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  1. Chapter 005. Principles of Clinical Pharmacology (Part 10) Multiple Variants Modulating Drug Effects As this discussion makes clear, for each drug with a defined mechanism of action and disposition pathways, a set of "candidate genes," in which polymorphisms may mediate variable clinical responses, can be identified. Indeed, polymorphisms in multiple genes have been associated with variability in the effect of a single drug. CYP2C9 loss-of-function variants are associated with a requirement for lower maintenance doses of the vitamin K antagonist anticoagulant warfarin. In rarer (
  2. warfarin dosages; these promoter variants are in tight linkage disequilibrium , i.e. genotyping at one polymorphic site within this haplotype block provides reliable information on the identity of genotypes at other linked sites (Chap. 62). Thus, variability in response to warfarin can be linked to both coding region polymorphisms in CYP2C9 and promoter haplotypes in the warfarin target VKORC1. As genotyping technologies improve and data sets of patients with well- documented drug responses are accumulated, it is becoming possible to interrogate hundreds of polymorphisms in dozens of candidate genes. This approach has been applied to implicate linked noncoding polymorphisms in the HMG-CoA reductase gene as predicting efficacy of HMG-CoA reductase inhibitors, and in variants in the gene-encoding corticotrophin-releasing hormone receptor 1 as predicting efficacy of inhaled steroids in asthma. Technologies are now evolving to interrogate hundreds of thousands of SNPs across the genome, or to rapidly resequence each patient's genome. These approaches, which have been applied to identify new genes modulating disease susceptibility (Chap. 62), may be applicable to the problem of identifying genomic predictors of variable drug effects. Prospects for Incorporating Genetic Information into Clinical Practice
  3. The examples of associations between specific genotypes and drug responses raise the tantalizing prospect that patients will undergo routine genotyping for loci known to modulate drug levels or response prior to receiving a prescription. Indeed, clinical tests for some of the polymorphisms described above, including those in TPMT, UGT1A1, CYP2D6, and CYP2C19, have been approved by the U.S. Food and Drug Administration (FDA). The twin goals are to identify patients likely to exhibit adverse effects and those most likely to respond well. Obstacles that must be overcome before this vision becomes a reality include replication of even the most compelling associations, demonstrations of cost- effectiveness, development of readily useable genotyping technologies, and ethical issues involved in genotyping. While these barriers seem daunting, the field is very young and evolving rapidly. Indeed, one major result of understanding of the role of genetics in drug action has been improved screening of drugs during the development process to reduce the likelihood of highly variable metabolism or unanticipated toxicity (such as torsades des pointes). Interactions between Drugs Drug interactions can complicate therapy by increasing or decreasing the action of a drug; interactions may be based on changes in drug disposition or in drug response in the absence of changes in drug levels. Interactions must be considered in the differential diagnosis of any unusual response occurring during drug therapy. Prescribers should recognize that patients often come to them with a
  4. legacy of drugs acquired during previous medical experiences, often with multiple physicians who may not be aware of all the patient's medications. A meticulous drug history should include examination of the patient's medications and, if necessary, calls to the pharmacist to identify prescriptions. It should also address the use of agents not often volunteered during questioning, such as over-the- counter (OTC) drugs, health food supplements, and topical agents such as eye drops. Lists of interactions are available from a number of electronic sources. While it is unrealistic to expect the practicing physician to memorize these, certain drugs consistently run the risk of generating interactions, often by inhibiting or inducing specific drug elimination pathways. Examples are presented below and in Table 5-2. Accordingly, when these drugs are started or stopped, prescribers must be especially alert to the possibility of interactions. Table 5-2 Drugs with a High Risk of Generating Pharmacokinetic Interactions Drug Mechanism Examples Antacids Reduced Antacids/tetracyclines absorption Bile acid Cholestryamine/digoxin
  5. sequestrants Proton pump Altered gastric Ketoconazole absorption inhibitors pH decreased H2-receptor blockers Rifampin Induction of Decreased concentration and hepatic metabolism effects of Carbamazepine warfarin Barbiturates quinidine Phenytoin cyclosporine St. John's wort losartan Glutethimide oral contraceptives methadone Tricyclic Inhibitors of Increased -blockade
  6. antidepressants CYP2D6 Decreased codeine effect Fluoxetine Quinidine Cimetidine Inhibitor of Increased concentration and multiple CYPs effects of warfarin theophylline phenytoin Ketoconazole, Inhibitor of Increased concentration and itraconazole CYP3A toxicity of Erythromycin, some HMG-CoA reductase clarithromycin inhibitors Calcium channel cyclosporine blockers cisapride, terfenadine (now Ritonavir withdrawn)
  7. Increased concentration and effects of indinavir (with ritonavir) Decreased clearance and dose requirement for cyclosporine (with calcium channel blockers) Allopurinol Xanthine Azathioprine and 6- oxidase inhibitor mercaptopurine toxicity Amiodarone Inhibitor of Decreased clearance (risk of many CYPs and of P- toxicity) for glycoprotein warfarin digoxin quinidine Gemfibrazol CYP3A Rhabdomyolysis when co- (and other fibrates) inhibition prescribed with some HMG-CoA
  8. reductase inhibitors Quinidine P-glycoprotein Risk of digoxin toxicity inhibition Amiodarone Verapamil Cyclosporine Itraconazole Erythromycin Phenylbutazone Inhibition of Salicylates increased risk of renal tubular methotrexate toxicity Probenecid transport Salicylates
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