Lecture 32: Pharmacogenomics Flashcards
What number cause of death are ADRs?
The 4th leading cause of death
What 5 things contribute to different response to medications?
- Pharmacogenetics
- Demographic factors
- Clinical factors
- Dosing factors
- Other factors
How can ethnicity and drugs affect African Americans?
African-Americans increased risk of heart failure from hydralazine
How can ethnicity and drugs affect Asian Americans?
East Asian descent people have issues with alcohol metabolism
How do Sex and Variation affect drug response?
Women tend to be underrepresented in drug trials and have more adverse events
How does age affect variation in drug response?
- Drug metabolism is less efficient in newborns and the elderly
- More side effects in vulnerable groups
- Body fat composition changes
How does age affect Renal Excretion?
- GFR rates is lower in neonates
- GFR decline from 20 years
- Takes longer to excrete drugs
How does age affect Drug Metabolism?
- Changes in enzyme expression levels
- CYPs and Phase II conjugating enzymes
- Disease of metabolic organs (kidney/liver)
What three ways can genetic variation in a gene cause altered enzyme activity?
- Regulatory variation
- Coding variation
- Splice-slice variation
How can Regulatory variation affect gene expression?
- Increased expression of the regulatory element
* Decreased expression
How can Coding variation affect gene expression?
- Missense
- Start/stop lost
- Inframe insertion/deletion
- Stop gained
- Frameshift
How can Splice-site variation affect gene expression?
- Create/abolish the acceptor site
* Create/abolish donor site
What parts of DNA are spliced out?
Introns
What occurs in a single nucleotide polymorphism?
One nucleotide is replaced with another nucleotide
What is the start codon?
AUG
What is a splicing defect?
When introns aren’t spliced out properly
What is expression quantitative trait loci (eQTL)?
A variant in a sequence is changing the expression level of another gene
What is the difference between cis and trans eQTL?
Trans - affecting a gene somewhere else
Cis - affecting a drug downstream
What does Precision health do?
Takes both genetic and non-genetic factors into account
What enzyme is important in metabolizing drugs?
CYP2D6
Why is CYP2D6 important?
There are so many genetic variants changing the function of CYP2D6
How is drug metabolism affected by increased or decreased CYP2D6?
Increased CYP2D6 will increase drug metabolism
Decreased CYP2D6 will decrease drug metabolism
What are the pharmacokinetics of Codeine?
It is converted to morphine by CYP2D6
Why should some people not be prescribed codeine?
Because ultrarapid metabolizers should not be prescribed codeine due to toxicity risks it will be converted into morphine at increased rates
What are important clinical considerations for pharmacogenomic biomarkers and clinical implementation?
- Association between genetic variants and adverse drug reactions should be reliably replicated
- Robust ADR phenotyping is essential
- Risk conferred by variants should be clinically relevant
- Implementation is assisted by clinical practice guidelines
What is CPIC?
An organization that helps drug therapy through phenotype
What is the issue with cancer treatments?
They are effective but not safe for children and associated with many health conditions
What is Cisplatin?
A cancer drug that causes hearing loss
What causes CIO susceptibility in people taking Cisplatin?
A variant in TCERG1L that changes levels of cytokines
What is Mercaptopurine (6-MP)?
A purine analog that is a treatment for cancer and autoimmune diseases
How does Mercaptopurine (6-MP) work?
It is a purine antagonist and inhibits DNA synthesis/replication
How does Mercaptopurine (6-MP) work?
It is a purine antagonist and inhibits DNA synthesis/replication
What are the side effects of Mercaptopurine (6-MP)?
It causes Myelosuppression (hematological toxicity)
What is Mercaptopurine metabolized by?
Thiopurine Methyltransferase (TPMT) gene
What do variants in TPMT and NUDT15 cause?
It can cause it to be inactive in some patients so Mercaptopurine cannot be cleared and it builds up even when dosed properly and cause cytotoxicity
