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%) individuals homozygous for these variant alleles, maintenance warfarin dosages may be difficult to establish, and the risk of bleeding complications appears increased. In addition to CYP2C9, variants in the promoter region of VKORC1, encoding a vitamin K epoxide reductase, predict 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 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 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 Bile acid Reduced absorption Antacids/tetracyclines Cholestryamine/digoxin sequestrants Proton pump inhibitors H 2 -receptor blockers Altered gastric pH Ketoconazole absorption decreased Rifampin Carbamazepine Barbiturates Phenytoin St. John's wort Glutethimide Induction of hepatic metabolism Decreased concentration and effects of warfarin quinidine cyclosporine losartan oral contraceptives methadone Tricyclic Inhibitors of Increased -blockade antidepressants Fluoxetine Quinidine CYP2D6 Decreased codeine effect Cimetidine In hibitor of multiple CYPs Increased concentration and effects of warfarin theophylline phenytoin Ketoconazole, itraconazole Erythromycin, clarithromycin Calcium channel blockers Ritonavir Inhibitor of CYP3A Increased concentration and toxicity of some HMG- CoA reductase inhibitors cyclosporine cisapride, terfenadine (now withdrawn) Increased concentration and effects of indinavir (with ritonavir) Decreased clearance and dose requirement for cyclosporine (with calcium channel blockers) Allopurinol Xanthine oxidase inhibitor Azathioprine and 6- mercaptopurine toxicity Amiodarone Inhibitor of many CYPs and of P- glycoprotein Decreased clearance (risk of toxicity) for warfarin digoxin quinidine Gemfibrazol (and other fibrates) CYP3A inhibition Rhabdomyolysis when co- prescribed with some HMG- CoA reductase inhibitors Quinidine Amiodarone Verapamil Cyclosporine Itraconazole Erythromycin P- glycoprotein inhibition Risk of digoxin toxicity Phenylbutazone Probenecid Salicylates Inhibition of renal tubu lar transport Salicylates increased risk of methotrexate toxicity . 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. 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. applicable to the problem of identifying genomic predictors of variable drug effects. Prospects for Incorporating Genetic Information into Clinical Practice The examples of associations between