6 - Pharmacogenetics Flashcards
What is the current empirical strategy for drug therapy? What is the problem with this?
Treat all patients with the same diagnosis with the same mediation at the same starting dose.
Problem: some people will respond, some will be nonresponders (which can be an ADR if the condition is serious), and some will have toxicity (ADR).
What are pharmacogenetics?
Genetic factors that alter an individuals response to a drug.
Based on genetic polymorphisms and less common genetic variants.
What is a genotype? What is a phenotype?
Genotype: individuals composition at the gene level, ie the specific genes they have determined by their DNA sequenece.
Phenotype: individuals expression of their genotype; the observable physical or biochem characteristics.
What is a genetic polymorphism?
Mendelian trait that exists in the population in at least two phenotypes, neither of which is rare.
-At least one variant needs to represent greater than 1% of the total pool (of the population).
What is a single nucleotide polymorphism (SNP)? Do these always have a consequence?
A change in one single base pair in the DNA sequence that differs from the wild type or predominant sequence.
May or may not result in a phenotype.
> 99% have no phenotypic influence and don’t influence expression.
In many cases ____ SNPS influence the phenotype. How do we categorize these?
Multiple SNPs.
We call this a haplotype: closely liked SNPs present on one chromosome that tend to be inherited together within a gene or closely linked genes.
What is a halotype? How does this differ from a haplotype?
A cluster of SNPs that occur together in an individual.
Could be in a single gene (like a haplotype) or could be in distant genes or chromosomes (not a haplotype).
Most commonly studied halotypes are in closely linked SNPs, making them also haplotypes (so just say haplotypes).
What is autosomal co-dominance? What does autosomal recessive mean? Autosomal dominant?
Co-dominance: each allele contributes to a a phenotype.
Recessive: wild-type allele has predominant effect; takes two alleles to see the effect
Dominant: single allele predominates other the others
What is homozygous? What is heterozygous?
Homozygous: having two identical alleles (AA, aa)
Heterozygous: having two different alleles (Aa)
What are the things that pharmacokinetics impact?
Transporters, plasma protein binding, metabolism, excretion.
What are things that pharmacodynamics impact?
Receptors, ion channels, enzymes, and signaling events.
What is the NAT-2 polymorphism associated with?
Increased neurological side effects in pts receiving drug ISONIAZID.
N-acetyltransferase 2 detoxifies isoniazid and polymorphisms in NAT-2 explain fast vs slow acetylators.
Describe slow and fast acetylators of isoniazid in the context of NAT2 polymorphisms?
Slow acetylators are homozygous for the slow allele and break down the drug more slowly (drug stays in body longer)
Fast acetylators have 1 or two copies of the fast allele.
What is a CYP2D6 polymorphism associated with?
DEBRISOQUINE effect:
- Excessive hypotension
- correlated with increased debrisoquine concentrations and decreased debrisoquine metabolism
(this drug used to treat high blood pressure)
CYP2D6 polymorphisms liked to poor metabolizers - drug stays in body longer and has a more severe effect.
How common are CYP2D6 variant alleles? What do they account for in the population?
There’s over 75 variant alleles, 7 of which account for more than 90% of the poor metabolizers.
What is the CYP2D6 poor metabolizer phenotypic frequency (2 copies of slow alleles) overall? What does this mean?
2-10% of patients will be poor metabolizers.
Poor metabolizers will have increased side effects because they can’t metabolize the drug fast enough.
What is the overall prevalence of CYP2D6 ultrafast metabolizers? What is this caused by? What does this mean?
1-30% of patients will be ultrafast metabolizers.
This means that they have a large number of copies of the normal allele.
Means they degrade the drug too quickly and don’t get a benefit from it.
What is an important drug type that’s metabolized by CYP2D6?
Antidepressants.
What percent of the population has the CYP2C19 polymorphism and are homozygous poor metabolizers? This effects the metabolism of which drugs?
3-20%.
Omeprazole: poton pump inhibitor
Phenytoin: anti-convulsant
Clopidogrel: anti-platelet
How can being a poor metabolizer with a CYP2C19 polymorphism be a benefit?
Poor metabolizers using Omeprazole have higher drug levels, which correlate with increased gastric pH and higher cure rates.
What is the function of Clopidogrel and how is it affected by CYP2C19? What results from having a slow allele?
It inhibits platelet aggregation following an MI.
Activated by CYP2C19.
Those with even one slow allele (34% of pop) have a 53% increase in serious cardiovascular outcomes.
What is dangerous about giving patients (even those who are normal metabolizers) clopidogrel post-MI and omeprazole to limit gastric irritation (from aspirin) at the same time?
Omeprazole and clopidogrel are both CYP2D6 substrates and competitive inhibition will occur, resulting in clopidogrel not being activated.
Higher rate of MI and death in patients getting both.
What are two low activity alleles associated with the CYP2C9 slow metabolizer polymorphism?
What percentage of patients have the first and/or second low activity allele?
CYP2C92 and CYP2C3 are low activity alleles
Together *2 and/or *3 alleles are in up to 31% of the patients.
What is an example of a drug impacted by CYP2C9 polymorphisms?
Warfarin: anticoagulant
What occurs when blood levels of warfarin are too high? What about when blood levels are too low?
Too high: serious bleeding events
Too low: intravascular clotting including stroke
How is warfarin cleared from the body? What impact do polymorphisms have?
Almost exclusively by CYP2C9.
CYP2C9*2 and *3 significantly reduce warfarin clearance and increase the half life.
-require lower maintenance dose and have increase rick of bleeding
What is VKORC1? what effect does warfarin have on it?
A vitamin K receptor - a subunit of the vitamin K epoxide reductase complex.
Warfarin is a vitamin K antagonist and competitively inhibits the activity of VKORC1.
What is the function of VKORC1?
Converts clotting factors to the mature form when they are needed.
When it’s inhibited (by warfarin) you can’t clot effectively).
What haplotpes of VKORC1 require low warfarin doses? What about the haplotypes that require high warfarin doses? What clade is each associated with?
Require low doses: H1 and H1 - clade A
Require high dose: H7. H8. H9 - clade B
What clade of VKORC1 is common in asian-americans? What about african americans or people of european descent
Asian americans: A clade
African americans: B clade
European descent: Mix of A and B
Does VKORC1 effect half life?
NO.
Are there ultrafast variants of CYP2C9?
NO.
How do the actions of CYP2C9 and VKORC1 differ?
CYP2C9 inactivates warfarin
VKORC1 is a competitive inhibitor of warfarin.
How should you dose a person with CYP2C9*2 or *3 alleles for warfarin?
They have a longer warfarin half life because they can’t metabolize the drug as fast.
They need lower doses.
What is a pseudocholinesterase polymorphism? What does it cause?
A variant response to SUCCINYLCHOLINE, a surgical skeletal muscle relaxant which effects usually last 5 min after dose stopped.
Atypical pts experience apnea and paralysis for 2-3 hrs.
May increase susceptibility to some insecticides and cocaine toxicity.
Is there only one pseudocholinesterase polymorphism? What is the incidence?
No, there’s multiple reduced activity variants of pseudocholinesterase.
1-6% of the population.
What is a TPMT polymorphism associated with? Spell out the drug this is related to. What is TPMT?
TPMT is thiopurine methyltransferase
An increased risk for life-threatening bone marrow suppression in cancer pts treated with 6-MERCAPTOPURINE.
What is the action of TPMT?
It methylates 6-mercaptopurine to inactivate it.
What is the frequency/risk of one or two low activity alleles of TPMT? What is the associated outcome of each?
11% of the population has one abnormal allele - elevated risk of bone marrow suppression from 6-MP
0.3% of the pop has two abnormal alleles - high risk of bone marrow suppression from 6-MP
DNA testing is recommended by the FDA.
What is SLCO1B1 (OATP1B1)?
An organic anion transported important for the uptake of some hydrophilic drugs in the liver.
What drugs are widely used for decreasing cholesterol? What is their action? What is the most concerning side effect?
Statins - competitively inhibit HMG-coA reductase (rate limiting step of cholesterol biosyn).
Skeletal muscle toxicity.
What do low activity polymorphisms of SLCO1B1 lead to? What is the risk of this?
Elevated blood levels of some statins such as SIMVASTATIN (less so for atorvastatin).
Elevated simvastatin levels are associated with increased risk of myopathy.
What is the risk of having one “C” low expression allele of SLCO1B1? What about 2? What does this mean for dosage?
One C allele: partial uptake into the liver; increased myopathy risk – consider lower dose or different statin
Two C alleles: further decreased in uptake into the liver; further increased myopathy risk – lower dose, CK monitoring, or try another statin.
Other drugs that interact with OATP1B1 have the potential to do what?
Affect statin levels/toxicity and could have even greater impact on pts with low activity alleles of SLCO1B1
Polymorphisms have a greater significance for what type of drugs?
Drugs with a relatively narrow therapeutic window.
The narrower the window, the more people that will fall outside of that window with a polymorphism.
Tylenol with codeine was given for post-operative pain and a child died. What did they likely die from and what caused this? What is the genetic basis for this?
Excessive morphine levels caused by CYP2D6 ultrafast metabolizers.
This is because CYP2D6 activates codeine to morphine.
Ultrafast metabolizers have multiple copies (up to 13) of the normal CYP2D6 allele.
Both ____ polymorphisms and ______ expression effect the dosage of warfarin that your patient needs.
CYP2C9 - warfarin clearance
VKORC1 expression - blocked by warfarin
What does 6-mercaptopurine normally do?
Inhibits purine synthesis and causes nucleotides to be mis-incorporated into DNA and RNA.
What polymorphism affects receptors or enzyme targets?
VKORC1
What polymorphisms affect drug absorption/uptake?
SLC01B1
What happens when a patient is given Tylenol with codeine? What does this mean for poor metabolizers and fast metabolizers?
CYP2D6 converts some of the codeine to morphine.
Poor metabolizers will not convert much codeine to morphine and have little pain relief.
High metabolizers will convert too much to morphine and have toxic effects.
