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 (...
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Chapter 005. Principles of Clinical Pharmacology (Part 10) 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 ofaction and disposition pathways, a set of candidate genes, in whichpolymorphisms may mediate variable clinical responses, can be identified. Indeed,polymorphisms in multiple genes have been associated with variability in theeffect of a single drug. CYP2C9 loss-of-function variants are associated with arequirement for lower maintenance doses of the vitamin K antagonistanticoagulant warfarin. In rarer (warfarin dosages; these promoter variants are in tight linkage disequilibrium , i.e.genotyping at one polymorphic site within this haplotype block provides reliableinformation on the identity of genotypes at other linked sites (Chap. 62). Thus,variability in response to warfarin can be linked to both coding regionpolymorphisms in CYP2C9 and promoter haplotypes in the warfarin targetVKORC1. As genotyping technologies improve and data sets of patients with well-documented drug responses are accumulated, it is becoming possible to interrogatehundreds of polymorphisms in dozens of candidate genes. This approach has beenapplied to implicate linked noncoding polymorphisms in the HMG-CoA reductasegene as predicting efficacy of HMG-CoA reductase inhibitors, and in variants inthe gene-encoding corticotrophin-releasing hormone receptor 1 as predictingefficacy of inhaled steroids in asthma. Technologies are now evolving to interrogate hundreds of thousands ofSNPs across the genome, or to rapidly resequence each patients genome. Theseapproaches, which have been applied to identify new genes modulating diseasesusceptibility (Chap. 62), may be applicable to the problem of identifying genomicpredictors of variable drug effects. Prospects for Incorporating Genetic Information into Clinical Practice The examples of associations between specific genotypes and drugresponses raise the tantalizing prospect that patients will undergo routinegenotyping for loci known to modulate drug levels or response prior to receiving aprescription. Indeed, clinical tests for some of the polymorphisms describedabove, including those in TPMT, UGT1A1, CYP2D6, and CYP2C19, have beenapproved by the U.S. Food and Drug Administration (FDA). The twin goals are toidentify patients likely to exhibit adverse effects and those most likely to respondwell. Obstacles that must be overcome before this vision becomes a reality includereplication of even the most compelling associations, demonstrations of cost-effectiveness, development of readily useable genotyping technologies, and ethicalissues involved in genotyping. While these barriers seem daunting, the field isvery young and evolving rapidly. Indeed, one major result of understanding of therole of genetics in drug action has been improved screening of drugs during thedevelopment process to reduce the likelihood of highly variable metabolism orunanticipated toxicity (such as torsades des pointes). Interactions between Drugs Drug interactions can complicate therapy by increasing or decreasing theaction of a drug; interactions may be based on changes in drug disposition or indrug response in the absence of changes in drug levels. Interactions must beconsidered in the differential diagnosis of any unusual response occurring duringdrug therapy. Prescribers should recognize that patients often come to them with alegacy of drugs acquired during previous medical experiences, often with multiplephysicians who may not be aware of all the patients medications. A meticulousdrug history should include examination of the patients medications and, ifnecessary, calls to the pharmacist to identify prescriptions. It should also addressthe use of agents not often volunteered during questioning, such as over-the-counter (OTC) drugs, health food supplements, and topical agents such as eyedrops. Lists of interactions are available from a number of electronic sources.While it is unrealistic to expect the practicing physician to memorize these, certaindrugs consistently run the risk of generating interactions, often by inhibiting orinducing specific drug elimination pathways. Examples are presented below and inTable 5-2. Accordingly, when these drugs are started or stopped, prescribers mustbe especially alert to the possibility of interactions. Table 5-2 Drugs with a High Risk of Generating PharmacokineticInteractions Drug Mechanism Examples Antacids Reduced Antacids/tetracyclines absorption Bile acid Cholestryamine/digoxinsequestrants Proton pump Altered gastric Ketoconazole absorptioninhibitors pH decreased H2-receptorblockers Rifampin Induction of Decreased concentration and hepatic metabolism effects of Carbamazepine warfarin Barbiturates quinidine Phenytoin cyclosporine St. Johns wort losartan Glutethimide oral contraceptives methadone Tricyclic ...