Drug Induced Dermatologic Disorders/Toxicities

When patients present with dermatologic disorders, including a suspected cutaneous adverse reaction, what standard approach to assessment should be used?

When patients present with dermatologic disorders, including a suspected cutaneous adverse reaction, what standard approach to assessment should be used?

1.                   Correct identification of the drug, its dose, and its duration of administration

2.                   Exclusion of other primary or secondary lung diseases

3.                   Temporal eligibility: Appropriate latent period (exposure to toxicity)

4.                   Recurrence with rechallenge (not commonly performed)

5.                   Singularity of drug (ie, other drugs the patient is taking)

6.                   Remission of symptoms with removal of the drug

7.                   Characteristic pattern of reaction to a specific drug (perhaps previously documented)

8.                   Quantification of drug levels that confirm abnormal levels (especially for overdoses)

9.                   Degree of certainty of drug reaction (ie, causative, probable, or possible)

True/False: Drug induced skin reactions are only caused by drugs given systemically.

False: systemic or topical medications may cause drug induced skin reactions and can be irritant ( if topical) or allergic ( topical or systemic route) in nature.

What is irritant reactions?

Irritant reactions are localized (irritant contact dermatitis).

What are examples of things that can cause irritant reactions?

Examples include chemical vaginitis, such as those resulting from vaginal douches, spermicides, imidazoles; and vesication (blistering), produced by drug extravasation, as with chemotherapy agents like anthracyclines.

What are allergic reactions?

Allergic reactions depend on inducing an immune response from the host; thus, the reaction may be systemic rather than limited to skin manifestations. Furthermore, even if the first reaction is a skin manifestation, on the next or subsequent exposures the reaction may become systemic.

Describe the 4 types of hypersensitivity reactions and classify cutaneous drug eruptions?

Type	Description	Type of Cutaneous Drug Eruptions	Examples
Type I	IgE-mediated. Activation of mast cells and basophils resulting in the release of chemical mediators (histamine, leukotrienes, etc.)	Urticarial	Urticaria, angioedema, anaphylaxis
Type II	Cytotoxic reactions. IgG or IgM-mediated. Antibody binding to cells with subsequent binding of complement and cell rupture.	N/A	Hemolytic anemia, autoimmune thrombocytopenia
Type III	Immune complex formation. Antigen-antibody immune complexes usually with IgG or IgM. Deposition of immune complexes in the skin, kidneys, joints, GI tract, etc.	N/A	Serum sickness, vasculitis
Type IV	Delayed cell-mediated hypersensitivity reactions. T-cell mediated. Can be further divided into subtypes based on Tlymphocyte subset and cytokine expression profiles.	Blistering (SJS/TEN) Exanthematous (DRESS)	Allergic contact dermatitis, SJS/TEN, DRESS

What are 3 severe cutaneous adverse reactions to drugs?

Stevens-Johnson syndrome / toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS).

What are the clinical signs/symptoms that may occur with a skin reaction and is indicative of a more serious disorder?

-Fever

How are drug induced dermatologic toicities diagnosed?

In clinical practice, a diagnosis of drug-induced skin reaction is often a diagnosis of exclusion (ie, the diagnosis is reached after other possible diagnoses have been ruled out). Potential foods and other causes have to be thoroughly investigated, and a detailed patient interview is important.

Different type of dermatologic disorders:

	Stevens-Johnson Syndrome (SJS)/ Toxic Epidermal Necrolysis (TEN)	Urticaria/Angioedema	Drug hypersensitivity syndrome (DRESS)	Maculopapular Skin Reaction	Fixed Drug Eruptions
Type of Immunologic Reaction	Type IV	Type I	Type IV	Type IV
Timing	7 to 14 days of drug exposure	Minutes to hours after starting drug; Angioedema may be delayed days to months	1 to 4 weeks after starting drug, and the reaction may be fatal if not promptly treated	7 to 10 days after starting drug; resolve 7 to 14 days after discontinuation	Minutes to days and disappear within days, leaving hyperpigmented skin for months
Clinical Presentation	Febrile Blistering complex eruptions; tender or painful bullous formation, headache, and respiratory symptoms, that rapidly deteriorate. Lesions show rapid confluence and spread, resulting in extensive epidermal detachment and sloughing.	Afebrile Urticarial eruptions; Hives, extremely pruritic red raised wheals, angioedema, and mucous membrane swelling.  Early symptoms of angioedema of tongue and larynx include the urge to clear the throat, hoarseness, and throat “tightness.”	Febrile Exanthematous eruption, lymphadenopathy, and multiorgan involvement (including the kidneys, liver, lung, bone marrow, heart, and brain)	Afebrile Exanthematous eruption; erythematous macules and papules that may be pruritic	Pruritic, red, raised lesions that may blister with burning or stinging. Lesions may evolve into plaques; Recur in the same area each time the offending drug is given
Notes (if necessary)	Rare, severe, and lifethreatening; Marked loss of fluids; drop in blood pressure; electrolyte imbalances; and secondary infections, including Staphylococcus epidermidis and MRSA. Immediate hospitalization in ICU— preferably in reverse isolation—is warranted; SJS involves <10% of the body TEN involves >30%.		For allopurinol, several factors increase the risk of serious skin reactions: renal impairment, hypertension, and use of thiazide diuretics or excessive allopurinol doses (i.e., not dose adjusted for renal impairment).
Common Inciting Drugs (Top 4) Use Tables in Chapter and article	Sulfonamides, Allopurinol, Anticonvulsants (hydantoins, carbamazepine, barbiturates, lamotrigine), NSAIDs, nevirapine	NSAIDs, Chemo agents, ACEI, Penicillins, Sulfonamides, Xray contrast media, opiates	Allopurinol, Sulfonamides, Anticonvulsants (barbiturates, phenytoin, carbamazepine, lamotrigine), and dapsone.	Penicillins, Cephalosporins, Sulfonamides, and Anticonvulsants (barbiturates, phenytoin, carbamazepine, lamotrigine)	Tetracyclines, Barbiturates, Sulfonamides, Codeine, APAP, and NSAIDs

A 38-yr-old male patient was admitted to the neurosurgery department, where immediately after administration of an antiepileptic drug he developed sloughing of 8% of the epidermis, high fever, and the clinical picture of a severe burn patient. What type of dermatologic disorder do they have?

-Stevens Johnson Syndrome

A 62-year-old woman presented to the emergency department with diffuse erythematous rashes over her body following the second dose of oral TMP-SMX prescribed for uncomplicated lower urinary tract infection. The lesion started as painful erythematous macules, progressed into blisters followed by 35% diffuse exfoliation of the skin involving bilateral lower extremities, back, abdomen, and both forearms. What type of dermatologic disorder do they have?

-toxic epidermal necrolysis

A 75-year-old African American female patient with type 2 diabetes and dyslipidemia was admitted to the hospital with recurrent night episodes of the facial, lip, and tongue swelling. The patient denies any rash during these episodes and mentioned that self-medication with diphenhydramine did not relieve her symptoms. What type of dermatologic disorder do they have?

-urticaria/angioedema

A 70-year-old male patient had undergone endovascular coil embolization for an intracranial aneurysm and experienced a generalized seizure postoperatively. He had been given phenytoin. Six days later, the patient had complained of widespread pruritis with exanthematous macules and papules What type of dermatologic disorders do they have?

-Maculopapular Skin Reactions

A 54-year-old female patient was admitted to the hospital with complaints of fever, purpuric rashes over the body with itching mainly in the oral cavity and lips, and the extent to the upper back and lower limbs for three days. She had known complaints of Type 2 Diabetes, Systemic hypertension, Coronary artery disease with recent NSTEMI, Dyslipidemia, Psychosis (20y), and Chronic kidney disease. She had been taking Allopurinol for the past three months for hyperuricemia. What type of dermatologic disorder do they have?

Drug hypersensitivity syndrome (DRESS)

A 25-year-old woman received 10 doses of ibuprofen once a month for recurrent cramps related to her menstrual cycle. She was healthy but had a family history of atopic dermatitis. She noticed a red erythematous macule behind her right knee after taking her fourth dose of ibuprofen. With time, the macule faded, but a violet pigmentation developed. A month later, after taking another dose, she again developed two macules; one developed on exactly the same site and the other behind the left knee. Both patches were symmetrical and similar in appearance. Again, the patches faded and hyperpigmented areas developed. What dermatologic disorder do they have?

-fixed drug eruptions

A 16-year-old female patient with eosinophilic gastroenteritis was on steroid therapy for 2 weeks, three months ago. She presented with complaints of nausea and bilious vomiting with upper abdominal pain and loose stools for two days. She developed reddish pustular rashes which had spread over both the cheeks and forehead and on the shoulders on and off during the past 3 months. What type of dermatologic disorder do they have?

-Acneiform rash

A 45-year-old Caucasian man developed blue-grey hyperpigmentation on his face after sun exposure while taking amiodarone. What type of dermatologic disorder do they have?

-Hyperpigmentation

A 57-year-old hypertensive man developed telangiectasia, initially on the forehead and rapidly extending to the upper back, shoulders, and chest. The reaction occurred particularly during the summer. The reaction began one month after his antihypertensive medication had been altered from furosemide to hydrochlorothiazide. What type of dermatologic disorder do they have?

-Photosensitivity

What is the 1st line treatment to manage drug induced dermatologic disorders?

If a drug-induced skin reaction is suspected, the most important treatment (first step) in nearly all cases is discontinuing the suspected drug as quickly as possible and avoiding the use of potential crosssensitizers.  A short course of systemic corticosteroids may be needed in severe cutaneous cases. In a few instances, it may be possible to continue the offending drug and “treat through” the reaction10 (e.g., ampicillin-associated maculopapular skin rash). When discontinuing the offending drug, consider whether it needs to be replaced by an alternate non-cross-sensitizing drug (e.g., a different antibiotic or class of antihypertensive agent etc.).

What is the role of the pharmacist in prevention and treatment of drug induced dermatologic toxicities?

a. Complete a detailed medication history (prescriptions, OTCs, herbal products, tobacco, alcohol, and illicit drug use)

b. Educate patient on avoiding similar eruptions in the future

c.        Before starting any medication, patients should be educated about the potential adverse effects 

d.       Reporting suspected ADR to FDA (MedWatch program) www.fda.gov/safety/medwatch/default.htm

e.       Provide supportive care and symptomatic relief, including corticosteroids (topical and/or systemic), systemic antihistamines, if necessary, epinephrine, beta-agonists, and sunscreen