ADVERSE DRUG REACTION

Chairul Effendi
Allergy and Immunology Division, Internal Department
Airlangga University School of Medicine
Dr. Soetomo Teaching Hospital
Surabaya

Introduction :
ADR :
Noxious
Unintended
Unpleasant reaction
Medical product
Future administration
Prevention
Specific treatment
Alteration the dose
Withdrawal of the product

Introduction :

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

Risk Factors for Development of

Adverse Drug Reactions
Patient related
Age

Young adults > infants/elderly

Sex

Women > men

Genetic

Atopy may predispose to more serious reactions

Genetic polymorphism

Concomitant
disease

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, NSAIDs

are 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.

Drugs to Avoid in Genetic Diseases

Affecting Drug Metabolism
Genetic disease

Drugs to avoid

Malignant hyperpyrexia

Volatile anaesthetic agents, suxamethonium

Glucose-6-phosphaledehydrogenase 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-methyltransferase) deficiency

Azathioprine (leading to marrow toxicity)

Classification of drug reactions

DRUG REACTION

Type A Reaction
Dose dependent
Predictable
More common

Type B Reaction
Dose independent
Unpredictable
Less common
Overdose

Intolerance

Side effects

Idiosyncrasy (pharmacogenetics)

Drug interaction

Drug allergy

Immunologic reaction
(Gell and Coombs classification)
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 in
large quantities

Pseudoallergic
reaction
Type IV Reaction
T-cell mediated
damage

Schuman Tam et al. Allergy & Asthma, 2008

Investigation of Drug Allergy/Hypersensitivity

Categorized by Immunological Mechanisms
Reaction Mechanism

Clinical features

Type I

IgE-mediated, immediate reaction

Urticaria*, angio-oedema*, anaphylaxis*, Skin prick testing

bronchospasm*
Intradermal testing
Specific IgE testing
Drug 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, serum
sickness

C3, C4, ANA, ANCA,

LFT, UEtE,
histology, CXR

Contact dermatitis, bullous exanthema

Patch tests

Type IVb Th2 cells drive eosinophilic inflammation Maculopapular and bullous rashes, etc.
via IL-5, IL-4, IL-13, eotaxin

Patch tests

Type IVc CD4+/CD8+ cytotoxic T cells kill targets

via perform, granzyme B, FasL

Contact dermatitis, maculopapular,

pustular and bullous exanthemata,
etc.

Patch tests

Type IVd T cells recruit and activate neutrophils

via CXCL-8, GM-CSF

Pustular xanthemata

Patch tests

Type IVa Th1 cells activate monocyte/

macrophages via IFN-/ and TNF-

Investigation

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

Sequence of Events in Immediate

Hypersensitivity Reactions
First exposure
to allergen

Repeated exposure
to allergen

Activation of
mast cells :
release of mediators

Allergen

B cell

TH2 cell

IgE-secretine
B cell

Antigen activation
of TH2 cells and
stimulation of
IgE class switching
in B cells

Mediators

Cytokines

Immediate
hypersensitivity
reaction (minutes
after repeated
exposure
to allergen)

Late-phase
reaction (2-4 hrs
after repeated
exposure
to allergen)

IgE

Mast cell

Production of IgE

Vasoactive amines,
lipid mediators

First exposure
to allergen

Types of Antibody-mediated Diseases

Mechanisms of T cell-mediated Diseases

Drugs Causing Adverse Drug Reactions

Commonly Presenting to the Allergy Clinic
Penicillins and other B-lactams
Non-B-lactam antibiotics
Reactions during general anaesthesia due to
Neuromuscular blockers
Anaesthetic agents
Latex (during general anaesthesia)
Local anaesthetics
Aspirin/NSAIDs
ACE inhibitors
Plasma expanders : gelatin, dextran
Others
Insulin
Heparin
Opiates
Vaccines
Radio-contrast media
Chlorhexidine
Povidone iodine
Corticosteroids
NSAIDs, non-steroidal anti-inflammatory drug

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
ACTH, adrenocorticotropic hormone

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

Penicillin and Penicillin Determinants

Penicillin

Penicilloyl : Major determinant

Side chain
Beta lactam ring

Thiazolidine ring
Protein ligand

Major determinant to penicillin

Laura Fisher et al. Managing the Allergic Patient, 2008

Mechanisms of
type II drug
hypersensitivity

N. Franklin Adkinson et al. Allergy,

3th Ed. 2006

Causes of pseufoallergic drug reactions

Medications associated with pseudoallergic reactions
Radiocontrast media (higher osmolar especially)
Nonsteroidal anti-inflammatory drugs
Aspirin
Narcotics
Paclitaxel
Vancomycin
Mannitol
Colloids
Iron dextran

Laura Fisher et al. Managing the Allergic Patient, 2008

Clinical Patterns of Immunological and

Non-immunological Adverse Drug Reactions1
Systemic reactions
Anaphylaxis

Antibiotics, neuromuscular blockers, general anaesthetics, radiocontrast media, recombinant proteins (e.g. omalizumab),
intravenous B vitamins (e.g. thiamine), allergen extracts
Serum sickness
Antibiotics, allopurinol, thiazides, pyrazolones, vaccines, phenytoin
SLE-like
Procainamide, hydralazine, isoniazid, minocycline, chlorpromazine,
infliximab, etanercept, -lactam antibiotics, propranolol,
streptokinase, sulphonamides, NSAIDs
Scleroderma-like
Bleomycin
Microscopic polyangiitis
Amphetamines
Drug rash with eosinophilia systemic
Anticonvulsants (particularly carbamazepine, phenobarbitone and
symptoms (DRESS) also called drug
phenytoin), allopurinol, sulphonamides, dapsone, minocycline,
hypersensitivity syndrome (DHS)
gold salts, strontium ranelate
Toxic epidermal necrolysis (TEN)
Antimicrobials: sulphonamides, nevirapine
Anticonvulsant agents, NSAIDs, allopurinol, corticosteroids,
moxifloxacin
Stevens-Johnson syndrome (SJS)
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 Reactions2
Organ-specific reactions
Cutaneous
Urticaria/angio-oedema

Antibiotics, recombinant proteins (e.g.omalizumab), ACE inhibitors,

anticonvulsants, NSAIDs, neuro-muscular blockers, salicylates, statins,
narcotic analgesics, azole antifungals
Pemphigus foliaceus
Penicillamine
Purpura
NSAID, sulphonamides, allopurinol, carbamazepine, warfarin,
corticosteroids, minocycline, phenobarbitone
Maculopapular rash
Ampicillin, other antibiotics and several other drugs
Contact dermatitis
Topical antibiotics, topical antihistamines, corticosteroids, excipients (e.g.
parabens)
Photodermatitis
Griseofulvin, sulphonamides, tetracycline, amiodarone, isotretinoin,
furosemide, all antipsychotics, barbiturates, ACE-inhibitors, nifedipine,
piroxicam
Acute generalized exanthematous
Antibiotics (e.g. -lactam, macrolides, cephalosporins, tetracyclines),
pustulosis (AGEP)
antimycotics (e.g. griseofulvin, nystatin, itraconazole), acetylsalicylic acid,
paracetamol, allopurinol, calcium channel blockers
Fixed drug eruption (FDE)
Antimicrobial agents (e.g. sulphonamide and tetracycline antibiotics),
NSAIDs (e.g. ibuprofen), paracetamol, acetylsalicylic acid, sedatives (e.g.
barbiturates, benzodia-zepines), phenolphthalein, dapsone, hyoscine
butylbromide, cytokines, chemo-therapeutic agents, anticonvulsants,
psychotropic agents, amide local anaesthetics
Erythema multiforme (EM)
Carbamazepine, phenytoin, abacavir
Nephrogenic systemic fibrosis (NSF) Gadolinium-containing MRI contrast agents

Clinical Patterns of Immunological and

Non-immunological Adverse Drug Reactions3
Pulmonary
Asthma
Cough
Interstitial pneumonitis

Pulmonary eosinophilia

Organizing pneumonia
Hepatic
Cholestatic hepatitis
Hepato-cellular hepatitis

Aspirin/NSAIDs, -blockers, ACE inhibitors, opiates

ACE 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
Phenothiazines, carbamazepine, erythromycin, anti-tuberculous
drugs
Methyldopa, halothane, isoniazide, gold, allopurinol

Clinical Patterns of Immunological and

Non-immunological Adverse Drug Reactions4
Renal
Interstitial nephritis
Methicillin, NSAIDs, sulphonamides, proton pump inhibitors
Membranous nephritis Gold, penicillamine, ACE inhibitors, NSAIDs, cyclosporin, gentamicin
Haematological
Haemolytic anaemia
Thrombocytopenia
Neutropenia

Penicillin, cephalosporins, mefenamic acid, methyldopa

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

Cardiac
Valvular disease

Ergotamine, dopamine agonists (cabergoline, pergolide)

Musculoskeletal/neurological
Polymyositis
Myasthenia gravis
Aseptic meningitis

Thiouracils
Penicillamine
NSAIDs, antimicrobials, vaccines

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

Urticaria 1

Laura Fisher et al. Managing the Allergic Patient, 2008

Urticaria 2

Laura Fisher et al. Managing the Allergic Patient, 2008

Urticarial reaction to penicillin

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

Angioedema

A. and B. Erythemia multiforme with toxic epidermal necrolysis

and mucosal involvement (Steven-Johnson Syndrome)
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006

A. Penicillamine-induced pemphigus foliaceus.

B. Direct immunofluorescence of a skin biopsy from the same
patient as in Penicillamine-induced pemphigus foliaceus
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006

Essential Information Required when Referring

a Patient with Suspected Drug Allergy
Detailed description of reaction
Symptom sequence and duration
Treatment provided
Outcome
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, 'over
the counter' and 'alternative' remedies)
Previous history
Other drug reactions
Other allergies
Other illnesses

Tests for Evaluating Drug Allergy

In Vivo

Assessment of

Gell and Coombs

Prick, intradermal skin tests

IgE to agent

Type I

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

Prick and Intradermal Skin Testing

Indicated

For the identification of IgEmediated conditions

Not indicated

For the identification of IgG/IgMmediated immune conditions

In 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.

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

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

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

Diagnostic work up of immediate drug

allergy to -lactams
History suggestive of drug allergy to -lactam
Skin prick test

Positive

Negative
Intradermal skin test
Positive

Negative
Oral challenge
Positive

Drug allergy

Negative

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

ALLERGIC

In Vitro Test +

DPT Drug

Repeat Study in 2 to 4 w.

NON ALLERGIC

Algorithm for the diagnosis of nonimmediated

allergic reactions to betalactams
First evaluation
(1st day)

Patch with BP, AP

and any suspect BL
and

Intradermal with
PPL, MDM and BP

Second evaluation
(3rd day)

Third evaluation
(5th day)

Intradermal with AP
and any suspect BL

2nd patch and BP

determinant late
intradermal reading

Immediate
hypersensitivity

and

Patch
reading
or

AP and any suspect BL

late intradermal reading

Late intradermal
reading

Delayed
hypersensitivity

Perform challenge with

the suspect BL

20 min

Suspect BL therapy
may be advised

Immediate
hypersensitivity

BP = benzylpenicillin
AP = aminopenicillins
(ampicillin and amoxicillin)
BL = -lactam

Advise avoidance of
positive BL therapy

Undetermined
pathogenic mechanism

Local anesthetic skin testing and test dosing protocol

Time
Adm.

Site

VS
BP/P

Subcutaneous
Prick
Challenge
Result

Diluent control

N/A

Histamine

N/A

LA (undiluted) 0 min

N/A

LA (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

The Predictive Value of Penicillin Skin Tests

History of penicillin allergy
Penicillin skin test status
Frequency of allergic reactions
associated with penicillin
administration

50-70%

1-3%

10%

0.5%

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

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 epinephrinecontaining 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.

Diagnostic Testing, T Cell Mediated

Eropa :
Lymphocyte transformation in vitro
Patch test in vivo

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)

Management of drug reactions depends on whether

or not the drug reaction was IgE mediated
Drug allergy suspected

Consistent w/IgE
mediated allergy ?

Consistent w/non IgE

mediated allergy ?

Skin test available?

High negative predictive value?

Reaction serious/
Life-threatening?

Yes

Test (+)
1. Alternative medication
2. Desensitization

No

Test ()

1. Alternative medication
2. Desensitization

Yes

No

1. Alternative medication
2. Cautious graded challenge

Alternative
medication

Administer drug
Laura Fisher et al. Managing the Allergic Patient, 2008

PCN Desensitization
Time
Dose
(min between doses)

Units/mg

Concentration
(Units/mL)

Volume
(mL)

Total Dose
(U/mg)

50 U/0.03 mg (IV/PO)

100 U/mL (0.0625 mg/mL)

0.5

50 U/0.03 mg

15

100 U/0.06 mg (IV/PO)

100 U/mL (0.0625 mg/mL)

150 U/0.09 mg

30

200 U/0.13 mg (IV/PO)

100 U/mL (0.0625 mg/mL)

350 U/0.22 mg

45

400 U/0.25 mg (IV/PO)

100 U/mL (0.0625 mg/mL)

750 U/0.47 mg

60 (1 h)

800 U/0.5 mg (IV/PO)

100 U/mL (0.0625 mg/mL)

1,550 U/0.97 mg

75

1,600 U/1 mg (IV/PO)

1000 U/mL (0.625 mg/mL)

1.6

3,125 U/1.97 mg

90

3,200 U/2 mg (IV/PO)

1000 U/mL (0.625 mg/mL)

3.2

6,350 U/3.97 mg

105

6,400 U/4 mg (IV/PO)

1000 U/mL (0.625 mg/mL)

6.4

12,750 U/7.97 mg

120 (2 h)

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)

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)

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 interruption

IV, intravenous; PO, by mouth

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 RCM

procedure

Ephedrine sulfate (25 mg)* Oral

Administer 1 hour before RCM

produce

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

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

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

Recent Advances :
T cell Type IV reaction
Mediated cytotoxicity
Cytokines
CD8 TEN

Recent Advances :

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

Summary
ADRS 6.5 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

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

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

Thank You