ADR Skin_คู่มือติดตามอาการไม่พึงประสงค์ที่เกิดขึ้นจากผิวหนัง

( Skin disorders )

63

(Skin Disorders)

(APR Center)

ISBN : 974-8071-69-3

(Skin Disorders)

(APRM Center)

ISBN : 974-8071-69-3

: (Skin Disorders)

. () . ()

( ISBN )ISBN 974-8071-69-3

1: .. 2542 1,000 2: .. 2542 1,000 3: .. 2542 1,000 4: .. 2542 1,000

(APRM Center) . . . 11000 . 0-2590-7261 0-2590-7253Email address: [email protected]

I () .. 2526 .. 2540 23,905 46,173 21,645 46.17 .. 2540 4,434 7,227 4,105 56.80%

. : (Skin Disorders)

.

II

I

II

III

IV

1 : 1

2 : (Pathogenesis) 5

3 : 10 Maculo-papular rash 10 Urticaria () 19 Fixed drug eruptin ( EM ) 25 Erythema multiforme 27 Toxic epidermal necrolysis ( TEN Lyells syndrome) 35 Exfoliative dermatitis ( Erythroderma ) 39 Eczematous drug eruption 45 Acneiform drug eruption 46 Drug-induced alopecia 47 Drug-induced hyperpigmentation 48 Photosensitive drug eruption 48 Erythema nodosum 53 Vasculitis 54 Bullous eruption 57

4 : 59

62

III

1 3

2 4

3 Maculo-popular rash 10

4 14

5 Reaction rate 500 15

6 Urticaria 19

7 Fixed drug eruption 25

8 Erythema multiforme 27

9 TEN (Lyells syndrome) 36

10 TEN (Lyells syndrome) 36

11 TEN SSSS 38

12 Exfoliative dermatitis or Erythroderma 40

13 Eczema 45

14 Acne and Pustules 46

15 48

16 Phototoxic reactions 49

17 Photoallergic reactions 49

18 Erythema nodosum 53

19 Vasculitis 54

20 Bullous eruption 57

IV

1,2,3 4 Maculo-popular rash (macule) (papule)

5 Maculo-popular rash (purpula)

6 Maculo-popular rash (papular eruption)

7 Maculo-popular rash (rubelliform rash)

8,9,10 11 Maculo-popular rash (marbelliform rash) rubelliform rash

12 (urticaria) (erythema) (wheal)



15 (urticaria) (angioedema)

16 (urticaria) (angioedema)

17 erythema annulare centrifugum

18 Fixed drug eruption

19 Fixed drug eruption

20,21 22 Fixed drug eruption

17

17

17

18

18

23

23

23

23

23

23

24

24

24

V ()

23,24,25 26 31

27 31

2829 32

30,31 32 32

33 32

34,35 36 33

37 38 33

39 40 33

41 33

42 43 41

44,45,46 47 41

48,49 50 42

51 42

52 43

53,54,55 56 43

57 58 44

Erythema multiform (EM) target lesion

Erythema multiform (EM)

Erythema multiform (EM)

Erythema multiform (EM) Amoxycilin Mefenamic acid Erythema multiform (EM)

Stevens Johnson syndrome Carbamazepine Stevens Johnson syndrome 2 Toxic epidermal necrolysis (TEN) Phenytoin Toxic epidermal necrolysis (TEN) Exfoliative dermatitis Cotrimoxazole Exfoliative dermatitis Hyderchlorothiazide Eczematous drug eruption Piroxicam Eczematous drug eruption contact dermatitis Sulfanilamide Eczematous drug eruption contact dermatitis Diclofenac Diclofenac Eczema Eczematous drug eruption Chlorpropamide

Steroid acne Prednisolone 2

Pastular drug eruption Cotrimoxazole Anagen effluvium Anagen effluvium Drug-induced hyperpigmentation Clofazimine (Melasma) Hyperpigmentation Hyperpigmentation Cyclophosphamide Phototoxic drug eruption Amiodarone 4 pigment Phototoxic dermatitis Phototoxic drug eruption Diclofenac Eczema Phototoxic drug eruption Diclofenac gel Erythema nodosum Allergic vasculitis Hydrochlorothiazide Palpablepurpura Progressive pigmentary dermatosis 2 Bullous drug eruption Furosemide 6

VI

()

59

606162

6364 65

66

67 68

69

70,71 72

73

74

75 76

77 78

79

44

444451

5151

51

52

52

52

52

55

55

55

56

V () 80 Bullous drug eruption Meladinine 56

Phototoxic reaction 81 Bullous pimphigoid-like eruption NSAID 56 82 Lichenoid drug eruption diuretic 56

lichen planus 83 84 Folliculitis Isotretinoin 2 56

( Skin disorders )

1

1

60

.. 1993 2,303 54.44% .. 1994 3,360 51.24% .. 1995 3,901 47.38% .. 1996 4,352 28.81%

( Skin disorders )

2

Boston Collaborative Drug Surveillance Programme . 1966 - 1982 39,665

2%

2 3 Penicillin, Sulfa, Blood product 1

10-20%

6 5% 15 40% case-fatalito ratio 2-12%

..2536-2539 450

( Skin disorders )

3

2,3034,0782,220

687619184282117

816349268

13-4

11191

56

87.7% 7 11.7%

1. Penicillin2. Sulfa ( Cotrimoxazole)3. Antituberculous drug4. NSAID ( Piroxicam )5. Phenytoin

1 2

1

1 rash, rash erythematous

.. (1993-1996)

450-

450---

207 (46%)103 (22.8)63 (14%)

--

15 (33%)-

6 (1.3%)-

8 (1.77%)--

23 (5.11%)25 (5.55%)

19961993 19944,352

10,0752,903

7117203672492611698861562525132811121196

3,9017,8383,7141,146

951536244292150

963335242918176

179

111

3,3606,5893,3761,108

961378261218120

7337353124191816141053

() Priritus Rash Rash, erythematous Rash, maculo-papular Urticaria Fixed drug eruption Steven-johnson syndrome Angioedema Erythema multiforme Rash, purpuric Exfoliative dermatitis Sweating increased Bullous Alopecia Toxic epidermal necrolysis Eczema Others

1995

( Skin disorders )

4

2,303

54.55%(62.06%)(25.77%)(7.46%)

11.32%10.86%1.60%

maculo-papular rash, eczema, erythema mulitforme

2

2 antiinfective

.. (1993-1996)

143

97 (67.8%)(86.6%)

-(13.4%)

28 (19.58%)11 (7.7%)

1995 19961993 19944,352

25.51%(60.10%)(27.70%)(8.88%)

5.62%4.54%

55.55%

3,901

51.71%(59.48%)(26.90%)(9.64%)

9.85%2.68%15.65%

()1. System antiinfectives

- Antiviotics- Chemotherapeutics- Antituberculous (excl.streptomycin)

2. Musculo-sketetal system drugs3. Central nervous system drugs4. Antiparasitic drugs

3,360

52.02 %(66.22%)(22.52%)(7.46%)

8.7%9.46%

11.31%

( Skin disorders )

5

2 I. Non-allergic adverse drug reactionII. Allergic adverse drug reaction

I. NON-ALLERGIC ADVERSE DRUG REACTION

1. Exaggerated toxicity

1) Overdose

2) bioavailability

, gastro-intestinal tract , drug interaction 3)

plasma binding protein Coumarin Phenylbutazone Phenylbutazone plasma binding protein

4) Digoxin , Aminoglycoside Barbiturate, Phenytoin

5) bioavailability, plasma binding protein, rate of metabolism, rate of excretion, receptorsite, -

2. drug metabolism metabolism drug metabolism smooth endoplasmic reticulum microsomal mixed function oxidase system cytochrome P450 enzyme cytochrome P450 enzyme

2 (Pathogenesis)

( Skin disorders )

6

(polymorphic) drug metabolism drug metabolite

drug metabolism INH

idiosyncrasy cytochrome P450

3. enzyme protein enzyme epoxide hydrolase Phenytoin

epoxide hydrolase toxic metabolite Phenytoin Arylamines dilantin hypersensitivity syndrome maculo-papular rash toxic epidermal necrolysis Phenytoin Phenobarbiturate,Carbamazipine

acetylation slow acetylator Hydralazine, Procainamide, Sulfonamide slow acetylator

enzyme enzyme Coumarinnecrosis heterozygote deficiency protein C Coumarin protein C thrombosis

G-6-PD deficiency enzyme G-6-PD oxidation

INH

Acetyl isoniazid

Acetyl hydrazine

Reactive metabolite

Hepatic molecules

Hepatic necrosis

Acetylation

Hydrolysis

Cytochrome P450

( Skin disorders )

7

4. Anaphylactoid reaction immediate-typed hypersensitivity IgE

1) mast cell Histamine Opiates,Polymyxin B , d-Tubocurarine , Radiocontrast media

2) complement mediator radiocontrast media

3) prostaglandins enzyme-cyclooxygenase pathway leukotriene mast cell Aspirin, NSAID

5. Cumulative toxicity metabolite cell tissue

- Arsenic diffuse macular pigment, skin cancer- Hypervitamin A - Phenothiazine slate gray pigmentation

6. Ecologic change normal flora organism candida

7. Secondary side effect - Antihistamine - Systemic steroid - Isotretinoin psoriasis - Oral contraceptive porphyria

II. ALLERGIC ADVERSE DRUG REACTION

4 Gells and Coombsclassification

1. Immediate type hypersensitivity reaction2. Cytotoxic type hypersensitivity reaction3. Immune complex type hypersensitivity reaction4. Delayed type hypersensitivity reaction

( Skin disorders )

8

1. Immediate type hypersensitivity reactionImmediate type hypersensitivity reaction anaphylactic type allergic drug

eruption Penicillin 2000Kd hapten drug metabolism reactive Penicillin metabolism Penicilloyl , Penicillic acid Penicillamine

protein drug-protein conjugate complete antigen plasma cell IgE IgE mast cell basophil IgE 2 molecule mast cell basophil permeability histamine

Immediate reaction , bronchospasm, laryngeal edema, wheeze, rhonchi, hypotension anaphylactic shock

Accelerated reaction 1-72 , laryngeal edema

Late reaction 72

2. Cytotoxic type hypersensitivity reactionCytotoxic type hypersensitivity reaction antibody

3

1) tissue hapten antibody

- Penicillin-induced hemolytic anemia- Quinine-induced thrombocytopenia

2) antibody drug-antibody complex platelete, WBC

3) antibody tissue-specific antigen Methyldopa antibody red blood cell hemolysis

( Skin disorders )

9

3. Immune complex type hypersensitivity reaction Immune complex type hypersensitivity reaction Serum sickness type Arthus

reaction imune complex antibody antibody 5 7 antibody IgE IgM immune complex complement inflammation (vasculitis) , vasculitis, maculo-papular rash erythema multiforme

4. Delayed type hypersensitivity reaction Delayed type hypersensitivity reaction

allergic contact dermatitis eczema eczema maculo-papular rash, fixed drug eruption, erythemanodosum, lichenoid eruption

antigen(hapten) () Langerhanscell antigen lymphocyte lymphocyte lymph node lymph node lymphocyte sensitized - T cell sensitization phase 14

sensitized lymphocyte lymphocyte lymphokines (inflammation)

( Skin disorders )

10

450

1. Maculo-papular rash 207 (46.00%)2. Urticaria,Angioedema 103 (22.80%)3. Fixed drug eruption 63 (14.00%)4. Eczema 23 (5.11%)5. Erythema multiforme, Stevens Johnson syndrome 15 (3.33%)6. Photosensitive 11 (2.44%)7. Acneiform drug eruption 9 (2.00%)8. Bullous/oral ulcer 8 (1.77%)9. Exfoliative dermatitis 6 (1.33%)

( : . . )

MACULO - PAPULAR RASH

Maculo-papular rash (maculo-papular eruption) ( 3) eczema, photosensitive,erythema multiforme

3 Maculo-papular rash

3

5% 1-5% AmikacinApalcillinAzlocillinBacampicllinCarbenicillinCephalosporinChloramphenicolCyclacillinDihydrostreptomycinEpicillinErythromycinFlucloxacillinGentamicinMezlocillin

Antibiotics

AmoxicillinAmpicillinMiconazoleNovobiocin

StreptomycinTalampicillin

( Skin disorders )

11

3 Maculo-papular rash () 5% 1-5%

Antibiotics

Sulfonamides andDerivatives

Other Antiinfective Agents

AnalgesicsAntipyretics

Antirheumatics

Neurologic andPsychiatric Drugs

-

Sulfamethoxazole(with Trimethoprim)

Nalidixic acidThiabendazole

Vidarabine

AclofenacGold

Metiazinic acidNaproxen

d-PenicillaminePiroxicam

CarbamazepineChlorpromazine

MephenytoinMetisuximide

Phenytoin

OxacillinPenicillin GPenicillin VPhenethicillinPiperacillinPivampicillinPolymyxin BPropicillinRifampicinTetracyclineTicarcillinVancomycinSulfapyridineSulfadimethoxinSulfadoxineSulfamethoxazoleSulfamethoxypyridazineSulfisoxazoleAcyclovirp-Aminosalicylic acidCapreomycinChloroquineDapsoneNitrofurantoinQuinacrineQuinineThioacetazoneTrimethoprimAcetylsalicylic acidAzapropazoneBucloxic acidDiclofenacIndomethacinMeclofenamateMefenamic acidMetamizoleNifulmic acidPhenylbutazoneSulindacEthiosuximideImipramineIsocarboxazidMaprotilineOpipramolPhenobarbitalPrimidone

( Skin disorders )

12

3 Maculo-papular rash ()

Maculo - papular rash 2 Macule

1 . patch

Papule Maculo - papular rash Rubelliform rash (rubella)

macule papule Morbiliform rash (measles)

rubelliform rash Papular rash (papular)

exfoliative dermatitis

( : Konrard Borke. , Cutaneous side effect of drugs : W.B. Sounders. 1988 )

1-5%


Antidiabetics

Cytostatic Agents

Diagnostic Aids

Thyroid Drugs

Cardiac Drugs

Uricosaric Agents

5%

-

Carbutamide

BleomycinDauxorubicin

Mitotane

-

Metamizole sodium (Dipyrone)Methimazole

Captopril

-

PyritinolSerineIsopropylhydrazineSulthiameTrimethadioneChlorpropamideGlyburideGlymidineTolbutamideAsparaginaseCytarabineMelphalanDintrizoate sodiumIodipamideIothalanic acidMethylthiouracilThiouracilDisopyramidePrazosinProcanamideTribenosideAllopurinolProbenecid

( Skin disorders )

13

(purpura)

Lag period 2 Allopurinol, Phenytoin

4 exfoliative dermatitis HIV Cloxacillin maculo-papular rash Cloxacillin

maculo-papular rash

macular-papular rash ( ) 2

maculo-papular rash inflammation mediator ( 4) mediator maculo-papular rash Immune-complex type : hypersensitivity Phenytoin, Dapsone, Carbamazipine, Phenobarbiturate

Amphotericin B Chemotherapy Dextran iron complexesDimercaprol Edetate calcium disodium StreptokinaseVaccine ( DPT)

( Skin disorders )

14

4

( : Konrard Borke. , Cutaneous side effect of drugs : W.B. Sounders. 1988 )

Systemic route 7 - 10

(Lymphadenopathy) Reactive hyperplasia Phyenytoin Pseudo-lymphoma syndrome

Eosinophilia eonsinophil 20.6% eosinophil 5%

1. 1)

maculo-papular rash Rate of metrabolism elimination (half-life) Phenobarbital immunologix process

2) reaction rate ( 5) reaction rate Systemic antiinfective, Musculo-skeletaldrug , CNS drug

(Antiinfectious Drugs) p-Aminosalicylic acidCephalosporinsChloramphenicolErythromycinIsoniazidNetrofurantoinPenicillin

PyrazinamideRifampicinSpectinomycinStreptomycinSulfonamidesTeracycline

AllopurinolBarbituratesHydralazineIodineMethyldopaD-PenicillaminePhenobarbital

ProcainamidePropylthiouracilQuinidineQounineSalicylates

( Skin disorders )

15

2. Paracetamol Aspirin, Antihistamine3. Corticosteroid

Systemic steroid Prednisolone 30-60 mg/ 3-5 2

Topical steroid mild potency

5 Reaction rate 500

: Bigby M, Jicks H, Aendt K. Drug-induced cutaneous reactions. JAMA 1986 ;256 (24) : 3358-3363

Amoxicillin Trimethoprim-sulfamethoxazole Ampicillin Semisynthetic penicillins Blood, whole human Penicillin G Cephalosporins Quinidine Gentamicin sulfate Packed red blood cells Mercurial diuretics Dipyrone (Metamizole sodium) Heparin Trimethohenzamide hydrochloride Nitrazepam Barbiturates Chlordiazepoxide Diazepam Propoxyphene Isoniazid Guaifenesin Chlorothiazide Furosemide Isophane insulin suspension Phenytoin Phytonadione Flurazepam hydrochloride Chloral hydrate

Reaction rate ( 1000 )51.047.042.029.028.016.013.012.010.08.19.58.07.76.64.04.04.04.03.43.02.92.82.61.31.10.90.50.2

( Skin disorders )

16

( Skin disorders )

17

Maculo-papular rash (Maculo-papular eruption)

1 2

3 4 1,2,3 4 : Maculo-papular rash ( maculo )

(papule)

5 : Maculo-papular rash ( purpula)

6 : Maculo-papular rash (papular eruption)

( Skin disorders )

18

7 : Maculo-papular rash (rubelliform rash)

8 9

10 11 8,9,10 11 : Maculo-papular rash (morbelliform rash) rubelliform rash

Maculo-papular rash (Maculo-papular eruption)

( Skin disorders )

19

5% 1-5% Antibiotics Novobiocin Amoxicillin

(no longer available) Ampicillin Apalcillin Azlocillin Bacampicillin Carbenicillin Cephalosporin, (including the third generation) Cyclacillin Dicloxacillin Epicillin Floxacillin Griseofulvin Mezlocillin Oxacillin Penicillin G Penicillin V Phenathicillin

URTICARIA

Wheal

(wheal) erythema wheal 24

(Urticaria) angioedema 2-5 angioedema

6 Urticaria

( Skin disorders )

20

5% 1-5% PiperacillinPivampicillinPolymyxin BPropicillinTicarcillinVancomycinSulfamethoxypyridazineAcyclovirEthionamideIsoniazidPiperazineQuinacrineThalidomideThiabendazole

AzapropazoneTolmetinBaclofenCarbamazepineEthiosuximideAmiodaroneProcainamideCarbuamideGlymidine sodiumMethimazoleThiouracilAluminum precipitatecd pollenExtractsEgg albumin in vaccines (Flu vaccine)

Whole bloodPlaceboDiatrizoate sodiumIocetamic acidIoglycamic acid

Antibiotics

Sulfonamides



Antirheumatics


Cardiovascular Drugs

Antidiabetic Drugs

Thyriod Drugs

ImmunotherapeuticsVaccines

Blood and Blood ProductsPlacebo

Diagnostic Agents

-

-

-

-

-

-

-

Antilymphocytic serumLevamisoleHorse serum

--

-

6 Urticaria ()

(Urticaria)

( Skin disorders )

21

anaphylactic shock anaphylactic shock Penicillin

(Urticaria) SLE

(Urticaria) 3 1) Type I hypersensitivity reaction (anaphylactic type)2) Type III hypersensitivity reaction (immune complex-mediated)3) Anaphylactoid reaction

Antihistamine Drug of choice antihistamine antihistamine H1 - receptor antagonist antihistamine 1-2

Sedative H1 antihistamine - Chlorpheniramine - Cyproheptadine - Dimenhydramine - Hydroxyzine

Non-sedative H1 antihistamine - Astemazole - Cetrizine Fexofenadine - Loratadine - Terfenadine *

( * Terfenadine Ketoconazole,Erythromycin)

Antihistamine 2 H2- receptorantagonist Cimetidine,Ranitidine

Adrenaline injection shock

( Skin disorders )

22

Bronchodilator bronchospasm Prednisolone 30-60 mg / Prednisolone antiinflammation ( anaphylactic shock Hydrocortisone injection) Calamine lotion Soothing agent

( Skin disorders )

23

( Urticaria )

12 : (urticaria) 13 : (urticaria) (erythema) (wheal) (erythema) (wheal)

15 : (urticaria) (angioederma)

14 : (urticaria) (erythema) (wheal)

17 : erythema annulare centrifugum

16 : (urticaria) (angioedema)

( Skin disorders )

24

Fixed drug eruption

18 : Fixed drug eruption

19 : Fixed drug eruption

20 21 22

20,21 22 : Fixed drug eruption

( Skin disorders )

25

Antibiotics

Sulfonamides and Their Derivatives

Cytostatic Drugs

Cardiovascular Drugs

FIXED DRUG ERUPTION

1-2 10

fixed drug eruption 30 24 fixed drug eruption fixed drug eruption

Cotrimoxazole

Fixed drug eruption Type III IV hypersensitivityreaction

7 Fixed drug eruption 1%

Chlortertracycline OxytetracyclineDemeclocycline Penicillin GDoxycycline Penicillin VErythromycin StreptomycinGriseofuvin TetracyclineMinocyclinePhthalylsufathiazole SulfamethoxydiazineSulfadiazine SulfaphenazoleSulfadimethoxine SulfasuxidineSulfamethoxazole SulfathiazoleSulfamethoxypyridaxine SalfaoxazoleHydroxyureaAmphetamine HydralazineDigitalis preparations Nicotinic acid derivativesCaptopril Pentaerythritol tetranitrateEpinephrine QuinidineGuanethidine

( Skin disorders )

26

7 Fixed drug eruption ()

Topical steroid cream Steroid cream

Prednisolone

1% BisacodylN-Butylscopolammonium bromideDihydroxyanthraquinoneDimenhydrinatePhenolphthaleinTolbutamideCortisoneDiethylstibestrolEstrogen/progesteronePrednisoloneTetracosactideThiouracilDextran solutionsGelatin solutionsCycilzineDimenhydrinateDiphenhydramineTripeleanamine

ChlorineAntimony GoldArsenic IodineBismuth MagnesiumBromine MercuryDimethyl sulfoxideFoscarnetDisulfiramBromsulfaleinEosin

Gastrointestina DrugsLaxatives

Antidiabetic Drugs

Hormones

Thyroid DrugsBlood, Blood Substitutes

Anticoagulants

Antihistamines

Heavy MetalsHalogens

Others

Diagnostic Aids

( : Konrard Borke. , Cutaneous side effect of drugs : W.B. Sounders. 1988)

( Skin disorders )

27

1-5% 1% AmpicillinBenzathine benzylpenicillinCephalosporin

Antibiotics - ChloramphenicolChlortetracytineClindamycinGriseofulvin

SulfadiazineSulfadimethoxine

Sulfonamides - SulfadoxineSulfamethizoleSulfamethoxasole

ERYTHEMA MULTIFORME ( EM )

Erythema multiforme 2

1. EM minor EM 1

2. EM major Stevens Johnson syndrome 1 Stevens Johnson syndrome

maculo-papular rash (target lesion iris lesion) erythema multiforme multiforme

5-7

LincomycinNovobiocinPenicillinRifampicinStreptomycinTetracycline

Sulfamethoxazolewith trimethoprim

SulfamethoxydiazineSulfamethoxypyridazineSulfasalazineSulfasoxazole

8 Erythema multiforme

( Skin disorders )

28

1-5% 1% 8 Erythema multiforme ()

EM : herpes simplex virus, mysoplasma, M.tuberculosis, histoplasmosis Autoimmune disease : SLE, rheumatoid arthritis, Behcets disease Inflammatory

bowel disease : lymphoma, leukemia, multiple myeloma Physical faction : X-ray therapy, sun light Pregnancy, menstruation

: EM type III hypersensitivity reaction cellular immunity response cell-mediated cytotoxicity

Stevens Johnson syndrome

1. Local treatment () Antibiotic eye ointment Vaselin Glycerin borax Oral hygiene care

OthersAntiinfective Agents


Antirheumatics

Antigout Drugs


-

d-Penicillamine

-

-

p-Aminosalicylic acid MethenamineChloroquine Nalidixic acidDapsone NitrofurantoinEthambutol QuinacrineFrnazolidine QuinineIodochlorhydroxyquin ThiabendazolIsoniazid ThioacetazoneAcetylsalicylic acid IbuprofenAminophenazone IsoxicamAntipyrine MeclofenamateBenoxaprofen NaproxenCodeine PhenacetineDiflunisal PhenylbutazoneFenbufen PiroxicamGold SulindacAllopurinolCinchophenCarbamazepineCarisoprodolChloral hydrateChlordiazepoxide


( Skin disorders )

29

(wet dressing) Burows solution normal saline

2. Systemic treatment

Prednisolone 30-60 mg/ 2-4 1)

stress-ulcer H2-antigonist Cimetidine 400 mg 2 200mg 6

2)


( Skin disorders )

30

( Skin disorders )

31

Erythema multiforme

23 24 25

26 23,24,25 26 : Erythema multiforme (EM) target lesion

27 : Erythema multiforme (EM)

( Skin disorders )

32

Erythema multiforme

28 29 : Erythema multiforme (EM)

30 31

32 30,31 32 : Erythema multiforme (EM)

Amoxycillin Mefenamic acid

33 : Erythema multiforme (EM)

( Skin disorders )

33


34

35

34,35 36 : Stevens Johnson syndrome Carbamazepine

36

37 38 37 38 : Stevens Johnson syndrome 2

( Skin disorders )

34

Toxic epidermal necrolysis (TEN)

39

40

39 40 : Toxic epidermal necrolysis (TEN) Phenytoin

41 : Toxic epidermal necrolysis (TEN)

( Skin disorders )

35

TOXIC EPIDERMAL NECROLYSIS ( TEN LYELLS SYNDROME )Toxic epidermal necrolysis (TEN) . 1956 Lyell

TEN TEN Stevens Johnson syndrome erythema multiforme

TEN delayed-type hypersensitivity 1. TEN 80-95% TEN 14

(1-45) Sulfonamide, Arbiturate, Phenytoin,Carbamazipine, Allopurinol, NSAID(Piroxicam, Phenylbutazone), Antituberculous drug (Thiacetazone)

2. 10 9 TEN (Lyells syndrome)

Antibiotics

Sulfonamides



Antirheumatics

1% Ampicillin Penicillin VChloramphenicol Procaine penicillinErythromycin TetracyclineNeomycin StreptomycinPenicillin GSulfadizine SulfamathoxypyridazineSulfadimethoxine SulfamathoxydiazineSulfadoxine SulfasalazineSulfamethoxazole Sulfathiazole

with trimethoprim SulfisoxazoleBenznidazole PyrimethamineChloroquine with sulfadoxineDapsone QuinineIsoniazid TetrachloroethyleneNitrofurantoin Thiabendazole

ThioacetazoneAcetylsalicylic acid OxyphenbutazoneAminophenazone PentazocineAntipyrine d-PenicillamineBenoxaprofen (no longer Pethidine

Available) PhenacetineCodeine PhynylbutazoneFenbufen PiroxicamGold PropyphenazoneIbuprofen SalicylamideIndomethazine SulindacIsoxicam TolmetinMetamizole Zomepirac

( Skin disorders )

36

9 TEN (Lyells syndrome) ()

10 TEN (Lyells syndrome)

Antigout Drugs

Neurologic and Psychiatric Drugs

CarDiobascular Drugs

Cytostatic Drugs

DiureticsGastrointestinal Drugs

Antidiabetic Drugs

Immunotherapeutic DrugsVaccines

Local Anesthetics

1% AllopurinolAmobarbital MephenytoinBarbital MephobarbitalCarbamazepine MeprobamateChlormezanone PhenytoinChlorpromazine PrimidoneDiphenhydramine PromethazineLevomepromazine PyritinolBeta-blockers EnalaprilCaptoprilActinomycin C MethotrexateChlorambucil MithramycinCyclophosphamide ProcarbazineMerceptopurineAcetazolamiideCimetidine PhenolphyhaleinCarbutaimide TolbutamideAntithymocyte Small pox vaccineBCG vaccine Tetanus antitoxinMeasles vaccineBenzocaine IodineBromide Phenolpthalein


VaccinationBCG

Diptheria toxoidMeasles

PoliomyelitisSmallpox

Tetanus antitoxinContaxt with a toxic fumigant

AcrylonitrileNeoplastic diseases

Hodgkins lymphomaNon-Hodgkins lymphoma

LeukemiaGraft vs host reaction

Idiopathic

Viral InfectionsMeaslesVaricella

Herpes zosterHerpes simplex

Fungus InfectionsAspergillosis

Bacteria InfectionsEscherichia coli

Radiation

( Skin disorders )

37

3

1. Morbiliform eruption Marculo-papular rash2. Discrete areas of erythema or Purplish macules 3. Target lesion EM

(Nikolskys sign positive) 50% (Beaus line)

Mucous membrane

: interstitial edema hypoxemia

pulmonary edema : disseminated intravascular coagulation :

pre-renal azotemia, (acute tubular necrosis), glomerulonephritis

1. Maculo-papular rash 2. Stevens Johnson syndrome TEN Stevens

Johnson syndrome 10% TEN

( Skin disorders )

38

3. Staphyllococcal scalded skin syndrome (SSSS) Staphyllococcus aureus toxin epidermolysis antibiotic

TEN ICU/Burn unit

1. Fluid management2. Nutrition3. Antibiotic4. Environmental temperature5. Supportive care GI bleed, respiratory failure6. Local skin care, eye care7. Alternative treatment hemodialysis,plasmaploresis,cyclosporine

TEN

TEN SSSS Target Nikolskys sign granular zoneExfoliative cytology neutrophils (Acan-tholytic cell)Degree of exudation 4+ 1+Healing/recovery 10-14 (20-50%)

11 TEN SSSS

( Skin disorders )

39

neutrolhil

symblepharon, entropion, ectropion,dry eye, corneal opacities, vaginalstenosis, urethral stenosis, anonychia, depigment

EXFOLIATIVE DERMATITIS (ERYTHRODERMA) TEN TEN



2 gynecomastia

exfoliative dermatitis maculo-papular rash

exfoliative dermatitis psoriasis, pityriasis rubra pilaris, pemphigus

foliaceus, Norwegians scabiasis Hodgkins lymphoma, mycois fumgoides, CA lung, CA rectum Graft-versus-host disease AIDS 25%

( Skin disorders )

40

12 Exfoliative dermatitis or Erythroderma

Prednilsolone 30-60 mg/ Topical treatment

- Mild-potency steroid cream Triamcinolone cream- Emolient Olive oil, Cream base

Acetylsalicylic acid Ethambutol d-PenicillamineAllopurino Furosemide Penicillinp-Aminosalicylic acid Gold salts PhenindioneAztreonam Isoniazid PhenylbutazoneBAL Iodide PhenytoinBarbiturates Ketoconazole PrimidoneCaptopril Lincomycin QuinacrineCarbamazepine Lithium QuinidineCefoxitin Meclofenamate StreptomycinChloroquine Mephenytoin Sulfamethoxazole ( with trimethoprim )Chlorpromazine Cimetidine Mercury compounds SulfonamidesCodeine Nitrofurantoin SulfonylureasDapsone Organic arsenicals(obsolete) SulindacEdetate Paramethadione Thioacetazone

Trimethadione

( Skin disorders )

41

Exfoliative dermatitis

42 43 42 43 Exfoliative dermatitis Cotrimoxazole

44 45

46 47

44,45,46 47 Exfoliative dermatitis Hydrochlorothiazide

( Skin disorders )

42

Eczematous drug eruption

48 49

50

48,49 50 Eczematous drug epuption Piroxicam

51 Eczematous drug eruption contact dermatitis Sulfanilamide

( Skin disorders )

43

Eczematous drug eruption

52 : Eczematous drug epuption contact dermatitis Diclofenac Diclofenac Eczema

53 54

55 56

53,54,55 56 : Eczematous drug eruption Chlorpropamide

( Skin disorders )

44

Acneiform drug eruption

55 56

57 58 : Steroid acne prednisolone 2

59 : Pastular drug eruption Cotrimoxazole Drug-induced alopecia

60 : Anagen effluvium - 61 : Anagen effluvium

( Skin disorders )

45

ECZEMATOUS DRUG ERUPTIONEczema

eczema eczema drug eruption eczema maculo-papular rash eczema drug eruption

Eczematous drug eruption (allergic) contact dermatitis (allergic) contact dermatitis drug eruption systemic route : 3

1 Acute eczema ()

2 Subacute eczema ()

3 Chronic eczema () eczematous-drug eruption

eczematous drug eruption acute eczema allergic contact dermatitis Diclofenac gel Diclofenac eczematous drug eruption sensitized lymphocyte allergic contact dermatitis contact dermatitis

AminophyllineArsphenamineChloral hydratesChlorpromazineChlorpropamideChlorothiazideDisulfiram

FormaldehydeGentamicinHexylresorcinolIodidesKanamycinKercurial diureticsMeprobamate

NeomycinNovobiocinPenicillinProcaine(andotherlocal anesthetics)PromethazineQuinacrine (atabrine)

ResorcinStreptomycinSulfonamidesThiamaineTolbutamide

13 Eczema

( Skin disorders )

46

ACTH Dantrolene Phenobarbetal ThioureasActinomycin D Desulfiram Phenytoin TroxidoneAmoxycillin Estrogens/progesterones Propranolol TrazodoneAndrogens (in women) (oral contraceptives) Prothionamide TrimethadioneAzathioprine Ethionamide Pyrazinamide Vitamin B2Bromides Halothane,Haloperidol Quinidine Vitamin B6Chloral hydrate Isoniazid Quinine Vitamin B12Clofazimine Iodides Lithium RifampicinCorticosteroids Methandienone TetracyclinesDanazol

Eczematous drug eruption allergic contact dermatitis typeIV hypersensitivity reaction (delayed type)

eczema Steroid Drug of choice topical systemic form : Antihistamine

ACNEIFORM DRUG ERUPTION Corticosteroid Anabolic hormone Androgen, Gonadotropin INH Phenytoin

Prednisolone INH

Steroid acne (monomorphic)

14 Acne and Pustules

( Skin disorders )

47

DRUG-INDUCED ALOPECIA 100,000 3

1 : Anagen hair

85-90% anagen hair 2-3 catagenhair

2 : Catagen hair anagen hair telogen hair catagen hair 1%

3 : Telogen hair (club-shape) telogen hair 10-15% 3 100 /

Anagen effuvium anagen hair anagen hair anagen effluvium

Azathioprine Borate Hydroxyurea MercuryArsenic Colchicine Lead ThaliumAsmuth Cyclophosphamide Methotrexate

Telogen effuvium telogen hair anagen hair telogen hair 2-4 anageneffluvium telogen hair anagen hair telogeneffluvium

Allopurinol Cocaine Oral contraceptive WarfarinClofibrate Heparin Propyl thiouracil

( Skin disorders )

48

DRUG-INDUCED HYPERPIGMENTATION

( Brown ) (melanocyte)

(melanin) (phototoxic) (Slate gray) (Dermis)

(Tyndall phenomenon)

volumn of distribution tissue

PHOTOSENSITIVE DRUG ERUPTION

2 1. Phototoxic drug eruption

AminodaronePhenothiazine

Minocycline

ClofazimineAnti-malarial

Phenytoin, pill, ACTHArsenic

Chemotherapeutic agent

Pigmentation changeSlate - graySlate - gray

Brown, muddyBlue-block

RedSlate-gray, yellow

BrownBrownBrown

Sun-exposedSun-exposed

Sun-exposedAcne scar, -

Sun-exposed

Diffuse macular

15

( Skin disorders )

49

16 Phototoxic reactions

2. Photoallergic drug eruption allergic drug eruption eczematous drug eruption (antigen) carrier protein photoantigen

eczema Fenofibrate 1

eczema photoantigen

Alimenazine Dacarbazine Mepazine Piroxicam SulfanilamideAmiodarone Dapsone Methacycline Procarbazine SulfisoxazoleBenzydamine Deneclocycline Methoxsalen Prochlorperazine SulindacCapreomycin Doxycycline Nalidixic acid Promazine ThiopropazateCaptopril 5-Fluorouracil Naproxen Protriptyline ThioridazineCarprofen Furosemide Nortriptyline Pyritinol Tiaprofenic acidChlorpromazine Hematoporphyrin Oxytetracycline Resorcin derivatives TriflupromazineChlortetracycline Levomepromazine Perazine VinblastinClofazimine Phenprocoumon Warfarin

Acetohexamide Chlorothiazide Gold QuinethazoneAmantadine Chlorphenoxamin Griseofulvin Quinidinep-Aminobensoic acid Chlorpromazine Hydrochlorothiazide QuinineAmitriptyline Chlorpropamide Imipramine SaccharineAzathioprine Chlortalione Indometacin SulfadimethoxineBarbiturates Cyamemzine Nalidixic acidSulfamethoxypyridazineBenzydamine Cyproheptadine Nitrofurantion SulfanilamideBuclosamide Dibucaine Phenylbutazone SulfathiazoleCapremycin Diltiazem Piroxicam SulfisoxasoleCarbamazepine Diphenhydramine Procaine ThiridazineCarbinoxamine Estrogens (oral contraceptives) Promazine TolazamideCarbutamide Ethionamide Promethazine TolbutamideCarprofen Lincomycin Pyrazinamide TrazodoneChlordiazepoxide Gilbenclamide Pyritinol TriacetydiphenolisatinChloroquine Glyburide Triflupromazine

17 Photoallergic reactions

( Skin disorders )

50

( Skin disorders )

51

Drug-induced hyperpigmentation

60 : Drug-induced hyperpigmentation Clofazimine

64 65 : Hyperpigmentation

53 54

66 : Hyperpigmentation Cyclophosphamide

( Skin disorders )

52

67 68 57 58 : Phototoxic drug eruption Aminodarone 4 pigment

Photosensitive drug eruption

69 : Phototoxic dermatitis

70

71 72 71 72 : Phototoxic drug eruption Diclofenac Eczema

73 : Phototoxic drug eruption Diclofenac gel

( Skin disorders )

53

ERYTHEMA NODOSUM type II IV hypersensitivity reaction

antigen Sulfonamide, Oral contraceptive, Bromide Tuberculosis, Leprosy, Histoplasmosis Enterpathy : Ulcerative colitis, Crohns disease : Lymphoma, Leukemia Behcet s disease

1% Penicillin G TetracyclinePenicillin V 13-cis-Retinoic acidStreptomycinSulfamethoxazole SulfanilamideSulfamethoxypryidazine SulfathiazoleDapsone NitrofurantoinIodochlorhydroxyquinAcetaminophen GoldAcetylsalicylic acid IndometacinCodeine d-PenicillamineDiclofenac PhenacetineCarbamazepine MeprobamateChlordiazepoxide PhenobarbitalBusulfanAmiodaroneCarbutamide TolbutamideChlorpropamideEstrogensEstrogens/progesterones (oral contraceptives)Thiouracil derivativesBCG vaccine Small pox vaccineDiphtheria vaccine Poliomyelitis vaccine(Salk)Arsenic IodineBromine

: Konrard Borke. , Cutaneous side effect of drugs : W.B. Sounders. 1988

Antibiotics

Sulfonamides

Other Antiinfective agents


Antirheumatics

Neurologic andPsychiatric DrugsCytostatic Drug

Cardiovascular Drug

Antidiabetic Drugs

HormonesThyroid Drugs

ImmunotherapeuticsVaccines

Heavy MetalsHalogens

18 Erythema nodosum

( Skin disorders )

54

NSAID, prednisolone, potassium iodidesolution

VASCULITIS

1. Allergic vasculitis Leukocytosclatic vasculitis post capilaryvenules immune complex antibody type III hypersensitivity reaction

palpable purpura palpable purpura 2

19 Vasculitis

Al lerg ic vascu l i t i s autoimmune disease SLE, rheumatoid arthritis

2. Lymphocytic vasculitis Progressive pigmentary dermatosis immune complex hemoglobin tissue

delay-type hypersensitivity reaction

KetoconazoleLevamisole

Nonsteroidal anti-inflammatory agentsPenicillin

Propylthiouracil

AllopurinolCimetidine

DilantinGold

Hydralazine

QuinidineSulfonamidesTetracycline

Thiazides

( Skin disorders )

55

74

74 : Erythema nodosum

Erythema nodosum

75 76 75 76 : Allergic vasculitis Hydrochlorothiazide Palpable purpura

77 78 77 78 : Progressive pigmentary dermatosis 2

Vasculitis

( Skin disorders )

56

Bullous drug eruption

79 : Bullous drug eruption 80 : Bullous drug eruption Furosemide Meladinine Phototoxic6 reaction

81 : Bullous pimphigoid-like eruption NSAID

82 : Lichenoid drug eruption diuretic Lichen planus

83

84 83 84 : Folliculitis Isotretinoin 2

( Skin disorders )

57

BULLOUS ERUPTION

fixed drug eruption, erythema multiforme, vasculitis, toxic epidermal necrolysis,phototoxic drug eruption

20 Bullous eruption


1-5% 1%

Antibiotics

Sulfonamides

Other AntiinfectiousAgents


Antirhematics

Antigout Drugs


Cytostatic DrugsCardiovascular

DrugDiuretics

-

-

Thalidomide

d-Penicillamine

-

Bleomycin

-

Ampicillin NeomycinBenzathinepenicillin Penicillin GChloramphenicol Penicillin VChlortetracycline RifampinDemeclocycline StreptomycinGriseofulvin TetracyclineSulfadoxin SulfamethoxypyridazinSulfamethoxazole SulfanilamideSulfamethoxazole with Sulfasalazine

trimethoprim SulfathiazoleSulfamethoxydiazin Sulfisoxazolep-Aminosalicylic acid NitrofurantoinChloroqiune phosphate Piperazine derivativesDapsone QuincrineIsoniazid QuinineNalidixic acidAcetylsalicylic acid IndometacineAminophenazone MetamizolAntipyrin MorphineAzapropazone PhenacetineCodeine (very rarely) PhenylbutazoneGold PiroxicamIbuprofen SalicylamideCinchophen ColchicineAmitriptyline MeprobamateCarbamazepine PhenobarbitalChloral hydrate PhenytoinChlorpromazine PromethazineEthotoin TrimethadioneMephenytoin5-Fluorouracil VinblastinDigitalis preparations PractololMinoxidil QuinidineAcetazolamide HydrochlorothiazideChlorothiazide QuinethazoneFurosemide

( Skin disorders )

58

1-5% 1%

20 Bullous eruption (9) ()

vesiculo-bullous disease autoimmune disease

Pemphigus-like drug eruption Penicillamine Captopril 2 antibody ( IgG) 6-12 pemphigus

Bullous pemphoid-like drug eruption antibody pemphigus papule nodule drug-inside bullous pemphigoid Thoial drugs, Sulfa Furosemide

case report Coumarin induced skin necrosis, Drug-induced LE,Liehenoid drug eruption etc.


Laxative

Antidiabetic DrugsHormone

Immunotherapeutic AgentsVaccinesVitamins

Heavy MetalsHalogensAntidotes

Local AnestheticsPhototherapeutic Agent

-

--

-

-

-

-

PhenolphthaleinCarbutamide InsulinChlorpropamide TulbutamideProgesteroneBCG vaccine TrichophytinSmall pox vaccineArsenic IodineBismuth MercutyBromine Vitamin B 12DimercaprolLidocaine MepivacaineMethoxsalen (with UVA therapy)

( Skin disorders )

59

4

1. 2. 3.

1. 54 450 11.7% 1

2. 30 2

3. (herpes simplex) erythema multiforme immune complex herpes simplex antibody EM lymphoma exfoliative dermatitis

( Skin disorders )

60

4. Lag period 1-2 87.7% 7

5. Dechallenge reactionrate reaction rate

6. Rechallenge

, maculo-papular rash erythema multiforme, toxic epidermalnecrolysis, erythema nodosum

, vasculitis SLE, exfoliative dermatitis (psoriaris)

1. SKIN TEST ( Prick test, Scratch test, Intradeermal test)

maculo-papular rash vasculitis

10-20

Immediate type hypersensitivity reaction anaphylactic reaction Penicillin

( Skin disorders )

61

2. PATCH TEST eczematous drug eruptionallergic contact dermatitisphotosensitive drug eruption (photopatch test)fixed drug eruption ( lesion)maculo-papular rash

petrolatum 24-48 photosensitive drug eruption UVA eczema 48 72 fixed drug eruption fixed drug eruption 3. LYMPHOCYTE CYTOTOXICITY ASSAYS

type III hypersensitivity reaction drug metabolism

incubate ( Phenytoin, Sulfonamide)

drug metabolism lymphocyte cytotoxictity 4. RAST ( Radioallergosorbent test )

IgE Penicillin, Insulin, ACTH 5. Hemagglutination test

IgG, IgM (agglutination) IgG IgM Penicillin 6. Histamine release test

IgG mast cell basophil 2 histamine 7. Lymphocyte proliferation test

lymphocyte lymphokines cellular-mediated immuneresponse

( Skin disorders )

62

1. . . 1996;3: 15-242. . Dermatology 2000. : 2540.3. Spontaneous report of advance drug reaction 1993 , 19944. Spontaneous report of advance drug reaction 1994 , 19955. Spontaneous report of advance drug reaction 1995 , 19966. Spontaneous report of advance drug reaction 1996 , 19977. ,

1. Bigby M,Jicks, Jick H, Arndt K. Drug - induced cutaneous reactions. JAMA 1986; 256 (24) : 3358-3363. 2. Fitzpatrick TB, Eisen AZ, wolff K, Freedberg IM, Austen KF. Dermatology in general medicine.4th ed. New York : McGraw-Hill, Inc. 1993.3. Isselbacher KJ, Braunwald, Wilson JD, Martin JB, Fauci AS, Karper DL. Harrisons Principles of internal medicine. 13th ed. International edition 1994.4. Konrard Borke, Cutaneous side effect of drugs : W.B. Sounders. 19985. Lever WF , Lever GS. Histopathology of the skin. 7th ed. Philadephia : Lippincott, 1990.6. Rook A, Wilkinson DS, Ebling FJG. Text-book of dermatology. 5th ed. Oxford : Blackwell Science,1996.

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