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59 Cards in this Set
- Front
- Back
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PharmacoGenetics
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The study of DNA variations in specific genes involved in drug metabolism and /or response.
**can limit definition to monogenic traits** |
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Pharmacogenomics
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Whole genome approaches to identify DNA variations related to drug metabolism and/or response
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What is newer? Pharmgenetics or Pharmgenomics?
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Pharmacogenomics is more recent
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what is pharmacokinetics?
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Plasma clearance, Delivery, of drug or metabolite to target cells
**what BODY does to the DRUG** |
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What is Pharmacodynamics
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Relationship between drug concentration and its effect on the body.
**What the DRUG does to the BODY** |
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What can genetic variability effect?
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*Pharmacokinetics
*Pharmacodynamics *Likelihood of adverse reactions |
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What are the goals of PharmacoGENETICS?
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* Improved drug choices
*Safer dosing options *Improvement in drug development *Decrease health care costs |
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PharmacoKINETIC :
What genetic variations could alter? |
Absorption
Distrubition Metabolism Excretion |
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Pharmacodynamics
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*Receptor Interactions
*Ion channel interactions *Enzyme Interactions *Signaling pathway Interactions |
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What drugs are recommended by FDA for PharmacoGENETIC testing?
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Warafin** - CYP2C9, VKORC1
(anticoagulation) Clopidogrel** - CYP2C19 (anti-platelet) |
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What is an allele?
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Sequence Differences in the Same Gene
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What is a polymorphism?
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Allele present in >1% of heterozygote individuals in a population
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What is a sequence variant?
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If Alleles Are Present in <1% of Heterozygous individuals in a given population
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What three discoveries gave rise to pharmacoGENETICS?
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–Primaquine Sensitivity (G-6-PD Deficiency)
–The Slow Metabolism of Isoniazid (Acetylation Polymorphism & Tuberculosis) -Atypical plasma cholinesterase give rise to prolonged effects on Succinylcholine (respiratory Apnea) |
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What gene controls the drug metabolism ( via cytochrome p450 enzyme)
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CYP2D6
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What gene is related to Warafin and Coagulation?
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CYP2C9
VKORC1 |
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What is Glucose 6 Dehydrogenase Deficiency?
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Enzyme in Hexose Monophosphate Shunt a principle source of NADPH generation
Reduces SH groups on glutathione GSH deficiency in RBC cause hemolytic anemia!!! |
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Who is most likely to have a G-6P variants?
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Mediterranean populations
& Blacks |
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How does NAT2 variations alter TB treatment?
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NAT2 is a gene that controls Liver N-acetyltransferase which acetylates Isoniazid
IT DETERMINES HOW QUICKLY ISONIAZID IS METABOLIZED! |
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What happens to people who are rapid acetylaters?
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*Higher failure rate for TB with Isoniazid
* Requires higher doses of Hydralazine to Control Hypertension and dapsone to Treat Leprosy and Other Infections! |
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What happens to people who are slow acetylaters?
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Get toxic effects from accumulating the drug --> peripheral neuropathy
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Are rapid metabolizers wildtype?
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Yes, they are either heterogenous dominant for WT or homogenous for WT
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Who are most common slow metabolizers?
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Egyptions
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What does Cytochrome P450 do?
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Responsible for metabolization of many compounds;
4 P450 enzymes are in over 80% of over the counter medications? |
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What are key genes involved in cytochrome P450?
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CYP2D6 & CYP2D9
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What happens to people who have slow breakdown of cytP450
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Postural hypotension
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What does CYPD26 code for?
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Microsomal Cytochrome
P450 Monoxygenase |
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Who is most likely to have an allelic variation with CYPD26
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Caucasions
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If you are an ultra rapid metabolizer do you need more or less of the drug to achieve optimal results?
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More drug..
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What does amplichip look for?
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Variations in CYP2D6 and CYP2C19
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How is Warafin metabolized?
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By cytochromeP450 which is controled by:
CYP2C9 And involves Vitamin K Epoxide Reducatase (VKORC1) |
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If you have a CYP2CP mutation, do you want a higher or lower dose of warafin?
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Lower dosage
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What is danger of being a overly sensitive to Warafin?
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Could cause CNS bleeding
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What is danger of being resistant to Warafin?
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Need higher dose to prevent strokes
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What drugs are metabolized by Thiopurine S-Methyltransferase (TPMT) ?
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Mercaptopurine and Azathiopurine
(both used to treat Cacer) |
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What is danger of VERY high TPMT?
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Decreased therapeutic effect (because metabolized too quickly)
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What is danger of low TPMT?
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Increased toxicity & increased risk for secondary neoplasm
*If have two non-functional alleles should be given about 6-10% of standard dose of Thiopurines |
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What should be done for patients who are heterozygous for TPMT?
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Start on full doses but more likely to require dose reduction to avoid toxicity
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What are two genomic approaches to identify genes and variants involved in drug metabolism?
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1)Genome –Wide Association Studies
2) RNA Expression Arrays! |
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What are the different ways to manipulate metabolism/
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1) Dietary
2) Substrate depletion (i.e. chelation or plasmapheresis) 3)Metabolic inhibitors 4) Product replacement |
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What are the current solutions to metabolic disease?
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1)Metabolic Manipulation
2)Protein/enzyme replacement 3) Cell/organ transplantation |
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What ways can you provide enzyme therapy?
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1)Cofactor supplementation
2) Protein/enzyme replacement |
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What is the metabolic defect causing Methylmalonic acidemia?
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3 different steps to take L methylmalonyl CoA to Succinyl Coa, with 4 different possible defects...
What ended up working was giving cofactor B12 |
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If screen for prenatal Methylmalonic acidemia, what is the best course?
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Give Vitamin B12 to the mother...
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Gaucher's metabolic defect?
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Defected enzyme (Glucocerebrosidase)
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Gaucher's symptoms?
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Hepaomegaly
Splenomegaly Neurodengeneration in type II and III |
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What is solution for Gaucher's?
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Enzyme replacement therapy
--> unexpectedly reversed lysosomal storage --> dose dependent response --> INEFECTIVE FOR NEURODISEASE!!! |
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What diseases do you use bone marrow transplantation for?
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SCIDS
Wiskott-Aldrich Syndrome Chronic Granulomatous Disease Sickle Cell anemia Hemolytic anemias |
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What percent of proteins are misfolded and degraded by proteasome?
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30%
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What is basic idea behind chaperone therapy
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They are reversible competetive inhibitors of the enzyme and would bind and induce change in the protein so they can be processed and leave the ER...when reached higher concentrations of substrate, the substrate has a greater affinity and the chaperone is displaced by enzyme
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Has Chaperone therapy been tested in humans?
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No, only mice & cells
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3 advantages of chaperone therapy
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1) oral administration
2) increased enzyme activity leads to clinical benefit 3)CROSSES BLOOD BRAIN BARRIER!!! |
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What percent of mutations are from stop codons in MPS?
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24%
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What is idea behind RNA interference?
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Use RNA interference (RNAi) to knockout selectively the mutant protein... so when assembly of subunits come, you are only assemblying normal subunits...
-->less mutant protein! |
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What is RNAi selective for?
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Disease transcript
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What are some viral vectors that could be used for Gene therapy?
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1)Retrovirus (defective)
2)Lentivirus (defective) 3) Adeno-Associated virus - coinfection w/ herpes |
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What is danger of gene therapy (seen w/ X-SCID patients)
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Leukemia
(to date, 4 patients have died) |
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Obstacles to Neuronal CNS therapy?
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•Global CNS Delivery
• Neuron-Specific Targeting • Prolonged Neural Cell-Specific Gene Expression |
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What are some gene therapy approaches for cancer?
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1) Incease tumor cell immunogenicity
2) Modify host immune respons (Ipi!) 3) modify other host tissues (drug resistant genes) 4)Correct tumor defect 5) Introduce enzyme for cytotoxic drug therapy |
