Cutaneous Drug Reactions [Autosaved].ppt 2.pdf

Drug recacuons

1. CUTANEOUS
DRUG REACTIONS
PROF. MIRIAM EMILY P. SORIANO, MD, FPDS
Chairperson of Dermatology, Davao Medical School Foundation
Chief, Section of Dermatology, Davao Doctors Hospital
Medical Director, MediSkinClinics
MUST READ: HARRISON’S PRINCIPLES OF INTERNAL MEDICINE ,
20th Ed Chapter 56 pp 362-371

2. Classification of ADR
(Adverse Drug Reactions)
Type A Pharmacological side effects
(Predictable Drug Interactions
in 80% of cases) Others
Type B Non-immunologic
(Unpredictable) Immunologic
Type I –IgEmediated drug rxn
Type II –IgG mediated cytotoxicity
Type III –Immune complex deposition
Type IV –Cell-mediated drug rxn

3. Predisposing Factors of ADR
1.INDIVIDUAL METABOLIC VARIATION
Poymorphismsin cytochrome P450 enzymes
increased toxicityfor drugs metabolized by cytochrome
P450 in the liver
Defective epoxide hydrolase
increased drug toxicity to Phenytoin and Su;fonamide
Rate of aceytylationby N-acetyltransferase
increased drug toxicity to Procainamide and hydralazine

4. 2. IMMUNOGENETIC ABILITY
Atopic individuals
Women
SLE
HIV positive
HLA types (Ex.HLA-B5801 and allopurinol)
3. AGE –infancy and elderly
4. VIRAL INFECTION-reactivation of HHV-6
5. MALIGNANCY-higher mortality rate with
severe drug reactions
Predisposing Factors of ADR

5. Collagen vascular diseases
Bone marrow graft recipients
Acute Epstein-barrvirus infection
HIV infection (Ex. Up to 40% of HIV patients
react to sulfamethoxazole compared to 3-5% of
non-HIV-infected populations.
*How HIV promotes sensitivity to certain drugs or
their metabolites remains unclear.
Increased Risk of ADR in Immunosuppresion

6. Prevalence of Adverse Drug Reactions (ADR’s)
in hospitals:
–Boston Collaborative drug surveillance
program-2.2%
–Harvard Medical practice study-14%
ADR that mainly involves the skin is called a
Cutaneous Drug Reaction (CDR)
Prevalence of ADR

7. 3% of hospitalized patients
3-7% for amoxicillin, sulfamethoxazole, many
anticonvulsants, and anti-HIV agents
Most occur a few days to 4 weeks after
initiation of drug therapy.
Cutaneous Drug Reactions
INCIDENCE

8. MOST ARE BENIGN
Ex. Maculopapular rashes accompanied by
pruritus, which resolve promptly after the
offending drug is discontinued.
FEW CAN BE LIFE-THREATENING
Ex, Stevens-Johnson Syndrome (SJS) and
Toxic Epidermal Necrolysis (TEN)
Prompt recognition, drug withdrawal, and
appropriate therapeutic interventions can minimize
toxicity.
Cutaneous Drug Reactions
PROGNOSIS

9. SCOPE OF THIS LECTURE
Pathogenesis of cutaneous drug reactions
NON-IMMUNOLOGIC
IMMUNOLOGIC
Different morphologies of drug reactions
Differential diagnoses for each morphologic
type
Management

10. PATHOGENESIS
NON-IMMUNOLOGIC
IMMUNOLOGIC

11. NON-IMMUNOLOGIC
Cutaneous Drug Reactions

12. PATHOGENESIS
Non-Immunologic Cutaneous Drug
Reactions
1. Photosensitivity
2. Warfarin Necrosis
3. Pigmentation Changes
4. Exacerbation or Induction of
Dermatologic Diseases

13. 1.Drug-induced Photosensitivity
Resmblessunburn
Most marked in sun-exposed areas
but may extend to sunprotectedareas
Mechanism: phototoxicity.
Occurs within 1
st
exposure to drug
Common Photosensitizing drugs:
fluoroquinolones, tetracycline antibiotics,
and trimethoprim/sulfamethoxazole.
Less common: chlorpromazine, thiazides,
NSAID, and BRAF inhibitors,voriconazole
Treatment: D/C offending drug
Avoid Sun Exposure
Use sunscreen.

14. 2. Warfarin Necrosis of Skin
Rarereaction (0.01–0.1%)
Lesions are sharply
demarcated, erythematous, or
purpuric, and may progress to
form large, hemorrhagic bullae
with necrosis and eschar
formation
occurs between 3
rd
-10
th
day
of warfarin
usually in women
(breasts, thighs,
buttocks);
can be life-threatening

15. Development is unrelated to drug dose
Course is not altered by drug discontinuation
Associated with Protein C deficiency
Warfarin may cause a fall in circulating
levels of Protein Chypercoagulability and
thrombosis in cutaneous microvasculature,
leading to necrosis.
Treatment: VitK,
Heparin,
Intensive wound care
Protein C concentrates
Warfarin Necrosis

16. 3. Pigmentation Changes
Mechanisms:
Drugs triggering melanin production
Deposition of drug or drug metabolites
Drug Pigmentation Changes
Minocycline and amiodarone blue-gray pigmentation
Phenothiazine, gold, and
bismuth
gray-brown pigmentation
Clofazimine red-brown coloration
Quinacrine yellow discoloration
Tetracycline Teeth disoloration
Pigmentation may occur in mucous
membranes, teeth, hair, or nails

17. The blue color
(ceruloderma) is due to
the deposition of a brown
pigment in the dermis,
contained in
macrophages and
endothelial cells.
Amiodarone: bluish grey pigmentation

18. 4. Exacerbation or Induction of
Dermatologic Diseases
Plaque
psoriasis
Pustular Psoriasis
Follicular papularor pustular eruptions
Acne
NSAIDs, lithium, beta
blockers, tumor
necrosis factor (TNF)
antagonists, interferon
(IFN) α, and
(ACE)inhibitors
Withdrawal of
Antimalarials and
systemic
glucocorticoids
glucocorticoids,
androgens,
lithium, and
antidepressants

19. Pustular Psoriasis(Von
ZumbuschDisease)
Life-threatening form of
Psoriasis
May develop in patients
with Plaque Psoriasis
when given Systemic
steroids orAntimalarials
Drug-induced Pustular Psoriasis

20. Dilantin-induced
acneiform lesions
Pustular acne
Drug-induced Acne
(Acneiform Eruption)

21. Acneiform eruptions
can be observed with the following drugs:
–Iodides -Androgens
–Bromides
–Lithium
–ActinomycinD
–Phenytoin
-Adrenocorticotropic
hormones
-Glucocorticoids
-Isoniazid

22. Drug-induced Lupus Erythematosus
(+) musculoskeletal
complaints, fever, weight loss,
pleuropulmonaryinvolvement,
renal, neurologic, vasculitis
(+) ANA homogenous pattern
(+) antihistoneantibodies
(+) dsDNA antibodies
HLA-DR4 associated
Drugs: (SHIPP)Sulfonamides,
Hydralazine, Isoniazid,
Procainamide, Phenytoin
Rasa Laurinaviciene, Linda Holm Sandholdt, Anette Bygum.
Drug-induced cutaneous lupus erythematosus: 88 new cases.
European Journal of Dermatology. 2017;27(1):28-33.
doi:10.1684/ejd.2016.2912

23. Drug-induced bullouspemphigoid
Large-tense bullae
arising from an
erythematous, urticarial
base
Scarring plaques and
nodules with bullae
Causes of bullousdrug
eruptions: penicillamine;
sulfadrugs

24. Looks like lichen planus but
involves larger areas of the trunk
No nail or mucosal involvement
Resolves within 2-4 mos.
Causes:
Beta blockers (within 1 yr.)
Penicillamine(within 2 months to
a year)
ACE inhibitors (within 3-6
months) Intensely pruritic flat-topped violaceous
papules on the volar aspect of the wrist
LICHEN PLANUS
Drug-induced Lichenoid Reaction

25. Lichenoid drug
eruption
Generalized lichen
planus

26. IMMUNOLOGIC
Cutaneous Drug Reactions

27. PATHOGENESIS
Immunologic
Hypersensitivity Reactions
(Gelland Coombs Classification)
Type I : IgE-mediated Drug Hypersensitivity
Type II: IgG-mediated Cytotoxicity
Type III: Immune Complex Deposition
Type IV: T-cell Mediated Drug Hypersensitivity
*Most ACDR’s observed are either Type I or Type IV

28. In a series of 48,005 Patients with
cutaneousdrug reactions over a
20-year period:
91% -Morbilliformrash (Type IV)
6% -Urticaria(Type 1)

29. Type of
Reaction
Pathogenesis Examplesof
Causative Drugs
Clinical Patterns
TypeI IgE-mediated
immediate type
Penicillin Urticaria
Angioedema
Type II Drug + cytotoxicantibodies
cause lysisof cells such as
platelets orWBC
Penicillin
Sulfonamides
Quinidine
Isoniazid
Petechiaedue to
thrombocytopenic
Purpura; drug-induced
pemphigus
Type IIIIgGand IgMantibodiesto
drug are formed; Immune
Complex deposition in small
blood vessels activate
complement
Immunoglobulins
Antibiotics
Vasculitis
Urticaria
Serum sickness
Type IV Cell-mediated immune
reaction;sensitized
lymphocytes react with drug,
liberating cytokines
Which trigger cutaneous
Inflammatory response.
Sulfamethoxazole
Anticonvulsants
Allopurinol
Morbilliformrash/
exanthematousrxns
Fixed DrugEruption
LichenoidEruption
SJS
TEN
IMMUNOLOGIC CUTANEOUS DRUG RXNS (Gell and Coombs Classification)

31. TYPE I: IgE-mediated
Clinical Presentation: URTICARIA & ANGIOEDEMA
Some drugs can trigger:
1.Tissue mast cells (in tissues)
2.Circulating basophils(in bloodstream)
to release pre-formed Inflammatory mediators:
histamine, leukotrienes, bradykinin,prostaglandins
platelet-activating factor, enzymes, proteoglycans,
causing IMMEDIATE hypersensitivity Reactions

32. Drugs can trigger inflammatory mediator release by:
a)Direct Mast Cell degranulation (in tissues)
“ANAPHYLACTOID” reaction
NSAIDS, Aspirin, Non-ionic Radiocontrast media
b) Indirectly thru IgE, causing mediator release
by circulating basophils (in bloodstream)
ANAPHYLAXIS
Penicillin,Musclerelaxants in general anesthesia

33. Anaphylactoidvs Anaphylaxis
Reaction
Anaphylactoid Reaction Anaphylaxis
Tissue mast cells Circulating basophils
Mediatorrelease by Direct mast cell
degranulation
Mediatorrelease by basophils trigerredby
IgE-specific antibodies
Occurs in first exposure Requires prior sensitization
NSAIDS, including aspirin, and radiocontrast
media
Penicillinsand muscle relaxants used in general
anesthesia
clinically similar event NOTmediated by IgE a systemic, immediate hypersensitivity reaction
caused by IgE–mediated immunologic release
of mediators from mast cells and basophils
Principles of Critical Care, 4e
Jesse B. Hall, Gregory A. Schmidt, John P. Kress
CHAPTER 128:Anaphylactic and Anaphylactoid Reactions

34. URTICARIA ANGIOEDEMA
SKINEDEMA
Wheals
TRANSIENT,rarely
last for more than 24
hours
LONGER LASTING,
may persist for more
than 24 hours
DEGREE OF EDEMA
in the Wheals
SUPERFICIAL,
Papillarydermis only
DEEP, papillary and
reticular dermis, and
subcutaneous tissue
BORDERS of the
Wheals
WELL-DEFINED ILL-DEFINED
MUCOSALEDEMA
(conjunctiva, oral
mucosa, laryngeal
mucosa,
gastrointestinal and
respiratory mucosa
NONE PRESENT(may lead to
asphyxiatiationand
DEATH)
SYMPTOMS PRURITIC NON-PRURITIC

35. Urticariaand Angioedema may be part of a life-
threatening Anaphylactic reaction
associated with flushing, nausea, vomiting,
diarrhea, abdominal pain, rhinorrhea, nasal
congestion, laryngeal edema, bronchospasm,
hypotension DEATH
If there is difficulty breathing,
Give: Epinephrine 0.3cc subcutaneous injection
Diphenhydramine Intravenous injection
Hydrocortisone Intravenous drip
Medical Emergency

36. Type I: IgE-mediated Urticaria
Drug-induced (Penicillin)
Cholinergic urticaria
Exercise-induced
Differential Diagnosis

37. Type I: IgE-mediated
Toxic erythema with
urticarial features (sulfas)
Solar urticariawith
dermographism
Differential Diagnosis

38. Type I: IgE-mediated
Angioedema
Upon resolution of
Angioedema

39. Type I: IgE-mediated
Angioedema
Hereditary angioedema
(C1INH deficiency)
Differential Diagnosis

40. Lack of C1 inhibitor allows
the kinin-forming pathway
to be markedly augmented.
Bradykinin is the mediator
of swelling
Estrogen-dependent form
of HAE: autosomal
dominant; angioedema w/o
urticaria, laryngeal edema
and abdominal pain w/o
vomiting; seen in
pregnancy & with OCP use
Hereditary Angioedema (HAE)

41. aminoglycoside
antibiotics
Wasp sting
Urticariadue to

42. Polymorphous lesions
+/-vesicles
Begins within the
abdominal striaetrunk
extremities
Spares umbilicus
3
rd
trim or immediately
post-partum
No fetalrisk
Pruritic Urticarial Papules &
Plaques of Pregnancy (PUPPP)

43. Regresses within days
of delivery
Rare recurrence with
subsequent pregnancies
or OCP use
Tx: chlorpheniramine
maleate; Topical
hydrocortisone or
desonidecream;
oatmeal soaks/bath
Pruritic Urticarial Papules &
Plaques of Pregnancy (PUPPP)

44. TYPE II: CYTOTOXIC ANTIBODY Rxn
Drug + Cytotoxic
Antibodies causes lysis
of cells such as platelets
and WBC
May present as
petechiaefrom
thrombocytopenic
purpura
Due to penicillin, sulfa
drugs,quinidine, INH

45. First described following administration of
NON-HUMAN SERUM (True“serumsickness”)
Drug-induced Serum sickness-like reaction
May occur with administration of:
1) MONOCLONAL ANTIBODIES
2)CEPHALOSPORINS (espin children)
TYPE III: Immune Complex Rxns

46. (+) immune complexes, hypocomplementenemia,
vasculitis, renal lesions
Results from tissue deposition of circulating immune
complexes with consumption of complement
S/Sx: Fever, arthritis, neuritis, edema,
Skin Manifestations:
1. COMMON : Urticarial, Papularor Purpuric rash
appearing 6 days or more after drug intake.
2. RARE: Vasculitis (Cutaneous or Systemic)
TRUE SERUM SICKNESS

47. Urticaria + fever, arthralgia,
lymphadenopathy, eosinophilia
Occurs 1 to 3 weeks after drug intake
Causes: cefaclor, cefprozil, minocycline,
infliximab, rituximab
DDx: True serum sickness:
Serum Sickness-like Drug Reaction

48. Palpable purpura on the
lower extremities
Urticaria; hemorrhagic bullae,
ulcers, nodules, Raynaud’s
disease; digital necrosis
Internal organs can have
vasculitis
Manifests in 7-21 day intake of
offending drug
DRUG-INDUCED VASCULITIS

49. after primary sensitization to a causative drug, a
second exposure causes affected T cells and
antibodies to enter the elicitation phase
Pen G, Amoxicillin, Cephalosporins,
Sulfamethoxazole, Phenobarbital, Lamotrigine.
TYPE IV: T-Cell Mediated

50. Mechanism:
Drug/hapten + peptide = drug-tissue macromolecular complex
processed by APC + MHC presented to a T-lymphocyte
APC = Antigen Presenting Cell MHC = Major histocompatibility Complex
TYPE IV: T-Cell Mediated

52. Mediated by Drug-specific T-cells
Clinical Presentations:
Type IVa: Tuberculin Skin Test, Contact Dermatitis
Type IVb: DIHS, MorbilliformRash, FDE
Type IVc: SJS, TEN, MorbilliformRash
Type IVd: AGEP
•FDE(Fixed Drug Eruption)
•DIHS(Drug-induced Hypersensitivity Reaction)
•AGEP(Acute Generalized ExanthematousPustulosis)
•SJS(Stevens-Johnson Syndrome)
•TEN (Toxic Epidermal Necrolysis)
TYPE IV: Delayed Hypersensitivity

53. Timing of disease onset from
drug Initiation:
4-14 days for MorbilliformEruptions
2-4 days for AGEP
5-28 days for SJS/TEN
14-48 days for DIHS

54. DIHS
Drug-Induced Hypersensitivity Syndrome (DIHS)
a.k.a. DRESS (Drug Reaction with Eosinophilia
and Systemic Symptoms)
Widespread erythema + fever + facial and
periorbital edema , tender and generalized
lymphadenopathy , leukocytosis, plus internal
organ involvement (hepatitis, sometimes
nephritis, encephalitis or pneumonitis)
Causes: anticonvulsants, sulfonamides, dapsone,
allopurinol, minocycline

55. DIHS due to PhenytoinDIHS due to Minocycline
Symmetric bright red
exanthematous eruption;
confluent in some sites;
(+) lymphadenopathy
Fever, pustular eruption
(+) hepatitis
Drug-Induced Hypersensitivity Syndrome

56. Most common (91%) of all CDR
Starts on: TRUNK or intertriginous areas
Moderate to Severe Pruritus with fever
Develops within 4-14daysof drug initiation
Resolves in 1-2 wks after drug discontinuation
DDx: Viral exanthems, collagen vascular
disease, bacterial infections, rickettsial
infection
Morbilliform Eruption
(Maculopapular rash)

57. Morbilliform Eruptions
CLINICAL HISTORY DRUG-INDUCED VIRALEXANTHEM
PRIOR DRUGINTAKE Yes None
PRURITUS Moderate to Severe Mildto Moderate
INITIALSITE OF RASHTrunk/BodyFolds Face
FEVER OccursWITH the rashOccursBEFOREthe
rash
ENANTHEMS None Yes
SKINLESIONS Polymorphism Mostly uniform
SYMPTOMSOF EAR,
NOSE, THROAT, URTI
Absent Present

58. Ampicillin exanthem; Measles
Differential Diagnosis

59. Cephalocaudad spread of RASH
Branny desquamation
3 C’s: Cough, Coryza, Conjunctivitis
Koplik’s spots
Measles (Rubeola)

60. Morbilliform eruption due to
Ampicillin German measles
Differential Diagnosis

61. Low grade fever,
headache,
conjunctivitis, cough,
rhinitis, striking
generalized
lymphadenopathy
3 day rash;
cephalocaudad
spread
Arthritis in adults
German Measles (Rubella)

62. Exanthematous eruption due
to ampicillin
HFMD
Differential Diagnosis

63. Hand, Foot, & Mouth Disease
Brief 12h-24h prodrome;
low grade fever, malaise,
abdominal pain, or
respiratory symptoms
Ulcerative oral lesions
Erythematous macule or
papule surmounted by a
grey vesicle
lesions on hands & feet

64. Ampicillin exanthem
Erythema infectiosum
Differential Diagnosis

65. 2 day prodromeof low
grade fever, headache,
coryza
Large joint arthritis
Slapped cheek
appearance
Cephalocaudadspread
Lacy or reticulate rash on
fading
Facial rash can reappear
triggered by sunlight,
exercise, stress,
temperature
Erythema Infectiosum

66. Exanthemsubitum
Differential Diagnosis
y
Ampicillin exanthem

67. High grade fever but child
not in distress
As fever abates, rash is
seen on the trunk, neck &
extremities then quickly
dissipates in a day
No desquamation or
hyperpigmentation
Berliner’s sign: palpebral
edema
Due to HHV6/7: can be
latent
Exanthemsubitum

68. Exanthematous eruption to
TMP-SMX in an HIV Px
Scarlet fever
Differential Diagnosis

69. Pharyngitis, fever
then after 24 –48h ,
rash
Strawberry tongue
Pastia’s line: linear
petechiae on
antecubital fossa and
axillae
Prominent
desquamation
Scarlet Fever

70. Most Common causes of
Morbilliform CDR
Ampicillin, amoxicillin, Penicillin
Sulfonamides
Non-nucleoside reverse transcriptase
inhibitors: Nevirapine
Anti-convulsants: Phenytoin

71. FIXED DRUG ERUPTION (FDE)
Erythematous, dusky red
macule(s) that may evolve
into an edematous plaque;
may be bullous
Burning, stinging, +/-Fever
If rechallenged, same site
is affected
Favoursthe glans penis
Phenolphthalein laxative-
induced FDE

72. FoscarnetFDE in
an HIV px
Steroid FDE

73. Common causes of
Fixed Drug Eruption:
•Ibuprofen
•Sulfonamides
•Naproxen
•Tetracyclines
•Doxycycline
Tetracycline FDE

74. Large-tense bullae
arising from an
erythematous, urticarial
base
Scarring plaques and
nodules with bullae
Causes of bullous fixed
drug eruptions:
penicillamine; sulfa drugs
Bullous FDE to Trimethoprim-
Sulfamethoxazole
Bullous Fixed Drug Eruption

75. SEVERE Type IV IMMUNOLOGIC
Cutaneous Drug Reactions
AGEP : Acute Generalised
ExanthematousPustulosis
Erythema MultiformeMajor
SJS: Stevens Johnson Syndrome
TEN: Toxic Epidermal Necrolysis

76. Severe Pustular eruption of face and body
(+)Fever and elevated neutrophil counts
Rare: 1-5 cases per 1 million population
Causes: beta-lactamantibiotics, ,macrolide
antibiotics, calcium-channel blockers, terbinafine
DDx: pustularpsoriasis, hypersensitivity reaction
with pustulation, subcornealpustular
dermatosis, pustularpsoriasis of pregnancy,
TEN (Toxic Epidermal Necrolysis)
AGEP: AcuteGeneralized
ExanthematousPustulosis

77. Secondary to ibuprofen
AGEP: AcuteGeneralized
ExanthematousPustulosis

78. AGEP: AcuteGeneralized
ExanthematousPustulosis
Secondary to ibuprofen

79. Secondary to ibuprofen Improvement after
prednisone
AGEP: AcuteGeneralized
ExanthematousPustulosis

80. Differential Diagnoses
Acute generalized
exanthematous pustulosis
(diltiazem)
Subcorneal pustular
dermatosis

81. SubcornealPustulardermatosis
Crops of flaccid
coalescing pustules in
annular or
serpiginouspattern
Usually symmetrically
distributed in the
axillae, groins,
submammary& flexor
aspects of the limbs ,
abdomen
Tx: sulfones
(dapsone); steroids

82. ERYTHEMA MULTIFORME(EM)
This is an eruption characterized by
multiple erythematous plaques with a
targetor irismorphology.
EM minor –caused by infection
Ex. HSV, mycoplasma
EM major –drug hypersensitivity
Ex. Sulfonamides

83. Target lesions
Usually due to HSV1,
mycoplasma; VZV,
Parvovirus, hepatitis
B&C, immunizations
Target Lesions in
symmetric acral
distribution,
centripetal spread
Koebner
phenomenon
Erythema multiformeminor
Infectious causes

84. Typical palmar target
lesions
Oral ulcers (70%)EM major
Erythema multiformemajor:
Drug-induced (SJS & TEN)

85. EM Major-oral erosions
Conjunctival erosions
Erythema multiformemajor:
Drug-induced (SJS & TEN)

86. TEN & SJS
Onset 5-28th day of drug administration
(within 8 weeks from intitiation of drug therapy)
Eruption initially distributed on the face, upper
trunk and proximal extremities
TARGET LESIONS on the palms and soles
Erythematous, dusky red, purpuric macules,
irregularly shaped which later coalesce
90% mucosal involvement, usually on 2 sites
Ex. Eyes and mouth

87. TEN & SJS
Massive oral
mucosa erosions
Note shedding of
eyelashes
scarring

88. SJS
TEN
Confluent erythema
Epidermal detachment

89. Stevens-Johnson syndrome (SJS)
Toxic epidermal necrolysis (TEN)
SJS
<10% of the body surface
have “detachable “ skin
(+) Nikolsky sign
ETIOLOGY OF SJS & TEN:
High risk: allopurinol,
sulfas, carbamazepine,
lamotrigine, phenytoin
phenobarbital, nevirapine
NSAIDS, oxicam,
thiacetazone
TEN
>30 % of the body surface
have “detachable” skin
Low risk drugs: NSAIDS,
macrolides, quinolones
aminopenicillins, cyclines
cephalosporins,
No evidence of risk: Aspirin,
sulfonylureas, thiazide,
furosemide,
calcium channel blockers
.

90. Extracutaneoussigns
of SJS & TEN
Pulmonary: dyspnea,
bronchial
hypersecretion,
expectoration of
bronchial mucosal
casts
GI: epithelial necrosis
of esophagus,
diarrhea, melena,
colonic perforation
Renal: proteinuria,
microalbuminemia,
hematuriaand
azotemia

91. SCORTEN : prognostic scoring system for TEN
Criteria Points
Age >40 1
Heart rate >120 bpm 1
CA or Hemamalignancy 1
Body Surface >10% 1
Serum urea level>10nM 1
Serum bicarbonate <20nM 1
Serum glucose >14 nM 1
TotalPoints Mortality Rate (%)
0-1 3.2
2 12.2
3 35.8
4 58.3
≥ 5 90.0

92. CLINICAL FINDINGS IN POSSIBLE
LIFE-THREATENING CUTANEOUS
DRUG REACTIONS
Confluent erythema
Facial edema or Central Facial Involvement
Skin Pain
Palpable purpura
Skin Necrosis
Blisters or epidermal detachment
Mucous membrane erosions
Urticaria/ Angioedema
Swelling of the tongue

93. Associated Findings in
Life-threatening ACDRs
S/Sx
High fever
(temp>40 C)
Enlarged lymph nodes
Arthralgiaor arthritis
Shortness of breath
Wheezing
Hypotension
LAB Exams:
Hematology:
Eosinophils> 1000/uL
Lymphocytosis with
atypical lymphocytes
Serology:
Abnormal LFT
(Liver Function Tests)

94. DIAGNOSIS
Implicating the causative drug
1. previous experience
2. timing of events
3. drug levels
4. dechallenge
5. rechallenge
6. ALTERNATIVE ETIOLOGIC AGENTS

95. MANAGEMENT
Even the most minor cutaneous drug
reaction should trigger a clinical review of
systems because the severity of systemic
involvement does not necessarily mirror
that of the skin manifestations.

96. *No gold standard investigative technique for
confirmation of a drug cause.
Instead look into:
1. TIMINGof drug exposure & reaction onset
2. DECHALLENGE =course of reaction with
drug withdrawal
3. RECHALLENGE =timing & nature of a
recurrent eruption on drug reinstitution
4. history of a similar response to a cross-
reacting medication (ex. PCN & Cefalosporins)
5. history of previous reports of similar reaction
to same medication (Fixed Drug reaction)

97. Laboratory/ Tests
In-vitro investigative methods
-lymphocyte toxicity & lymphocyte
transformation assays
Skin testing for Antibiotics
-for Penicillin
Patch testing
-for Allergic Contact Dermatitis

98. TREATMENT
Prednisone1-2 mg/kg/day –for severe
cases EXCEPTfor TEN or SJS where IV Ig
Intravenous Immunoglobulinis preferred
Antihistamines
Topical steroids
MOST IMPORTANT:
Withdraw the offending drug!

99. HAIR & NAILS
(Drug-induced Disorders)

100. DRUG-INDUCED HAIR DISORDERS
ALOPECIA–excessive hair loss (scalp)
usually nonscarring/reversible diffuse hair loss
that occurs within days to weeks of starting a
new medication or changing the dose
occurrence depends both on the drug and
individualpredisposition
HIRSUTISM–excessive growth of terminal hair
(face and body) resulting from androgenic
stimulation of hormone-sensitive hair follicles

101. Drug-induced Alopecia
Drugs can affect hair at different phases of hair growth cycle
Anageneffluvium–shedding of actively growing hairs
causes: Cancer Chemotherapy drugs
-occurs within days of drug administration
Telogeneffluvium–shedding of resting, or bulb hairs
causes: anticonvulsants (carbamazepine,valproate),
antihypertensives(B-blockers), antidepressants(lithium)
antithyroiddrugs, OCP, cholesterol-lowering agents
-occurs 2-4 months after initiation of a new drug, or after
childbirth, severe illness (fever,hospitalization), or stress.

102. Drug Induced Hair Disorders
Drug Induced Hair Loss Drug Induced Hair Growth
Anagendeffluvium
Telogeneffluvium
Hair growth Cycle:
* Anagen= actively growing
hair (90% of scalp hair
*Telogen= resting hair (10%
of scalp hair)
Hirsutism-androgenic
stimulation of hormone-
sensitive hair follicles
antineoplastic agents
anticonvulsants, beta
blockers, antidepressants,
antithyroid drugs, IFNs,
oralcontraceptives, and
cholesterol-lowering agents.
anabolic steroids
oral contraceptive
testosterone
corticotropin

103. Drug-Induced Hirsutism
Excessive hairgrowthof
terminal hair
Drugs: MAD OCP
Minoxidil
Androgens
Diazoxide
Oral Contraceptives
Cyclosporine
Phenytoin

104. Drug-induced Nail Changes
Onycholysis= distal
separation of nailplate
from the nailbed
Onychomadesis=
proximal separation of
nailplatefrom nailbed
Dyschromias
Nail discoloration

105. Drug Induced Nail Disorders
Beau’s line
Onycholysis
Onychomadesis
Paronychia
anthracycline
s, taxanes,
fluorouracil,
psoralens,
and
zidovudine
carbamazepine,
lithium,
retinoids,
chemotherapeut
ic agents.
retinoids,
lamivudine,
indinavir, and
anti-EGFR
monoclonal
antibodies.

106. Drug-Induced Onycholysis
Results from damage to
the nail bed epithelium
(with epidermolysis and
loss of nail bed-plate
adhesion
Drugs: tetracyclines,
fluoroquinolones, NSAIDS,
phenothiazines, psoralens,
captopril, retinoids, sodium
valproate, anthracyclines,
taxanes(paclitaxel, docetaxel),
cytotoxic drugs.
Photo Courtesy of DermNet New Zealand
(http://www.dermnetnz.org/assets/Upload
s/hair-nails-sweat/olysis1.jpg).

107. Drug-Induced Onychomadesis
proximal separation of
nailplatefrom nailbed.
caused by temporary
arrest of nail matrix
mitotic activity
Drugs: carbamazepine,
lithium, retinoids,
chemotherapeutic drugs
( cyclophosphamide,
vincristine)

108. Drug-Induced Nail Dyschromias
Leukonychia= milky
white spots on the
nailplatesurface
Melanonychia= black
streaks on the nailbed
Drugs:
anthracyclines, taxanes,
fluorouracil, zivudine
Cancer Chemotherapy
drugs
Nail changes with Chemotherapy:
Wiley Online Library

109. LEARNING POINTS
Morbilliform eruptions are usually
viral in children and drug-induced in adults.
SevereDrug Reactions:
10–20% :anaphylaxis and vasculitis
70% and 90% of AGEP, DIHS, SJS, and TEN.
Skin biopsy helps characterize the reaction but
does not indicate drug causality.
Blood counts, Liver and kidney function tests
are important for evaluating organ involvement.

110. WHAT DRUG(S) TO SUSPECT?
New medication Medications introduced for the first time in the
relevant time frame are prime suspects
Characteristic Timing
4–14 days for morbilliform eruption
2–4 days for AGEP
5–28 days for SJS/TEN,
14–48 days for DIHS
Drug Chart key diagnostic tool for identifying the inciting drug.
–Compile info of all current and past medications/supplements
–Timing of administration relative to the rash, is a key diagnostic tool
for identifying the inciting drug.
Coordinate with clinical pharmacist to determine drug interaction

111. CROSS-SENSITIVITY
2types of cross-sensitivity
1) Drugs that target the same pathway, whether the
drugs are structurally similar or not.
Ex. Angioedema caused by NSAIDs and ACE
inhibitors.
2)Immune recognition of structurally related drugs
Ex. Hypersensitivity to aromatic antiepileptics
(barbiturates, phenytoin, carbamazepine) with up to
50% reaction to a second drug in patients who
reacted to one.

112. WHAT DRUG(S) TO
WITHRAW?
The decision to continue or discontinue any
medication depends on the ff:
–severity of the reaction
–severity of the primary disease undergoing
treatment
–degree of suspicion of causality
–feasibility of finding an alternative safer treatment
In any potentially fatal drug reaction,
elimination of all possible suspect drugs or
unnecessary medications should be
immediately attempted.

113. RECOMMENDATION FOR
FUTURE USE OF DRUGS
GOAL:
–Prevent the recurrence of the drug eruption
–Avoid compromising future treatment by
inaccurately excluding otherwise useful
medications.
A thorough assessment of drug causality
is based on timing of the reaction,
evaluation of other possible causes, and
effect of drug withdrawal or continuation..

114. RECOMMENDATION FOR
FUTURE USE OF DRUGS
Establish causality by using screening tools:
–Algorithm of Drug Causality for Epidermal Necrolysis
(ALDEN)
–Naranjo adverse drug reaction
Medication(s) with a “definite” or “probable” causality
should be contraindicated,a warning card or medical
alert tag (e.g., wristband) should be given to the patient,
and the drugs should be listedin the patient’s medical
chart as allergies

115. ROLE OF TESTING
FOR CAUSALITY AND DRUG RECHALLENGE
The usefulness of laboratory tests
skin prick tests or patch tests to
determine causality is debated
Skin prick test
Desensitization

116. Any severedrug reaction should be reported to:
1.National drug regulating agency (FDA)
2.Drug monitoring companies such as
MedWatch
(http://www.fda.gov/Safety/MedWatch/default.htm)
3.Pharmaceutical Company producing the
drug that caused the ADR
To be useful, the report should contain enough
details to permit ascertainment of severity and
drug causality.
FINAL NOTE: REPORTING

117. Thank you
for your
Kind Attention!