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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
Laura Fisher et al. Managing the Allergic Patient, 2008
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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
Clinical Patterns of Immunological and
Non-immunological Adverse Drug Reactions2
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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
Clinical Patterns of Immunological and
Non-immunological Adverse Drug Reactions3
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Clinical Patterns of Immunological and
Non-immunological Adverse Drug Reactions4
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
Laura Fisher et al. Managing the Allergic Patient, 2008
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Urticaria 2
Laura Fisher et al. Managing the Allergic Patient, 2008
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Urticarial reaction to penicillin
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006
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Angioedema
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A. and B. Erythemia multiforme with toxic epidermal necrolysis
and mucosal involvement (Steven-Johnson Syndrome)
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006
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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
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006
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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
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006
* 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
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006
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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%
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006
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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
Laura Fisher et al. Managing the Allergic Patient, 2008
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
30 3 200 U/0.13 mg (IV/PO) 100 U/mL (0.0625 mg/mL) 2 350 U/0.22 mg
45 4 400 U/0.25 mg (IV/PO) 100 U/mL (0.0625 mg/mL) 4 750 U/0.47 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
90 7 3,200 U/2 mg (IV/PO) 1000 U/mL (0.625 mg/mL) 3.2 6,350 U/3.97 mg
105 8 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) 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
N. Franklin Adkinson et al. Allergy, 3th Ed. 2006
* 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