CUTANEOUS DRUG REACTIONS

Dr. Frances Rose Palabrica

INTRODUCTION:
Adverse cutaneous reactions to drugs can arise as a result of
immunologic or non immunologic mechanisms.
Immunologic
- True for most drug reactions
- Gell and Coombs classification:
Type I: immediate type hypersensitivity rxns
Type II: cytotoxic reactions
Type III: immune complex reactions
Type IV: delayed type hypersensitivity rxns
Type I: Immediate type
IgE mediated
Reactions occur within minutes of exposure to the drug
Symptoms:
- Urticaria
- Laryngeal edema
- Wheezing
- Cardiorespiratory collapse
Wide variety of drugs, biological and drug formulation agents
- Antibiotics: most important cause
- Insulin
- Enzymes (asparginase)
- Heterologous antisera (equine antitoxins, antilymphocyte globulin)
- Murine monoclonal antibodies
- Protamine
- Heparin
Type II: Cytotoxic Reactions
Involve IgG or IgM antibodies that recognize drug antigen on cell
membrane
In the presence of complement, the Ab-coated cell is either cleared by
monocyte-macrophage system or destroyed.
Acquired haemolytic anemia (a-methyldopa and penicillin)
Thrombocytopenia (quinidine)
Very serious and life threatening

Type III: Immune Complex Reactions

Mediated by immune complexes formed in slight antigen excess
Immune complex is deposited in blood vessel walls and causes injury by
activating the complement cascade (e.g. serum sickness
Penicillin, sulphonamide, thiouracils and phenytoin associated with serum
sickness-like symptoms
Signs and symptoms appear 1-3 weeks after starting use of an offending
drug and begin to subside when the drug and /or its metabolites are
completely eliminated from the body
- Fever
- Rash
- Urticaria
- Lymphadenopathy
- Arthralgias
Type IV: Delayed type or cell mediated reactions
Mediated by cellular immune mechanisms
Classic reaction: allergic contact dermatitis
Responsible for delayed cutaneous eruptions (e.g. maculopapular rash
due to antbiotic like amoxicillin and sulphonamides)
May also be systemic and involve lymphoid organs and other tissues
throughout the body
Cutaneous manifestations are the most common presentation for drug
allergic reactions
Characterization of cutaneous lesions is important in regard to
determining the cause, further diagnostic tests and management
decisions
EXANTHEMATOUS ERUPTIONS
Most common manifestation of drug allergy is a generalized exanthema
(maculopapular eruptions)
Lesions are pruritic
Often begins as macules that can evolve into papules and eventually may
coalesce into plaques
Typically involve the trunk and spread outward to the limbs in a bilateral
symmetric manner
Many drug-induced exanthems are manifestations of delayed-type
hypersensitivity
- Development of exanthema evolves after several days of taking the
offending drug

- Do not evolve into anaphylactic reactions because they are not IgEmediated
Scaling may occur with resolution
Frequent drug implicated:
Allopurinol
Aminopenicillins
Cephalosporins
Anti epileptic agents
Antibacterial sulphonamides
FIXED DRUG ERUPTIONS
Eruptions recur at the same skin or mucosal site on reintroduction of the
causative drug
Round or oval, sharply demarcated, red to livid, slightly elevated plaques,
ranging from a few mm to several cm in diameter
May also present as vesicles; mucosal lesions are usually bullous
Predilection for the lips, hands, and genitalia (esp in men)
Common meds implicated:
Tetracycline
NSAIDs
Carbamazepine
URTICARIA AND ANGIOEDEMA
Most common manifestation of IgE-mediated drug allergy
Important to recognize that non-IgE mediated drug allergic reactions can
manifest with urticaria and angioedema as well
Serum sickness: urticaria is one of its most common manifestation
Angioedema due to ACE inhibitors: bradykinin-mediated
PUSTULAR ERUPTIONS
Common drugs implicated:

Glucocorticoids
Androgens
Lithium
Phenytoin
Isoniazid
Sirolimus

ACUTE GENERALIZED ECZEMATOUS PUSTULOSIS (AGEP)

Rare type of drug eruption
Begins with erythema or edema in the intertriginous areas or face
development of fine nonfollicular sterile pustules
Fever, neutrophilia and eosinophilia ( of cases) may be present
Drugs: antibiotics and calcium channel blockers
T cell mediated drug reactions
BLISTERING ERUPTIONS
Erythema multiforme minor
Cell mediated hypersensitivity reactions associated with viruses, other
infectious agents and drugs
Polymorphic maculopapular lesion that spreads peripherally and clears
centrally to form an annular pattern know as a target lesion
3 zones
- Erythematous central papule that may blister
- Edematous middle ring
- Erythematous outer ring
May progress to the development of blisters and progressive involvement of
the mucous membraneserythema multiforme major
STEVEN-JOHNSON SYNDROME (SJS) AND TOXIC EPIDERNAL
NECROLYSIS (TEN)
Characterized by blisters and epidermal detachment resulting from the
epidermal necrosis in the absence of substantial dermal inflammation
Drugs with high relative risk of developing SJS/TEN

Sulphonamides
Cephalosporins
Imidazole agents
Oxicam derivatives

Drugs with moderate risk

Quinolones
Carbamazepine
Phenytoin
Valproic acid
Glucocorticoids

SJS
Epidermal detachment <10%
Widespread blistering purpuric masule on face, trunk and proximal
extremities

Severe explosive mucosal erosions, usually at >1 mucosal surface

Associated with high temperature and severe constitutional symptoms
Ocular involvement may be particularly serious
Liver, kidney and lungs may involved singly or in combination
Treatment: discontinuation of drug; use of steroid is controversial
If treatment is started too late (3-4 days after the onset), it is possible
that TEN could supervene, in which case systemic steroids are
contraindicated

TEN
Epidermal detachment 30% or more
- 10-30% detachment:overlap between SJS & TEN
Almost always drug induced
Widespread areas of confluent erythema followed by epidermal necrosis
and etachment with severe mucosal involvement
Significant loss of skin equivalent to a 3rd degree burn
Glucocorticoids are contraindicated
Must be managed in a burn unit
Significant risk of infection; mortality rates as high as 50% have been
reported
Should be distinguished from Staph scalded syndrome
DRUG RASH WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS
(DRESS)
Drug induced multiorgan inflammatory response that may be life
threatening
Phenytoin hypersensitivity syndrome, drug hypersensitivity syndrome,
drug induced hypersensitivity syndrome, drug induced delayed
multiorgan hypersensitivity syndrome
Characteristic features
- Cutaneous eruptions (exanthems, erythema multiforme purpura)
- Fever
- Eosinophilia
- Hepatic dysfunction
- Renal dysfunction
- Lymphadenopathy
Implicated medications:
- Anti convulsants
- Sulphonamides

Allopurinol
Minocycline
Dapson
Sulfasalazine
Abacavir
Nevirapine
Hydroxychloroquine

Reactions develop later, usually 2-8 wks after the therapy is started
Symptoms may worsen after the drug is discontinued
May persist for weeks or months after drug is discontinued

Management:
Withdrawal of the offending drug/s
1:1000 epinephrine, 0.3-0.5ml IM anterolateral thigh
for anaphylactic reactions (IgE-mediated)
Glucocorticosteroids
Immune complex reactions, drug induced hematologic diseases, early
stages of SJS and contact sensitivities
Oral anti histamines

Drug desensitization
Induction of drug tolerance
Modifies a patients response to a drug to temporarily allow treatment
with it safely
Indicated only in situations where an alternate medication cannot be used
Contraindicated for patients who had SJS/TEN, except when benefit of
treatment of a life threatening reaction