Chapter 005. Principles of Clinical Pharmacology (Part 10) doc

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

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

Antacids

Bile acid

Reduced absorption

Antacids/tetracyclines

Cholestryamine/digoxin

sequestrants

Proton pump

inhibitors

H2-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 Inhibitor 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 tubular transport

Salicylates increased risk of methotrexate toxicity