Pharmacogenetics Flashcards
Define pharmacogenetics
A drug response related to a single or a few genes.
Define pharmacogenomics
The study of variations of DNA and RNA characteristics as related to drug response.
- We can’t do this yet most of the time.
Define SNPs
Single Nucleotide Polymorphisms
- Account for 90% of all human DNA polymorphisms.
- Synonymous
- Non-synonymous: matters
Relevant pharmacogenetic examples:
- Aliskiren: ACE and REM
- ACE-Is: ACE
- ARBs: AGTR1
- Aldosterone antagonists: NR3C2
Relevant polymorphisms
Drug metabolizing enzymes (CYPs)
- Ultra, rapid, normal, intermediate, and poor.
Drug transporters
- Increased, normal, decreased, and poor.
Human Leukocyte Antigen (HLA)
- Positive: carrier
- Negative: non-carrier
Genotype nomenclature
For clinicians: Gene*number/*number - *1/*1 = normal - *1/*2 = intermediate - *2/*2 = poor
- That is generally speaking; can be gene-specific!
- Not all use star-number system at this point in time.
The Three Rights
Right person.
- Someone that will actually benefit.
Right test.
- To gather the right information.
Right interpretation.
- How relevant and how to proceed.
Methods of Variant Interrogation
Chip/Panel
- Look for a collection of predetermined variant SNPs
- May miss rare variants
Next Generation Sequencing
- Whole Genome Sequencing (WGS)
- Whole Exome Sequence (WES)
- Information overload.
Phenotype can be affected by…
Drug interactions
In-vitro manipulations
Blood transfusions
Abacavir
HLA-B*57:01
- Asian*
- Caucasian
0 - All good.
1 or 2 - change, unless already on it and okay.
Allopurinol
HLA-B*58:01
- Asian*
- African American
- Middle Eastern
0 - All good.
1 or 2 - change, unless already on it and okay.
CBZ/Ox/Phenytoin
HLA-A15:02
HLA-A31:01
- Asian
0 - All good.
1 or 2 - change, unless already on it and okay.
2D6 and Codeine
2D6 polymorphisms that with increased activity lead to higher rates of conversion to morphine - dangerous in children.
- M6G: analgesia
- M3G: SE’s
2D6 and Tramadol
2D6 polymorphisms with increased activity lead to higher rates of conversion to O-desmethyl tramadol
- M1: analgesia
2D6 and Oxycodone
to Oxymorphone
2D6 and Hydrocodone
to Hydromorphone
Ethnic variability in 2D6 phenotypes
Ultra-rapid most common in Africans/Ethiopian and African American
CPIC guidelines for 2D6 and Codeine
Ultrarapid metabolizers
- Avoid Codeine
- Try morphine or non-opiods.
Extensive (normal) - okay
Intermediate - okay
Poor metabolizer
- Avoid Codeine
- Try morphine or non-opioids.
2C19 and Clopidogrel
Do not use in poor metabolizers b/c required for activation.
Pertinent 2C19 medications:
Clopidogrel
PPI’s
Some antidepressants
Voriconazole
CYP2C19 Polymorphisms
- 2 - loss of function
- 1/3 asians
- 2/3 oceanians
- 3 - loss of function
- asians
- 17 - gain function
- caucasians
- africans
CPIC guidelines for 2C19 and Clopidogrel
Use something else if intermediate or poor metabolizer.
Enzymes relevant to Warfarin
CYP 2C9
VKORC1
2C9 and Warfarin
Required for inactivation of S-Warfarin Common poly: *2 and *3 Effects: reduced metabolism Prevalence: mostly caucasian Clinical significance: reduce initial dose
KVORC1 and Warfarin
Reduces VitK to active form
Common poly: 1639G (more) and A(rs9923231)
Effects: Alters VKORC1 transcription binding site, leading to lower protein expression
Prevalence: Asian > Caucasian > AA
Clinical Significance: reduce initial dose
Role of the Pharmacist
Recommend
- pharmacogenomic testing
Design
- patient-specific regimen
Educate
- other healthcare professionals
Communicate
- to team
- on patient’s health record
