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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 :
Sex
Genetic
Concomitant
disease
Immune status
Drug related
Drug chemistry
Route
Dose
Drugs to avoid
Malignant hyperpyrexia
Glucose-6-phosphaledehydrogenase deficiency
Porphyria
Pseudocholinesterase deficiency
Suxamethonium
Slow acetylators
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
Pseudoallergic
reaction
Type IV Reaction
T-cell mediated
damage
Clinical features
Type I
Type II
FBC/Coombs Test
Type III
Patch tests
Type IVb Th2 cells drive eosinophilic inflammation Maculopapular and bullous rashes, etc.
via IL-5, IL-4, IL-13, eotaxin
Patch tests
Patch tests
Pustular xanthemata
Patch tests
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)
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
Complete antigens
Penicillins
Cephalosporins
Sulfonamide antimicrobials
Foreign antitoxins
Muscle relaxants
Antituberculous drugs
Vaccines
Anticonvulsants
Thiopental
Quinidine
cis-Platinum
ACTH, adrenocorticotropic hormone
Side chain
Beta lactam ring
Thiazolidine ring
Protein ligand
Mechanisms of
type II drug
hypersensitivity
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
Pulmonary eosinophilia
Organizing pneumonia
Hepatic
Cholestatic hepatitis
Hepato-cellular hepatitis
Cardiac
Valvular disease
Musculoskeletal/neurological
Polymyositis
Myasthenia gravis
Aseptic meningitis
Thiouracils
Penicillamine
NSAIDs, antimicrobials, vaccines
Urticaria 1
Urticaria 2
Angioedema
Assessment of
IgE to agent
Type I
Tolerance
AII
Patch testing
DTH
Type IV
Biopsy
Immunohistopathology
Types III, IV
In Vitro
Assessment of
RAST
IgE in serum
Type I
IgE
Type I
Lymphocyte proliferation
T-cell responsiveness
Type IV
T-cell responsiveness
Type IV
Lymphocyte cytotoxicity
T-cell responsiveness
Type IV
Not indicated
In documenting DTH
Foreign antitoxins
Cephalosporins
Antituberculous drugs
Insulin
Anticonvulsants
Chymopapain
Quidinine
Local anesthetics
cis-Platinum
Muscle relaxants
Penicillamine
Thiopental
Vaccines
Positive
Negative
Intradermal skin test
Positive
Negative
Oral challenge
Positive
Drug allergy
Negative
ID PPL/MDM/AX/Drug
In Vitro Test
ALLERGIC
In Vitro Test +
DPT Drug
Repeat Study in 2 to 4 w.
NON ALLERGIC
Intradermal with
PPL, MDM and BP
Second evaluation
(3rd day)
Third evaluation
(5th day)
Intradermal with AP
and any suspect BL
Immediate
hypersensitivity
and
Patch
reading
or
Late intradermal
reading
Delayed
hypersensitivity
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
Site
VS
BP/P
Subcutaneous
Prick
Challenge
Result
Diluent control
N/A
Histamine
N/A
LA (undiluted) 0 min
N/A
N/A
N/A
N/A
N/A
N/A
50-70%
1-3%
10%
0.5%
Consistent w/IgE
mediated allergy ?
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)
0.5
50 U/0.03 mg
15
150 U/0.09 mg
30
350 U/0.22 mg
45
750 U/0.47 mg
60 (1 h)
1,550 U/0.97 mg
75
1.6
3,125 U/1.97 mg
90
3.2
6,350 U/3.97 mg
105
6.4
12,750 U/7.97 mg
120 (2 h)
12.8
25,550 U/15.97 mg
135
10
2.5
50,550 U/31.57 mg
150
11
100,550 U/62.9 mg
165
12
10
200,550 U/125 mg
180 (3 h)
13
400,550 U/250 mg
195
14
10
800,550 U/500 mg
210
15
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/
ROUTE
INTRUCTIONS
Oral or i.m.
Oral or i.m.
Patient Education
Make the patient aware that he/she is responsible
for future avoidance of the culprit drug
Recent Advances :
T cell Type IV reaction
Mediated cytotoxicity
Cytokines
CD8 TEN
Recent Advances :
Sulfamethoxazole
Lidocaine
Mepicaine
Celecoxide
Carbamazepine
Quinolone
Summary
ADRS 6.5 6.8% hospital admissions
Summary
Detailed history is required
Summary
Skin tests patch test DRESS, SJS and TEN
Thank You