Pharmacogenetics: Abnormal Responses

Abnormal Pharmacogenetic Responses

Overview of Abnormal Responses

  • Type B Adverse Reactions: Also termed bizarre reactions; characterized by:

    • Dose-independent

    • Unpredictable

    • Rare and potentially fatal (e.g., anaphylaxis to penicillin)

  • Contrasted with Type A Adverse Reactions:

    • Dose-dependent

    • Predictable based on pharmacology (e.g., insulin inducing hypoglycemia)

  • Abnormal responses often stem from complex immune responses influenced by genetic background.

Types of Abnormal Responses

  • Evidence suggests that abnormal responses are tied to genetic variations affecting immune hypersensitivity.

  • Examples include:

  • Rhabdomyolysis

  • Skin Reactions such as Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis

Drug Examples Associated with Abnormal Responses

1. Abacavir (Antiretroviral for HIV)

  • Genetic Association: HLA-B*5701 allele presence leads to hypersensitivity reactions in 4-8% of patients.

  • Mechanism: Drug binds to antigen receptor, triggering abnormal immune response via T-cells.

  • Significance of Testing: Mandatory genetic testing to identify the presence of HLA-B*57:01 before prescribing.

  • If the variant is present, alternatives should be used to prevent severe hypersensitivity (like Stevens-Johnson Syndrome).

2. Carbamazepine (Antiepileptic & Bipolar Treatment)

  • Genetic Association: HLA-B*15:02 allele is common in East Asian populations.

  • Study Findings: Taiwan trial showed reduced incidence of Stevens-Johnson and toxic epidermal necrolysis when alternatives were used instead of carbamazepine in HLA-B*15:02 carriers.

  • Recommendation: While not yet mandatory, strong recommendations exist for genetic testing, particularly in East Asian communities to mitigate risk of adverse reactions.

3. Statins (e.g., Simvastatin)

  • Genetic Association: SLCO1B1*5 variant correlates with increased risk of rhabdomyolysis.

  • Mechanism: The variant affects the OATP1B1 transporter protein on liver cells, reducing statin absorption and increasing toxicity risks due to higher systemic exposure.

  • Study Observations:

  • Statin exposure increased by 221% in carriers of SLCO1B1*5 compared to non-carriers

  • Variability in response among different statins depending on their uptake mechanisms, but all generally rely on OATP1B1.