Pharmacogenetics Flashcards
Define pharmacogenetics
involves the search for genetic variations that lead to interindividual differences in drug response. Pharmacogenetics generally refers to monogenetic variants that affect drug response.
Pharmacogenetics aims to use genetic information to choose a drug, drug dose, and treatment duration that will have the greatest likelihood for achieving therapeutic outcomes with the least potential for harm in a given patient.
Define pharmacogenomics
Pharmacogenomics refers to the entire spectrum of genes that interact to determine drug efficacy and safety.
All the genetic changes that together are part of the picture
State the goals of pharmacogenetics (2)
- Optimize drug therapy- do all that you can to achieve a good response and do all you can do to minimize a bad response
- Limit drug toxicity based on an individual’s genetic profile
Identify factors that influence a patient’s response to a drug (5)
- Age
- Body size
- Renal function
- Hepatic function
- Concomitant drug use
Succinylcholine
(depolarizing muscle relaxant) – In the early 1950’s, Werner Kalow observed that some patients had prolonged effects from the muscle relaxant succinylcholine. Study of this problem indicated defects or differences in the enzyme that metabolizes succinylcholine in these patients.
Isoniazid
(antibiotic used to treat tuberculosis) – Shortly after observing the varying succinylcholine effect in a subset of patients, clinicians observed that some patients experienced peripheral neuropathies when taking usual doses of isoniazid. Studies identified much higher levels of isoniazid in these patients because of reduced levels of N-acetyltransferase enzyme activity, an enzyme responsible for metabolizing isoniazid in the liver. This reduced enzyme activity was later discovered to result from genetic variations in the gene that encodes the N-acetyltransferase enzyme.
Primaquine
(antibiotic used to treat malaria) – In the mid-1950’s, it was observed that some patients treated with primaquine developed hemolytic anemia. The cause of this adverse reaction was impaired glucose-6-phosphate dehydrogenase (G6PD) activity. Studies found that G6PD-impaired activity is caused by genetic variation in the gene that encodes the G6PD enzyme. Later, it was shown that African Americans had a relatively high frequency of this genetic variation, which is likely because it protected its carriers from malaria, an important genetic selection mechanism in Africa.
Polymorphisms
defined as variations in the genome that occur at a frequency of at least 1% in the human population. For example, the genes encoding the CYP enzymes 2A6, 2C9, 2C19, 2D6, and 3A4/5 are polymorphic, with functional gene variants of greater than 1% occurring in different racial groups.
Must be in at least 1% of the people
rare mutations
occur in less than 1% of the population and cause inherited diseases such as cystic fibrosis, hemophilia, and Huntington’s disease. Common diseases such as essential hypertension and diabetes mellitus are polygenic in that multiple genetic polymorphisms in conjunction with environmental factors contribute to the disease susceptibility.
In <1% of the people
State the most common genetic variation in human DNA
Single-nucleotide polymorphisms, abbreviated as SNPs and pronounced “snips,” are the most common genetic variations in human DNA
Define what occurs in a single-nucleotide polymorphism
- SNPs occur when one nucleotide base pair replaces another. SNPs are single-base differences that exist between individuals.
- Nucleotide substitution results in two possible alleles.
One allele, typically either the most common occurring allele or the allele originally sequenced, is considered the wild type.
The alternative allele is considered the variant allele. - A SNP may result in amino acid substitution, which may or may not alter the function of the encoded protein.
- If a SNP changes the amount or function of a protein that contributes to drug response, it may alter pharmacokinetic properties or a patient’s sensitivity to a drug or predispose a patient to adverse reactions to drug therapy.
wild type allele
One allele, typically either the most common occurring allele or the allele originally sequenced, is considered the wild type
variant allele
the alternative allele to the wild type
Name the major polymorphic drug metabolizing enzymes
- phase 1 enzymes
- phase 2 enzymes
- nucleotide base metabolizing enzymes
phase 1 enzymes
CYP superfamily of isoenzymes
