Sunday, April 1, 2012

USMLE Review

USMLE Review

Importance of Pharmacogenetics to help Variability in Narcotic Response.

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The exaggerated responses are an inherited trait (Eichelbaum et al., 1975; Mahgoub et al., 1977). At present, a very large number of medications (estimated at 15% to 25% of all medicines in use) have been shown to be substrates for CYP2D6 (Table 4-3). The molecular and phenotypic characterization of multiple racial and ethnic groups has shown that seven variant alleles account for well over 90% of the "poor metabolizer" low-activity alleles for this gene in most racial groups; that the frequency of variant alleles varies with geographic origin; and that a small percentage of individuals carry stable duplications of CYP2D6, with "ultra-rapid" metabolizers having up to 13 copies of the active gene (Ingelman-Sundberg and Evans, 2001). Phenotypic consequences of the deficient CYP2D6 phenotype include increased risk of toxicity of antidepressants or antipsychotics (catabolized by the enzyme), and lack of analgesic effects of codeine (anabolized by the enzyme); conversely, the ultra-rapid phenotype is associated with extremely rapid clearance and thus inefficacy of med school antidepressants (Kirchheiner et al., 2001).

A promoter region variant in the enzyme UGT1A1, UGT1A1*28, which has an additional TA in comparison to the more common form of the gene, has been associated with a reduced medical video transcription rate of UGT1A1 and lower glucuronidation activity of the enzyme. This reduced activity has been associated with higher levels of the active metabolite of the cancer chemotherapeutic agent irinotecan (see Chapters 3 and 51). The metabolite, SN38, which is eliminated by glucuronidation, is associated with the risk of toxicity (Iyer et al., 2002), which will be more severe in individuals with genetically lower UGT1A1 activity. Medicine

CYP2C19 codes for a cytochrome P450, historically termed mephenytoin hydroxylase, that displays penetrant pharmacogenetic variability, with just a few SNPs accounting for the majority of the deficient, poor metabolizer phenotype (Mallal et al., 2002). The deficient phenotype is much more common in Chinese and Japanese populations. Several video odd proton pump inhibitors, including omeprazole and lansoprazole, are inactivated by CYP2C19. Thus, the deficient patients have higher exposure to active parent drug, a greater pharmacodynamic effect (higher gastric pH), and a higher probability of ulcer cure than heterozygotes or homozygous wild-type individuals (Figure 4-10).

The anticoagulant warfarin is catabolized by CYP2C9. Inactivating polymorphisms in CYP2C9 are common (Goldstein, 2001), with 2% to 10% of most populations being homozygous for low-activity variants, and are associated with lower warfarin clearance, a higher risk of bleeding complications, and lower dose requirements (Aithal et al., 1999).

Thiopurine methyltransferase (TPMT) where to get a physical exam methylates thiopurines such as mercaptopurine (an antileukemic drug that is also the product of azathioprine metabolism). One in 300 individuals is homozygous deficient, 10% are heterozygotes, and about 90% are homozygous for the wild-type alleles for TPMT (Weinshilboum and Sladek, 1980). Three SNPs account for over 90% of the inactivating alleles (Yates et al., 1997). Because methylation of mercaptopurine competes with activation of the drug to thioguanine nucleotides, the concentration of the active (but also toxic) thioguanine metabolites is inversely related to TPMT activity and directly related to the probability of pharmacologic effects.

Importance of Pharmacogenetics to Variability in Medication Response.

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If proportions of the observed three genotypes, which must add up to one, differ significantly from those predicted, it may indicate that a genotyping error Medical Books may be present.

Because polymorphisms are so common, haplotype (the allelic structure that indicates whether polymorphisms within a gene are on the same or different alleles) may also be important. Thus far, experimental methods to unambiguously confirm whether polymorphisms are allelic has proven to be feasible but technically challenging (McDonald et al., 2002). Most video odd investigators use statistical probability to assign putative or inferred haplotypes; e.g., because the two most common SNPs in TPMT (at 460 and 719) often are allelic, a genotyping result showing heterozygosity at both SNPs will have a >95% chance of reflecting one allele wild-type and one allele variant at both SNP positions (resulting in a "heterozygote" genotype for TPMT). However, the remote prospect that each of the two alleles carries a single SNP variant, thereby conferring a homozygous variant/deficient phenotype, is a theoretical possibility. Medicine

Candidate Gene versus Genome-Wide Approaches

Because medical mcq pathways involved in drug response are often known or at least partially known, pharmacogenetic studies are highly amenable to candidate gene association studies. After genes in drug response pathways are identified, the next step in the design of a candidate gene association pharmacogenetic study is to identify the genetic polymorphisms that are likely to contribute to the therapeutic and/or adverse responses to the drug. There are several databases that contain information on polymorphisms and mutations in human genes (Table 4-1), which allow the investigator to search by gene for polymorphisms that have been reported. Some of the databases, such as the Pharmacogenetics and Pharmacogenomics Knowledge Base (PharmGKB), include phenotypic as well as genotypic data.

Because it is currently not practical to what is a physical exam analyze all polymorphisms in a candidate gene association study, it is important to select polymorphisms that are likely to be associated with the drug-response phenotype. For this purpose, there are two categories of polymorphisms. The first are polymorphisms that do not, in and of themselves, cause altered function of the expressed protein (e.g., an enzyme that metabolizes the drug or the drug receptor). Rather, these polymorphisms are linked to the variant allele that produces the altered function. These polymorphisms serve as biomarkers for drug-response phenotype. However, their major shortcoming is that unless they are in 100% linkage with the causative polymorphism, they are not the best markers for the drug-response phenotype.

The second type of polymorphism is the causative polymorphism, which directly precipitates the phenotype. For example, a causative SNP may change an amino acid residue at a site that medical schools is highly conserved throughout evolution. This substitution may result in a protein that is nonfunctional or has reduced function. Whenever possible, it is desirable to select polymorphisms for pharmacogenetic studies that are likely to be causative (Tabor et al., 2002). If biological information indicates that a particular polymorphism alters function, for example, in cellular assays of nonsynonymous variants, this polymorphism is an excellent candidate to use in an association study.

Importance of Pharmacogenetics to Variability in Meds Response.

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New methods in comparative genomics are being refined to identify conserved elements in noncoding regions of genes that may be functionally important (Bejerano et al., 2004; Boffelli et al., 2004; Brudno et al., 2003). Medicine

Pharmacogenetic Phenotypes

Candidate genes for therapeutic and adverse response can be divided into three categories: pharmacokinetic, receptor/target, and disease-modifying.

Pharmacokinetics. what is a physical exam Germline variability in genes that encode determinants of the pharmacokinetics of a drug, in particular enzymes and transporters, affect drug concentrations, and are therefore major determinants of therapeutic and adverse drug response (Table 4-3; Nebert et al., 1996). Multiple enzymes and transporters may be involved in the pharmacokinetics of a single drug. Several polymorphisms in drug metabolizing enzymes were discovered as monogenic phenotypic trait variations, and thus may be referenced using their phenotypic designations (e.g., slow vs. fast acetylation, extensive vs. poor metabolizers of debrisoquine or sparteine) rather than their genotypic designations that reference the gene that is the target of polymorphisms in each case (NAT2 and CYP2D6 polymorphisms, respectively) (Grant et al., 1990). CYP2D6 is now known to catabolize the two initial probe drugs (sparteine and debrisoquine), each of which was associated with exaggerated responses in 5% to 10% of treated individuals. The exaggerated responses are an inherited trait (Eichelbaum et al., 1975; Mahgoub et al., 1977). At present, a very large number of medications (estimated at 15% to 25% of all medicines in use) have been shown to be substrates for CYP2D6 (Table 4-3). The molecular and phenotypic characterization of multiple racial and ethnic groups has shown that seven variant alleles account for well over 90% of the "poor metabolizer" low-activity alleles for this gene in most racial groups; that the frequency of variant alleles varies with geographic origin; and that a small percentage of individuals carry stable duplications of CYP2D6, with "ultra-rapid" metabolizers having up to 13 copies of the active gene (Ingelman-Sundberg and Evans, 2001). Phenotypic consequences of the deficient CYP2D6 phenotype include increased risk of toxicity of antidepressants or antipsychotics (catabolized by the enzyme), and lack of analgesic effects of codeine (anabolized by the enzyme); conversely, the ultra-rapid phenotype is associated with extremely rapid clearance and thus inefficacy of medical mcq antidepressants (Kirchheiner et al., 2001).

A promoter region variant in the enzyme UGT1A1, UGT1A1*28, which has an additional TA in comparison to the more common form of the gene, has been associated with a reduced videos medical transcription rate of UGT1A1 and lower glucuronidation activity of the enzyme. This reduced activity has been associated with higher levels of the active metabolite of the cancer chemotherapeutic agent irinotecan (see Chapters 3 and 51). The metabolite, SN38, which is eliminated by glucuronidation, is associated with the risk of toxicity (Iyer et al., 2002), which will be more severe in individuals with genetically lower UGT1A1 activity.

CYP2C19 codes for a cytochrome P450, historically termed mephenytoin hydroxylase, that displays penetrant pharmacogenetic variability, with just a few SNPs accounting for the majority of the deficient, poor metabolizer phenotype (Mallal et al., 2002). The deficient phenotype is much more common in Chinese and Japanese populations.

Importance of Pharmacogenetics to Variability in Narcotic Response.

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For some multigenic phenotypes, such as response to antihypertensives, the large numbers of candidate genes will necessitate a large patient sample size to produce the statistical power required to solve the "multigene" problem. Medicine

GENOMIC BASIS OF PHARMACOGENETICS

Phenotype-Driven Terminology

Because initial discoveries in osce medical pharmacogenetics were driven by variable phenotypes and defined by family and twin studies, the classic genetic terms for monogenic traits apply to some pharmacogenetic polymorphisms. A trait (e.g., CYP2D6 "poor metabolism") is deemed autosomal recessive if the responsible gene is located on an autosome (i.e., it is not sex-linked) and a distinct phenotype is evident only with nonfunctional alleles on both the maternal and paternal chromosomes. For many of the earliest identified pharmacogenetic polymorphisms, phenotype did not differ enough between heterozygotes and homozygous "wild-type" individuals to distinguish that heterozygotes exhibited an intermediate (or codominant) phenotype (e.g., for CYP2D6-mediated debrisoquine metabolism). Other traits, such as TPMT, exhibit three relatively distinct phenotypes, and thus were deemed codominant even in the premolecular era. With the advances in molecular characterization of polymorphisms and a genotype-to-phenotype approach, additional polymorphic traits (e.g., CYP2C19 metabolism of drugs such as mephenytoin and omeprazole) are now recognized to exhibit some degree of codominance. Some pharmacogenetic traits, such as the long QT syndrome, segregate as dominant traits; the long QT syndrome is associated with heterozygous loss-of-function mutations of ion channels. A prolonged QT interval is seen on the electrocardiogram, either basally or in the presence of certain drugs, and the individual is predisposed to cardiac video odd arrhythmias

In an era of detailed molecular characterization, two major factors complicate the historical designation of recessive, codominant, and dominant traits. First, even within a single gene, a medical mcqs vast array of polymorphisms (promoter, coding, noncoding, completely inactivating, or modestly modifying) are possible, making the assignment of "variant"vs. "wild-type" to an allele a designation that depends upon a complete survey of the gene's polymorphisms and is not necessarily easily assigned. Secondly, most traits (pharmacogenetic and otherwise) are multigenic, not monogenic. Thus, even if the designations of recessive, codominant, and dominant are informative for a given gene, their utility in describing the genetic variability that underlies variability in drug response phenotype is diminished, because most phenotypic variability is likely to be multigenic.

Types of Genetic Variants

A polymorphism is a variation in the DNA sequence that is present at an allele frequency of 1% or greater in a population. Two major types of sequence variation have been associated with variation in human reading ecg phenotype: single nucleotide polymorphisms (SNPs) and insertions/deletions (indels) (Figure 4-3). In comparison to base pair substitutions, indels are much less frequent in the genome and are of particularly low frequency in coding regions of genes (Cargill et al., 1999; Stephens et al., 2001). Single base pair substitutions that are present at frequencies of 1% or greater in a population are termed single nucleotide polymorphisms (SNPs) and are present in the human genome at approximately 1 SNP every few hundred to a thousand base pairs, depending on the gene region (Stephens et al., 2001).

HOW HUMANS OVERCOME EXPOSURE TO XENOBIOTICS.

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Metabolism by the phase 1 cytochrome P450 isoenzymes (CYPs) followed by phase 2 uridine diphosphate-glucuronosyltransferase (UGT) enzymes produces a metabolite that is highly water soluble and readily eliminated from the body (Figure 3-1). Metabolism also terminates the biological activity of the drug. In the case of phenytoin, metabolism also increases the molecular weight of the compound, which allows it to medical lecture be eliminated more efficiently in the bile. Medicine

While xenobiotic-metabolizing ekg ecg enzymes are responsible for facilitating the elimination of chemicals from the body, paradoxically these same enzymes can also convert certain chemicals to highly reactive toxic and carcinogenic metabolites. This occurs when an unstable intermediate is formed that has reactivity toward other compounds found in the cell. Chemicals that can be converted by xenobiotic metabolism to cancer-causing derivatives are called carcinogens. Depending on the structure of the chemical substrate, xenobiotic-metabolizing enzymes produce electrophilic metabolites that can react with nucleophilic cellular macromolecules such as DNA, RNA, and protein. This can cause cell death and organ toxicity. Reaction of these electrophiles with DNA can sometimes result in cancer through the mutation of genes such as oncogenes or tumor suppressor genes. It is generally believed that most human cancers are due to exposure to chemical carcinogens. This potential for carcinogenic activity makes testing the safety of drug candidates of vital importance. Testing for potential cancer-causing activity is particularly critical for drugs that will be used for the treatment of chronic diseases. Since each species has evolved a unique combination of xenobiotic-metabolizing enzymes, nonprimate rodent models cannot be solely used during drug development for testing the safety of new drug candidates targeted for human diseases. Nevertheless, testing in rodent models such as mice and rats can usually identify potential mcq medical carcinogens.

THE PHASES OF DRUG METABOLISM

Xenobiotic metabolizing video odd enzymes have historically been grouped into the phase 1 reactions, in which enzymes carry out oxidation, reduction, or hydrolytic reactions, and the phase 2 reactions, in which enzymes form a conjugate of the substrate (the phase 1 product) (Table 3-1). The phase 1 enzymes lead to the introduction of what are called functional groups, resulting in a modification of the drug, such that it now carries an -OH, -COOH, -SH, -O- or NH2 group. The addition of functional groups does little to increase the water solubility of the drug, but can dramatically alter the biological properties of the drug. Phase 1 metabolism is classified as the functionalization phase of drug metabolism; reactions carried out by phase 1 enzymes usually lead to the inactivation of an active drug. In certain instances, metabolism, usually the hydrolysis of an ester or amide linkage, results in bioactivation of a drug. Inactive drugs that undergo metabolism to an active drug are called prodrugs. An example is the antitumor drug cyclophosphamide, which is bioactivated to a cell-killing electrophilic derivative (see Chapter 51). Phase 2 enzymes facilitate the elimination of drugs and the inactivation of electrophilic and potentially toxic metabolites produced by oxidation. While many phase 1 reactions result in the biological inactivation of the drug, phase 2 reactions produce a metabolite with improved water solubility and increased molecular weight, which serves to facilitate the elimination of the drug from medical surgical the tissue.
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