Pharmacogenetics Flashcards
Lecture 5
Every year, more than 100,000 people in die in the US because they carry ____ genes that make medications either ineffective or deadly
Misspelled
In addition to drug-drug interactions, there are also ____ interactions
gene-drug
Genetic differences in plasma proteins results in:
Differences in affinity and extent of drug binding
Genetic differences in metabolic enzymes results in:
Differences in concentration of drug, active metabolites, toxic derivatives
Genetic differences in membrane proteins results in:
Differences in absorption, distribution, excretion
Genetic differences in receptors results in:
Differences in abundance or sensitivity –> therapeutic vs adverse effects
____ is the study of differences in drug response due to allelic variation in genes affecting drug efficacy, metabolism, toxicity (variable response due to individual genes)
Pharmacogenetics
Every person carries ____ copies of every gene
Two (homozygous or heterozygous)
What is pharmacogenomics?
Genomic approach to pharmacogenetics concerned with the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy
____ is involved with a variable response due to multiple loci across the genome (different alleles across many different genes affecting the response of a drug)
Pharmacogenomics
Large single-variant effect caused by:
Pharmacogenetics
Smaller effect with multiple variants caused by:
Pharmacogenomics
What two types of genetic mutation events create all forms of variations?
- Single nucleotide polymorphisms (substitute one nucleotide for another)
- Insertion or deletion polymorphisms
What is a polymorphism?
A genetic variation observed at a frequency of more than 1% in a population
What is a mutation?
Genetic variation in less than 1% in a population
True or false: SNPs are rare in the human population
False - very common
Between any two people, there is an average of one SNP every ____ bases
1000
Do most SNPs have a phenotypic effect?
No
Estimate that ____ SNPs in the genome (how many bases total in the genome?)
3.2 million; 3 billion total
Only ____ of all human SNPs impact protein function (most in non-coding regions)
< 1%
What is a missense mutation?
Mutated codon codes for a different amino acid (could be significant)
What is a nonsense mutation?
Mutated codon is a premature stop codon (usually serious)
Insertion/deletion (INDEL) polymorphisms are ____ and ____ distributed throughout the human genome
Quite common; widely
INDEL that add or subtract amino acids may:
Have no effect, alter the activity or abolish all activity of the affected protein
LARGE deletions result in:
Complete loss of protein expression
Gene duplication results in:
Stably transmitted inherited genes that cause increased protein expression and activity
Every person has two copies of every gene that are inherited ____
Independently
CYP450 genotypes result in:
Various combinations of wild-type or decreased activity, inactive, or duplicated alleles
List the different CYP450 Phenotypes
- Poor metabolizer
- Intermediate metabolizer
- Extensive metabolizer
- Ultrarapid metabolizer
Poor metabolizer - genotype
2 inactive alleles of CYP450
Intermediate metabolizer - genotypes?
- 2 decreased activity alleles
- One active allele and one inactive
- One decreased activity allele and one inactive
(CYP450)
Extensive metabolizer - genotype
2 functional alleles (wild type)
Ultrarapid metabolizer - genotype
Gene duplication in the absence of inactive or decreased alleles
Describe the pharmacokinetic effects of a poor metabolizer (CYP450)
Drug enters toxic range and tapers off but remains in toxic range
Describe the pharmacokinetic effects of an intermediate metabolizer (CYP450)
Drug enters toxic range but tapers off into therapeutic range and doesn’t go below that
Describe the pharmacokinetic effects of an extensive metabolizer (CYP450)
Drug concentration peaks at therapeutic range and tapers off below this range as it is being broken down
Describe the pharmacokinetic effects of an ultrarapid metabolizer (CYP450)
Drug enters therapeutic range but quickly decreases below therapeutic range
If a patient is an ultrarapid metabolizer, how do you modify their treatment?
May have to prescribe a higher dose due to much more CYP450 being available
List examples of gene-drug interactions
- CYP2D6 and Codeine
- ALDH2 and Ethanol
- CYP2D6 and Tamoxifen
What is codeine?
Analgesic (painkiller)
____ is a prodrug
Codeine (inactive compound that when metabolized becomes an active drug)
____ is critical for codeine’s analgesic effect
CYP2D6-mediated bioactivation
What is codeine metabolized into?
Morphine
What is the difference in structure between codeine and morphine?
Methyl group removed to create morphine
Codeine is more ____
Morphine is more ____
Lipophilic; hydrophilic
A poor metabolizer (CYP2D6) of codeine would result in:
No analgesic effect of morphine (no metabolism = no activation of codeine)
An intermediate metabolizer (CYP2D6) of codeine would result in:
Slight analgesic effect of morphine
An extensive metabolizer (CYP2D6) of codeine would result in:
Effective pain relief from morphine
An ultra metabolizer (CYP2D6) of codeine would result in:
“overdose” effect
Low dose of ethanol causes:
- Muscle relaxant
- Euphoria
- Impaired judgment
High dose of ethanol causes:
- CNS depressant
- Impaired sensory/motor function
When does ethanol become toxic?
When BAC > 400mg/dL (0.4%)
How does ethanol metabolism occur?
Two steps:
- Alcohol dehydrogenase (ADH) converts ethanol to acetaldehyde
- Aldehyde dehydrogenase (ALDH2) converts acetaldehyde to acetic acid (detoxification step)
____ is a toxic metabolite during ethanol metabolism
Acetaldehyde
ALDH2 has an alternative allele in which:
Lysine residue replaces a glutamate in the active site at position 487 of ADH2
ALDH2 alternative allele can result in what genotypes?
- ALDH2 1/1 wild type homozygous
- ALDH2 1/2 Heterozygous
- ALDH2 2/2 Variant homozygous
Homozygous individuals (ALDH2 2/2) with the variant allele have:
Almost no ALDH2 activity (8% of normal)
Heterozygous individuals (ALDH2 1/2) have:
Reduced activity
ALDH2 is a ____ (structure)
Tetramer
ALDH2 influence on acetaldehyde blood levels following ethanol ingestion: WT
No flushing, no hangover effects
ALDH2 influence on acetaldehyde blood levels following ethanol ingestion: Heterozygous
Some flushing, some hangover effects
ALDH2 influence on acetaldehyde blood levels following ethanol ingestion: Homozygous variant
Flushing, hangover effects (not converting acetaldehyde toxic metabolite into acetic acid)
What is disulfiram?
- Drug used to treat chronic alcoholism
- Inhibits aldehyde dehydrogenase resulting in acetaldehyde accumulation
Estrogen receptor-positive breast cancer is under the control of ____ and can be effectively treated with ____
Estrogen; anti-estrogens
Anti-estrogens work by:
Binding to estrogen receptors, blocking estrogen from binding, stopping cell proliferation
____ is an anti-estrogen
Tamoxifen
CYP2D6 biotransforms tamoxifen into:
Endoxifen (potent antiestrogen)
CYP2D6 genotypes have been associated with ____ of endoxifen
Variability in plasma concentrations
PM phenotype results in ____ endoxifen plasma concentrations in tamoxifen-treated breast cancer patients
Reduced
EM phenotype results in ____ serum concentrations of endoxifen
Significantly higher
PM phenotype serves as:
A predictor of breast cancer outcome in postmenopausal women taking tamoxifen for breast cancer (shorter time to cancer recurrence, worse relapse-free survival)
True or false: Dentists will be accountable for prescribing drugs appropriately to genetic subgroups
True
