Complications of Antiepileptic Drugs - Block 1 Flashcards
What are the types of Dermatologic Drug Reactions?
Irritant: topical
Allergic: topical or systemic route
What kind of hypersensitivity is SJS/TEN?
Type 4: Delayed cell-mediated
What are the types of drug eruptions?
What are Severe Cutaneous Adverse Reactions to Drugs (SCARs)? Types?
Skin reactions accompanied by fever are generally more serious systemic disorders:
1. Dress
2. SJS
3. TEN
What is DRESS?
S/s
characterized by an extensive skin rash and fever
S/S: 2-8 weeks
- mortality rate is very high
What causes DRESS?
Exact pathogenesis is still unknown:
1. Mutations in genes encoding drug detox enzymes have a higher risk of DRESS
2. Reactivation of human herpes virus (Epstein barr and HHV6 and 7)
3. Ethnic predisposition with certain human leukocyte antigen (HLA) alleles
What is the proposed diagnostic marker for DRESS?
HHV-6
What is the relationship between carbamazepine and DRESS?
Chinese, Koreans, Japanese, & Europeans who express the HLA serotype (HLA-A*3101) have a higher risk of developing DRESS
What are presentation of DRESS?
Latency: later onset of fever, malaise, lymphadenopathy
Cutaneous and mucosal: maculopapular eruption -> coalescing erythema
* Target-like lesions
* Facial edema
* > half BSA
(50% of patients have mucosal involvement, but it is mild in comparison to SJS/TEN)
What are the lab presentation of DRESS?
- Fever ≥101.3
- Lymphadenopathy
- Hematologic abnormalities (Eosinophilia, leukocytosis, lymphocytosis, atypical lymphocytes)
- Liver, kidney, lung, heart abnormalities
What is the diagnostic approach to DRESS?
- New drug treatment (especially high-risk drugs/AEDs) within the last 2-8 weeks
- Presenting with systemic involvement
What are we looking for in DRESS through the assessment of drug causality?
- Prolonged latency
- Drugs that have been stopped can still be suspected
- Exposure to high-risk drugs
- Unlikely culprit if drug was taken for less than 2 weeks or more than 3 months
- Risk for drug accumulation can increase risk for DRESS (RENAL DOSING!)
What are the high risk drugs that cause DRESS?
Aromatic AED:
1. Carbamazepine
2. Phenytoin
3. Lamotrigine
4. Oxcarbazepine
5. Phenobarbital
1.
What is the tx goals for DRESS?
Identify and dc causative drug
What is the tx for DRESS?
ID and withdrawal of causative drug
* Avoid introduction of new drugs like aromatice drugs)
Supportive: Fluid, electrolyte, nutritional support, gentile skin care
What are examples of nonaromatic agents?
- VA
- Topiramate
- Gabapentin
- Keppra
Monitoring of DRESS Tx?
- Clinical, lab, imaging
- Timely consultation with specialists
What is mild DRESS? How do you treat it?
No organ involvement or mild liver involvement:
* Liver transaminases <3x ULN
* Tx symptoms
Tx for pruritis:
* Topical corticosteroids (high potency) BID-TID until resolution: Clobetasol, betamethasone
What is severe DRESS? How do you treat it?
- Lungs (dyspnea, abnormal CXR, hypoxemia)
- Kidneys (SCr > 1.5xbaseline & proteinuria or hematuria)
Tx: Glucocorticoids
* Moderate to high dose prednisone oral 0.5 to 1 mg/kg/day or equiv until clin improvement and normalization of labs
* Then slowly taper over at least 8-12 weeks
* alt. reg. -> methylprednisolone IV 200-500 mg daily x 2-4 days followed by prednisolone PO 1 mg/kg/day tapered over 8-12 weeks
* Systemic GCC may increase infection
What are the 2nd line for DRESS?
Cyclosporine have limited evidence
How do we prevent DRESS?
- Educate survivors on avoidance of offending drug
- Record drug allergy
- Avoid unnecessary drug tx
- Genetic screening for HLA alleles
What is SJS and TEN? How do they differ?
Severe cutaneous adverse reactions that causes extensive necrosis and detachment of the epidermis: mucous membrane affected >90% of patients at ≥2 sites
* Medical emergency
* Type 4 rx
RF of EN?
- HIV
- Connective tissue dx
- Malignancy
- Older adults
What medications cause SJS/TEN?
Strong: Lamotrigine, Carbamazepine, Phenytoin, sulfonamides, phenobarbital
Associated: Oxcarbazepine
Low risk: Levetiracetam
What is the protopathic bias?
Meds used to tx initial symptoms of SJS/TEN (e.g. cold/flu meds, abx) are erroneously implicated
What is timing of onset fro SJS/TEN?
Between 1 week to 1 month prior
Describe the mechanisms of SJS/TEN?
- Genetic predisposition
- Drug antigen presentation
- T-cell mediated response and immune dysregulation
- Release of cytotoxic mediators, death signals, and keratinocyte death
What are the pharmacogenomics associated with SJS/TEN?
- HLA B*1502 / carbamazepine - in Han Chinese, Thai, and Malay populations
- carriers of HLA B*1502 are at higher risk of phenytoin-induced SJS/TEN.
- Screening is recommended in Asian ancestry prior to initiating tx
What are the presentations of SJS/TEN?
Prodromal:
* Malaise
* Fever
* Myalgia
* Sore throat
* Conjunctivitis
Cutaneous lesions:
* Initially – exanthematous rash
* Start on face and thorax – then spread symmetrically
* Early lesions – ill-defined, purpuric spots, 2-ring targets, and flaccid bullae
What are the later signs of SJS/TEN?
- Extensive, sheet-like detachment and erosions occur
- Nikolsky sign is positive
- Edematous erythema on palms and soles
- Skin tenderness
What are Extracutaneous involvement and complications of SJS/TEN?
- Mucosal involvement: oral cavity
- Eye involvement: conjunctival hyperemia
- Bacteremia and sepsis
- GI involvement
- Liver injury
- Hematologic abnormalities
How do we diagnose SJS/TEN?
Dx must be suspected in anyone who presents with tender, extensive, mucocutaneous rash
Drug causality assessment:
Latency: 1-4 weeks of rx
Drug notoriety: drugs most frequently associated with SJS/TEN
Skin biopsy, labs, imaging
What occurs in the Acute, progressive phase of SJS/TEN?
- Fluid/electrolyte imbalances
- Increased metabolic demands
- Sepsis
- Hypothermia
- Organ decompensation
- Death
From dx arrest, the skin re-epithelizes over 7-21 days
What occurs during the first initial in-hosptial eval of SJS/TEN?
- ID and withdrawal of offending drug
- Assess severity/prognosis (SCORTEN)
- Pts with > 10% BSA detachment -> specialized units (e.g. burn / ICU)
How do you use SCORTEN?
- 0-1 dx not rapidly progressing may be treated in non-specialized wards.
- More severe disease >1 should be in ICU or burn unit
What is the supportive care for SJS/TEN?
- Wound care
- Fluid and electroly mgmt
- Nutritional support
- Temp mgmt (lower temp to prevent higher caloric expenditure)
- Pain control
- Ocular care (CCS eye drops)
- Infection prevention
How should we montior and treat superinfection associated with SJS/TEN?
Prophylactic systemic antibiotics cannot be advised:
* Sterile handling is essential
* Silver sulfadiazine should be AVOIDED if EN suspected to be from sulfonamides
* Silver nitrate and silver impregnated nanocrystalline gauze
Monitoring:
* Repeated cultures of skin, blood, catheters, gastric, and any other tubes Q 48 hrs
* Ab choice based on culture
What are examples of adjunct tx for SJS/TEN? Are they commonly used?
Adjunctive pharmacologic therapies
No established pharmacologic treatment but can be beneficial:
1. Cyclosporine
2. Alt: etanercept
Systemic corticosteroids is not recommended, as well as, combo IVIG plus systemic CS
What is the cornerstone of SJS/TEN tx?
Supportive care
Is systemic CS recommended for TEN/SJS?
No, increases the risk for sepsis and protein catabolism, and decrease rate of epithelialization in patients with extesive skin detachment
How do you prevent SJS/TEN?
- Educate survivors about avoiding causative drugs
- Re-exposure may be fatal
- Update med records/allergy lists
