Chairul-Adverse Drug Reaction

8/10/2019 Chairul-Adverse Drug Reaction

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ADVERSE DRUG REACTION

Chairul Effendi

Allergy and Immunology Division, Internal Department

Airlangga University School of Medicine

Dr. Soetomo Teaching Hospital

Surabaya


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Introduction :

ADR : Noxious

Unintended

Unpleasant reaction

Medical product

Future administration

Prevention

Specific treatment

Alteration the dose

Withdrawal of the product


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In t roduc t ion :

True incidence of ADR is unknown

6.5-6.8% hospitalized patient

0.32% fatal reaction

76% Type A

24% Type B

Any drugs ADR majority reaction


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Risk Factors for Development of

Adverse Drug Reactions

Patient relatedAge Young adults > infants/elderly

Sex Women > men

Genetic Atopy may predispose to more serious reactions

Genetic polymorphism

Concomitantdisease

HIV, infections with Herpes viruses (EBV, CMV and others),cystic fibrosis (because of frequent antibioic use)

Immune status Previous drug reaction or previous positive skin test for drug

Drug related

Drug chemistry -lactam compounds, NMBA, radio-contrast media, NSAIDsare the most frequently involved

High MW compounds/hapten-forming drugs are more

immunogenic

Route Topical route >parenteral/oral

Dose Frequent or prolonged doses

NSAIDs, non-steroidal anti-inflammatory drugs ; NMBA, neuromuscular blocking agent.


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Drugs to Avoid in Genetic Diseases

Affecting Drug Metabolism

Genetic disease Drugs to avoid

Malignant hyperpyrexia Volatile anaesthetic agents, suxamethonium

Glucose-6-phosphale-

dehydrogenase deficiency

Dapsone (and other sulphones), nitrofurantoin, methylene

blue, primaqume, quinolones, sulphonamides

Caution with: aspirin, chloroquine, menadione, quinidine,

quinine

Porphyria Amphetamines, anabolic steroids, antidepressants, some

antihistamines, barbiturates, some benzodiazepines,

cephalosporins, some oral contraceptives, diuretics, ergot

derivatives, gold salts, hormone replacement therapy,

progestogens, sulphonamides, sulphonylureas

Pseudocholinesterase deficiency Suxamethonium

Slow acetylators Procainamide, hydralazine, sulphasalazine

TPMT (thiopurine S-methyl-

transferase) deficiency

Azathioprine (leading to marrow toxicity)


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Classification of drug reactions

Schuman Tam et al. Allergy & Asthma, 2008

DRUG REACTION

Type A ReactionDose dependent

Predictable

More common

Type B ReactionDose independent

Unpredictable

Less common

Overdose

Side effects

Drug interaction

Intolerance

Idiosyncrasy (pharmacogenetics)

Drug allergy

Immunologic reaction(Gell and Coombs classification)

Pseudoallergicreaction

Type I Reaction IgE mediated Anaphylactic Urticaria Angioedema Bronchospasm

Hypotension

Type II Reaction Antibody-dependent

cytotoxicity IgG/IgM bind to

antigens on cells Complement

Phagocyte

Type III Reaction Immune complex

damage Antibody binding

to antigens inlarge quantities

Type IV Reaction T-cell mediated

damage


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Investigation of Drug Allergy/Hypersensitivity

Categorized by Immunological Mechanisms

(From Gell and Coombs, Pichler and Posadas and Pichler 2007)

Reaction Mechanism Clinical features Investigation

Type I IgE-mediated, immediate reaction Urticaria*, angio-oedema*, anaphylaxis*,bronchospasm* Skin prick testingIntradermal testingSpecific IgE testingDrug provocation

Type II IgG/M-mediated cytotoxic reaction Anaemia, cytopenia, thrombocytopenia FBC/Coombs Test

Type III IgG/M-mediated immune complexes Vasculitis, lymphadenopathy, fever,

arthropathy, rashes, serumsickness

C3, C4, ANA, ANCA,

LFT, UEtE,histology, CXR

Type IVa Th1 cells activate monocyte/macrophages via IFN-/ and TNF-

Contact dermatitis, bullous exanthema Patch tests

Type IVb Th2 cells drive eosinophilic inflammationvia IL-5, IL-4, IL-13, eotaxin

Maculopapular and bullous rashes, etc. Patch tests

Type IVc CD4+/CD8+cytotoxic T cells kill targetsvia perform, granzyme B, FasL

Contact dermatitis, maculopapular,pustular and bullous exanthemata,etc.

Patch tests

Type IVd T cells recruit and activate neutrophilsvia CXCL-8, GM-CSF

Pustular xanthemata Patch tests

These may also be non-immunologically mediated. ANA, antinuclear antibody; ANCA, antineutrophil cytoplasmic antibody; LFT, liver

function test; U&E, urea and electrolytes; CXR, chest X-ray.


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Sequence of Events in Immediate

Hypersensitivity Reactions

Antigen activationof TH2 cells and

stimulation of

IgE class switching

in B cells

First exposure

to allergen

Production of IgEFirst exposure

to allergen

Repeated exposure

to allergen

Activation of

mast cells :

release of mediators

CytokinesVasoactive amines,

lipid mediators

Late-phase

reaction (2-4 hrs

after repeated

exposure

to allergen)

Immediate

hypersensitivity

reaction (minutes

after repeated

exposure

to allergen)

Allergen

B cell

TH2 cell

IgE-secretineB cell IgE

Mast cell

Mediators


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Types of Antibody-mediated Diseases


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Mechanisms of T cell-mediated Diseases


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Drugs Causing Adverse Drug Reactions

Commonly Presenting to the Allergy Clinic

Penicillins and other B-lactams

Non-B-lactam antibioticsReactions during general anaesthesia due to

Neuromuscular blockers

Anaesthetic agents

Latex (during general anaesthesia)

Local anaesthetics

Aspirin/NSAIDsACE inhibitors

Plasma expanders : gelatin, dextran

Others

Insulin

Heparin

Opiates Vaccines

Radio-contrast media

Chlorhexidine

Povidone iodine

Corticosteroids

NSAIDs, non-steroidal anti-inflammatory drug


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Allergenic Drugs in Common Use

Haptenic drugs Complete antigens

Penicillins Insulin and other recombinant proteins

Cephalosporins Enzymes (chymopapain, asparaginase)

Sulfonamide antimicrobials Foreign antitoxins

Muscle relaxants Organ extracts (ACTH, hormones)

Antituberculous drugs Vaccines

Anticonvulsants

Thiopental

Quinidine

cis-Platinum

N. Franklin Adkinson et al. Allergy, 3th Ed. 2006

ACTH, adrenocorticotropic hormone


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Penicillin and Penicillin Determinants

Laura Fisher et al. Managing the Allergic Patient, 2008

Penicillin

Side chain

Beta lactam ring Thiazolidine ring

Penicilloyl : Major determinant

Protein ligand

Major determinant to penicillin


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Mechanisms of

type II drug

hypersensitivity

N. Franklin Adkinson et al. Allergy,

3th Ed. 2006


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Causes of pseufoallergic drug reactions

Medications associated with pseudoallergic reactions

Radiocontrast media (higher osmolar especially)

Nonsteroidal anti-inflammatory drugs

AspirinNarcotics

Paclitaxel

Vancomycin

MannitolColloids

Iron dextran



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Systemic reactions

Anaphylaxis

Serum sickness

SLE-like

Scleroderma-like

Microscopic polyangiitis

Drug rash with eosinophilia systemic

symptoms (DRESS) also called drug

hypersensitivity syndrome (DHS)

Toxic epidermal necrolysis (TEN)

Stevens-Johnson syndrome (SJS)

Antibiotics, neuromuscular blockers, general anaesthetics, radio-contrast media, recombinant proteins (e.g. omalizumab),

intravenous B vitamins (e.g. thiamine), allergen extracts

Antibiotics, allopurinol, thiazides, pyrazolones, vaccines, phenytoin

Procainamide, hydralazine, isoniazid, minocycline, chlorpromazine,

infliximab, etanercept, -lactam antibiotics, propranolol,

streptokinase, sulphonamides, NSAIDsBleomycin

Amphetamines

Anticonvulsants (particularly carbamazepine, phenobarbitone and

phenytoin), allopurinol, sulphonamides, dapsone, minocycline,

gold salts, strontium ranelate

Antimicrobials: sulphonamides, nevirapineAnticonvulsant agents, NSAIDs, allopurinol, corticosteroids,

moxifloxacin

Antimicrobials: sulphonamides, nevirapine

Anticonvulsant agents, allopurinol, corticosteroids, carbamazepine,

modafinil, NSAIDs (especially piroxicam) highest risk early in the

course of therapy, lamotrigine, phenytoin, minocycline

Clinical Patterns of Immunological and

Non-immunological Adverse Drug Reactions1


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Organ-specific reactionsCutaneous

Urticaria/angio-oedema

Pemphigus foliaceusPurpura

Maculopapular rashContact dermatitis

Photodermatitis

Acute generalized exanthematouspustulosis (AGEP)

Fixed drug eruption (FDE)

Erythema multiforme (EM)Nephrogenic systemic fibrosis (NSF)

Antibiotics, recombinant proteins (e.g.omalizumab), ACE inhibitors,anticonvulsants, NSAIDs, neuro-muscular blockers, salicylates, statins,narcotic analgesics, azole antifungals

PenicillamineNSAID, sulphonamides, allopurinol, carbamazepine, warfarin,

corticosteroids, minocycline, phenobarbitoneAmpicillin, other antibiotics and several other drugsTopical antibiotics, topical antihistamines, corticosteroids, excipients (e.g.

parabens)Griseofulvin, sulphonamides, tetracycline, amiodarone, isotretinoin,

furosemide, all antipsychotics, barbiturates, ACE-inhibitors, nifedipine,piroxicam

Antibiotics (e.g. -lactam, macrolides, cephalosporins, tetracyclines),antimycotics (e.g. griseofulvin, nystatin, itraconazole), acetylsalicylic acid,paracetamol, allopurinol, calcium channel blockers

Antimicrobial agents (e.g. sulphonamide and tetracycline antibiotics),NSAIDs (e.g. ibuprofen), paracetamol, acetylsalicylic acid, sedatives (e.g.barbiturates, benzodia-zepines), phenolphthalein, dapsone, hyoscinebutylbromide, cytokines, chemo-therapeutic agents, anticonvulsants,psychotropic agents, amide local anaesthetics

Carbamazepine, phenytoin, abacavirGadolinium-containing MRI contrast agents




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PulmonaryAsthma

Cough

Interstitial pneumonitis

Pulmonary eosinophilia

Organizing pneumonia

Aspirin/NSAIDs, -blockers, ACE inhibitors, opiatesACE inhibitors

Bleomycin, methotrexate, cyclophosphamide, gold, penicillamine,

nitrofurantoin, NSAIDs, amiodarone, ACE inhibitors, -blockers,phenytoin, granulocyte macrophage colony stimulating factor

(GM-CSF)NSAIDs, penicillin, minocycline, nitrofurantoin, metotrexate,

sulphasalazine, amiodarone, ACE inhibitors, -blockers,phenytoin, bleomycin, sulphonamides, iodinated radio-contrast

media

Bleomycin, methotrexate, cyclophosphamide,amiodarone, -blockers, carbamazepine

Hepatic

Cholestatic hepatitis

Hepato-cellular hepatitis

Phenothiazines, carbamazepine, erythromycin, anti-tuberculous

drugs

Methyldopa, halothane, isoniazide, gold, allopurinol




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Renal

Interstitial nephritis

Membranous nephritis

Methicillin, NSAIDs, sulphonamides, proton pump inhibitors

Gold, penicillamine, ACE inhibitors, NSAIDs, cyclosporin, gentamicin

Haematological

Haemolytic anaemia

ThrombocytopeniaNeutropenia

Penicillin, cephalosporins, mefenamic acid, methyldopa

Heparin, quinine, sulphonamides, cephalosporins, thiazides, gold saltsPenicillin, cephalosporins, anticonvulsants, thiouracils, gold salts

Cardiac

Valvular disease Ergotamine, dopamine agonists (cabergoline, pergolide)

Musculo-

skeletal/neurologicalPolymyositis

Myasthenia gravis

Aseptic meningitis

Thiouracils

Penicillamine

NSAIDs, antimicrobials, vaccines

NSAIDs, non-steroidal anti-inflammatory drugs ; NMBA, neuromuscular blocking agent.


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Urticaria 1



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Urticaria 2



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Urticarial reaction to penicillin



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Angioedema


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A. and B. Erythemia multiforme with toxic epidermal necrolysis

and mucosal involvement (Steven-Johnson Syndrome)



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A. Penicillamine-induced pemphigus foliaceus.

B. Direct immunofluorescence of a skin biopsy from the samepatient as in Penicillamine-induced pemphigus foliaceus



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Essential Information Required when Referring

a Patient with Suspected Drug Allergy

Detailed description of reaction

Symptom sequence and durationTreatment providedOutcome

Timing of symptoms in relation to drug administration Has the patient had the suspected drug before this course of treatment ?

How long had the drug(s) been taken before onset of reaction ?

When was/were the drug(s) stopped ?What was the effect ?

Witness description (patient, relative, doctor) Is there a photograph of the reaction ? Illness for which suspected drug was being taken, i.e. underlying illness (this may be

the cause of the symptoms, rather than the drug) List of all drugs taken at the time of the reaction (including regular medication, 'overthe counter' and 'alternative' remedies)

Previous historyOther drug reactionsOther allergies

Other illnesses


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Tests for Evaluating Drug Allergy

In Vivo Assessment of Gell and Coombs

Prick, intradermal skin tests IgE to agent Type IProvocation (dose escalation) Tolerance AII

Patch testing DTH Type IV

Biopsy Immunohistopathology Types III, IV

In Vitro Assessment of Gell and Coombs

RAST IgE in serum Type I

Leukocyte histamine release* IgE Type I

Lymphocyte proliferation T-cell responsiveness Type IV

Lymphocyte cytokine production T-cell responsiveness Type IV

Lymphocyte cytotoxicity T-cell responsiveness Type IV


* Alternative: CD63 or CD202 marker expression on basophils using flow cytometry.

DTH, delayed type hypersensitivity; RAST, radioallergosorbent test


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Prick and Intradermal Skin Testing

Indicated For the identification of IgE-

mediated conditions

Not indicated For the identification of IgG/IgM-

mediated immune conditionsIn SJS, TEN and DRESS but

patch tests can be useful

Can be helpful (delayed

intradermal reading)

In documenting DTH

SJS, Stevens-Johnson syndrome; DTH, delayed-type hypersensitivity; DRESS, drug

reaction/rash with eosinophilia and systemic symptoms; TEN, toxic epidermal necrolysis.


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Drugs for which Intradermal Skin Testing

may be Useful

Penicillins Foreign antitoxins

Cephalosporins Antituberculous drugs

Insulin Anticonvulsants

Chymopapain Quidinine

Local anesthetics cis-Platinum

Muscle relaxants Penicillamine

Thiopental Vaccines



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Indications for Investigating Patients

with Penicillin Allergy

1. Patients with a history of an allergic reaction when

on multiple drugs, e.g. during GA

2. Patients allergic to multiple antibiotics

3. Patients with an absolute requirement for penicillin,

e.g. those with central nervous system syphilis,

immunodeficiency, post-splenectomy, or with

cardiac valve disorders requiring prophylaxis

Di ti k f i di t d


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Diagnostic work up of immediate drug

allergy to -lactams

Positive Negative

Positive Negative

Positive Negative

Drug allergy

History suggestive of drug allergy to -lactam

Skin prick test

Intradermal skin test

Oral challenge


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Short Algorithm for the Diagnosis of Immediate

Allergic Reactions to Betalactams

CLINICAL HISTORY AND BLOOD SAMPLE

Prick PPL/MDM/AX/Drug

ID PPL/MDM/AX/Drug

In Vitro Test In Vitro Test +

DPT Drug Repeat Study in 2 to 4 w.

NON ALLERGIC

ALLERGIC


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Algorithm for the diagnosis of nonimmediated

allergic reactions to betalactams

BP = benzylpenicillin

AP = aminopenicillins

(ampicillin and amoxicillin)BL = -lactam

First evaluation

(1stday)

Patch with BP, AP

and any suspect BL

and

Intradermal with

PPL, MDM and BP

Immediate

hypersensitivity

Second evaluation

(3rdday)

Patch

reading

Late intradermalreading

or

Delayed

hypersensitivity

Intradermal with AP

and any suspect BL

Immediate

hypersensitivity

Third evaluation

(5th day)

2ndpatch and BP

determinant late

intradermal reading

and

AP and any suspect BLlate intradermal reading

Perform challenge with

the suspect BL

Suspect BL therapy

may be advised

Undetermined

pathogenic mechanism

Advise avoidance of

positive BL therapy

20 min


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Local anesthetic skin testing and test dosing protocol

TimeAdm.

Site VSBP/P

PrickSubcutaneous

ChallengeResult

Diluent control N/A

Histamine N/A

LA (undiluted) 0 min N/ALA (0.1 ml of 1:100) at 15 min N/A

LA (0.1 ml of 1:100) at 30 min N/A

LA (0.1 ml of 1:100) at 45 min N/A

LA (0.1 ml of 1:100) at 60 min N/A

LA (0.1 ml of 1:100) at 75 min N/A

Schuman Tam et al. Allergy & Asthma, 2008


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The Predictive Value of Penicillin Skin Tests

History of penicillin allergy +

Penicillin skin test status + +

Frequency of allergic reactionsassociated with penicillin

administration

50-70% 1-3% 10% 0.5%



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Protocol for Test Dosing with

Local Anesthetics

Proceed in order, advancing to the nest step every 15 minutes

1. Skin prick test with undiluted anesthetic (do not use epinephrine-

containing agents)

2. If negative, 0.1 mL of 1 in 100 dilution is given subcutaneously (s.c.)

3. If no reaction, 0.1 mL of 1 in 10 dilution is given s.c.

4. If no reaction, administer 1 mL undiluted anesthetic s.c.5. If no reaction, administer 2 mL undiluted anesthetic s.c.


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Diagnostic Testing, T Cell Mediated

Eropa :

Lymphocyte transformation in vitro Patch test in vivo


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Key Features of Acute Management

1. Stop suspected drug (e.g. IV infusion)

2. Treat the reaction

3. Identify and avoid potential cross-reacting drugs

4. Record precise details of the reaction and its treatment

5. If possible identify a safe alternative

6. If necessary-consider desensitization (rarely indicated)


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Management of drug reactions depends on whether

or not the drug reaction was IgE mediated


Drug allergy suspected

Consistent w/IgEmediated allergy ?

Skin test available?High negative predictive value?

Consistent w/non IgEmediated allergy ?

Reaction serious/Life-threatening?

1. Alternative medication2. Desensitization

Administer drug

1. Alternative medication2. Desensitization

1. Alternative medication2. Cautious graded challenge

Alternativemedication

Yes No Yes No

Test (+) Test ()

PCN D iti ti


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PCN DesensitizationTime

(min between doses)Dose Units/mg

Concentration

(Units/mL)

Volume

(mL)

Total Dose

(U/mg)

0 1 50 U/0.03 mg (IV/PO) 100 U/mL (0.0625 mg/mL) 0.5 50 U/0.03 mg

15 2 100 U/0.06 mg (IV/PO) 100 U/mL (0.0625 mg/mL) 1 150 U/0.09 mg



60 (1 h) 5 800 U/0.5 mg (IV/PO) 100 U/mL (0.0625 mg/mL) 8 1,550 U/0.97 mg

75 6 1,600 U/1 mg (IV/PO) 1000 U/mL (0.625 mg/mL) 1.6 3,125 U/1.97 mg



120 (2 h) 9 12,800 U/8 mg (IV/PO) 1000 U/mL (0.625 mg/mL) 12.8 25,550 U/15.97 mg

135 10 25,000 U/15,6 mg (IV/PO) 10,000 U/mL (6.25 mg/mL) 2.5 50,550 U/31.57 mg

150 11 50,000 U/31,3 mg (IV/PO) 10,000 U/mL (6.25 mg/mL) 5 100,550 U/62.9 mg

165 12 100,000 U/62,5 mg (IV/PO) 10,000 U/mL (6.25 mg/mL) 10 200,550 U/125 mg

180 (3 h) 13 200,000 U/125mg (IV/PO) 40,000 U/mL (25 mg/mL) 5 400,550 U/250 mg

195 14 400,000 U/250 mg (IV/PO) 40,000 U/mL (25 mg/mL) 10 800,550 U/500 mg

210 15 800,000 U/500 mg (IV/PO) 40,000 U/mL (25 mg/mL) 20 1.6 MU/1000 mg

225 16 800,000 (IV) 40,000 U/mL 20 2.4 MU/

585 17 1,000,000 (IV) 40,000 U/mL 25 3.4 MU/

After dose 17, then q6h without dose interruptionIV, intravenous; PO, by mouth


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Pretreatment Guidelines for the Prevention

of Anaphylactoid RCM Reactions

DRUG (DOSE) ROUTE INTRUCTIONS

Prednisone (50 mg) Oral or i.m. Administer 13, 7, and 1 hour

before RCM procedure

Diphenhydramine (50 mg) Oral or i.m. Administer 1 hour before RCMprocedure

Ephedrine sulfate (25 mg)* Oral Administer 1 hour before RCM

produce


* Withhold if there is a history of coronary artery disease or arrhythmia


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Patient Education

Make the patient aware that he/she is responsible

for future avoidance of the culprit drug

Encourage patient to wear an allergy bracelet

stating the cause of the reaction

Warn patient to avoid over-the-counter medications

where precise constituents are unclear


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Recent Advances :

T cell Type IV reaction Mediated cytotoxicity

Cytokines CD8 TEN


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Recent Ad vances :

Non covalent drugs immune receptor drug hypersensitivity reaction

Antigen APC T cell

Non covalent T cell receptor hours

p.i concept pharmacologic interaction Sulfamethoxazole

Lidocaine

Mepicaine Celecoxide

Carbamazepine

Quinolone


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Summary

ADRS6.5 6.8% hospital admissions 15% prolonged in hospital

Affect quality of life, delayed treatment and death

Under reporting adults and children

Topical, prolonged, frequent doses sensitisation

Atopy is not a risk factor more severe reaction Herpes viruses, HIV drug reaction


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Summary

Detailed history is required General anesthesi anesthetic chart

IgE mediated :

SPT

Intradermal test

Non-IgE patch tests or delayed intradermal tests

Skin test not to be used to screen drug allergy in the

abscence of clinical history


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Summary

Skin tests patch test DRESS, SJS and TEN Serum Tryptase 2-24 hours

Drug Challenge to be considered

Other investigation (-)

Diagnosis still doubt

Drug provocation test (-) life threatening

No alternative drug desensitisation

Prevention of future reaction essential part of patients

management

Th k Y


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Thank You

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Chairul-Adverse Drug Reaction