DRUG REACTIONS

Presenter: ASIA .M. MOHAMEDI

Facilitator: Dr Shani (Dermatologist)
INTRODUCTION
The skin is one of the most common sites for adverse drug reactions.
Up to 5% of patients treated with antibiotics and aromatic anticonvulsants
may develop a cutaneous eruption
Definitions and Classifications
• The terms “drug reaction,” “drug hypersensitivity,” and
“drug allergy” are often used interchangeably.
• Drug reactions encompass all adverse events related to
drug administration, regardless of etiology
• Drug hypersensitivity is defined as an immune-mediated
response to a drug agent in a sensitized patient.
• Drug allergy is restricted specifically to a reaction
mediated by IgE.
Drug reactions can be classified into:
• Immunologic etiologies.
• Nonimmunologic etiologies.
 Unpredictable, nonimmune drug reactions can be
classified as pseudo allergic, idiosyncratic, or intolerance
• . Pseudo allergic reactions are the result of direct mast
cell activation and degranulation by drugs such as opiates,
vancomycin (Vancocin), and radiocontrast media.
• Idiosyncratic reactions are reactions that cannot be
explained by the known pharmacologic action of the drug
and occur only in a small % of the population.
A classic eg is drug-induced hemolysis in persons with
(G6PD) deficiency
• Drug intolerance is defined as a lower threshold to the
normal pharmacologic action of a drug, such as tinnitus
after a single average dose of aspirin.
• Approximately 2% of all drug-induced skin reactions are considered “serious”
• According (WHO) definition: “if it results in death, requires hospitalization
or prolongation of existing hospital stay, results in persistent or significant
disability/incapacity, or is life-threatening”.
• Toxic epidermal necrolysis(TEN) and drug reaction with eosinophilia and
systemic symptoms (DRESS) also referred to as drug-induced
hypersensitivity syndrome [DIHS]) are examples of such “serious”
• Roujeau and Stern2 estimated that 1 of every 1000 hospitalized patients has a
serious cutaneous drug reaction”
• Prompt identification of severe cutaneous adverse reactions (SCARs) is an
important goal.
• Followed by discontinuation of the offending drug(s) and thereby
decreasing morbidity.
• It is more useful to examine the specificity of the clinical, pathologic and
biologic patterns, thus allowing classification of each type of adverse
cutaneous reaction as a single entity with a well-defined and specific
mechanism.
 EPIDEMIOLOGY
• Cutaneous reactions to drugs occur in up to 8% of hospitalized patients
• The incidence of fatalities due to drug reactions (systemic and cutaneous)
among inpatients is between 0.1% and 0.3%.
Risk factors
- Female gender,
- Immunosuppression (e.g. HIV-infected individuals have a 10- to 50-fold
greater risk of developing an exanthematous eruption to sulfamethoxazole)
- Dermatomyositis (specifically for hydroxychloroquine), and specific HLA
alleles.
• Genetic factors Specific HLA alleles have emerged as important genetic risk
factors for SCARs, especially SJS/TEN and DRESS.
• The primary responsible drugs were penicillin, sulfonamides, and nonsteroidal
anti-inflammatory drugs (NSAIDs)
• The drugs responsible for a particular CAR can be placed into low-, medium-,
or high-probability categories.
• The two most common skin reactions are an exanthematous (or
morbilliform) eruption and urticaria
• The majority (75 to 80%) of adverse drug reactions are caused
by predictable, nonimmunologic effects.
• The remaining 20 to 25% of adverse drug events are caused
by unpredictable effects that may or may not be immune
mediated.
• Immune-mediated reactions account for 5 to 10% of all drug
reactions and constitute true drug hypersensitivity.
 Immunologically Mediated Drug Reactions
• IgE-dependent drug reactions (formerly type I, Gell–Coombs classification)
Urticaria, angioedema, and anaphylaxis.
• Cytotoxic drug-induced reactions (antibody against a fixed antigen; formerly
type II)
Petechiae secondary to drug-induced thrombocytopenia.
• Immune complex-dependent drug reactions (formerly type III):
Vasculitis, serum sickness, and certain types of urticaria.
• Delayed-type, cell-mediated drug reactions (activation of CD4+ and CD8+ T
cells; formerly type IV)
Exanthematous, fixed, and lichenoid drug eruptions, as well as Stevens–
Johnson syndrome (SJS) and TEN
• SCARs have several immunologic mechanisms including:
(1) The hapten/pro-hapten concept – the drug or its metabolite covalently
binds to an endogenous peptide and the resultant hapten is recognized by a
highly restricted major histocompatibility complex (MHC)
(2) The pharmacoimmune reaction (“p-i concept”) – drugs induce formation of
HLA–drug complexes that can directly activate T-cell immune responses
without the need for a specific peptide ligand3,8;
(3) Direct HLA–drug interactions – certain drugs such as carbamazepine,
abacavir and sulfamethoxazole bind non-covalently within the peptide groove
of a specific HLA and modify the antigen binding cleft, thereby altering the
endogenous peptide repertoire
1 Methotrexate toxicity. Increased serum levels of methotrexate secondary to decreased renal excretion can lead to epidermal
necrosis. A Large erosions and areas of epidermal necrosis with a shellac-like appearance in a patient with rheumatoid arthritis.
B Epidermal necrosis limited to psoriatic plaques.
 Diagnostic or confirmatory assays
Diagnostic or confirmatory assays to establish the responsible drug are not
available
With the exception of assays for IgE antibodies.
A number of in vitro tests have been designed including,
• The histamine release test
• Migration inhibition factor test,
• lymphocyte toxicity assay,
• lymphocyte transformation test,
• Basophil degranulation test(basophils activation test or CAST TEST)
However, their sensitivity and specificity have not been assessed in a reliable way
with relevant controls.
• Prick and intradermal tests can be performed in patients with urticaria and
angioedema
• Contraindicated in SJS/TEN due to the risk of relapse.
• Delayed reading of prick, intradermal, and patch tests is particularly important
in the case of amoxicillin-induced morbilliform eruptions.
The Gell and Coombs classification system
• Describes the predominant immune mechanisms that lead to
clinical symptoms of drug hypersensitivity
• This classification system includes: Type I ---- Type IV reactions
.
• These include certain cutaneous drug reactions
( maculopapular rashes, erythroderma, exfoliative dermatitis,
and fixed drug reactions) and specific drug hypersensitivity
syndromes
 Urticaria
Synonyms( Wheals – hives, nettle rash)
Definition
• Skin lesion consisting of a wheal and flare reaction in which localized
intracutaneous edema (wheal) is surrounded by an area of redness that
is typically pruritic.
• In urticaria, there is vasodilation and transient edema within the dermis
• Dramatic outbreaks of acute urticaria usually represent an immediate
hypersensitivity reaction mediated by IgE antibodies, especially when
the urticaria is associated with angioedema and/or anaphylaxis
• The hallmark of wheals is that the lesions that come and go rapidly
generally within 24 hours.
Common causes
• Acute urticaria
• Allergic reactions to medications e.g NSAIDS
• Infections; Viral, bacterial, Parasitic
• 80% of cases of acute urticaria in some pediatric series-UTI
• Mycoplasma pneumoniae
• Ancylostoma, Strongyloides, Filaria, Echinococcus, Trichinella, Toxocara, Fasci
ola, Schistosoma mansoni, and Blastocystis homini
• foods, or insect stings and bites;
 PATHOPHYSIOLOGY
• Cutaneous mast cells in the superficial dermis.
• Basophils have also been identified in lesioned biopsies
• STEPS
• IgE response to allergen and form antigen+IgE immune complex-bind surface mast
cells and basophils.
• Mast cells and basophils release multiple mediators upon
activation(histamine,bradykinin, leukotrine C4 , prostaglandin D2….)
• histamine (which causes itching)
• vasodilatory mediators (cause localized swelling in the uppermost layers of the
skin).
• Histamine bind H1R on endothelial and smooth MMs-increase capillary
permeability
• When it bind to H2R-arteriolar and venule vasodilation
 Dermatological presentations
• Urticaria presents as transient,round ,oval in shape.
• Often pruritic, erythematous and edematous papules and plaques
that may appear anywhere on the body, including the palms, soles,
and scalp.
• Lesions can vary significantly in size 1<cm and number
• The primary effector cell is the cutaneous mast cell which releases
histamine and other inflammatory mediators
Lesions may coalesce as they enlarge.
• not normally painful and resolve w/o leaving marks on the skin, unless
there is trauma from scratching.
• Chronic urticaria-leave residual bruising-urticarial vasculitis
• Typically, compressed areas become more severely affected.
• Antibiotics, like penicillin and cephalosporins, and less often,
sulfonamides and minocycline are mostly frequency produce
immunological based urticaria.
• The use of monoclonal antibodies for neoplastic and inflammatory
dses increases, so will cases of urticaria
• In anaphylactoid reactions, vasodilation results from the liberation of
large amounts of histamine, bradykinin, and/or leukotrienes
• Acetylsalicylic acid is the classic example of a drug that induces an
anaphylactoid reaction and it does so via cyclooxygenase inhibition
and subsequent accumulation of leukotrienes.
• Urticarial reactions to radiocontrast media are also non-immunologic
 Classification by duration
• Acute-short lived ( days to <6wks)
• Immunological rxn to medication, foods, contact allerg.
• Self limited
• Chronic-lasting longer than 6wks.
• Collagen vascular disorders,Hodkings lymphoma
• Idiopathic-autoimmune, drug induced, complement
mediated. Systemic disorders.
• Chronic with episode of exacebations
 Investigations
• Specific test
• Skin test(Prick test) for IgE
• Hepatitic B and C
• Radioallergosorbent tests(RAST )for specific IgE
• Histamine release assay for IgE.
• Stool exam for ova and parasites
Other tests
• CBC
• Urinalysis
• Thyroid microsomal antibodies
• Antithyroglobulin
• TSH
• NB: Only 10–20% of pts who reported a hx of penicillin allergy were truly allergic
• For severe refractory urticaria- consider 2nd line-leukotriene
modifiers, hydrochloroquine, cyclosporine,methotraxate

DIFFERENCIAL DX
Insects bites(Papular urticaria)
Urticarial pemphigoids
Acute eyelid contact
Angioedema
Synonym(Quincke edema, angioneurotic edema)
Angioedema is a reflection of transient edema of the deep dermal,
subcutaneous and submucosal tissues
• It is associated with urticaria in 50% of cases and may be complicated by life-
threatening anaphylaxis.
• Angioedema occurs in 1 to 2 per 1000 new users of ACE inhibitors and is
due to an accumulation of bradykinin
• Painful rather than pruritic, larger and less well-defined than wheals
• last for 2 to 3 days.
• Severe cases of angioedema may start within a few minutes after drug
administration.
• However, in the case of ACE inhibitor-induced angioedema, lesions may
appear from 1 day to several years after starting the drug;
• Most appear within the first year. African-Americans and women are at
increased risk for developing ACE inhibitor-induced angioedema
• The major drugs implicated in angioedema, are penicillins and ACE inhibitors
and NSAIDs.
• Radiographic contrast media and monoclonal antibodies
• Angiotensin II receptor antagonists they are also associated with
angioedema, albeit less frequently
• Drug-induced angioedema may actually represent an unmasking of another
cause for angioedema, e.g. acquired C1 inhibitor deficiency due to
autoimmune or lymphoproliferative disorders.
Classifications
• Hereditary AE
• Autosomal dominant disorder in which there is either mutation in
gene codding for C1 esterase INH or dysfunction of F XII.
• Type 1= def of C1 INH
• Type 2=dysfunction of C1 INH
• Type 3=Normal C1 INH but abnormal FXII-overactivated
• Acquired angioedema
• Autoantibodies against C1 esterase inhibitor (C1 INH)
Clinical presentation
• Is an acute, asymmetric, pale or pink, subcutaneous swelling
involving the face
• Involvement of the oropharynx, larynx, and epiglottis can lead to
impaired swallowing and stridor.
• Occasionally, in drug-induced angioedema, there is edema of the
intestinal wall with abdominal pain, nausea, vomiting, and diarrhea
• Chronic pain due to chronic inflammation
• Natriuresis → hypotension
• In acute state-swelling lips, eyes and face
• Other parts-respiratory(laryngeal swelling-life threatening
condition), GI mucosa
 TREATMENT
DRUGS NOT TO BE USED
• C1 INH protein infusion
• ACE inhibitors
• Icatiban –bradikinin receptor
blocker • Antihistamines
• Ecallantide-kallikrein inhibitor • Steroids
• Nasotracheal intubation- laryngeal • Epinephrine
edema
• NB; AAE-treat underlying cause-
paraproteinemia & lymphoma
• Prophylaxix
• Danazole- atenuated
androgen
• FFP
• C1 INH Infusion
 Anaphylaxis
• Anaphylaxis consists of an acute life-threatening reaction that occurs
within minutes of drug administration usually parenteral.
• It occurs in about 1 per 5000 exposures to penicillin and combines skin
signs (urticaria and/or angioedema) with systemic manifestations such
as hypotension and tachycardia
• Occasionally, there is hypotension in the absence of cutaneous lesions.
• In severe cases, the patient becomes unconscious as a result of
cardiovascular shock and may die.
• Antibiotics, in particular the penicillins/aminopenicillins but also
cephalosporins and quinolones
• Muscle relaxants (e.g suxamethonium), acetaminophen, and gadolinium-
based contrast media17.
• Anaphylaxis can also be seen following exposure to latex while
anaphylactoid reactions are usually seen with NSAIDs and radiocontrast
media
• Rarely, anaphylaxis occurs following cutaneous injections (e.g. local
anesthetics) or topical applications of medications (e.g. bacitracin,
chlorhexidine)
 TREATMENTS
• Prompt discontinuation of the offending drug
• SC epinephrine (adrenaline)to reduce the body s allergic response
• IV antihistamines and systemic corticosteroids to reduce inflammation of
the air passage and improve breathing
• Oxygen therapy to help the breathe
• A beta agonist (such as Albuterol) to relieve breathing symptoms
• Of note, patients taking β-blockers may have a limited response to
epinephrine.
• Strict avoidance of the drug in the future.
 Exanthematous Drug Eruptions
Synonyms: ( Morbilliform drug eruption , Maculopapular drug eruption ,
Urticarial drug eruption .
• Are the most common adverse drug reactions affecting the skin.
• The primary underlying patho mechanisms are most likely immunologic
complex, and cell-mediated.
• The drug or drug-peptide hapten presented by dendritic cells to T lymphocytes
can either bind covalently or noncovalently to MHC molecules12.
• CD4+ and CD8+ T cells that strongly express perforin and granzyme are then
recruited and their cytotoxic activity leads to death of keratinocytes
• Overall, most drug classes can induce an exanthematous eruption in ~1% of
treated patients.
• Higher risk medications (>3% of treated patients develop an eruption) include
aminopenicillins, allopurinol, sulfonamides, cephalosporins, and aromatic
anticonvulsants.
• Viral infections like Rhinovirus increase the incidence of drug reactions.
• The frequency of aminopenicillin induced exanthematous eruptions in
patients with infectious mononucleosis ranges from 33% to 100%
• One theory is that reactive drug metabolites disturb the balance between
cytotoxic and regulatory immune responses, leading to a cytotoxic reaction
that targets virally infected keratinocytes
• A morbilliform eruption classically begins 7 to 14 days after the initial drug
administration.
• Symmetrically distributed erythematous macules, papules and/ or urticarial
lesions initially appear on the trunk and upper extremities; over time they can
become confluent
• The eruption is typically more polymorphous than a viral exanthem, due to
dependency, the lesions on the distal lower extremities become petechial or
purpuric
• Mucous membranes are usually spared but pruritus and a low-grade fever are
often present
• There may also be annular plaques or atypical “target” lesions, leading to a
misdiagnosis of erythema multiforme.
• Once the offending drug is discontinued, the eruption gradually resolves
over one to two weeks, without complications and/or sequelae.
• However, for 1 to 3 days immediately following discontinuation of the
responsible medication, an increase in extent and intensity may be
observed.
Fig. 21.3 Morbilliform (exanthematous) drug eruptions. A Erythematous
papules and urticarial lesions with confluence on the midback induced by
amoxillin. B Due to dependency, lesions on the distal lower extremities can
become petechial or purpuric. C Pink papules and annular lesions on the
forehead due to phenobarbita
 Signs and symptoms
• Include edema of the face, pustules, vesicles, dusky or painful lesions, skin fragility, mucous
membrane involvement, and marked peripheral blood eosinophilia
• usually appears 1–2 weeks after starting the drug, but it may occur up to 1
week after stopping it
• usually first appears on the trunk and then spreads to the limbs and neck.
The distribution is bilateral and symmetrical.
• The primary lesion is a pink-to-red flat macule or papule.
• Annular, targetoid, urticaria-like or polymorphous morphology may occur.
• Lesions mostly blanch with pressure but may be non-blanchable (purpuric)
on the lower legs.
• Axilla, groin, hands and feet are usually spared
On re-exposure to the causative (or related) drug, skin lesions appear within
1–3 days.
Drug eruptions are favored in adults whereas viral exanthems are favored in children
DIAGNOSIS
They include
• Routine blood count, liver and kidney function tests, C- reactive protein
• Serology for infections that can cause similar rashes
• Skin biopsy which shows interface dermatitis mixed perivascular
infiltration and other histopathological features
• Eosinophilia is supportive but not diagnostic
 Treatment
• Discontinuing the offending agent .
• Topical antipruritics and corticosteroids may help to alleviate pruritus
• “Treating through” If the reaction is mild, and the drug is essential and
not replaceable, obtain a specialist opinion whether it is safe to
continue the drug before doing so.
• Apply emollients and potent topical steroid creams.
• Apply wet wraps for very red, inflamed skin.
• Antihistamines are often prescribed, but in general they not very
helpful.
• The eruption will disappear, but a few patients may experience progressive worsening,
leading to erythroderma.
• Desensitization may be considered in HIV-infected patients who require sulfonamides
Differential diagnosis
Includes
• Measles.
• Rubella
• Scarlet fever
• Non-specific toxic erythema associated with infection.
• Kawasaki disease.
• A viral exanthem (e.g. Epstein–Barr virus [EBV], enterovirus,
adenovirus, early HIV infection, human herpes virus type 6 [HHV-6]
• Connective tissue disease acute
graft-versus-host disease
complications
• Patients should be hospitalized for specialist assessment
and supportive care
• Drug hypersensitivity syndrome
• Stevens Johnson syndrome – toxic epidermal necrolysis
(SJS/TEN)
• Acute generalised exanthematous pustulosis (AGEP)
• Erythroderma (whole-body involvement) High
fever ,significant malaise
• Evidence of other organ involvement (eg liver, kidneys,
lungs, blood)
 Neutrophilic Drug Eruptions
Acute generalized exanthematous pustulosis (AGEP)
Synonyms: ( Pustular drug eruption , Toxic pustuloderma )
• Is an acute febrile drug eruption characterized by numerous small, primarily non-
follicular, sterile pustules arising within large areas of edematous erythema.
• More than 90% of cases of AGEP are drug-induced, but its incidence has been
underestimated, in part because the eruption may be misdiagnosed as pustular
psoriasis.
• Occasionally, AGEP is due to other causes, e.g. enteroviral infection, exposure to
mercury.
• HLA-B5, -DR11 and -DQ3 have been found more frequently in patients with AGEP,
and mutations in IL36RN may be a risk factor as well
• Prior sensitization (including contact sensitization) would explain the short
interval(<4 days) btn drugs administration and the onset of eruption as this suggest
an immunological recall phenomenon
• Blood neutrophilia and the accumulation of neutrophils within the lesions
suggest the release of neutrophil activating cytokines by drugs specific T
lymphocyte eg(IL-3, IL-8, IL-17, G-CSF), but the precise underlying mechanisms
of AGEP are still unknown.
• Clinically, AGEP is characterized by a high fever, with skin lesions beginning on
the face or in the major intertriginous zones (i.e. axillae and groin), followed by
dissemination over a few hours
• . Numerous small (<5mm) primary non follicular ,sterile pustules arise within
large areas of edematous erythema
• There may be associated burning and or pruritus Edema of the face
or hands purpurar vesicles ,bullae erythema multiform like lesions
and or mucous membranes involvements are observed in 50% of the
patients
• Lesion typically last from 1-2 wks and are followed by superficial
desquamation .
• In a series of 58 patients systemic involvement was detected
• In a minority of 17%of pts with the primary sites being the liver and
kidneys followed by the lungs (acute respiratory distress)
• A validation score developed by the EuroSCAR study group assists in
categorizing cases as definite, probable, possible, or no AGEP40.
• AGEP must be differentiated from acute pustular psoriasis of the von Zumbusch
type
• Common exanthematous drug eruptions may have a few pustules, but they are
usually follicular
• In severe forms of AGEP, the confluence of the pustules and subsequent
superficial epidermal detachment may lead to confusion with TEN
• The presence of subcorneal pustules in biopsy specimens allows one to
distinguish between the two entities.
• Responsible drugs for AGEP include: (1) antibiotics, e.g. aminopenicillins,
cephalosporins, clindamycin,, pristinamycin; (2) CCB e.g. diltiazem.
TREATMENT
Withdrawal of the responsible drug
topical corticosteroids and antipyretics.
 Bullous Eruptions Fixed drug eruption
• In fixed drug eruptions (FDE), lesions develop from a few days to two weeks
after the initial exposure
• . With subsequent exposures, they appear within 24 hours
• Clinically, one or a few, round to oval, sharply demarcated, erythematous and
edematous plaques
• Sometimes they have a dusky violaceous hue or develop vesiculobullae and
become erosive due to epidermal detachment
• common sites being the lips, face, hands, feet, and genitalia.
• Over several days, the lesions fade and often leave residual post inflammatory
brown pigmentation
• Upon re administration of the causative drug, lesions recur in exactly the same
sites. With each subsequent recurrence, additional sites of involvement may
appear or the number of lesions may remain constant.
• The presence of numerous lesions is referred to as generalized bullous FDE
and it may be difficult to distinguish from erythema multiforme or SJS (when
the oral mucosa is also involved
• A non-pigmenting variant of FDE, occurring primarily after administration of
pseudoephedrine
• It has been also observed with other drugs, e.g. NSAIDs, acetaminophen,
tetrahydrozoline (eye drops)
• Linear FDE is a rare variant that may be confused with linear lichen planus.
 Clinical variants of fixed drug eruption
• Mucosal fixed drug eruption
• Involves lips, tongue, hard palate, genital mucosa
• Blisters and erosions are common
• Can be isolated/localised or may occur with cutaneous lesions
• Oral mucosal lesions commonly due to cotrimoxazole and naproxen
• Genital mucosal lesions: glans penis – cotrimoxazole; vulva – NSAIDs.
 Complications
• Blisters and erosions
• Post-inflammatory hyperpigmentation
• Recurrence
• Cross-reaction with other medications
• Generalised bullous fixed drug eruption can be complicated by fluid
loss, electrolyte imbalance, and secondary infection.
Investigations :
• Skin biopsy — shows an interface dermatitis in an early lesion with
scattered apoptotic keratinocytes, vacuolar degeneration,
dermal oedema.
• Oral challenge test —
• Patch test — using the suspected drug in soft paraffin applied to the
lesion site is positive in 50% of cases.
 Differential diagnosis
• Insect bite reaction,
• Bullous pemphigoid
• Targetoid lesions — erythema multiforme
• Multiple bullous lesions —
Stevens-Johnson syndrome/toxic epidermal necrolysis
• Oral lesions — herpes simplex, aphthous ulcer,
oral autoimmune blistering diseases
 Treatment for FDR
• Discontinuation of suspected medication
• Avoiding implicated medication indefinitely
• Topical steroids/systemic corticosteroids
• Generalised bullous fixed drug eruption requires intensive care or
burns unit
 The drugs most frequently If there is a single lesion, the DDX
associated with FDE include includes
antibiotics • A spider or arthropod bite
• Sulfonamides, reaction
• Tetracyclines When there are multiple lesions,
• β-lactams, it includes
• fluoroquinolones, • Erythema multiforme and
SJS/TEN. Genital and periungual
• Macrolides) lesions may be misdiagnosed as
• NSAIDs, acetaminophen, aspirin, a recurrent HSV infection or
barbiturates, paronychia
• Dapsone,
• proton pump inhibitors and
azole antifungal drugs
 Refferences
• Up to Date
• Bolognia 4th Edition

•THANKS