Professor
Ihab Younis, M.D.
Etiology
• It occurs in approximately 2-5% of inpatients
and in greater than 1% of outpatients
• Most estimates of the incidence of 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
• It may be divided into immunologically and
nonimmunologically mediated reactions
A - Immunologically mediated
reactions
The 4 types of hypersensitivity occur:
Type I
(IgE-Dependant)
• The drug or 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 may produce pruritus, urticaria,
bronchospasm, laryngeal edema and in
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 but may involve laryngeal
oedema
• Penicillins are the commonest cause of IgEdependent drug eruptions
Type II
(Antibody Mediated)
• An immune complex is formed from: The
drug + a cell + Ig G antibodies with
subsequent
complement
fixation
• Example:thrombocytopenic 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)
• First,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 consequent exposure to the
drug T cells & keratinocytes release cytokines
causing inflammation
• Example:Contact dermatitis to neomycin
B- Nonimmunologicallymediated 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
10-Teratogenicity and other effects on the
fetus:Thalidomide, retinoids and cytotoxic drugs
are proven teratogens and tetracyclines are
deposited in developing bones and cause
discoloration and enamel hypoplasia of teeth
11-Effects on spermatogenesis: A number
of drugs cause oligospermia e.g. estrogens,
androgens, cyproterone acetate, colchicine,
most monoamine oxidase inhibitors,
ketoconazole. Conception should also be
avoided after griseofulvin for 3 months as it
potentially can damage sperm
Clinically
• They usually begin 7-20 days after the
medication is started
• They may involve blood or tissue eosinophilia
• They may recur if drugs chemically related to
the causative agent are administered
•
•
•
•
During history taking note and detail the
following:
All prescription and over-the-counter drugs,
including topical agents, vitamins, herbal,
laxatives, oral contraceptives, vaccines,
homeopathic medicines, etc. as these may not
be volunteered as medications
The interval between the introduction of a drug
and onset of eruption
Route, dose, duration, and frequency of drug
administration
Any improvement after drug withdrawal and any
reaction with readministration
• Determining the morphology of drug
eruptions can help the clinician determine
the causative medication :
Eruption
Common drugs
1- Morbilliform
(exanthematous(:
•It is the most common
pattern
•Lesions are symmetric,
with confluent
erythematous macules and
papules that spare the
palms and soles
•It typically develops within
2 weeks after the onset of
therapy
Ampicillin,penicillin,
phenylbutazone,sulphonamides, gold, gentamycin, cephalosporins,
barbiturates,
thiazides
Eruption
Common drugs
2- Urticaria:
•It is the 2 nd most
common eruption
•Occurs as small
wheals that may
coalesce or have
cyclical or gyrate forms
•Lesions appear within
36h of intake and
resolve rapidly when
the drug is withdrawn
ACEI ,aspirin/NSAIDs,blood
products,cephalosporins,
cetirizine, dextran, infliximab,
inhaled steroids, opiates,
penicillin, radiologic contrast
material, ranitidine, tetracycline, vaccines, zidovudine
Eruption
3- Purpura:
•Can occur alone or as a
component of vasculitis
Common drugs
Aspirin, cephalosporins,
cytotoxics,heparin
Eruption
Common drugs
4- Pityriasis rosea-like:
•Eruption is similar to PR
•Itching is severe not
responding to antihistamines
•There is no tendency of
spontaneous remission
Gold,ACE inhibitors,
thiazides, bismuth,
barbiturates, griseofulvine,
metronidazole
Eruption
Common drugs
5-Erythroderma:It
is a scaling
erythematous
dermatitis
involving 90% or
more of the
cutaneous surface
Allopurinol,sulphonamides,anticonvulsants, aspirin, barbiturates,
captopril, cefoxitin, chloroquine,
chlorpromazine,
cimetidine,
griseofulvin,
lithium,
nitrofurantoin
Eruption
6- Serum sickness:
•Cutaneous signs begin
with erythema on the
sides of the fingers,
hands, and toes and
progress to a widespread
eruption (most often
morbilliform or urticarial)
• Viscera may be
involved, and fever,
arthralgia, and arthritis
are common
Common drugs
Antithymocyte globulin
for bone marrow failure,
human rabies vaccine,
penicillin and vaccines
containing horse serum,
aspirin
Eruption
Common drugs
7- Erythema multiforme
minor:
It is characterized by
target lesions distributed
predominantly on the
extremities. Mucous
membrane involvement
may occur but is not
severe. Patients with EM
minor recover fully, but
relapses are common
Sulphonamides,cephalosporins,penicillins,tetracyclines, phenytoin,
barbiturates, aspirin,
NSAID,thiazides
Eruption
Common drugs
8-Stevens Johnson synd. As EM
•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
Eruption
Common drugs
9-Toxic epidermal necrolysis: As EM
•Starts with a burning
morbilliform eruption accompanied
by systemic flu-like symptoms
•This is quickly followed by
rapid, widespread, fullthickness skin sloughing
affecting 30% or more the total
body surface area
Eruption
10- Fixed drug eruptions:
• Lesions recur in the same
area ½ -8 h after the drug
is reused
•Circular, violaceous,
edematous plaques that
resolve with macular
hyperpigmentation
•Hands, feet&genitalia are
the most common sites but
perioral and periorbital
lesions may occur
Common drugs
Sulfonamides,penicillin,
tetracyclines,
aspirin/NSAID,
barbiturates, cetirizine,
ciprofloxacin, dapsone,
fluconazole,
hydroxyzine, loratadine,
metronidazole, oral
contraceptives,
phenytoin, vancomycin
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 14 months or more
Common drugs
Antimalarials, gold,
diuretics,antihypertensives,
hypoglycaemicagents,
NSAI,antituberculous,tetracyclines, allopurinol,
phenytoin
Eruption
12- Phototoxic dermatitis
•Min. to h. after sun exposure
•Exaggerated sunburn
•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
•May spread to non-exposed area
Common drugs
Chlorpromazine,
psoralens,sulphonamides,tetracyclines,
NSAI, thiazides
Eruption
13- Acneiform:
•Characterized by
inflammatory papules or
pustules that have a
follicular pattern
•Localized primarily on the
upper body
•In contrast to acne
vulgaris, comedones are
absent
Common drugs
Corticosteroid, anabolic
steroids, oral
contraceptives,halogens,
isoniazid, lithium,
phenytoin
Eruption
Common drugs
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
Frusemide, cyclosporine,
dapsone, etretinate, 5-fluorouracil,thiazides,isotretinoin,
NSAIDs, oral contraceptives,
tetracyclines
Eruption
15 - Bullous
pemphigoid:
•Patients tend to be
younger
•Tissue-bound and
circulating antibasement-membrane
zone IgG antibodies
may be absent
Common drugs
Frusemide, penicillamine,
penicillins, sulphasalazine,
PUVA
Eruption
16- Pemphigus:
•Pemphigus folliacius
&erythematosus may
occur but pemphigus
vulgaris is rare
•Most patients have
tissue and serum
autoantibodies as in
idiopathic pemphigus
Common drugs
Captopril, D-penicillamine,
captopril, gold, penicillins
Eruption
17- Leukocytoclastic
vasculitis:
•It is the most common
severe drug eruption
•There are blanching
erythematous macules
quickly followed by
palpable purpura
• Fever, myalgias, arthritis,
abdominal pain may occur
• It appears 7-21 days
after the onset of therapy
Common drugs
Sulphonamides, frusemide,
aspirin /NSAIDs, cimetidine,
gold, hydralazine,minocycline, penicillins,
phenytoin,
quinolones,
sulfonamide,
tetracycline,
thiazides
Eruption
Common drugs
18- Erythema nodosum:
•Tender, red,
subcutaneous nodules
•Appear on the anterior
aspect of the legs
•Lesions do not suppurate
or become ulcerated
Oral contraceptives (most
common), halogens,
penicillin, sulfonamides,
tetracyclines
Eruption
Common drugs
19- Sweet syndrome (acute
febr. neutrophilic dermatosis):
•Tender erythematous papules
and plaques occur most often on
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
Retinoic acid,
nitrofurantoin, oral
contraceptives,
tetracyclines,trimethoprimsulfamethoxazole
Eruption
Common drugs
20- Acral erythema:
Cytotoxic
•It is a relatively common drugs
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
Eruption
Common drugs
21- Acute generalized
Beta-lactam antibiotics,
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
Eruption
22- Hair loss:
Common drugs
Cytotoxic drugs,
anticoagulants,
anticonvulsants,
levodopa,
antithyroids
Eruption
23 - Hypertichosis:
Common drugs
Androgens, corticosteroids,
minoxidil, phenytoin,
penicillamine, cyclosporin,
psoralens ,streptomycin
Nail changes
Silver : lunula discoloration
D-penicillamine: Yellow nail
Cytotoxics: Beau’s lines
Minocycline: blue nails
Rates of reactions to commonly
used drugs
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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
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•
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•
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Allopurinol
Anticonvulsants
NSAIDs
Sulfa drugs
Bumetanide
Captopril
Furosemide
Penicillamine
Thiazide diuretics
Drugs unlikely to cause skin
reactions
•Digoxin
•Acetaminophen
•Diphenhydramine
•Aspirin
•Aminophylline
•Prochlorperazine
•Ferrous sulfate
•Prednisone
•Codeine
•Tetracycline
•Morphine
•Regular insulin
•Warfarin
•Folic acid
•Methyldopa
•Chlorpromazine
•Serotonin-specific
reuptake inhibitors
Investigations
• If history and physical examination are not
sufficient for diagnosis, the following
investigations may help:
– Biopsy e.g. by showing eosinophils in
morbilliform eruptions or numerous
neutrophils without vasculitis in persons
with Sweet syndrome
– CBC count with differential may show
leukopenia, thrombocytopenia, and
eosinophilia in patients with serious drug
eruptions
– Special attention should be paid to the
electrolyte balance and renal and/or hepatic
function indices in patients with severe
reactions such as SJS, TEN, or vasculitis
– Urinalysis, stool guaiac tests (for occult blood),
and chest radiography are important for
patients with vasculitis
– Drug reactions, apart from fixed drug eruption,
have non-specific clinical features, and it is
often impossible to identify the offending
chemical with certainty, especially when a
patient with a suspected reaction is receiving
many drugs simultaneously
Treatment
• Once the offending drug has been identified, it
should be promptly stopped. Failure of a rash to
subside on drug withdrawal does not necessarily
exonerate it, since traces of the drug may persist
for long periods, and some reactions, once
initiated, continue for many days without
reexposure to the drug
• Patients with morbilliform eruptions can continue
medication even in presence of rash as the
eruption often resolves, especially if the
individual is being treated for a serious disease
• Treatment of a drug eruption depends on the
specific type of reaction
-Therapy for exanthematous drug eruptions is
supportive in nature. First-generation
antihistamines are used with mild topical
steroids (e.g. hydrocortisone( and moisturizing
lotions, especially 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 may provide some relief
• If signs and symptoms are severe, a 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.