DRUG INDUCED CUTANEOUS

REACTIONS
DR MBURU
Drug induced cutaneous reactions
Occurs in approximately 2-5% of inpatients and in 1% of
outpatients
Most estimates drug eruptions are inaccurate, because
many mild and transitory eruptions are not recorded, and
because skin disorders are sometimes falsely attributed to
drugs
Elderly patients have an increased prevalence of adverse
drug reactions
Divided into immunologically and nonimmunologically
mediated reactions
A - Immunologically mediated reactions

The 4 types
Type I
(IgE-Dependant)
The drug / protein conjugates with two or more specific IgE
molecules, then gets fixed to sensitized mast cells or
circulating basophil
 This triggers the cell to release a variety of chemical
mediators e.g. histamine and cytokines
• Clinically, this produces pruritus, urticaria,
bronchospasm, laryngeal edema
• Severe cases: anaphylactic shock with hypotension and
possible death
• Immediate reactions: occur within minutes of drug
administration; accelerated reactions may occur within
hours or days, and are generally urticarial and may
involve laryngeal oedema
• Penicillins are the commonest cause of IgE-dependent
drug eruptions
 Type II
(Antibody Mediated)
An immune complex is formed from: The drug + a cell
+ Ig G antibodies with subsequent
complement
fixation
Example:thrombo-
cytopenic purpura
that may result
from antibodies to quinidine
 Type III
(Immune Complex Reaction)
Soluble immune complexes are formed from Ig G class antibodies
& a soluble antigen (not attached to the organ involved)
Example:Vasculitis induced
by antibiotics results from
deposition of immune
complexes on vascular
endothelium resulting in
activation of the
complement cascade
Type IV
(Delayed or cell-mediated)
• Sensitization to the drug occurs when Langerhans' cells
take up and process antigen, and migrate to regional lymph
nodes, where they activate T cells with the consequent
production of memory T cells, which end up in the dermis
• On subsequent exposure to the drug T cells &
keratinocytes release cytokines causing inflammation
• Example:Contact dermatitis to neomycin
B- Nonimmunologically-
mediated reactions
1-Accumulation: e.g. argyria (blue-gray discoloration of
skin and nails) observed with use of silver nitrate nasal
sprays
2-Side effects: unwanted or toxic effects, which are not
separable from the desired pharmacological action of
the drug e.g. the drowsiness induced by antihistamines
3-Direct release : The direct release of mast cell
mediators is a dose-dependent phenomenon that
does not involve antibodies. For example, aspirin
and other NSAIDs cause a shift in leukotriene
production, which triggers the release of histamine
and other mast-cell mediators
4-Idiosyncrasy: a response, not predictable from
animal experiments, and its cause is often unknown,
but genetic variation in metabolic pathways may be
involved e.g. dapsone induced hemolysis due to
glucose-6-phosphate dehydrogenase deficiency
 5-Intolerance:The characteristic effects of the drug are
produced to an exaggerated extent by an abnormally small
dose. This may simply represent an extreme within normal
biological variation or may occur in patients with altered
metabolism. For example, individuals who are slow acetylators
of the enzyme N-acetyltransferase are more likely than others
to develop drug-induced lupus in response to procainamide
6-Imbalance of endogenous flora: may occur when
antimicrobial agents preferentially suppress the growth
of one species of microbe, allowing other species to
grow vigorously. For example, candidiasis frequently
occurs with antibiotic therapy
7-Overdosage: is an exaggerated response to an
increased amount of a medication. For example,
increased doses of anticoagulants may result in purpura
8-Jarisch-Herxheimer phenomenon: is a reaction due
to bacterial endotoxins and microbial antigens that are
liberated by the destruction of microorganisms. The
reaction is characterized by fever, tender
lymphadenopathy, arthralgias, transient macular or
urticarial eruptions, and exacerbation of preexisting
cutaneous lesions. The reaction is not an indication to
stop treatment because symptoms resolve with
continued therapy. This reaction can be seen with
penicillin therapy for syphilis, griseofulvin or
ketoconazole therapy for dermatophyte infections
9-Metabolic effects: Drugs may induce cutaneous changes
by their effects on metabolism e.g. isotretinoin may cause
xanthomas by increasing lipoproteins
 Clinically

They begin 7-20 days after the medication is started

They involve blood or tissue eosinophilia
They may recur if drugs chemically related to the
causative agent are administered
HISTORY TAKING : note the following
1. All prescription and over-the-counter drugs, vitamins,
herbal, laxatives, oral contraceptives, vaccines,
homeopathic medicines as these may not be volunteered
as medications
2. The interval between the introduction of a drug and onset of
eruption
3. Route, dose, duration, and frequency of drug administration
4. Any improvement after drug withdrawal and any reaction
with readministration
 Common drugs Eruption
Ampicillin,penicillin, 1- Morbilliform
phenylbutazone,sulpho- (exanthematous(:
namides, gold, genta- •It is the most common
mycin, cephalosporins, pattern
barbit- •Lesions are symmetric,
urates, with confluent
thia- erythematous macules and
papules that spare the
zides palms and soles
•It typically develops within
2 weeks after the onset of
therapy
 Common drugs Eruption
ACEI ,aspirin/NSAIDs,blood 2- Urticaria:
products,cephalosporins, •It is the 2 nd most
cetirizine, dextran, infliximab, common eruption
inhaled steroids, opiates, •Occurs as small
penicillin, radiologic contrast
wheals that may
material, ranitidine, tetra- coalesce or have
cycline, vaccines, zidovudine
cyclical or gyrate forms
•Lesions appear within
36h of intake and
resolve rapidly when
the drug is withdrawn
 Common drugs Eruption

Aspirin, cephalosporins, 3- Purpura:

cytotoxics,heparin •Can occur alone or as a
component of vasculitis
 Common drugs
Gold,ACE inhibitors,
thiazides, bismuth,
barbiturates, griseofulvine,
metro-
nidazole
Eruption
4- Pityriasis rosea-like:
•Eruption is similar to PR
•Itching is severe not
responding to antihist-
amines
•There is no tendency of
spontaneous remission
 Common drugs Eruption
Allopurinol,sulphonamides,antico- 5-Erythroderma:It
nvulsants, aspirin, barbiturates, is a scaling
captopril, cefoxitin, chloroquine, erythematous
-chlorpro dermatitis
,mazine involving 90% or
,cimetidine more of the
cutaneous surface
,griseofulvin
,lithium
nitrofurantoin
 Common drugs Eruption
Antithymocyte globulin 6- Serum sickness:
for bone marrow failure, •Cutaneous signs begin
human rabies vaccine, with erythema on the
penicillin and vaccines sides of the fingers,
containing horse serum, hands, and toes and
aspirin progress to a widespread
eruption (most often
morbilliform or urticarial)
• Viscera may be
involved, and fever,
arthralgia, and arthritis
are common
 Common drugs Eruption
Sulphonamides,cephalo- 7- Erythema multiforme
sporins,penicillins,tetra- minor:
cyclines, phenytoin, It is characterized by
barbiturates, aspirin, target lesions distributed
NSAID,thiazides predominantly on the
extremities. Mucous
membrane involvement
may occur but is not
severe. Patients with EM
minor recover fully, but
relapses are common
 Common drugs Eruption
As EM 8-Stevens Johnson synd.
•Bloody bullae, eroded,
bloody or crusted lips,
stomatitis and genitals
mucosal ulceration
•Conjunctivitis
•Extensive EM on limbs
•Sloughing of >10% of skin
• Constitutional symptoms
•Lymphadenopathy
 Common drugs Eruption
As EM Toxic epidermal-9
:necrolysis
•Starts with a burning
morbilliform eruption accompanied
by systemic flu-like symptoms
•This is quickly followed by
rapid, widespread, full-
thickness skin sloughing
affecting 30% or more the total
body surface area
 Common drugs Eruption
Sulfonamides,penicillin, 10- Fixed drug eruptions:
tetracyclines, • Lesions recur in the same
aspirin/NSAID, area ½ -8 h after the drug
barbiturates, cetirizine, is reused
ciprofloxacin, dapsone, •Circular, violaceous,
fluconazole, edematous plaques that
hydroxyzine, loratadine, resolve with macular
metronidazole, oral
hyperpigmentation
contraceptives,
•Hands, feet&genitalia are
phenytoin, vancomycin
the most common sites but
perioral and periorbital
lesions may occur
 Common drugs
Antimalarials, gold,
diuretics,antihypertensives,
hypoglycaemicagents,
NSAI,antituberculous,tetra-
cyclines, allopurinol,
phenytoin
Eruption
11- Lichenoid:
•May develop weeks or
months after initiation of
therapy
•Lesions are more
extensive, more itchy
and psoriasi-form than
in idiopathic lichen
•Oral lesions are rare
•Resolution may take 1-
4 months or more
 Common drugs Eruption
Chlorpromazine, 12- Phototoxic dermatitis
psoralens,sulphona- •Min. to h. after sun exposure
mides,tetracyclines, •Exaggerated sunburn
NSAI, thiazides
•Vesicles& bullae in severe cases
•Burning is the main symptom
•Limited to sun-exposed skin
Photoallergic dermatitis
•1-3 days after sun exposure
•Lesions are eczematous
•Pruritus is the main symptom
•
 Common drugs Eruption
Corticosteroid, anabolic 13- Acneiform:
steroids, oral •Characterized by
contraceptives,halogens, inflammatory papules or
isoniazid, lithium, pustules that have a
phenytoin follicular pattern
•Localized primarily on the
upper body
•In contrast to acne
vulgaris, comedones are
absent
 Common drugs
Frusemide, cyclosporine,
dapsone, etretinate, 5-fluoro-
uracil,thiazides,isotretinoin,
NSAIDs, oral contraceptives,
tetracyclines
Eruption
14- Pseudoporphyria:
•Blistering and skin
fragility that is clinically
and pathologically
identical to that of
porphyria cutanea tarda,
but hypertrichosis and
sclerodermoid changes
are absent and urine
and serum porphyrin
levels are normal
 Common drugs Eruption
Frusemide, penicillamine, 15 - Bullous
penicillins, sulphasalazine, pemphigoid:
PUVA •Patients tend to be
younger
•Tissue-bound and
circulating anti-
basement-membrane
zone IgG antibodies
may be absent
 Common drugs Eruption

Captopril, D-penicillamine, 16- Pemphigus:

captopril, gold, penicillins •Pemphigus folliacius
&erythematosus may
occur but pemphigus
vulgaris is rare
•Most patients have
tissue and serum
autoantibodies as in
idiopathic pemphigus
 Common drugs Eruption
Sulphonamides, frusemide, 17- Leukocytoclastic
aspirin /NSAIDs, cimetidine, vasculitis:
gold, hydralazine,mino- •It is the most common
cycline, penicillins, severe drug eruption
phenytoin, •There are blanching
quinolones, erythematous macules
sulfonamide, quickly followed by
tetracycline, palpable purpura
• Fever, myalgias, arthritis,
thiazides
abdominal pain may occur
• It appears 7-21 days
after the onset of therapy
 Common drugs Eruption
Oral contraceptives (most :Erythema nodosum -18
common), halogens, •Tender, red,
penicillin, sulfonamides, subcutaneous nodules
-tetracy •Appear on the anterior
clines aspect of the legs
•Lesions do not suppurate
or become ulcerated
 Common drugs Eruption
Retinoic acid, 19- Sweet syndrome (acute
nitrofurantoin, oral febr. neutrophilic dermatosis):
contraceptives, •Tender erythematous papules
tetracyclines,trimetho- and plaques occur most often on
primsulfamethoxazole the face, neck, upper trunk, and
extremities
•The surface of the lesions may
become vesicular or pustular
•Systemic findings are common
and include fever, arthritis,
conjunctivitis, oral ulcers
 Common drugs Eruption
Cytotoxic 20- Acral erythema:
drugs •It is a relatively common
reaction to chemotherapy
•There is symmetric
tenderness, edema, and
erythema of the palms
and soles thought to be a
direct toxic effect on skin
•It resolves 2-4 weeks
after chemotherapy
withdrawal
 Common drugs Eruption
Beta-lactam antibiotics, 21- Acute generalized
macrolides, and mercury exanthematous
pustulosis :
Acute-onset fever and
generalized scarlatiniform
erythema occur with
many small, sterile,
nonfollicular pustules.
The clinical presentation
is similar to pustular
psoriasis
 Common drugs Eruption
Cytotoxic drugs, 22- Hair loss:
anticoagulants,
anticonvulsants,
,levodopa
antithyroids
 Common drugs Eruption
Androgens, corticosteroids, :Hypertichosis - 23
minoxidil, phenytoin,
penicillamine, cyclosporin,
psoralens ,streptomycin
 Rates of reactions to commonly used
drugs

Amoxicillin - 5.1%
Trimethoprim sulfamethoxazole - 4.7%
Ampicillin - 4.2%
Semisynthetic penicillin - 2.9%
Blood (whole human) - 2.8%
Penicillin G - 1.6%
Cephalosporins - 1.3%
Quinidine - 1.2%
Gentamicin sulfate - 1%
Drugs that commonly cause serious
reactions
• Allopurinol
• Anticonvulsants
• NSAIDs
• Sulfa drugs
• Bumetanide
• Captopril
• Furosemide
• Penicillamine
• Thiazide diuretics
Investigations
Biopsy e.g. by showing eosinophils in
morbilliform eruptions or numerous
neutrophils without vasculitis in persons with
Sweet syndrome
Total blood cell count with differential may
show leukopenia, thrombocytopenia, and
eosinophilia in patients with serious drug
eruptions
electrolyte balance and renal and/or hepatic
function indices in patients with severe reactions
such as SJS, TEN, or vasculitis
Urinalysis, stool tests (for occult blood), and
chest radiography are important for patients with
vasculitis
when a patient with a suspected reaction is
receiving many drugs simultaneously it is often
impossible to identify the offending chemical
with certainty
 Treatment
Stop the offending drug
Patients with morbilliform eruptions can continue medication
even in presence of rash as the eruption often resolves,
especially if being treated for a serious disease
Treatment of a drug eruption depends on the specific type of
reaction .E.g.Therapy for exanthematous drug eruptions is
supportive in nature with 1st gen antihistamines are used
with mild topical steroids (e.g. hydrocortisone( and
moisturizing lotions during the late desquamative phase
Oral antihistamines
A drying antipruritic lotion (calamine with or without 0.25%
menthol and/or 1% phenol) or lubricating antipruritic
emollients will help relieve the pruritus
Lotions with phenol should not be given to pregnant women
Topical steroids provide relief
severe signs and symptoms : 2-week course of systemic
corticosteroids (prednisone, starting at 60 mg) will usually
stop the symptoms and prevent further progression of the
eruption within 48 hours of the onset of therapy
Treatment of erythroderma : maintenance of body
temperature and fluid and electrolyte balance, treatment
of cardiac failure by use of digitalization and diuretics
and administration of intravenous albumin for
hypoalbuminaemia
The management of TEN is perhaps best carried out on
an intensive care or burns unit
Management of anaphlyaxis
Stop drug administration
Give i.m. 0.5-1ml 1:1000 adrenaline immediately
Check airway and give oxygen
Antihistamines:Chlorpheniramine maleate 1020 mg i.v.
Corticosteroids:Hydrocortisone 250mg i.v. and 100mg 6 hourly
+ Prednisolone 40mg/day for 3 d
 I.V. Saline or glucose 5%
Monitor BP and pulse
For bronchospasm:aminophylline 250mg i.v. over 5 mins and
250mg in 500ml saline over 6 h.