Lecture 9

• Adverse drug reactions


  • Intrinsic (Type A) - Predictable based on drug concentrations, e.g. bleeding due to warfarin dose + liver toxicity due to paracetamol overdose
  • Idiosyncratic (Type B) - Not predictable, not related to dose, rare and often serious, e.g. liver toxicity due to range of drugs + cardiotoxicity, hypersensitivity/skin rash, hepatotoxicity, myopathy, cardiotoxicity
• HLA genes


  Human MHC gene occurring in all vertebrates, serious ADRs - Class I expressed the most (A, B + C), Class II on APCs (DR, DQ + DP), normally present peptide antigens to T cells, inappropriately present drug-peptide complexes
• Abacavir hypersensitivity


  • Antiretroviral reverse-transcriptase inhibitor, 5% of patients develop hypersensitivity, 100% cases have one or two HLA B*57:01 alleles (not all patients show reaction), 4.2% freq in normal controls, 2% in HIV-pos tolerant patients, 78% frequency in abacavir hypersensitive patients, T cells from HLA-B*57:01 pos donors differentiate in vitro when stimulated giving CD8-pos cytotoxic T cells, activated abacavir (or metabolite) binds directly to B*57:01 gene product, inappropriate T cell response, genotyping now required
• Carbamazepine (CBZ) serious skin rashes

  • Stevens-Johnson Syndrome (SJS) - positive for HLA B*15:02 in East Asian populations, Europeans + Japanese - role for A*31:01
• Allopurinol serious skin rashes

  • Chinese with SJS positive for B*58:01, minor effects in Europeans, effect size not sufficient to justify phenotyping
• Flucloxacillin drug-induced liver injury (DILI)

  • Beta-lactamase resistant penicillin, treat staphylococcal infections, established cause of liver injury, second most important cause of DILI in UK, B*57:01 - similar to abacavir, sensitivity + specificity of B*57:01 genotyping as predictor of flucloxacillin DILI than abacavir hypersensitivity, other risks + includes age, inappropriate T cell response, mechanism for HLA protein interaction with drug appears different to that for abacavir - covalent binding of drug or metabolite to protein may occur, HLA protein interacts with drug complex, peptide inappropriately presents, T cells causing reaction, local cellular damage
• Statin-induced myopathy


  • Myalgia → rhabdomyolysis, GWAS show important role myopathy - simvastatin (SLCO1B1) → decreased hepatic uptake, SLCO1B1 → main inward hepatic statin transporter, higher plasma level of drug in *5 variant (decreased activity), may cause increased uptake into muscle tissue, SLCO1B1*5 = high risk allele (Val174Ala), 80 cases showed effect, patients treated with simvastatin
• Drug-induced cardiotoxicity


  • Role of ion channels - prolong cardiac repolarisation → blockage of outward ion channel with K channels, slight genetic abnormalities in K channel → increased risk of sudden death due to drug-induced ventricular fibrillation, candidate gene studies on drug-induced long QT - KCNE2, KCNE1 D85N, KCNH2 (hERG), KCNQ1, SCN5A, NOS1AP gene effecting length of QT interval, GWAS → SNP in NOS1AP affects QT length in population study (absence of drug treatment), NO signalling → cardiac repolarisation, more common in patients showing QT prolongation in response to several drugs, GWAS - no GWAS seen, likely due to small sample sizes (200-300), common genetic variations are not important predictors for drug-induced cardiotoxicity, more difficult to screen for rare variants but possible by exome sequencing