Pharmacogenetics Flashcards
What is pharmacogenetics?
branch of pharmacology that involves identifying genetic variations that lead to interindividual differences in drug response
What is the difference between pharmacogenetics and pharmacogenomics?
PHARMACOGENETICS = monogenetic variants that affect a patient’s response to a particular drug
PHARMACOGENOMICS = entire spectrum of genes that are involved in determining a patient’s response to a particular drug
What is the goal of drug therapy?
produce a specific pharmacologic effect in a patient without producing adverse effects
What are the 7 main causes of variability to drug response?
- age
- health/disease status
- species
- gender
- breed
- drug interactions
- patient’s genome (mutations, deletions, polymorphisms)
What 2 things does individual variations to drug therapy cause? What tends to cause these effects?
- lack of therapeutic efficacy
- unexpected harmful effects (toxicity)
polymorphisms in drug receptors, drug transporters, or drug-metabolizing enzymes
How does pharmacogenetics use aspects of pharmacokinetics and pharmacodynamics?
studies how genetics differences alter ADME and receptors/signal molecules
Individualization of drug therapy has what 2 important clinical implications?
- predict what patients are at high risk for developing drug toxicity, allowing for alterations in drug doses to be made or the use of an alternative drug
- help identify patients that are most likely to benefit from a particular drug
How many nucleotide bases and genes make up the human genome?
3 billion nucleotide bases represent roughly 30,000 genes
What is a gene?
DNA sequence containing several codons that specify a particular protein
What is the difference between a mutation and a silent mutation?
MUTATION: alteration of the sequence of nucleotide bases in a DNA molecule that changes the transcribed RNA and translated amino acids, creating a new codon that can result in the translation of a new protein, or the creation of a stop codon —> change in protein structure and function can be deleterious
SILENT MUTATION: a mutation that results in a base change that creates a codon for the same amino acid —> no change in protein structure or function
What is an allele? How do they affect genotype?
at each gene locus, an individual carries 2 sets of alternative genes, one from each parent
- if an individual has 2 identical alleles, they have a homozygous genotype
- if an individual has 2 different alleles, they have a heterozygous genotype
What is a phenotype?
outward, physical manifestation of a given genotype - may be immediately obvious, but can also not be apparent until a particular drug is administered
What are polymorphisms? What is a good example in humans?
genetic variations occurring at a frequency of 1% or greater in the population
cytochrome P450
(cystic fibrosis < 1% = not polymorphic)
What is the MDR1 defect? What dogs is it common in?
4 bp deletion in the multi-drug resistance gene that leads to an early stop codon, which leads to the production of a shorter, non-functional P-glycoprotein that is no longer able to work as an efflux transporter to pump drugs out of cells —> macrocyclic lactone drugs (ivermectin!) able to get inside vulnerable areas of the body
Collies (also Shetland sheepdog, Australian shepherd, border collie)
Where was the P-glycoprotein coded for by MDR1 first found in? Where are they commonly found in the body?
described in highly resistant cell tumor lines, resulting in the tumor cells being cross-resistant to various anticancer agents
several body barriers - intestine, kidney, BBB, BTB, placenta, liver (bile canaliculi)
How do brain scans of a dog with an MDR1 defect compare to one without the defect after given IV P-glycoprotein substrate?
scan with defect = drug accumulation within brain tissue
scan without defect = no accumulation
How do abdominal scans of a dog with an MDR1 defect compare to one without the defect after given IV P-glycoprotein substrate??
scan with defect = void of activity of gallbladder, allowing drug to spread out to the surrounding tissue and organs
scan without defect = drug concentrated in gallbladder
