Chapter 6 Flashcards
pharmacogenomics is the branch of science
Concerned with the identification of genetic attributes of an individual to lead to variable responses to drugs.
Pharmacogenomics seeks to identify
Patterns of genetic variation that are subsequently employed to guide the design of optimal medication regimen for individual patients
This Human Genome Project
The groundbreaking effort to map the entire human genome. While 95% of the sequence of all human DNA was established, resulting in identification of open reading frames for many human proteins
Single nucleotide polymorphisms
Genetic differences that account for allotypic phenotype variations
How many SNP’s have been identified
1.4 million
What is the importance of the 2011 study by LII, Zhang, Zhou, Stoneking, and Tang on the heterogeneity in drug metabolizing genes in globally defined populations
Explains the origin of genetic polymorphism and drug metabolism enzymes and purports to provide an evolutionary rationale for such differences across ethnicities
Another word for an individual’s genetic makeup
Genotype
Genotypes result from
Genetic recombination or mixing of genes from that individual’s parents. All of the DNA contained in an individual cell is known as the genome of the individual, a word formed by combination of gene and chromosome. It represents all of the genes that individual can express. Interestingly, even though two unrelated people share about 99.9% of the same DNA sequences, less than 0.1% difference between them translate into difference in 3 million nucleotides.
The 0.1% difference in DNA sequence between two unrelated people create variance that are known as
Snips or SNP’s
Haplotypes
Her large portions of genetic material that tend to travel together. Understanding how S&P’s and haplotypes make humans genetically unique to the current focus of much genetic research. The completion of the Human Genome Project, as well as the mapping of snips and haplotypes, has allowed for the field of pharmacogenetics to understand the variability of drug metabolism seen across individuals and populations
Genetic polymorphism
Multiple differences of DNA sequence found in at least 1% of the population
Genomics
The study of complete set of genetic information present in the cell, an organism, or species
Pharmacogenetics
The study of influence of hereditary factors on response of individual organisms to drugs
Pharmacogenomics
The study of the effects of genetic differences among people and the impact that these differences have on the uptake, effectiveness, toxicity, and metabolism of drugs
SNP
Single nucleotide polymorphism
Standard adopted nomenclature is used in identifying specific genes. Provide an example
CYP2D6 written in italics refers to the normal copy of the gene, whereas CYP2D6*1 (prnounced star 1) refers to the first identified natural variant or mutant copy of this gene
The Greek philosopher and mathematician Pythagoras
Recorded the first individual difference of drug administration and 510 BCE when he noted that some patients developed hemolytic anemia after ingesting the fava bean.
The term pharmacogenetics was first coined by
Vogel in 1959, and until 1962 was it defined as the study of hereditary and in response to drugs by callow. Since 1962 the term has been used to refer to the effects of genetic differences on a person’s response to drugs.
Attribution of peripheral neuropathy slow acetylation of isoniazid in some patients treated for tuberculosis due to genetic diversity and enzyme
N-acetyltransferase
The rate of acetylation of a drug such as isoniazid is clinically relevant because it determines the rate of
Elimination of the drug from body. Thus the visuals known as slow acetylators will metabolize the drum slowly, allowing greater residence time in the body and enhanced toxicity.
the ultimate promise of pharmacogenomics is the
Possibility that knowledge of the patient’s DNA sequence might be used enhance drug therapy to maximize efficacy, target drugs only to those patients were likely to respond, avoid ADRs. Increasing number of patients respond to therapeutic regimen with a con commitment decrease in the incidence of ADRs is the promise of this information.
Genetic differences in metabolism were first realized by the observation that sometimes
Very low or very high concentrations of drug were found in some patients despite their heaven been given the same amount of the drug.
Genetic polymorphism occurs when
Difference in the allele responsible for the variation is a common occurrence.
An allele is an alternative form of a gene. The gene is called polymorphic when
Allelic variations occur throughout a given population and a stable rate of less than 1%. Under such circumstances, genes will exist somewhat frequently alongside wild type chains. The mutant genes one code for production of immune proteins in these populations. Immune proteins will, in turn, interact with drugs in different manners, sometimes wide, sometimes significant.
Mono genic traits by themselves cannot explain
The complexity of drug metabolism. Genes interact on a complex level yielding different responses with honey upon which genes a wild type which show mutant phenotypes.
Poor metabolizes
Lack a working enzyme
Intermediate metabolizes
Are heterogeneous for one working, one wild type allele and one mutant allele
Extensive metabolizes
Have to normally functioning alleles;
Ultra-rapid metabolizes
Have more than one copy of functioning enzymes
Drug metabolism generally involves the conversion of lipophilic substances and
Metabolites into more easily excludable water-soluble forms.
Drug metabolism takes place mostly in the
Liver and is divided into two major categories
Phase 1 metabolism
Oxidation reduction in hydrolysis reactions
Phase 2
Conjugation reactions
Poor to intermediate metabolizes clinical implications
Prodrug will be metabolized slowly into the active drug metabolite. May have accumulation prodrug. After drug will be metabolized slowly into inactive metabolite. Potential for accumulation of active drug. Patient requires lower dosage of medication.
Ultra-rapid metabolizes clinical implications
Prodrug rapidly metabolized into active drug. No dosage adjustment needed. Active drug rapidly metabolized into inactive metabolites leading to potential therapeutic failure. Patient requires hot dose of active drug.
Phase 1 metabolism enzymes are responsible for approximately
59% of the ADRs cited in the literature.
CYP’s are generally located in
In the plasmid reticulum and mitochondrial human cells, of which the ER isoforms are of particular importance to the field of drug metabolism. In terms of their organ distribution, they are found in greater amounts in the liver and in the intestine and to somewhat lesser extent in other organs, such as the skin, brain, lungs, and kidneys.
Hepatic, renal, and intestinal ER CYP’s are involved in
The biotransformation of a plethora of drugs and Indo genus substances in humans mainly by oxygenation of the target substrate molecule and mediated by differential oxidation states of the central iron atom and the enzyme. Due to this oxygenation reaction, CYP’s are classified as monooxygenases.
High genetic variability of the cytochrome P4 50 (CYP 450)
Constitutes the most important of the phase 1 metabolizing enzymes, the total of 57 genes encoding for CYP 450 enzymes.
CYP2d6
Up to 90% of drugs are metabolized via cyp2D6. Phenotypic variations in some enzymes can have an astounding outcome on drug therapy. For example, 1000 fold difference has been observed in the rate of metabolism of some substrates due to differences in CYP2d6 isoenzymes
CYP 2D six is a well studied instance of a DME coding gene that exhibits polymorphism. This gene product acts on many Zeno biotics, including many common prescription drugs such as
Selective serotonin reuptake inhibitors, tricyclic antidepressants, beta blockers, calcium channel blockers, and others.
21% of this population has the altar metabolize or phenotype
Asian
35% of the population carries
Nonfunctional 2D six allele. This nonfunctional allele may increase the risk of ADRs especially in patients with polypharmacy.
CYP2C9 Medications and drug effect linked ot polymorphism
tolbutamide, warfarn, phenytoin, nsaids
Anticoagulant effect on warfarin
CYP2D6 medications and side effects
Beta-blockers, antidepressants, antipsychotics, coding, and many more
Tardive dyskinesia from antipsychotics, narcotic side effects, efficacy, independence,
Dihydropyrimidine dehydrogenase medicaitons an effects
fluorouricil
flurouracil neurtoxicity
thiopurine methyltranferase medications and effects
mercaptopurine, thioguanine, azathioprine
thiopurine t toxicity and efficacy; risk of second cancers
Angiotensin-converting enzyme’s medications and effects
Lisinopril
Renal protective effects, cardiac indices, blood pressure, immunoglobulin a, nephropathy
