Pharmacogenomics by johnson pdf download

On the following two pages are examples of drugs in this category. The hypersensitivity symptoms include a combination of fever, rash, gastrointestinal tract symptoms and respiratory symptoms that become more severe with continued dosing. Codeine is a prodrug with analgesic properties due primarily to its conversion into morphine. Variations that decrease the metabolic activity of CYP2D6 result in a poor analgesic response due to the reduced conversion of codeine into morphine,3 and patients carrying such a variation are considered poor metabolizers and receive little therapeutic benefit from codeine.

It is estimated that 5—10 percent of Caucasians are CYP2D6 poor metabolizers; the percentage is approximately 2—3 percent in other racial and ethnic groups. Patients who carry such variations are at risk for opioid toxicity, which includes moderate to severe central nervous system depression. The prevalence of the CYP2D6 ultra-rapid metabolizer phenotype has been estimated at 1—10 percent in Caucasians, 3—5 percent in African Americans, 16—28 percent in North Africans, Ethiopians and Arabs, and up to 21 percent in Asians.

Food and Drug Administration FDA Public Health Advisory warns about the dangers to neonates of codeine use in breast-feeding mothers and states that the only way to determine prior to drug administration whether a patient is an ultra-rapid metabolizer is by the use of a genetic test.

Case study. DS is a 30 year-old woman who gave birth by caesarian section 10 days ago. Her physician prescribed codeine for post-caesarian pain. Despite taking no more than the prescribed dose, DS experienced nausea and dizziness while she was taking codeine. She also noticed that her breastfed infant was lethargic and feeding poorly. When DS mentioned these symptoms to her physician, he recommended that she discontinue codeine use.

How would genetic testing help DS and her physician? Using pharmacogenomics to predict effectiveness. Several drugs are subtherapeutic or ineffective in patients with variations in genes that encode drug-metabolizing proteins or targets of the drugs. Below is an example of a drug in this category. It is often prescribed for secondary prevention following acute coronary syndromes and for those undergoing percutaneous coronary intervention. However, despite Clopidogrel treatment, up to one-quarter of patients experience a subtherapeutic antiplatelet response, resulting in a higher risk for ischemic events.

Patients who carry certain variations in CYP2C19 are considered poor metabolizers and show reduced ability to convert Clopidogrel into its active metabolite, resulting in a diminished antiplatelet effect. JM is a 58 year-old man who recently had an acute myocardial infarction. Six months later, JM suffered another acute MI, and his physician suspects that the patient has been non-adherent, or alternatively, that Clopidogrel therapy may have been ineffective.

How would genetic testing help JM and his physician? If this were the case, alternative anti-platelet therapies may have been considered, reducing the chance that JM would suffer a second cardiac event. In patients taking both Clopidogrel and the proton pump inhibitors omeprazole or esomeprazole, diminished antiplatelet activity and adverse cardiac outcomes have been observed. In these patients, drugs that require the activity of CYPC19, such as Clopidogrel, will not be metabolized at the same rate as in most people.

Using pharmacogenomics to predict optimal dose. Genetic variations can lead to an altered dosage regimen. Knowing whether a patient carries these genetic variations can assist physicians in determining optimal therapeutic dose.

An example of a drug with an altered dosage regimen in patients with certain genetic variations is warfarin. Variation in the CYP2C9 gene causes some patients to have slow metabolism of warfarin and a longer half-life of the drug, resulting in higher than usual blood concentrations of warfarin and greater anticoagulant effect.

Certain variations in the VKORC1 gene result in reduced activity of the enzyme and subsequently reduced synthesis of coagulation factors. The combination of slow warfarin metabolism caused by CYP2C9 gene variations and reduced coagulation caused by VKORC1 gene variations increases the risk of bleeding during warfarin therapy.

Warfarin has a narrow therapeutic index; variations in CYP2C9 and VKORC1, in addition to several other patient characteristics, make it difficult to predict the effective dose. The product labeling suggests that this table of expected therapeutic doses can be used to assist prescribers in choosing initial warfarin dose for patients whose CYP2C9 and VKORC1 genotypes are known.

Dosing algorithms that rely on clinical features such as age, sex and weight, along with genotype, can also assist in the determination of optimal dose visit www. Careful monitoring of INR is still required during titration to steady state and monitoring of long-term therapy. ML is a 65 year-old woman who has recently been diagnosed with atrial fibrillation. However, ML will need to return to the clinic every day for INR monitoring until a stable dose is determined, and then every few weeks thereafter for maintenance monitoring.

How would genetic testing help ML and her physician? Knowing about any gene variations before initiating therapy allows for more accurate initial dosing and faster INR stabilization, and can reduce the risk for bleeding or clotting events. Pharmacogenomics and genetic testing. Promise of pharmacogenomics in smoking cessation Pharmacogenomics, George Uhl. A short summary of this paper.

Promise of pharmacogenomics in smoking cessation. Editorial For reprint orders, please contact: reprints futuremedicine. Improving these odds is a major goal of academic and pharmaceutical therapeutic development programs Twin studies document smoker. Failure to incorporate genetics exerts strong, ca 0. This behavior change yields sizable attempt follows use of a strategy that does not Molecular Neurobiology health benefits.

Smoking remains one of the larg- match the individual smoker or when a trial of Research Branch, PO Box , est preventable causes of death, causing more than a promising smoking cessation medication fails National Institutes of Health, , premature US deaths per year [3]. Many due to unidentified stratification for smoking Baltimore, MD , USA of these deaths could have been deferred by suc- cessation alleles among trial participants.

This rate can be augmented regarding informative markers for smoking two- or more-fold by treatments that target the brain nicotinic acetylcholine receptors at which cessation success increases Nevertheless, the odds that a smoker who tion studies of smokers who attempt to quit attempts to quit will relapse are still much greater in clinical trial and community settings dis- than the chances that he will achieve and main- play gratifyingly high overall degrees of con- tain abstinence.

Improving these odds is a major vergence [5—7]. This conclusion springs from goal of academic and pharmaceutical therapeutic the identification of the same chromosomal development programs, and a promising setting regions and genes by SNPs whose allele fre- in which thoughtfully applied pharmacogenomics quencies display nominally significant differ- could provide substantial health improvements ences between successful versus unsuccessful with favorable cost:benefit ratios.

Elsewhere, we suggest use of primary pharmacogenomics for individual differences n Providing controls to reduce genetic variance in absorption, distribution, metabolism, excre- and add to power of studies of pharmaco- tion and toxicology ADMET , secondary logical or other environmental influences on pharmacogenomics for differences in the sites quit success; that initially recognize drugs and higher order pharmacogenomics based on individual dif- n Providing controls for stratification based on ferences in post-receptor sites that influence quit success alleles in clinical trials for drug actions [8].

There is no large influ- ence of variants at any particular gene locus. The overlap with genome-wide We have recently documented the striking association data from studies of dependence cost—effectiveness of genotyping participants on addictive substances, while significant, is in medium-sized smoking cessation clinical modest. Neither we nor others have identified trials [13]. It is reasonable to add the a physiological nicotine-dependence pheno- costs of a failed quit success attempt to the lost type [9—11].

No current molecular or classical opportunity costs for smokers who become dis- genetic results invalidate additive, polygenic couraged.