63

( Skin disorders )

(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:
2:
3:
4:

.. 2542
.. 2542
.. 2542
.. 2542

1,000
1,000
1,000
1,000

(APRM Center)

. . . 11000 . 0-2590-7261 0-2590-7253
Email address: adr@fda.moph.go.th

(
)
.. 2526 .. 2540 23,905
46,173

21,645 46.17 .. 2540

4,434 7,227
4,105 56.80%



.
: (Skin Disorders)





.

II

II

III

IV

1 :

2 : (Pathogenesis)

3 :

Maculo-papular rash

Urticaria ( )

Fixed drug eruptin ( EM )

Erythema multiforme

Toxic epidermal necrolysis ( TEN Lyells syndrome)

Exfoliative dermatitis ( Erythroderma )

Eczematous drug eruption

Acneiform drug eruption

Drug-induced alopecia

Drug-induced hyperpigmentation

Photosensitive drug eruption

Erythema nodosum

Vasculitis

Bullous eruption

10
10
19
25
27
35
39
45
46
47
48
48
53
54
57

4 :

59

62

III

Maculo-popular rash

10

14

Reaction rate 500

15

Urticaria

19

Fixed drug eruption

25

Erythema multiforme

27

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)

17

Maculo-popular rash
(purpula)

17

Maculo-popular rash
(papular eruption)

17

Maculo-popular rash (rubelliform rash)

18

Maculo-popular rash (marbelliform rash)

rubelliform rash

18

12

(urticaria) (erythema) (wheal)

23

13

(urticaria) (erythema) (wheal)

23

14

(urticaria) (erythema) (wheal)

23

15

(urticaria) (angioedema)

23

16

(urticaria) (angioedema)

23

17

erythema annulare centrifugum

23

18

Fixed drug eruption

24

19

Fixed drug eruption 24

8,9,10 11

20,21 22

Fixed drug eruption

24

()

23,24,25 26 Erythema multiform (EM) target lesion

27
2829

31

Erythema multiform (EM)

31

Erythema multiform (EM)

32

30,31 32 Erythema multiform (EM)

Amoxycilin Mefenamic acid
33
Erythema multiform (EM)

32

34,35 36 Stevens Johnson syndrome Carbamazepine

33

37 38 Stevens Johnson syndrome 2

Toxic epidermal necrolysis (TEN) Phenytoin
39 40

Toxic epidermal necrolysis (TEN)

41

Exfoliative dermatitis Cotrimoxazole

42 43

44,45,46 47 Exfoliative dermatitis Hyderchlorothiazide
Eczematous drug eruption
48,49 50
Piroxicam
51
52

Eczematous drug eruption contact dermatitis

Sulfanilamide
Eczematous drug eruption contact dermatitis Diclofenac
Diclofenac Eczema

53,54,55 56 Eczematous drug eruption Chlorpropamide

Steroid acne Prednisolone 2
57 58

32

33
33
33
41
41
42
42
43
43
44

VI

()

59

Pastular drug eruption Cotrimoxazole

44

60

Anagen effluvium

44

61

Anagen effluvium

44

62

Drug-induced hyperpigmentation Clofazimine

51

63
64 65

(Melasma)

51

Hyperpigmentation

51

66

Hyperpigmentation

51

Cyclophosphamide
67 68

Phototoxic drug eruption Amiodarone

52

4
69

pigment

52

Phototoxic dermatitis

70,71 72 Phototoxic drug eruption Diclofenac

52

Eczema
73

Phototoxic drug eruption Diclofenac gel

52

74

Erythema nodosum

55

75 76

Allergic vasculitis Hydrochlorothiazide Palpable

55

purpura
77 78

Progressive pigmentary dermatosis 2

55

79

Bullous drug eruption Furosemide

6

56

()

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 )

60

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

( Skin disorders )

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 )

87.7% 7
11.7%

1. Penicillin
2. Sulfa ( Cotrimoxazole)
3. Antituberculous drug
4. NSAID ( Piroxicam )
5. Phenytoin
1 2

1

()

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

1993
1994
1996
1995
3,360
3,901
4,352
2,303
6,589
7,838
10,075
4,078
3,376
3,714
2,903
2,220
1,108
1,146
711
687
961
951
720
619
378
536
367
184
261
244
249
282
218
292
261
117
120
150
169
81
73
96
88
63
37
33
61
49
35
35
56
26
31
24
25
8
24
29
25
13
19
18
13
18
17
28
4
16
6
11
11
14
17
12
19
10
9
11
1
53
111
96
56

..
(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%)

1
rash, rash erythematous

( Skin disorders )

maculo-papular rash, eczema, erythema mulitforme
2

()

1. System antiinfectives
- Antiviotics
- Chemotherapeutics
- Antituberculous
(excl.streptomycin)
2. Musculo-sketetal system drugs
3. Central nervous system drugs
4. Antiparasitic drugs

1993
1994
1995
1996
2,303
3,360
3,901
4,352

..
(1993-1996)
143

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

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

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

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

97 (67.8%)
(86.6%)
(13.4%)

11.32%
10.86%
1.60%

8.7%
9.46%
11.31%

9.85%
2.68%
15.65%

5.62%
4.54%
55.55%

28 (19.58%)
11 (7.7%)

2
antiinfective

( Skin disorders )

(Pathogenesis)
2
I. Non-allergic adverse drug reaction
II. 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, receptor

site, -


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

( Skin disorders )

(polymorphic) drug metabolism

drug metabolite
drug metabolism INH
INH
Acetylation
Acetyl isoniazid
Hydrolysis
Acetyl hydrazine
Cytochrome P450
Reactive metabolite
Hepatic molecules
Hepatic necrosis
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 Coumarin
necrosis heterozygote deficiency protein C Coumarin
protein C thrombosis
G-6-PD deficiency
enzyme G-6-PD oxidation

( Skin disorders )

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 Coombs
classification
1. Immediate type hypersensitivity reaction
2. Cytotoxic type hypersensitivity reaction
3. Immune complex type hypersensitivity reaction
4. Delayed type hypersensitivity reaction

( Skin disorders )

1. Immediate type hypersensitivity reaction

Immediate 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 reaction

Cytotoxic 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 )

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, erythema
nodosum, lichenoid eruption
antigen(hapten) () Langerhans
cell 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

Antibiotics

5%

Amoxicillin
Ampicillin
Miconazole
Novobiocin
Streptomycin
Talampicillin

1-5%
Amikacin
Apalcillin
Azlocillin
Bacampicllin
Carbenicillin
Cephalosporin
Chloramphenicol
Cyclacillin
Dihydrostreptomycin
Epicillin
Erythromycin
Flucloxacillin
Gentamicin
Mezlocillin

11

( Skin disorders )

3 Maculo-papular rash ()

5%

Antibiotics

Sulfonamides and
Derivatives

Sulfamethoxazole
(with Trimethoprim)

Other Antiinfective Agents

Nalidixic acid
Thiabendazole
Vidarabine

Analgesics
Antipyretics
Antirheumatics

Aclofenac
Gold
Metiazinic acid
Naproxen
d-Penicillamine
Piroxicam

Neurologic and
Psychiatric Drugs

Carbamazepine
Chlorpromazine
Mephenytoin
Metisuximide
Phenytoin

1-5%
Oxacillin
Penicillin G
Penicillin V
Phenethicillin
Piperacillin
Pivampicillin
Polymyxin B
Propicillin
Rifampicin
Tetracycline
Ticarcillin
Vancomycin
Sulfapyridine
Sulfadimethoxin
Sulfadoxine
Sulfamethoxazole
Sulfamethoxypyridazine
Sulfisoxazole
Acyclovir
p-Aminosalicylic acid
Capreomycin
Chloroquine
Dapsone
Nitrofurantoin
Quinacrine
Quinine
Thioacetazone
Trimethoprim
Acetylsalicylic acid
Azapropazone
Bucloxic acid
Diclofenac
Indomethacin
Meclofenamate
Mefenamic acid
Metamizole
Nifulmic acid
Phenylbutazone
Sulindac
Ethiosuximide
Imipramine
Isocarboxazid
Maprotiline
Opipramol
Phenobarbital
Primidone

12

( Skin disorders )

3 Maculo-papular rash ()

5%

Neurologic and
Psychiatric Drugs

Antidiabetics

Carbutamide

Cytostatic Agents

Bleomycin
Dauxorubicin
Mitotane

Diagnostic Aids

Thyroid Drugs

Metamizole sodium (Dipyrone)

Methimazole

Cardiac Drugs

Captopril

Uricosaric Agents

1-5%
Pyritinol
Serine
Isopropylhydrazine
Sulthiame
Trimethadione
Chlorpropamide
Glyburide
Glymidine
Tolbutamide
Asparaginase
Cytarabine
Melphalan
Dintrizoate sodium
Iodipamide
Iothalanic acid
Methylthiouracil
Thiouracil
Disopyramide
Prazosin
Procanamide
Tribenoside
Allopurinol
Probenecid

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

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

13

( Skin disorders )

(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 complexes
Dimercaprol
Edetate calcium disodium
Streptokinase
Vaccine ( DPT)

14

( Skin disorders )

4
(Antiinfectious Drugs)
p-Aminosalicylic acid
Cephalosporins
Chloramphenicol
Erythromycin
Isoniazid
Netrofurantoin
Penicillin

Pyrazinamide
Rifampicin
Spectinomycin
Streptomycin
Sulfonamides
Teracycline

Allopurinol
Barbiturates
Hydralazine
Iodine
Methyldopa
D-Penicillamine
Phenobarbital

Procainamide
Propylthiouracil
Quinidine
Qounine
Salicylates

( : 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-skeletal
drug , CNS drug

15

( Skin disorders )

2. Paracetamol Aspirin, Antihistamine

3. Corticosteroid
Systemic steroid Prednisolone
30-60 mg/ 3-5
2
Topical steroid mild potency

5 Reaction rate 500

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 )

51.0
47.0
42.0
29.0
28.0
16.0
13.0
12.0
10.0
8.1
9.5
8.0
7.7
6.6
4.0
4.0
4.0
4.0
3.4
3.0
2.9
2.8
2.6
1.3
1.1
0.9
0.5
0.2

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

16

( Skin disorders )

17

( Skin disorders )

Maculo-papular rash (Maculo-papular eruption)

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

5 : Maculo-papular rash

( purpula)

6 : Maculo-papular rash

(papular eruption)

18

( Skin disorders )

Maculo-papular rash (Maculo-papular eruption)

7 : Maculo-papular rash
(rubelliform rash)

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

19

( Skin disorders )

URTICARIA

Wheal

(wheal)
erythema
wheal
24
(Urticaria)


angioedema
2-5 angioedema

6 Urticaria

Antibiotics

5%
Novobiocin
(no longer available)

1-5%
Amoxicillin
Ampicillin
Apalcillin
Azlocillin
Bacampicillin
Carbenicillin
Cephalosporin,
(including the third generation)
Cyclacillin
Dicloxacillin
Epicillin
Floxacillin
Griseofulvin
Mezlocillin
Oxacillin
Penicillin G
Penicillin V
Phenathicillin

20

( Skin disorders )

6 Urticaria

5%

Antibiotics

Sulfonamides

Other Antiinfective Agents

-

Analgesics
Antipyretics
Antirheumatics

Neurologic and
Psychiatric Drugs
Cardiovascular Drugs

Antidiabetic Drugs

Thyriod Drugs

Immunotherapeutics
Vaccines
Blood and Blood Products
Placebo

Antilymphocytic serum
Levamisole
Horse serum
-

Diagnostic Agents

()

1-5%
Piperacillin
Pivampicillin
Polymyxin B
Propicillin
Ticarcillin
Vancomycin
Sulfamethoxypyridazine
Acyclovir
Ethionamide
Isoniazid
Piperazine
Quinacrine
Thalidomide
Thiabendazole
Azapropazone
Tolmetin
Baclofen
Carbamazepine
Ethiosuximide
Amiodarone
Procainamide
Carbuamide
Glymidine sodium
Methimazole
Thiouracil
Aluminum precipitatecd pollen
Extracts
Egg albumin in vaccines (Flu vaccine)
Whole blood
Placebo
Diatrizoate sodium
Iocetamic acid
Ioglycamic acid

(Urticaria)

21

( Skin disorders )

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- receptor
antagonist Cimetidine,Ranitidine
Adrenaline injection shock

22

( Skin disorders )

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

( Skin disorders )

23

( Urticaria )

12 : (urticaria)
(erythema) (wheal)

13 : (urticaria)
(erythema) (wheal)

15 : (urticaria) (angioederma)

14 : (urticaria) (erythema) (wheal)

17 : erythema annulare centrifugum

16 : (urticaria) (angioedema)

24

( Skin disorders )

Fixed drug eruption

18 : Fixed drug eruption

19 : Fixed drug eruption

20

21

22

20,21 22 : Fixed drug eruption

25

( Skin disorders )

FIXED DRUG ERUPTION

1-2
10
fixed drug eruption
30 24
fixed drug eruption


fixed drug eruption

Cotrimoxazole

Fixed drug eruption Type III IV hypersensitivity

reaction
7 Fixed drug eruption

Antibiotics

Sulfonamides and Their Derivatives

Cytostatic Drugs
Cardiovascular Drugs

1%

Chlortertracycline
Demeclocycline
Doxycycline
Erythromycin
Griseofuvin
Minocycline
Phthalylsufathiazole
Sulfadiazine
Sulfadimethoxine
Sulfamethoxazole
Sulfamethoxypyridaxine
Hydroxyurea
Amphetamine
Digitalis preparations
Captopril
Epinephrine
Guanethidine

Oxytetracycline
Penicillin G
Penicillin V
Streptomycin
Tetracycline
Sulfamethoxydiazine
Sulfaphenazole
Sulfasuxidine
Sulfathiazole
Salfaoxazole
Hydralazine
Nicotinic acid derivatives
Pentaerythritol tetranitrate
Quinidine

26

( Skin disorders )

7 Fixed drug eruption ()

1%

Gastrointestina Drugs
Laxatives
Antidiabetic Drugs
Hormones
Thyroid Drugs
Blood, Blood Substitutes
Anticoagulants
Antihistamines

Heavy Metals
Halogens
Others
Diagnostic Aids

Bisacodyl
N-Butylscopolammonium bromide
Dihydroxyanthraquinone
Dimenhydrinate
Phenolphthalein
Tolbutamide
Cortisone
Diethylstibestrol
Estrogen/progesterone
Prednisolone
Tetracosactide
Thiouracil
Dextran solutions
Gelatin solutions
Cycilzine
Dimenhydrinate
Diphenhydramine
Tripeleanamine

Antimony
Arsenic
Bismuth
Bromine
Dimethyl sulfoxide
Foscarnet
Disulfiram
Bromsulfalein
Eosin

Chlorine
Gold
Iodine
Magnesium
Mercury

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

Topical steroid cream

Steroid cream

Prednisolone

27

( Skin disorders )

ERYTHEMA MULTIFORME ( EM )

Erythema multiforme 2
1. EM minor EM
1
2. EM major Stevens Johnson syndrome 1
Stevens Johnson syndrome

maculopapular rash
(target lesion iris lesion)
erythema multiforme multiforme
5-7


8 Erythema multiforme

1-5%

Antibiotics

Sulfonamides

1%
Ampicillin
Lincomycin
Benzathine benzylpenicillin Novobiocin
Cephalosporin
Penicillin
Chloramphenicol
Rifampicin
Chlortetracytine
Streptomycin
Clindamycin
Tetracycline
Griseofulvin
Sulfamethoxazole
Sulfadiazine
with trimethoprim
Sulfadimethoxine
Sulfamethoxydiazine
Sulfadoxine
Sulfamethoxypyridazine
Sulfamethizole
Sulfasalazine
Sulfamethoxasole
Sulfasoxazole

28

( Skin disorders )

8 Erythema multiforme ()

1-5%

Others
Antiinfective Agents

Analgesics
Antipyretics
Antirheumatics

d-Penicillamine

Antigout Drugs

Neurologic and
Psychiatric Drugs

1%
p-Aminosalicylic acid
Methenamine
Chloroquine
Nalidixic acid
Dapsone
Nitrofurantoin
Ethambutol
Quinacrine
Frnazolidine
Quinine
Iodochlorhydroxyquin
Thiabendazol
Isoniazid
Thioacetazone
Acetylsalicylic acid
Ibuprofen
Aminophenazone
Isoxicam
Antipyrine
Meclofenamate
Benoxaprofen
Naproxen
Codeine
Phenacetine
Diflunisal
Phenylbutazone
Fenbufen
Piroxicam
Gold
Sulindac
Allopurinol
Cinchophen
Carbamazepine
Carisoprodol
Chloral hydrate
Chlordiazepoxide

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

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

29

( Skin disorders )

(wet dressing) Burows solution

normal saline
2. Systemic treatment

Prednisolone 30-60 mg/ 2-4

1)
stress-ulcer H2-antigonist
Cimetidine 400 mg 2 200
mg 6
2)



Stevens Johnson syndrome

30

( Skin disorders )

31

( Skin disorders )

Erythema multiforme

23

24

25

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

27 : Erythema multiforme (EM)

32

( Skin disorders )

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

Stevens Johnson syndrome

35
34

34,35 36 : Stevens Johnson syndrome

Carbamazepine

36

37

38

37 38 : Stevens Johnson syndrome 2

34

( Skin disorders )

Toxic epidermal necrolysis (TEN)

39

40
39 40 : Toxic epidermal necrolysis (TEN) Phenytoin

41 : Toxic epidermal necrolysis (TEN)

35

( Skin disorders )

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

Other Antiinfective Agents

Analgesics
Antipyretics
Antirheumatics

1%
Ampicillin
Penicillin V
Chloramphenicol
Procaine penicillin
Erythromycin
Tetracycline
Neomycin
Streptomycin
Penicillin G
Sulfadizine
Sulfamathoxypyridazine
Sulfadimethoxine
Sulfamathoxydiazine
Sulfadoxine
Sulfasalazine
Sulfamethoxazole
Sulfathiazole
with trimethoprim
Sulfisoxazole
Benznidazole
Pyrimethamine
Chloroquine
with sulfadoxine
Dapsone
Quinine
Isoniazid
Tetrachloroethylene
Nitrofurantoin
Thiabendazole
Thioacetazone
Acetylsalicylic acid
Oxyphenbutazone
Aminophenazone
Pentazocine
Antipyrine
d-Penicillamine
Benoxaprofen (no longer
Pethidine
Available)
Phenacetine
Codeine
Phynylbutazone
Fenbufen
Piroxicam
Gold
Propyphenazone
Ibuprofen
Salicylamide
Indomethazine
Sulindac
Isoxicam
Tolmetin
Metamizole
Zomepirac

36

( Skin disorders )

9 TEN (Lyells syndrome) ()

Antigout Drugs
Neurologic and Psychiatric Drugs

CarDiobascular Drugs
Cytostatic Drugs
Diuretics
Gastrointestinal Drugs
Antidiabetic Drugs
Immunotherapeutic Drugs
Vaccines
Local Anesthetics

1%
Allopurinol
Amobarbital
Mephenytoin
Barbital
Mephobarbital
Carbamazepine
Meprobamate
Chlormezanone
Phenytoin
Chlorpromazine
Primidone
Diphenhydramine
Promethazine
Levomepromazine
Pyritinol
Beta-blockers
Enalapril
Captopril
Actinomycin C
Methotrexate
Chlorambucil
Mithramycin
Cyclophosphamide
Procarbazine
Merceptopurine
Acetazolamiide
Cimetidine
Phenolphyhalein
Carbutaimide
Tolbutamide
Antithymocyte
Small pox vaccine
BCG vaccine
Tetanus antitoxin
Measles vaccine
Benzocaine
Iodine
Bromide
Phenolpthalein

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

10 TEN (Lyells syndrome)

Vaccination
BCG
Diptheria toxoid
Measles
Poliomyelitis
Smallpox
Tetanus antitoxin
Contaxt with a toxic fumigant
Acrylonitrile
Neoplastic diseases
Hodgkins lymphoma
Non-Hodgkins lymphoma
Leukemia
Graft vs host reaction
Idiopathic

Viral Infections
Measles
Varicella
Herpes zoster
Herpes simplex

Fungus Infections
Aspergillosis
Bacteria Infections
Escherichia coli

Radiation

37

( Skin disorders )

3

1. Morbiliform eruption Marculo-papular rash
2. 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
11 TEN SSSS
TEN

SSSS

Target

Nikolskys sign

granular zone

Exfoliative cytology

neutrophils

(Acan-tholytic cell)

Degree of exudation

4+

1+

Healing/recovery

10-14

(20-50%)

TEN
ICU/Burn unit

1. Fluid management
2. Nutrition
3. Antibiotic
4. Environmental temperature
5. Supportive care GI bleed, respiratory failure
6. Local skin care, eye care
7. Alternative treatment hemodialysis,plasmaploresis,cyclosporine

TEN

39

( Skin disorders )

neutrolhil


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

EXFOLIATIVE DERMATITIS (ERYTHRODERMA)

TEN TEN
exfoliative dermatitis

exfoliative dermatitis



2 gynecomastia

exfoliative dermatitis maculopapular 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%

40

( Skin disorders )

12 Exfoliative dermatitis or Erythroderma

Acetylsalicylic acid
Allopurino
p-Aminosalicylic acid
Aztreonam
BAL
Barbiturates
Captopril
Carbamazepine
Cefoxitin
Chloroquine
Chlorpromazine Cimetidine
Codeine
Dapsone
Edetate

Ethambutol
Furosemide
Gold salts
Isoniazid
Iodide
Ketoconazole
Lincomycin
Lithium
Meclofenamate
Mephenytoin
Mercury compounds
Nitrofurantoin
Organic arsenicals(obsolete)
Paramethadione

d-Penicillamine
Penicillin
Phenindione
Phenylbutazone
Phenytoin
Primidone
Quinacrine
Quinidine
Streptomycin
Sulfamethoxazole ( with trimethoprim )
Sulfonamides
Sulfonylureas
Sulindac
Thioacetazone
Trimethadione

Prednilsolone 30-60 mg/

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

41

( Skin disorders )

Exfoliative dermatitis

42 43
42 43 Exfoliative dermatitis Cotrimoxazole

44 45

46 47
44,45,46 47 Exfoliative dermatitis Hydrochlorothiazide

42

( Skin disorders )

Eczematous drug eruption

48

49

50

48,49 50 Eczematous drug epuption

Piroxicam

51 Eczematous drug eruption contact dermatitis Sulfanilamide

43

( Skin disorders )

Eczematous drug eruption

52 : Eczematous drug epuption contact dermatitis Diclofenac

Diclofenac Eczema

53

54

55

56

53,54,55 56 : Eczematous drug eruption Chlorpropamide

44

( Skin disorders )

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 ERUPTION

Eczema

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
13 Eczema

Aminophylline
Arsphenamine
Chloral hydrates
Chlorpromazine
Chlorpropamide
Chlorothiazide
Disulfiram

Formaldehyde
Gentamicin
Hexylresorcinol
Iodides
Kanamycin
Kercurial diuretics
Meprobamate

Neomycin
Novobiocin
Penicillin
Procaine
(andotherlocal anesthetics)
Promethazine
Quinacrine (atabrine)

Resorcin
Streptomycin
Sulfonamides
Thiamaine
Tolbutamide

46

( Skin disorders )

Eczematous drug eruption allergic contact dermatitis type

IV hypersensitivity reaction (delayed type)

eczema
Steroid Drug of choice topical systemic form
: Antihistamine

ACNEIFORM DRUG ERUPTION

Corticosteroid
Anabolic hormone Androgen, Gonadotropin
INH
Phenytoin
14 Acne and Pustules

ACTH
Actinomycin D
Amoxycillin
Androgens (in women)
Azathioprine
Bromides
Chloral hydrate
Clofazimine
Corticosteroids
Danazol

Dantrolene
Desulfiram
Estrogens/progesterones
(oral contraceptives)
Ethionamide
Halothane,Haloperidol
Isoniazid
Iodides Lithium
Methandienone

Phenobarbetal
Phenytoin
Propranolol
Prothionamide
Pyrazinamide
Quinidine
Quinine
Rifampicin
Tetracyclines

Thioureas
Troxidone
Trazodone
Trimethadione
Vitamin B2
Vitamin B6
Vitamin B12

Prednisolone
INH

Steroid acne
(monomorphic)

( Skin disorders )

47

DRUG-INDUCED ALOPECIA
100,000 3

1 : Anagen hair
85-90% anagen hair 2-3 catagen
hair
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
Arsenic
Asmuth

Borate
Colchicine
Cyclophosphamide

Hydroxyurea
Lead
Methotrexate

Mercury
Thalium

Telogen effuvium telogen hair

anagen hair telogen hair
2-4 anagen
effluvium telogen hair anagen hair telogen
effluvium
Allopurinol
Cocaine
Oral contraceptive
Warfarin
Clofibrate
Heparin
Propyl thiouracil

48

( Skin disorders )

DRUG-INDUCED HYPERPIGMENTATION


( Brown ) (melanocyte)
(melanin) (phototoxic)
(Slate gray) (Dermis)

(Tyndall phenomenon)

volumn of distribution tissue

15

Aminodarone
Phenothiazine

Pigmentation change
Slate - gray
Slate - gray

Sun-exposed
Sun-exposed

Minocycline
Clofazimine
Anti-malarial

Brown, muddy
Blue-block
Red
Slate-gray, yellow

Sun-exposed
Acne scar, -
Sun-exposed

Phenytoin, pill, ACTH

Arsenic
Chemotherapeutic agent

Brown
Brown
Brown

Diffuse macular

PHOTOSENSITIVE DRUG ERUPTION

2
1. Phototoxic drug eruption

( Skin disorders )

49

16 Phototoxic reactions

Alimenazine
Amiodarone
Benzydamine
Capreomycin
Captopril
Carprofen
Chlorpromazine
Chlortetracycline
Clofazimine

Dacarbazine
Dapsone
Deneclocycline
Doxycycline
5-Fluorouracil
Furosemide
Hematoporphyrin
Levomepromazine

Mepazine
Methacycline
Methoxsalen
Nalidixic acid
Naproxen
Nortriptyline
Oxytetracycline
Perazine
Phenprocoumon

Piroxicam
Procarbazine
Prochlorperazine
Promazine
Protriptyline
Pyritinol
Resorcin derivatives

Sulfanilamide
Sulfisoxazole
Sulindac
Thiopropazate
Thioridazine
Tiaprofenic acid
Triflupromazine
Vinblastin
Warfarin

2. Photoallergic drug eruption allergic drug eruption

eczematous drug eruption (antigen)
carrier protein photoantigen

eczema
Fenofibrate 1

eczema
photoantigen
17 Photoallergic reactions

Acetohexamide
Amantadine
p-Aminobensoic acid
Amitriptyline
Azathioprine
Barbiturates
Sulfamethoxypyridazine
Benzydamine
Buclosamide
Capremycin
Carbamazepine
Carbinoxamine
Carbutamide
Carprofen
Chlordiazepoxide
Chloroquine

Chlorothiazide
Chlorphenoxamin
Chlorpromazine
Chlorpropamide
Chlortalione
Cyamemzine
Cyproheptadine
Dibucaine
Diltiazem
Diphenhydramine
Estrogens (oral contraceptives)
Ethionamide
Lincomycin
Gilbenclamide
Glyburide

Gold
Griseofulvin
Hydrochlorothiazide
Imipramine
Indometacin
Nalidixic acid
Nitrofurantion
Phenylbutazone
Piroxicam
Procaine
Promazine
Promethazine
Pyrazinamide
Pyritinol

Quinethazone
Quinidine
Quinine
Saccharine
Sulfadimethoxine
Sulfanilamide
Sulfathiazole
Sulfisoxasole
Thiridazine
Tolazamide
Tolbutamide
Trazodone
Triacetydiphenolisatin
Triflupromazine

50

( Skin disorders )

51

( Skin disorders )

Drug-induced hyperpigmentation

60 : Drug-induced hyperpigmentation Clofazimine

53

54

64 65 : Hyperpigmentation

66 : Hyperpigmentation Cyclophosphamide

52

( Skin disorders )

Photosensitive drug eruption

67
68
57 58 : Phototoxic drug eruption Aminodarone 4
pigment

70
69 : Phototoxic dermatitis

71
72
71 72 : Phototoxic drug eruption Diclofenac Eczema

73 : Phototoxic drug eruption Diclofenac gel

53

( Skin disorders )

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

18 Erythema nodosum

Antibiotics
Sulfonamides
Other Antiinfective agents
Analgesics
Antipyretics
Antirheumatics
Neurologic and
Psychiatric Drugs
Cytostatic Drug
Cardiovascular Drug
Antidiabetic Drugs
Hormones
Thyroid Drugs
Immunotherapeutics
Vaccines
Heavy Metals
Halogens

1%
Penicillin G
Tetracycline
Penicillin V
13-cis-Retinoic acid
Streptomycin
Sulfamethoxazole
Sulfanilamide
Sulfamethoxypryidazine Sulfathiazole
Dapsone
Nitrofurantoin
Iodochlorhydroxyquin
Acetaminophen
Gold
Acetylsalicylic acid
Indometacin
Codeine
d-Penicillamine
Diclofenac
Phenacetine
Carbamazepine
Meprobamate
Chlordiazepoxide
Phenobarbital
Busulfan
Amiodarone
Carbutamide
Tolbutamide
Chlorpropamide
Estrogens
Estrogens/progesterones (oral contraceptives)
Thiouracil derivatives
BCG vaccine
Small pox vaccine
Diphtheria vaccine
Poliomyelitis vaccine(Salk)
Arsenic
Iodine
Bromine

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

54

( Skin disorders )

NSAID
, prednisolone, potassium iodidesolution
VASCULITIS

1. Allergic vasculitis Leukocytosclatic vasculitis post capilary
venules immune complex antibody type III hypersensitivity reaction
palpable purpura

palpable purpura
2
1 9 Vasculitis
Allopurinol
Cimetidine
Dilantin
Gold
Hydralazine

Ketoconazole
Levamisole
Nonsteroidal anti-inflammatory agents
Penicillin
Propylthiouracil

Quinidine
Sulfonamides
Tetracycline
Thiazides

Allergic vasculitis
autoimmune disease SLE, rheumatoid arthritis
2. Lymphocytic vasculitis Progressive pigmentary dermatosis
immune complex
hemoglobin
tissue

delay-type hypersensitivity reaction

55

( Skin disorders )

Erythema nodosum

74
74 : Erythema nodosum

Vasculitis

75
76
75 76 : Allergic vasculitis Hydrochlorothiazide Palpable purpura

77
78
77 78 : Progressive pigmentary dermatosis 2

( Skin disorders )

56

Bullous drug eruption

79 : Bullous drug eruption

Furosemide
6

80 : Bullous drug eruption

Meladinine Phototoxic
reaction

81 : Bullous pimphigoid-like eruption

NSAID

82 : Lichenoid drug eruption diuretic

Lichen planus

83

84
83 84 : Folliculitis Isotretinoin 2

57

( Skin disorders )

BULLOUS ERUPTION

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

1-5%

Antibiotics

Sulfonamides

Other Antiinfectious
Agents

Thalidomide

Analgesics
Antipyretics
Antirhematics

d-Penicillamine

Antigout Drugs
Neurologic and
Psychiatric Drugs

Cytostatic Drugs
Cardiovascular
Drug
Diuretics

Bleomycin

1%
Ampicillin
Benzathinepenicillin
Chloramphenicol
Chlortetracycline
Demeclocycline
Griseofulvin
Sulfadoxin
Sulfamethoxazole
Sulfamethoxazole with
trimethoprim
Sulfamethoxydiazin
p-Aminosalicylic acid
Chloroqiune phosphate
Dapsone
Isoniazid
Nalidixic acid
Acetylsalicylic acid
Aminophenazone
Antipyrin
Azapropazone
Codeine (very rarely)
Gold
Ibuprofen
Cinchophen
Amitriptyline
Carbamazepine
Chloral hydrate
Chlorpromazine
Ethotoin
Mephenytoin
5-Fluorouracil
Digitalis preparations
Minoxidil
Acetazolamide
Chlorothiazide
Furosemide

Neomycin
Penicillin G
Penicillin V
Rifampin
Streptomycin
Tetracycline
Sulfamethoxypyridazin
Sulfanilamide
Sulfasalazine
Sulfathiazole
Sulfisoxazole
Nitrofurantoin
Piperazine derivatives
Quincrine
Quinine
Indometacine
Metamizol
Morphine
Phenacetine
Phenylbutazone
Piroxicam
Salicylamide
Colchicine
Meprobamate
Phenobarbital
Phenytoin
Promethazine
Trimethadione
Vinblastin
Practolol
Quinidine
Hydrochlorothiazide
Quinethazone

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

58

( Skin disorders )

20 Bullous eruption (9)

Laxative

1-5%
-

Antidiabetic Drugs

Hormone
Immunotherapeutic Agents
Vaccines

Vitamins
Heavy Metals
Halogens
Antidotes
Local Anesthetics
Phototherapeutic Agent

()

1%
Phenolphthalein
Carbutamide
Insulin
Chlorpropamide
Tulbutamide
Progesterone
BCG vaccine
Trichophytin
Small pox vaccine
Arsenic
Iodine
Bismuth
Mercuty
Bromine
Vitamin B 12
Dimercaprol
Lidocaine
Mepivacaine
Methoxsalen (with UVA therapy)

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

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.

59

( Skin disorders )

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

60

( Skin disorders )

4. Lag period 1-2

87.7% 7
5. Dechallenge


reaction
rate reaction rate

6. Rechallenge

, maculo-papular rash
erythema multiforme, toxic epidermal
necrolysis, 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

61

( Skin disorders )

2. PATCH TEST

eczematous drug eruption
allergic contact dermatitis
photosensitive 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 immune
response

62

( Skin disorders )

1. . . 1996;3: 15-24
2. . Dermatology 2000. : 2540.
3. Spontaneous report of advance drug reaction 1993
, 1994
4. Spontaneous report of advance drug reaction 1994
, 1995
5. Spontaneous report of advance drug reaction 1995
, 1996
6. Spontaneous report of advance drug reaction 1996
, 1997
7.
,

1. Bigby M,Jicks, Jick H, Arndt K. Drug - induced cutaneous reactions. JAMA 1986; 256 (24) : 33583363. 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. 1998
5. 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.