IgE on mast cells, which
degranulate and
 Release pre-formed inflammatory mediators
 Synthesize other mediators
Preformed inflammatory
mediators:
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Histamine
Tryptase
Synthesized mediators:
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PGD2
LTC4
Heparin
Lehman JM & Blaiss MS. Drugs 2006:66918):2309-2319.
DRUG
 Urticaria
 Angioedema
 Bronchospasm
 Localised or whole-body immediate type (anaphylactic)
reactions
DISEASE/CONDITION
 Atopic dermatitis
 Food allergies
 Asthma
 Rhinitis
Lymph
node
IgE
Mucous
membrane
Sensitised
mast cell
1ST dose
of antigen
2nd dose
of antigen
Release of
mediators
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Any organ may be affected, but the skin is most commonly
involved
The most common reactions are maculopapular rashes, urticaria
and pruritis
Penicillin induced anaphylaxis occurs in 1 in 5000 to 1 in 10,000
courses
Patients with HIV and infectious mononucleosis have higher rates
of allergic reactions
For patients with a history of penicillin allergy who require a
cephalosporin, treatment depends on whether the previous
reaction was mediated by IgE
N Engl J Med 2006;354(6): 601-07
Urticaria, angioedema, anaphylaxis,
maculopapular skin eruptions, exfoliative
dermatitis, vesicular eruptions, erythema
multiforme, Stevens-Johnson syndrome,
toxic epidermal necrolysis, serum-sicknesslike reactions, vasculitis, cytopenia’s.
N Engl J Med 2006; 354(6): 601-7
Urticaria, angioedema, anaphylaxis,
maculopapular skin eruptions, erythema
multiforme, Stevens-Johnson syndrome,
toxic epidermal necrolysis, renal dysfunction,
toxic nephropathy, hepatic dysfunction,
aplastic anemia, hemolytic anemia.
N Engl J Med 2006; 354(6): 601-7
An antigen must be a macromolecule, either a
large protein or polysaccharide, in order to
activate lymphocytes to generate antibody
formation.
If an antigen is too small to generate an
immune response by itself, it is called a
hapten.
Mucocutaneous – rhinitis, conjunctival erythema and
tearing, flushing, itch, urticaria, angioedema.
Abdominal/pelvic – nausea, vomiting, abdominal pain.
Neurological – vascular (throbbing) headache, dizziness,
confusion, incontinence, collapse (with or without
unconsciousness (associated with hypoxia)
Respiratory/chest – upper airway angioedema dysphagia
and stridor, throat and/or chest tightness, dyspnoea, cough,
wheeze, cyanosis
Cardiovascular – palpitations, tachycardia, hypotension,
arrest.
COMMON
Insect stings: most commonly honeybee, Australian
native ants, wasps
 Foods ; most commonly peanuts, tree nuts, egg,
seafood, cows milk, dairy products, seeds
 Medications: most commonly antibiotics, NSAID’s
 Unidentified: no cause found
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MJA Practice Essentials Allergy 2007
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Stop administration of causative agent
Call for assistance
Give adrenaline IM (lateral thigh) 0.01 mg/kg
(maximum dose 0.5 mg)
Lay patient flat (elevate legs if tolerated)
Give high flow oxygen + airway/ventilation
support if needed
If hypotensive, IV saline bolus 20ml/kg over
1-2 minutes under pressure.
Medications such as antihistamines and
corticosteroids have no proven impact on the
immediate and dangerous effects of
anaphylaxis, although they may ameliorate
mild allergic reactions confined to the skin.
MJA Practice Essentials Allergy 2007
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NSAID ingestion (including aspirin) may provoke asthma and
rhinitis
This may affect 5-10% of people with asthma
It involves a non-immune hypersensitivity mechanism of
increased leukotriene production caused by inhibition of
COX-1 enzyme
MJA Practice Essentials Allergy 2007
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Angioedema is a well recognised adverse
reaction that affects 0.1 - 0.5% of patients
It can first appear anywhere from a few hours
to 8 years after an ACEI is taken
Up to 20% of cases can be life threatening
The reaction involves a non-immune
hypersensitivity mechanism caused by the
accumulation of plasma kinins
MJA Practice Essentials Allergy 2007
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Mediated by antigen/antibody complexes
Complexes may settle in tissues and
excessively activate complement
Complement in turn activates neutrophils
and macrophages (or the complex may do
this directly)
Tissue destructive lytic enzymes or
phagocytosis follows
Complexes commonly affect blood vessels,
renal glomeruli and synovial joints
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Takes longer than antibody mediated
reactions
Damage may be caused by cytokines
released from T helper cells or by activated T
cytotoxic cells