Cutaneous Drug Reactions (3) Flashcards
Which drug classes are more commonly known for inducing skin reactions?
NSAIDs
Antibiotics
Antiepileptics
Drug related skin reaction severity background
Most drug related skin eruptions are NOT serious
But they can be severe or life threatening
Serious reactions include:
angioedema, erythroderma, Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN)
In most cases drug eruptions are reversible - resolve after causative drug is withdrawn
What can cause a cutaneous drug reaction?
Any medicine the patient is currently taking or has recently been exposed to including…
-prescribed and over-the-counter medicines
-herbal or homoeopathic preparations
-vaccines
-contrast media
Note - non drug components (inactive ingredients) may cause hypersensitivity reactions in patients as well
2 Mechanisms of cutaneous drug reactions, which one is more common?
Can be immunological or non-immunological
Non-immunologic causes are more common
Immunological cutaneous drug reaction mechanism
Immunological - hypersensitivity reactions (Type I-IV)
-drugs or their metabolites act as haptens and bind to peptides, modifying them to become immunogenic
-this induces a cell mediated or humoral immune response
-subsequent exposures can results in more severe reactions (because the immune system develops memory, so it reacts faster and stronger the second time)
Nonimmunological cutaneous drug reaction mechanism
-could be due to hereditary enzyme deficiencies or idiopathic
-could be dose dependent (cumulation)
-could be due to photosensitivity - formation of toxic products due to the effect of UV radiation
-could be direct physical/chemical toxicity (due to irritant)
-pseudo immunologic: causes direct release of cytokines (Mast cell degranulation, alternate complement system, cycloxyginase inhibitors)
-could be due to drug interactions
How does the route of administration have an effect on potential to induce cutaneous reaction?
In general topical application has the greatest potential to induce allergy, followed by parenteral, and then oral administration
Certain patient groups appear to be predisposed to cutaneous drug reactions… (2)
Patients with altered immune status
-like those with viral infections - Epstein Barr or HIV
Patients with altered drug metabolism
-could be due to organ impairment or genetic components
Timing and diagnosis
Timing of skin reactions is a useful diagnostic tool
-in general the onset is within a few weeks of starting the causative drug
But can vary…
Hypersensitivity reactions to penicillin can occur several weeks after stopping drug
Skin eruption seen with beta blocker generally occurs after many months of treatment
Gold can also lead to very late reactions
Guidelines for assessing/diagnosing cutaneous drug reactions
Exclude other causes (especially infections)
Examine interval between drug introduction and induction
Determine if similar reactions occurred previously with same/similar compounds
Note any improvement after withdrawal of drug and any reaction after readministration
Biopsy is helpful in defining the type of reaction pattern but not in identifying the offending drug
CBC - elevated eosinophil count, lymphocytosis with atypical lymphocytes
Skin test helpful in IgE mediated reaction (penicillin)
Skin prick or blood tests - not usually helpful in skin manifestations of allergy
-skin prick tests are risky - due to possibility of a late phase reaction
Skin test/RAST for penicillin allergy consideration
This can only detect a IgE mediated allergy (type 1)
Penicillin allergy can be type 1-4
(so it may not detect the other type of allergy)
General treatments of cutaneous drug reactions
For pruritus
-calamine lotion or systemic antihistamines
For inflammation and itch
-topical corticosteroids
For more serious reactions
-systemic corticosteroids
Exanthematous drug eruptions
Aka morbilliform or maculopapular drug rashes
Often pruritic
Typically appear 4-21 days after starting offending medication
Symmetrically distributed pink/red macules and papules that spread rapidly and may coalesce
Patients with HIV or bone marrow transplant are at increased risk of developing this
Management of exanthematous drug reaction
Identify and discontinue causative agent - most important!
Symptomatic treatment
-antipruritic agents
-topical steroids
Signs with exanthematous drug reaction that should alert clinician of possibility of a severe reaction… (5)
-mucous membrane involvement
-temperature greater than 38.5 C
-blisters
-facial edema and erythema
-lymphadenopathy (swollen lymph nodes)
2 types of ampicillin rashes (and the difference regarding future use)
Urticarial reaction - mediated by skin sensitizing antibody
Exanthematous maculopapular reaction - no allergic basis established, much more common
Ampicillin and other penicillins should not be given to patients who have had previous urticarial reactions while taking ampicillin.
Ampicillin may safely be given to patients who have previously had a maculopapular ampicillin rash.
Urticaria
Hives
-red, itchy welts
Drug-induced urticaria is the second most common form of cutaneous drug reaction after exanthematous reactions
Hives typically fade in less than 24 hours and recur in another area
Angioedema
Urticarial swelling of deep dermal and subcutaneous tissues and mucous membranes
-this can be a life threatening reaction
Mechanisms of drug induced urticaria (3)
- Anaphylactic and accelerated reactions (immunological histamine release)
-IgE dependent immediate reaction (minutes to hours) and accelerated reaction (late phase reaction) - type 1 hypersensitivity
-penicillin is most common cause - Nonimmunological histamine release
-reaction can occur within minutes
-drug exerts direct action on mast cell or other pathways (causing histamine release) - Serum sickness
-circulating immune complexes cause serum sickness (type III hypersensitivity)
-urticaria occurs 4-21 days after drug ingestion
Serum sickness presentation
Type III hypersensitivity
Presents with: fever, malaise, and lymphadenopathy (most common); arthralgias, urticaria, and morbilliform skin eruption also possible
-the skin eruptions (urticaria) is usually preceded with a prodromal phase (consisting of these flu like symptoms)
aspirin/NSAID induced urticaria
Anaphylactoid
Mechanism is thought to be due to cyclooxygenase inhibition which results in augmented production of leukotrienes
-arachidonic acid is converted by cox enzymes but also by lipoxygenase (LOX) to generate leukotrienes
-so when cox enzymes are inhibited, more of the arachidonic acid goes down the LOX pathway, producing more leukotrienes which result in the anaphylactoid reaction
Antihistamines are therefore less effective for treating these reactions
ACE inhibitor induced angioedema
ACE inhibitors are one of the most common causes of angioedema
-higher occurrence in African Americans
Mechanism is believed to be due to increased levels of bradykinin
So- this is NOT immunologic induced and therefore NOT a true allergy (it should however definitely still be recorded in the patients chart)
Opiates
Nonimmunologic histamine releasers
-induce mast cells on skin to generate by a direct effect on the cell and release histamines
(other non immunologic histamine releasers are polymyxin B, lobster, and strawberries)
What are the 4 SCAR (severe cutaneous adverse drug reactions)
- SJS (Stevens-Johnson Syndrome)
- TEN (Toxic epidermal necrolysis)
- DRESS (Drug reaction with eosinophilia and systemic symptoms aka drug induced hypersensitivity syndrome)
- AGEP (Acute generalized exanthemous pustulosis)
Drug reaction with eosinophilia and systemic symptoms (DRESS) causes
Pathogenesis - hereditary or idiopathic
Common causes:
-allopurinol
-antiepileptics (phenytoin, carbamazepine, phenobarbital)
-sulfonamides (antimicrobials, dapsone, sulfasalazine)
-vancomycin
What type of reaction is DRESS?
Immune mediated - type 4 hypersensitivity
-so it is a delayed hypersensitivity - presents ~3-8 weeks after drug initiation
DRESS presentation
Diffuse maculopapular rash
With lab abnormalities including eosinophilia and increased liver function tests (LFTs)
Presents as a triad of…
1. rash
2. eosinophilia
3. internal organ involvement
What are 2 severe forms of erythema multiforme?
SJS and TEN
-they both have mucus membrane involvement
-TEN has over 30% BSA involvement
Erythema multiforme and SJS
Can result from several underlying causes
-most cases are due to herpes virus infection
-but can be drug induced
Patients typically have fever and flu like symptoms before developing skin eruption
May present with blisters, papular lesions, and redness
Characteristic sign - concentric rings (looks like bullseye)
Involvement of mucosa is common (mouth, eyes, genitalia) - then this is called SJS
SJS presentation
fever, malaise, myalgia, arthralgia, and extensive erythema multiforme of the trunk and face.
-frequently drug induced
Toxic epidermal necrolysis (TEN)
More severe than SJS
Highest mortality (30-35%)
Considered a medical emergency
Characterized by widespread full thickness epidermal necrosis with involvement of over 30% BSA (if its less than that, its considered SJS)
Involvement of mucus membranes as well!
What type of reactions are SJS and TEN
Type 4 hypersensitivity (immunologically mediated)
Which drugs most commonly cause SJS?
Penicillins, tetracyclines, sulfonamides and NSAIDs
Which patient population is more susceptible to SJS?
Patients with HIV when taking cotrimoxazole.
Which patients are most susceptible to TEN? (3)
Patients with HIV, lupus, and bone marrow transplant
Which antiepileptic causes severe skin reactions including SJS and TEN?
Lamotragine
Treatment of TEN
Protection of exposed dermis and eroded mucosal surfaces
Managing fluid and electrolyte balance
Nutritional support
Close monitoring for infection - antibiotic therapy should be given at first signs of sepsis
Fluid rehydration is essential
use of systemic corticosteroids for TEN is controversial
Acute Generalized Exanthematous Pustulosis (AGEP) presentation
Acute onset following drug intake
Presentation:
-fever
-numerous nonfollicular, sterile pustules on an erythematous background predominantly in the folds and/or on the face
-elevated levels of blood neutrophils (makes sense since there is lots of puss)
AGEP most common causes (4)
Calcium channel blockers
NSAIDs
Anticonvulsants
Antimicrobials (particularly those with beta lactam and macrolide properties)
Fixed drug eruption presentation
eruptions that occur at the same site each time the same drug is administered
eruption can appear within day to few weeks of ingesting the drug and can occur on any part of skin or mucus membranes
- frequently occurs at mucocutaneous junctions (where mucosa transitions to skin)
-hands, feet, tongue, penis or perianal areas are most frequently affected
consists of reddish, dusky purple, or brown round/oval lesions
sometimes features blisters (bullae or vesicles)
initially one lesion appears, more may follow
Fixed drug eruption mechanism
Caused by activation of cytotoxic T lymphocytes in the basal layer by drugs
-so this is immune based
-every time the drug is taken the reaction occurs in the same place because of memory that has been established by the t cells in the basal layer in that location
What are common causes of fixed drug eruptions?
NSAIDs
Tetracyclines
Sulfa drugs
Phenacetin
hypnogenics
food additives
Which drugs can cause or exacerbate acne?
Corticotropin (ACTH)
corticosteroids
androgens (in females)
oral contraceptives
haloperidol
isoniazid
phenytoin
lithium
Which agents can cause psoriasis eruptions?
Interferon treatment (cause it in patients with or without history of psoriasis)
Beta blockers (worsen psoriasis)
Effect of chloroquine and hydroxychloroquine on psoriasis is variable
Vasculitis mechanism
Inflammation of blood vessels
Drugs can cause both systemic vasculitis with cutaneous manifestations and cutaneous vasculitis with other organ involvement
Exact mechanism is unknown - appears to be a type 3 hypersensitivity - immune complex deposition in postcapillary blood vessels
Vasculitis presentation
Purpuric lesions that vary in size and number - most commonly on lower extremities
May be limited to skin or involve multiple organs including kidneys, liver, joints, or CNS
Which drugs cause vasculitis?
Allopurinol
Beta lactam antibiotics
Sulfonamides
Thiazide diuretics
Phenytoin
Vancomycin
Which drug is associated with a hypersensitivity syndrome that typically manifests as a vasculitis involving one or more organ systems
Propylthiouracil (PTU)
Blistering drug eruptions
pemphigus and bullous pemphigoid are autoimmune disorders
blistering drug eruptions consist of drug induced pemphigus and pemphigoid
Caused by drugs containing thiol or sulfhydryl group in their molecular structure (penicillamine or captopril)
Lichenoid drug eruptions
Resemble idiopathic lichen planus
Caused by arsenicals used to treat syphilis
small, shiny, purplish polygonal papules sometimes with white lines known as Wickham’s striae
Photosensitivity
Reaction that occurs when a photosensitizing agent in or on the skin reacts to normally harmless doses of UV or visible light.
May be due to topical or systemic drugs
Drug induced photosensitivity is classified as either phototoxic or photoallergic - photo-allergy is immune mediated, phototoxicity is not (causes direct cell damage)
Sunscreens, fragrances, and occasionally soaps may also cause photoallergic reactions
Patients taking potent photosensitising agents on a long-term basis should be warned of the problem and counselled on the need to avoid direct sunlight, to wear protective clothing and to use sunblocks
Which drugs are associated with photosensitivity?
Several antibiotic classes - sulfonamides, tetracyclines, quinolones
Amiodarone
Chlorpromazine (at high doses)
Photo-allergy
Less common than phototoxicity
Occurs when UV energy causes drug to bind as hapten to protein on epidermal cells creating antigen that sensitizes nearby lymphocytes - so this is immune mediated (true allergy)
Unlike phototoxic reactions, photo-allergy may spread beyond irradiated areas
-since it is immune based, the immune cells can spread to other parts of the body
-whereas phototoxicity causes direct cell damage to the parts exposed to light
Pigmentary disorders
Changes in skin color
May occur after lichenoid eruptions or fixed drug eruptions
Drug-induced alteration in skin color may result from increased (or more rarely decreased) melanin synthesis, increased lipofuscin synthesis, or cutaneous deposition of drug-related material
Examples of drugs that cause pigmentary disorders
Hyperpigmentation - long term use of minocycline, imipramine, imatinib
Brown patchy pigmentation - prolonged use of phenytoin
TRUE allergies are ________________ mediated cutaneous skin reactions
immunologically mediated
(involves antibody or immune cells)
A rabbit hunter in Arkansas is diagnosed with ulceroglandular tularemia (also known as rabbit fever) and treated with streptomycin. Within a week, he returns to the hospital. The tularemic papule, lymphadenopathy, and bacteremia have resolved, but he has now developed a raised, itching skin rash and a fever. The drug was discontinued, and the symptoms subsided. What was the role of streptomycin in this case?
Is it an antigen?
No! The streptomycin acts as a hapten
Antibodies recognize proteins
The streptomycin acts as a hapten, covaletnly binds to proteins and alters them making them immunogenic proteins - this is what the antibody will recognize
A 62-year-old man presented at the Accident and Emergency department with unilateral swelling of the face, lips, jaw line and cheek. About 24 hours ago he had noticed some swelling of his cheek, and since then it had gradually progressed and there was now massive swelling of his lips and face. He described having experienced several previous episodes of localised swelling of the face over the last 6-12 months. Medical history included hypertension and depression.
Current drug therapy:
● Enalapril 10mg daily
● Bendroflumethiazide 2.5mg daily
● Citalopram 20mg daily
He had been taking all of these medicines for at least 5 years and had not taken any others recently.
What condition do the symptoms suggest?
Which of the patient’s medicines is most likely to be responsible?
Is this a true allergy?
The condition is angioedema
The agent causing it is likely enalapril (ACE inhibitor)
This is NOT a true allergy (it is caused by an increase in bradykinin by the ACE inhibitor, it is NOT immune mediated) - however it can still be life threatening and should be noted in the patient’s chart
Ms. B, a 34-year-old woman, presented to her doctor with a painful pruritic rash on her arms, legs and neck. The rash had begun within a day or so of sun exposure and was not completely confined to sun-exposed areas. The affected skin was erythematous, with some blistering vesicles. Ms. B had no recent use of any new skincare products or cosmetics. There was no significant medical history. Her only prescribed medication was the combined oral contraceptive pill, which she had been taking for the past 10 years. Ms. B also reported taking ibuprofen when required for painful periods; she had been taking it over the last 48 hours.
1.What type of drug eruption do the symptoms suggest?
2.How should the patient be managed?
- Photo allergy - immune mediated (since it was not confined to sun exposed areas, this can happen with photo allergy but not phototoxicity)
- The drug responsible for this is the NSAID (ibuprofen) - stop this and switch to acetaminophen instead
Co-administration of lamotragine and _______________ can increase the risk of an allergic reaction
Valproate
Immediate vs non immediate drug allergies
Immediate
-type 1 - IgE mediated
-initially reaction may happen in 5-7 days, but upon first re-exposure can occur within an hour
Delayed/nonimmediate
-typically mediated by t cells
-occur weeks-months after initial exposure
Which cutaneous drug eruptions is type 1 mediated allergy?
Urticaria (hives)
WM is a 58 year old female with a history of seizures. She began therapy with phenytoin ~4 weeks ago. Today she presents to the hospital with a diffuse maculopapular rash, eosinophilia (1,700 cells/mm3) and increased LFTs. All other labs are within normal limits. Temp 100.2F
What kind of reaction is WM experiencing?
DRESS
Which anticonvulsants have cross reactivity? (7)
Aromatic anticonvulsants:
-Carbamazepine
-Oxcarbazepine
-Lamotragine
-Phenytoin
-Phenobarbital
-Felbamate
-Zonisamide
BV is a 18 year old who began taking minocycline ~ 2 weeks ago for treatment of acne. Today she presents to the hospital with an urticarial rash. For the past 48 hours she reports subjective fever and arthralgias. Lab results are pending.
What kind of reaction is BV experiencing?
Serum sickness
-this is a type 3 hypersensitivity immune reaction
-occurs 7-14 days after drug exposure
-presents with fever, malaise, and lymphadenopathy (most common); arthralgias, urticaria, and morbilliform skin eruption also possible
AZ is a 45 year old male with bipolar 1 disorder. He began carbamazepine ~ 1 week ago. Today he presents to the hospital with fever (temp 102.4 F) and a blistering rash that covers ~15% of his body including his mucus membranes.
SJS
-mucus membranes are involved but it is only 15% (if it were over 30% then it would be TEN)
(technically <10% is SJS, > 30% is TEN, 10-30% is SJS-TEN overlap)
Long term consequences of SJS/TEN
permanent visual impairment, temporary nail loss, cutaneous scarring, and irregular pigmentation
TEN: systemic organ involvement, including acute kidney failure, neutropenia, respiratory failure, and death
HF is a 61 year old male who started therapy with diltiazem 3 days ago for heart rate control in atrial fibrillation. Today he presents with fever and a pustular rash. Laboratory abnormalities include high neutrophils.
What type of reaction is HF experiencing?
AGEP
-puss and high neutrophils
PJ is a 78 year old female presenting today with purpuric lesions on the lower extremities. She started sulfamethoxazole/trimethoprim ~5 days ago for treatment of a complicated urinary tract infection. Lab values show an increase in Scr from 0.9 to 1.2 mg/dL
What type of reaction is PJ experiencing?
Vasculitis
-purpuric lesions on lower extremities and kidney complications
