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DRUG HYPERSENSITIVITY &

DRUG-INDUCED DISEASES

Dhany Prafita E
Departemen/SMF Ilmu Kesehatan Kulit dan Kelamin
Fakultas Kedokteran Universitas Brawijaya/RSUD dr.Saiful Anwar Malang
Adverse Drug Reaction
(ADR)

Any noxious, unintended & undesired effect of a


drug, which occurs at doses used in humans for
diagnosis, prophylaxis and therapy.

adverse cutaneous drug reaction (ACDR) /


SKIN drug-induced skin reactions
Ring J and Brockow K. Adverse Drug Reactions: Mechanisms and Assessment. Eur Surg Res 2002;34;170-175
Adverse Drug Reaction

Type A Type B
Type A
• Common • Pharmacokinetic, • Antihypertensive
(80%)
pharmacodynamic  orthostatic
• Non- hypotension
immune • Drug toxicity
• NSAID 
mediated • Drug interaction gastritis
• Dose-
dependent • Side effect • Antihistamine 
• Predictable • Disease  dry mouth
1-5
bioavailability 3,4

3. Hypersensitivity Reactionsoncalo M. Dan Bruynzeel DP. 2007. Mechanisms in Cutaneous Drug. Dalam Zhai H, Wilhelm K, Maibach HI Editor. Marzulli and Maibach’s Dermatotoxicology 7th edition. CRC Press. Florida. h.259-268.
4. Schnyder B dan Pichler WS. 2009. Mechanisms of Drug-Induced Allergy. Mayo Clin Proc. 84(3):268-272.
5. Abdollahi M, Karimpour H, Khalai S. 2003. Review of Drug-Induced Skin Reactions. Journal of Pharmacy Practice and Research. 33(1).
• Less common
• Dose-independent
• Unpredictable
• Immune & non-immune
mediated
Type B • Certain predisposition
• Drug intolerance
• Idiosyncrasy
• Hypersensitivity reactions

1. Schatz SN dan Weber RJ. 2015. Adverse Drug Reactions. PSAP 2015.
https://www.accp.com/docs/bookstore/psap/2015B2.SampleChapter.pdf
3. Hypersensitivity Reaction. Gsoncalo M. Dan Bruynzeel DP. 2007. Mechanisms in Cutaneous Drug. Dalam Zhai H, Wilhelm K, Maibach HI
Editor. Marzulli and Maibach’s Dermatotoxicology 7th edition. CRC Press. Florida. h.259-268.
4. Schnyder B dan Pichler WS. 2009. Mechanisms of Drug-Induced Allergy. Mayo Clin Proc. 84(3):268-272.
drug toxicities/intolerance – toxicity
of a drug (or several drugs) at low and
sometimes subtherapeutic doses
Pichler WJ. 2017. Drug Allergy : Classification and Clinical Features. https://www.uptodate.com/contents/drug-allergy-classification-and-clinical-
features

Idiosyncratic drug reactions - untoward


reactions to drugs that occur in a small fraction of
patients and have no obvious relationship to dose
or duration of therapy
Roth RA, Luyendyk J, Maddox JF, Ganey PE. Inflammation and drug idiosyncrasy--is there a connection?. J Pharmacol Exp Ther. 2003
Oct;307(1):1-8
Drug reaction Examples
Type A: Reactions occurring in most normal patients, given sufficient dose and duration of therapy: Common and predictable
Hepatic failure (acetaminophen)
Overdose
Metabolic acidosis (aspirin)
Nausea, headache (with methylxanthines)
Side effects Oral thrush or vaginal candidiasis (with glucocorticoids)
Nephrotoxicity (with aminoglycosides)
Diarrhea due to alteration in GI bacteria after antibiotics
Secondary or indirect effects
Phototoxicity (with doxycycline or thiazide diuretics)
Drug interactions Macrolide antibiotics increasing theophylline, digoxin, or statin blood levels

Type B: Drug hypersensitivity reactions restricted to a small subset of the general population: Rare and mostly unpredictable
Intolerance* Tinnitus after a single aspirin tablet
G6PD deficiency: Hemolytic anemia after antioxidant drugs (eg, dapsone) Δ
Idiosyncrasy¶ (pharmacogenetics) TMPT deficiency: Toxicity during azathioprine therapyΔ
Pseudoallergic reaction (with NSAIDs)
Anaphylaxis from beta-lactam antibiotics
Photoallergy with quinidine
Immune-mediated thrombocytopenia (with heparin)
Immunologic drug reactions (allergy) Serum sickness (with antivenom preparations)
Vasculitis (with phenytoin)
Stevens-Johnson syndrome (with trimethoprim-sulfamethoxazole)
Drug-induced hypersensitivity syndrome (with allopurinol in HLA-B*58:01 individuals)
Pichler WJ. 2017. Drug Allergy : Classification and Clinical Features. https://www.uptodate.com/contents/drug-allergy-classification-and-clinical-features.
Drug
Hypersensitivity
Pembagian Tipe
Reaksi Hipersensitivitas
Coombs & Gell
.

Pichler WJ. 2007. Drug Hypersensitivity Reactions : Classification and Relationshipto T-Cell Activation. Dalam Pichler WJ Editor. Drug Hypersensitivity.
Karger. Basel. H.168-189
Drug-Induced
Diseases
drug-induced lupus
drug-induced drug-induced
eritemathosus
pemphigus psoriasis
(DILE)

drug-induced drug-induced
photosensitivity hyperpigmentation

Imune / Non-immune
Drug-induced pemphigus
Sulfhydryl Captopril,
radical/ penicillamine,
Variety of Thiol drug
pemphigus Similar
manifestation
with the
Phenol Aspirin, rifampin,
classic drug levodopa, heroin
Immune/non-
immune
mechanism
Non-thiol, NSAID, CCB,
non- ACEI
phenol

✢Brenner S, Goldberg I. Drug-induced pemphigus. Clinics in Dermatology. 2011. 29. 455-457.


Inhibition of enzymes that aggregate keratinocyte
Activation of plasminogen activator  disaggregate
Thiol keratinocyte  disturbance cell adhesion
Formation of neoantigen  immunological reaction

Release of cytokine (TNFα, IL1) from


Phenol keratinocytes.
Regulation & synthesis of complement
& protease  acantholysis
Drug-induced Lupus Erythemathosus

Appear : continous drug


Similar manifestation to consuming (at least 1 mo)
classic SLE
Disappear : stopped drug

No drug-specific T cells or Cummulative dose for


antibody several months/years 
symptoms developed

Certain genetic
predisposition

✢Pretel M, Marques L, Espana A. 2014. Drug-Induced Lupus Erythematous. Actas Dermosifiliogr. 105(1):18-30.
Common DILE

Definite Probable Possible Recent case


reports
Hydralazine Sulphasalazine Antibiotics Infliximab
Procainamide Anticonvulsant NSAID Etanercept
Isoniazid Anti-thyroid Antihypertensive Zafirlukast
Methyldopa Statin Lithium Clobazam
Quinidine Terbinafine Interferons Tocainide
Minocycline Penicillamine Gold salts Lisinopril
Chlorpromazine Fluorouracil agents Bupropione
Hydrochlorothiazide
Vasoo S. 2006. Drug-Induced Lupus : an update. Lupus 15:757-761
Drug-provoked Psoriasis
Kim GK dan Del Rosso JQ. 2010. Drug-Provoked
Psoriasis : Is It Drug Induced or Drug Aggravated?
Understanding Pathophysiology and Clinical
Relevance. The Journal of Clinical and Aesthetic
Dermatology. 3(1).

Drug-provoked psoriasis : Subtype


Drug-induced Psoriasis Drug-Aggravated Psoriasis

Discontinuation of the causative drug Progresses even after the


stops the further progression of the discontinuation of the offending drug
disease

Tends to occur de novo in patients Propensity to occur in patients with


with no previous history and/or family history of or a genetic predisposition
history of psoriasis for psoriasis

Clinical presentation often mimic Exacerbation of pre-existing psoriatic


pustular variant, with no nail lesions or the development of new
involvement or arthritis psoriatic lesions in previously
uninvolved skin

Abscense of Munro microabses Histologically reveals psoriasis


vulgaris
Beta blocker Lithium Antimalarial Antibiotics

• Delayed type • Decrease cAMP • Inhibition of • Tetracycline


hypersensitivity • Increase IL-2, transglutaminase • decrease cAMP
• Immunological mechanism TNFα, IFNγ  cellular • Photosensitization
• Decrease cAMP  proliferation Koebner  phototoxicity
keratinocyte
hyperproliferation

Kim GK dan Del Rosso JQ. 2010. Drug-Provoked Psoriasis : Is It Drug Induced or Drug Aggravated? Understanding Pathophysiology and Clinical Relevance. The Journal of Clinical and Aesthetic
Dermatology. 3(1).

Hong J dan Bernstein D. 2012. A Review of Drug That Induced or Exacerbate Psoriasis. Psoriasis Forum. 18(1).
Drug-induced Photosensitivity

Zuba EB, Koronowska S, Osmola-Mankowska A, Jenerowicz D. 2016. Drug-Induced Photosensitivity. Acta Dermatovenereol Croat. 24(1):55-64
Golongan Obat Obat Reaksi Reaksi
Drugs often Fototoksik Fotoalergi
Terapi Oral
involved in Obat-obatan Furosemide + -
Kardiovaskuar dan Amiodarone + -
drug-induced Diuretik Quinidine + +

photosensitivity Antibiotik
Thiazide
Dapson
+
-
+
+
Sulfonamid + +
Tetracycline + -
Ciprofloxacine + -
Antifungal Griseofulvine + -
Ketoconazole + -
DMARD Hydroxychloroquine - +
NSAID Piroxicam +
Ibuprofen + -
Ketoprofen + +
Terapi Topikal
Zuba EB, Koronowska S, Antineoplastik 5-FU + +
Osmola-Mankowska A,
Jenerowicz D. 2016. Drug-
Furocoumarin Psoralen + +
Induced Photosensitivity. Acta Keratoplastic Coal tar + -
Dermatovenereol Croat.
24(1):55-64 NSAID Ketoprofen + +
Drug-induced Hyperpigmentation
Induced by chemotherapeutic agent
(Bleomycin) 
flagellate
hyperpigmentation

Alteration to normal
Localized pigmentation pattern
increase in Toxic effect
of the drug secondary to
melanogenesis inflammation
✢Resende C, Araujo C, Gomes J, Celeste B. Bleomycin-induced flagellate hyperpigmentation. Case Report. BMJ Case Rep. 2013.
✢Larson KN, Gagnon AL, Wison BB. Bleomycin-induced Flagellate. Case Report. Clinical Case Reports 2107; 5(4): 429-430.