HLA Pharmacogenetics and Adverse Drug Reactions

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Questions and Answers

What is one main role of Human Leukocyte Antigen (HLA) in the immune response?

To produce antibodies against invaders

To enhance the production of white blood cells

To directly kill pathogens

To present peptides to T cells (correct)

Which HLA type is associated with hypersensitivity reactions to Abacavir?

HLA-DQ

HLA-B (correct)

HLA-DR

HLA-A

How are HLA types connected to autoimmune diseases?

They impair T cell function, leading to reduced immunity.

They are involved in the presentation of self-peptides.

They have genetic polymorphisms that correlate with disease prevalence. (correct)

They trigger uncontrolled cell proliferation.

What is the clinical significance of understanding HLA pharmacogenetics?

It assists in predicting patient responses to specific drugs. Signup and view all the answers

Which of the following medications is associated with HLA-A and may cause hypersensitivity?

Carbamazepine Signup and view all the answers

Which severe skin condition is linked to specific HLA types?

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis Signup and view all the answers

What are the two main classes of Human Leukocyte Antigen (HLA)?

Class I and Class II Signup and view all the answers

What is the consequence of HLA genetic polymorphism?

It is associated with the risk of various diseases. Signup and view all the answers

What is the consequence of re-challenging a patient who has experienced a hypersensitivity reaction to abacavir?

Re-challenge is contraindicated even if symptoms have resolved. Signup and view all the answers

Which of the following genotypes is associated with a high risk of hypersensitivity reactions to abacavir?

HLA-B*57-01 positive Signup and view all the answers

What percentage of patients are identified as HLA-B*57-01 positive?

6% Signup and view all the answers

What is one of the severe cutaneous adverse reactions (SCARs) that can be caused by allopurinol?

Drug hypersensitivity syndrome Signup and view all the answers

What is the main mechanism by which allopurinol exerts its therapeutic effect?

It inhibits conversion of purines to uric acid. Signup and view all the answers

What symptom is NOT commonly associated with hypersensitivity reactions to abacavir?

Hair loss Signup and view all the answers

Abacavir is NOT recommended for individuals who are carriers of which genotype?

HLA-B*57-01 Signup and view all the answers

What condition is allopurinol FDA approved to treat?

Gout Signup and view all the answers

Which of the following statements is true regarding the risk of hypersensitivity reactions in the first three months of carbamazepine therapy?

Highest incidence of hypersensitivity reactions occurs during the first three months. Signup and view all the answers

Which of the following is a characteristic of a genotype that is HLA-B*57-01 positive with regard to hypersensitivity reactions to abacavir?

Markedly increased risk of hypersensitivity reactions Signup and view all the answers

What is the CYP2C9 phenotype classification for poor metabolizers of phenytoin?

One no function allele and one decreased function allele Signup and view all the answers

If a patient is HLA-B*15-02 positive and phenytoin-naïve, what is the recommended action?

Avoid using phenytoin Signup and view all the answers

What should be done for HLA-B*15-02 negative patients who are intermediate metabolizers with an Activity Score of 1.0 when dosing phenytoin?

Use the typical initial dose and 25% less for subsequent doses Signup and view all the answers

Which HLA-B variant is linked with a higher risk of SJS and TEN in phenytoin users?

HLA-B*15-02 Signup and view all the answers

In patients who are HLA-B*15-02 negative and categorized as poor metabolizers of CYP2C9, what adjustment is recommended for their subsequent phenytoin doses?

Use 50% less than the typical maintenance dose Signup and view all the answers

What is the general recommendation for phenytoin dosing in HLA-B*15-02 negative and CYP2C9 normal metabolizers?

No specific adjustment needed Signup and view all the answers

What is the highest incidence risk period for SJS and TEN when using phenytoin?

In the first three months of therapy Signup and view all the answers

What is the recommended action for a patient who is HLA-B*15-02 positive and has not previously taken carbamazepine?

Do not use carbamazepine Signup and view all the answers

For an HLA-B*15-02 negative patient, what is the risk level of using oxcarbazepine?

Normal risk of SJS/TEN Signup and view all the answers

What should be done for a patient on oxcarbazepine who is HLA-B*15-02 positive and has been taking it for 4 months?

Continue oxcarbazepine cautiously Signup and view all the answers

What is a significant characteristic of the pharmacodynamics of phenytoin?

Non-linear saturable pharmacokinetics Signup and view all the answers

In which scenario is phenytoin indicated for use?

Prevention and treatment of seizures during neurosurgery Signup and view all the answers

What would classify someone as an intermediate metabolizer of CYP2C9?

Having one normal function and one no function allele Signup and view all the answers

What is the consequence of having higher plasma concentrations of phenytoin?

Increased risk of toxicity Signup and view all the answers

What should be monitored in patients taking phenytoin due to its pharmacokinetics?

Therapeutic drug levels to avoid toxicity Signup and view all the answers

What is advised for a patient who is both carbamazepine-naïve and HLA-B*15-02 positive?

Avoid carbamazepine use completely Signup and view all the answers

Why might a patient with a CYP2C9 autoinduction phenotype experience varying drug levels over time?

Metabolic pathway becomes increasingly efficient Signup and view all the answers

What is the primary trigger of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

Medications Signup and view all the answers

Which of the following is TRUE regarding the severity of Stevens-Johnson Syndrome compared to Toxic Epidermal Necrolysis?

TEN is considered more severe than SJS. Signup and view all the answers

What is a common initial symptom of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

Fever and flu-like symptoms Signup and view all the answers

Which of the following complications can arise from Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

Pneumonia Signup and view all the answers

Which of the following describes the process of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

It involves immune system reactions to certain medications. Signup and view all the answers

What is the potential long-term effect of Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis on the skin?

Scar tissue formation Signup and view all the answers

What percentage of patients taking Abacavir might experience hypersensitivity reactions without genetically-guided therapy?

5-8% Signup and view all the answers

What role do HLA-B gene variations play in Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

They can cause the immune system to react with specific medications. Signup and view all the answers

Which of the following substances is released by immune T cells and NK cells during Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis?

Granulysin Signup and view all the answers

What may severe damage from Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis lead to?

Life-threatening complications Signup and view all the answers

Study Notes

HLA Pharmacogenetics and Cutaneous Adverse Drug Reactions

HLA (human leukocyte antigen) pharmacogenetics is crucial
HLA and cutaneous adverse reactions are closely related
HLA function is vital in the pathogenesis of serious cutaneous adverse drug reactions
HLA genotypes have clinical applications in pharmacogenetics

Human Leukocyte Antigen (HLA)

HLA shows genetic polymorphism
Two classes of HLA: Class I and Class II
HLA's function: presents peptides from pathogens to T cells, starting immune response

HLA and Disease Association

HLA types are associated with various diseases
Relationships between HLA types, development, and progression of autoimmune diseases are explained

HLA and Hypersensitivity Reactions

Risks of hypersensitivity reactions to specific medications are linked to HLA types
Examples: Abacavir (HLA-B), Allopurinol (HLA-B), Carbamazepine/oxcarbazepine (HLA-A and HLA-B), Phenytoin (HLA-B)

Stevens-Johnson Syndrome/Toxic Epidermal Necrolysis (SJS/TEN)

SJS/TEN is a severe overall skin reaction
SJS is less severe, while TEN is more severe
Often triggered by medications
Symptoms often start with fever and flu-like symptoms
Can lead to blistering and skin erosions, causing damage to mucous membranes
Severe damage can result in life-threatening disease
Several complications include: pneumonia, infections, shock, multiple organ failure, and death
Long-term effects include skin changes, dryness, excess sweating, hair loss, taste impairment, urination issues

Abacavir

Used in HIV treatment; nucleoside reverse transcriptase inhibitor
Inhibits viral reverse transcriptase, suppressing HIV's ability to convert RNA to DNA
About 5-8% of patients can experience hypersensitivity reactions (HSRs) if genetically-guided therapy is not used
Different symptoms: fever, rash, nausea, vomiting, abdominal pain, fatigue, dyspnea
Drug re-challenge is contraindicated
Hypersensitivity is associated with HLA-B*57-01 allele
HLA-B*57-01 negative genotype with low risk of hypersensitivity
HLA-B*57-01 positive genotype with high risk of hypersensitivity
Carrier of HLA-B*57-01: high risk of abacavir hypersensitivity reactions
Non-carrier of HLA-B*57.01: lower risk of reactions so abacavir use is recommended

Allopurinol

Cause of severe cutaneous adverse reactions (SCARs)
Can include hypersensitivity syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis, or less severe rash
An analog of the purine-based hypoxanthine
Inhibits conversion of hypoxanthine and xanthine to uric acid
FDA approved in 1966; used to treat gout and inflammatory arthritis
Goal of therapy: keep serum and plasma urate level below 6 mg/dL
Can treat and prevent uric acid kidney stones during chemotherapy
General starting dose: 100 mg/day; increase to up to 800 mg/day
Most common dose: 300 mg/day
Variant HLA-B, HLA-B*58-01 genotype associated with allopurinol-induced SCARs
Developed guidelines for allopurinol use with HLA-B*58-01 genotype test results
Non-carrier of HLA-B*58-01: low risk, use per standard guidelines
Carrier of HLA-B*58-01: high risk, allopurinol contraindicated
2-3% incidence of less severe rash unassociated with systemic symptoms or organ damage
FDA recommends discontinuing allopurinol if rash develops; alternative agent (e.g., febuxostat, non-purine xanthine oxidase inhibitor) should be used

Carbamazepine and Oxcarbazepine

Aromatic anticonvulsant related to tricyclic antidepressants
FDA approved for epilepsy, trigeminal neuralgia, bipolar disorders
Adverse effects are dose/concentration dependent
Complex dose-response relationships
Carbamazepine has adverse effects that include dizziness, ataxia, nystagmus, aplastic anemia, hyponatremia, leucopenia, liver injury
Oxcarbazepine is a keto-analog of carbamazepine with similar structure, indications, and side effects
HLA-B*15-02 is specific to carbamazepine and oxcarbazepine, inducing SJS and TEN
FDA included in carbamazepine package labeling a boxed warning for the risk of SJS/TEN associated with HLA-B*15-02 presence
Oxcarbazepine package labeling does not have a boxed warning but mentions association between HLA-B15-02 and SJS/TEN risk; advises avoiding oxcarbazepine if HLA-B15.02 is positive unless benefits clearly outweigh the risk
HLA-A*31-01 associated with a wider range of carbamazepine-induced HSRs, including SJS/TEN and maculopapular exanthema (MPE)
Drug rash with eosinophilia and systemic symptoms (DRESS) is a generalized cutaneous eruption, potentially life-threatening
CPIC recommendations based on HLA-B and HLA-A genotypes for carbamazepine and oxcarbazepine use

Phenytoin and Fosphenytoin

Used for focal and generalized convulsive status epilepticus, seizure control for tonic-clonic and complex partial seizures, prevention/treatment during/after neurosurgery
Narrow therapeutic index; higher plasma concentrations increase risk of toxicity
Non-linear, saturable pharmacokinetics
CYP2C9 autoinduction
CYP2C9 pharmacogenetics, categorized as normal, intermediate, or poor metabolizers
HLA-B*15-02 associated with an increased risk of SJS and TEN

Practice Questions and Answers

Practice questions are included about the conditions and pharmacogenetics

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Description

Explore the critical role of HLA pharmacogenetics in understanding cutaneous adverse drug reactions. This quiz covers the genetic polymorphism of HLA, its association with diseases, and the risks of hypersensitivity reactions to various medications. Test your knowledge on the clinical applications of HLA genotypes and their implications in pharmacogenetics.