Lecture 34: Pharmacogenomics Flashcards
What are adverse drug reactions (ADRs)?
negative/undesirable effects of drug treatment
can influence different systems
severely debilitating and potentially fatal
How are ADRs a serious healthcare burden?
4th leading cause of death
6.5% of hospital admissions in the United Kingdom attributed to ADRs
What are sex differences in drug response?
8 of 10 withdrawn drug effect women more than men
women underrepresented in the research pipeline
How does pregnancy influence drug response?
physiological changes
relevant for both the mother and fetus
How does age cause variation in drug response?
drug metabolism/elimination less efficient in newborns/elderly; renal excretion rates, metabolic enzyme expression levels
more side effects in vulnerable groups: polypharmacy
How can genetic variation in a gene cause altered enzyme activity?
regulatory variation: increased expression, decreased expression
coding variation: missense, start/stop lost, inframe insertion/deletion, stop gained, frameshift
splice-site variation: create/abolish acceptor site, create/abolish donor site
What is the genetic variation caused by regulatory regions?
examine the association between genetic variants and gene expression levels
called expression quantitative trait loci (eOTL)
can be cis or trans
What is the pharmacogenomic influence on drug response??
drug response is heritable
key determinant of response to mediation
What is the research potential of pharmacogenomics?
predict and prevent non-optimal treatments
gain mechanistic insight into disease pathophysiology
What is precision health?
precision health takes both genetic and non-genetic factors into account
previously terms personalized medicine
often framed as the right treatment, for the right patient, at the right time
What is CYP2D6?
CYP2D6 is an important drug metabolizing enzyme
polymorphic (PGx applications)
currently: 16 drugs with clinical guidelines for CYP2D6 PGx
How do genetic variants change the function of CYP2D6?
more than 100 genetic variants changing the function of CYP2D6
in addition to single nucleotide variants, CYP2D6 has large scale rearrangements in some patients
What is the interaction between codeine and CYP2D6?
pharmacokinetics: codeine is converted to morphine by CYP2D6
breast feeding cases: drug label changes
ultrarapid metabolizers should not be prescribed codeine: non-opioid alternatives, population differences
What is the Clinical Pharmacogenetic Implementation Consortium (CPIC)?
standardized, peer-reviewed
international consortium, formed in 2009
systematic grading of evidence and clinical recommendations
What is the relationship between mercaptopurine (6-MP) and myelosuppression?
thiopurine drug used in treatment of: cancer (e.g., all)
mechanism: purine antagonist (inhibits DNA synthesis/replication), which is cytotoxic
serious adverse drug reactions: hematological toxicity (myelosuppression)
