Pharmacogenomics Flashcards
three types of interindividual genetic variation that can influence pharmacotherapy
- proteins involved in drug metabolism or transport (pharmacokinetic)
- drug targets or pathway (pharmacodynamics)
- idiosyncratic adverse drug effects
enzymes involved in drug metabolism that display polymorphism
- butyrylcholinesterase (pseudocholinesterase)
- N acetyltransferase 2
- CYP2D6
- Thiopurine S-methyltransferase
what is the function of butyrylcholinesterase
it metabolizes succinylcholine
what occurs if there is a polymorphism in butyrylcholinesterase
-there would be a decreased rate of metabolism of succinylcholine leading to prolonged flaccid paralysis
type of inheritance of butyrylcholinesterase
hereditary autosomal recessive trait
how do you treat those with polymorphism in butyrylcholinesterase
you treat with continued mechanical ventilation until muscle function returns to normal
function of N acetyltransferase 2 and the types
- catalyzed the acetylation of isoniazid and other drugs
- slow acetylators: metabolize isoniazid slowly and have high drug blood levels
- fast acetylators: metabolizes isoniazid fast and have low drug blood levels
inheritance of slow acetylators
autosomal recessive
adverse effects of slow acetylators
since it keeps drug in plasma high and longer, it causes toxicity
examples of slow acetylators effects on drugs
- keeps isoniazid high in blood so lead to neuropathy and hepatotoxicity
- keeps hydralazine and procainamide high in blood leading to SLE
- keeps sulfonamides high leading to hypersensitivity, hemolytic anemia, and SLE
function of CYP2D6
it is part of the CYP450 family and hence metabolizes a lot of drugs
discuss different types of metabolizers of CYP2D6
- poor metabolizers: homozygous for recessive the allele leading hence low activity
- extensive metabolizers: heterozygous or homozygous for wild type allele
- ultrarapid metabolizers: multiple copies of CYP2D6 genes –> up to 13 copies
name drugs that are metabolized by CYP2D6
- beta blocker metoprolol
- neuroleptic haloperidol
- opioids codeine and dextromethorphan
- antidepressants: fluoxetine, imipramine, desipramine
what happens with poor metabolizers of CYP2D6 and give some examples
they suffer side effects when treated with standard doses as seen with metoprolol
or with codeine, it is ineffective since it needs to be converted by the enzyme to morphine
what happens when you give standard doses of codeine to ultrarapid metabolizers
overdose on codeine –> respiratory depression or respiratory arrest
what does thiopurine S-methyltransferase (TPMT) do
it methylates anti cancer drugs thiopurines 6 mercaptopurine and azathioprine which is good because they have a small therapeutic window
what happens then if one is homozygous for the polymorphism in TPMT (thiopurine S-methyltransferase)
they have to be given 1/10 of the standard dose so as not to have a toxic effects of the cancer drugs
when is EGFR (epidermal growth factor receptor) expressed
in non-small cell lung cancer (NCLC)
what drugs is approved for non-small cell lung cancer and how does it work
Gefitinib and it is an inhibitor of tyrosine kinase on EGFR
drug that is affected by both pharmocokinetics and pharmacodynamics
warfarin
lower doses of warfarin should be considered in what types of patients
those with polymorphism in CYP2C9 and VKORC1
how does racemic mixture of warfarin affects its metabolism
- S-warfarin is 3-5 times more potent than R-warfarin
- S-warfarin is metabolized by CYP2C9 which has a highly polymorphic gene while R-warfarin is metabolized by CYP3A4 and other CYP isoforms
what is idiosyncratic effect a result of
interaction between the drug and unique aspect of the physiology of the individual patient
condition that causes an idiosyncratic adverse effect
G6PD deficiency –> formation of heinz bodies (oxidized hemoglobin)
drugs that cause oxidative stress in G6PD deficiency
sulfonamides
antimalarials (primiquine and chloroquine)
chloramphenicol
what happens to individuals with G6PD deficiency who are exposed to drugs that cause oxidative stress
can cause acute hemolytic anemia
