DRUG ALLERGYDRUG ALLERGY

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Definition of drug allergyDefinition 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.

Adverse Drug ReactionsAdverse Drug Reactions

Adverse drug reactions - majority of iatrogenic illnesses

- 1% to 15% of drug courses1. 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 immunogensDrugs 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 Factors that influence the development of drug allergydevelopment 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 Factors that influence the development of drug allergydevelopment of drug allergy

Nature of the drug:

80% of allergic drug reactions due to: - penicillin

- cephalosporins

- sulphonamides (sulpha drugs) - ASA/NSAIDs

Gell and Coombs reactionsGell and Coombs reactions

Type 1 : Immediate Hypersensitivity- IgE-mediated

- 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 reactionsGell 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)

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Classification of hypersensitivityClassification 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.

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I (immediate)I (immediate) II (cytotoxic)II (cytotoxic) III (immune III (immune complex)complex)

IV (delayed)IV (delayed) V V (stimulating/blocki(stimulating/blocking)#ng)#

AntigensAntigens Pollens, moulds, Pollens, moulds, mites, drugs, mites, drugs, food and food and parasitesparasites

Cell surface or Cell surface or tissue boundtissue bound

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

AutoantigenAutoantigenss

Cell/tissue Cell/tissue boundbound

Cell surface Cell surface receptorsreceptors

MediatorsMediators IgE and mast IgE and mast cellscells

IgG, IgM and IgG, IgM and complementcomplement

IgG, IgM, IgG, IgM, IgA and IgA and complementcomplement

TD, Tc TD, Tc activated activated macrophages macrophages and and lymphokineslymphokines

IgGIgG

Diagnostic Diagnostic teststests

Skin-prick tests: Skin-prick tests: wheal and flare wheal and flare

Specific IgE in Specific IgE in serumserum

Coombs’ test Coombs’ test

Indirect Indirect immunofluorescenimmunofluorescence (antibodies) ce (antibodies)

Red cell Red cell agglutinationagglutination

Precipitating Precipitating antibodies antibodies

ELISAELISA

Immune Immune complexescomplexes

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

IndirectIndirect

ImmunofluorescenImmunofluorescencece

Time taken Time taken for reaction for reaction to developto develop

5-10min5-10min 6-36 hours6-36 hours 4-12 hours4-12 hours 48-72 hours48-72 hours VariableVariable

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

Hypersensitivity Reactions

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I (immediate)I (immediate) II (cytotoxic)II (cytotoxic) III (immune III (immune complex)complex)

IV (delayed)IV (delayed) V V (stimulating/blocki(stimulating/blocking)ng)

ImmunopathologyImmunopathology Oedema, Oedema, vasodilation, mast vasodilation, mast cell degranulation, cell degranulation, eosiniophilseosiniophils

Antibody-mediated Antibody-mediated damage to target damage to target cellscells

Acute Acute inflammatory inflammatory reaction, reaction, neutrophils, neutrophils, vasculitisvasculitis

Perivascular Perivascular inflammation, inflammation, mononuclear cells, mononuclear cells, fibrinfibrin

GranulomasGranulomas

Caseation and Caseation and necrosis in TBnecrosis in TB

Hypertrophy or Hypertrophy or normalnormal

Diseases and Diseases and conditions conditions producedproduced

Asthma (extrinsic)Asthma (extrinsic)

Urticaria/oedemaUrticaria/oedema

Allergic rhinitisAllergic rhinitis

AnaphylaxisAnaphylaxis

Autoimmune Autoimmune

Haemolytic Haemolytic anaemiaanaemia

Transfusion Transfusion reactionsreactions

Haemolytic Haemolytic disease of disease of newbornnewborn

Goodpasture’s Goodpasture’s syndromesyndrome

Addisonian Addisonian pernicious pernicious anaemiaanaemia

Myasthenia gravisMyasthenia gravis

Autoimmune (e.g. Autoimmune (e.g. SLE, SLE, glomerulonephritisglomerulonephritis, rheumatoid , rheumatoid arthritis)arthritis)

Low-grade Low-grade persistent persistent infections (e.g. infections (e.g. viral hepviral hepaatitis)titis)

Disease caused by Disease caused by environmental environmental antigens (e.g. antigens (e.g. fafarrmer’s lung)mer’s lung)

Pulmonary TB Pulmonary TB

Contact dermatitisContact dermatitis

Graft-versus-host Graft-versus-host diseasedisease

InInsectsect bites bites

LeprosyLeprosy

Neonatal Neonatal hyperthyroidismhyperthyroidism

Graves’ diseaseGraves’ disease

Myasthenia gravisMyasthenia gravis

TreatmentTreatment Antigen avoidanceAntigen avoidance

AntihistaminesAntihistamines

Corticosteroids Corticosteroids (usually topical) (usually topical)

Sodium Sodium cromoglicatecromoglicate

Epinephrine for Epinephrine for life-threatening life-threatening conditionsconditions

Exchange Exchange transfusion transfusion

PlasmapheresisPlasmapheresis

ImmunosuppressivImmunosuppressives/cytotoxicses/cytotoxics

CorticosteroidsCorticosteroids

ImmunosuppressivImmunosuppressiveses

PlasmapheresisPlasmapheresis

ImmunosuppressivImmunosuppressiveses

CorticosteroidsCorticosteroids

Removal of Removal of antigenantigen

Treatment of Treatment of individual diseaseindividual disease

RAST, radioallergosorbent test; SLE, systemic lupus erythematosus; TB, tuberculosis; Tc, T cytotoxic; TD, T delayed hypersensitivity

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Overview of Drug AllergyOverview 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 body’s response can affect many organ systems, but the skin is the most frequently involved.

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The most common drug to cause allergyThe 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

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Risk factors for Drug AllergyRisk 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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Drug Allergy Symptoms Drug Allergy Symptoms

Drug allergies may cause many different types of symptoms

It depends on the drug and how often you have taken it.

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RashFever Muscle and joint aches Lymph node swelling Inflammation of the kidney Anaphylactic shock

Most common allergic reactions

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MaculopapularMaculopapular PenicillinPenicillin

UrticariaUrticaria Penicillin, aspirinPenicillin, aspirin

VasculitisVasculitis Gold, hydralazineGold, hydralazine

Fixed drug rashFixed drug rash Phenolphthalein in Phenolphthalein in laxatives, tetracyclines, laxatives, tetracyclines, paracetamolparacetamol

PigmentationPigmentation Minocycline (black), Minocycline (black), amiodarone (slate grey)amiodarone (slate grey)

Lupus erythematosusLupus erythematosus Penicillamine, isoniazidPenicillamine, isoniazid

PhotosensitivityPhotosensitivity Thiazides, chlorpromazine, Thiazides, chlorpromazine, sulphonamide, amiodaronesulphonamide, amiodarone

PustularPustular CarbamazepineCarbamazepine

Erythema nodosumErythema nodosum Sulphonamides, oral Sulphonamides, oral contraceptivecontraceptive

Morphological types of drug rashes Morphological types of drug rashes and some common causesand some common causes

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Erythema multiformeErythema multiforme AnticonvulsantsAnticonvulsants

AcneiformAcneiform CorticosteroidsCorticosteroids

LichenoidLichenoid Chloroquine, thiazides, Chloroquine, thiazides, gold, allopurinolgold, allopurinol

PsoriasiformPsoriasiform Methyldopa, gold, lithium, Methyldopa, gold, lithium, beta-blockersbeta-blockers

Toxic epidermal necrolysisToxic epidermal necrolysis Penicillin, co-trimoxazole, Penicillin, co-trimoxazole, carbamazepine, NSAIDscarbamazepine, NSAIDs

PemphigusPemphigus Penicillamine, ACE Penicillamine, ACE inhibitorsinhibitors

ErythrodermaErythroderma Gold, sulphonylureas, Gold, sulphonylureas, allopurinolallopurinol

Morphological types of drug rashes Morphological types of drug rashes and some common causesand some common causes

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Allergic reactions on skinAllergic 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 skinAllergic 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

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Stevens Johnson’s syndromeStevens Johnson’s syndrome

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Toxic epidermal necrosisToxic epidermal necrosis

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SJS & TENSJS & 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.

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Signs and Symptoms of SJS & TENSigns 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

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Signs and Symptoms of SJS & TENSigns 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

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Admit to intensive care or burn unitDiscontinue culprit medication and

all unnecessary medicationsSterile technique in handling patientPlace intravenous or central line in

area of uninvolved skin if possible

Guideline for Treatment of SJS & TEN

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Culture skin, blood, urine dailyAvoid 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

Guideline for Treatment of SJS & TEN

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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

Guideline for Treatment of SJS & TEN

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UrticariaUrticaria

What is urticaria?It is local wheals and erythema in

the superficial dermisUrticaria induced by drug is

generally acute and is limited to the skin and subcutaneous tissues.

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UrticariaUrticaria

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UrticariaUrticaria

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

UrticariaUrticaria

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.

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Drugs for Acute UrticariaDrugs 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)

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Management for Chronic UrticariaManagement 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 ½ cases.

Control of stress often helps reduce the frequency and severity of episodes

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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

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AngioedemaAngioedema

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Management for AngioedemaManagement 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

Penicillin AllergyPenicillin 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 AllergyPenicillin 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”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 allergyCephalosporin 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 hypersensitivitySulphonamide 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 sensitivityASA 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 sensitivityASA & NSAID sensitivity

ASA sensitivity: cross-reactive with all NSAIDs that inhibit cyclo-oxygenase

ASA & NSAID sensitivityASA & 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 ASA-induced urticaria

Allergy skin testingAllergy 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 allergyManagement 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 allergyManagement 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 medicationsDesensitization to medications

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

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