Personalized Medicine Flashcards
what are different responses to a single dose
- hyperractive
2. hyporeactive
pharmacokinetic
changes in the disposition of the drug that influence the relative concentration of the drug in the body
pharmacodynamic
changes in cellular sensitivity
change in receptor # or function
name examples of pharmacodynamics
- desensitization (down regulation or refractoriness)
- supersensitivity
- malfunction
- changes in other components of the cellular response (“downstream”) from the drug-receptor interaction
changes in the [ ] of an endogenous ligand may affect response to
antagonists
what is tolerance
a condition in which increasing disease of a drug are required to generate the same effect
see diagrams: slide 5 &6
see diagrams: slide 5 &6
what is pharmacogenomics
the study of how inherited genetic differences in humans influence individual response to drugs
genetic factors are the major determinants of what
normal variability of drug effects and are responsible for a # of striking quantitative and qualitative differences in pharmacological activity
the phenotype is influenced by what other factors
- age
- sex
- disease state
- smoking
- alcohol
- diet
if the mutation is relatively common (more than 1%) it creates a
polymorphism
what are the objectives of pharmacogenomics
- identify variation in human drug response
- elucidate the molecular mechanisms
- evaluate the clinical significance
- develop genetic screening test
- individualize treatment and drug therapy
what are the major categories of variant responses
- drug metabolism
- drug transporters
- direct targets (receptors)
- indirect targets (other components affecting response or adverse reactions)
how many nucleotide bases does the human genome contain
~3 billion chemical nucleotide
the average gene consists of how many bases
3000 bases but sizes vary greatly with the largest known human gene being dystophin at 2.4 million bases
the total number of genes is estimated at
30,000
–% nucleotide bases are exactly the same in all people
99.9%
the function of over –% of discoveredgenes is unknown
50
what is polymorphism
-a variation in which one in every 1000 bases is different in any 2 humans
polymorphism is a result of
several types of mutations
polymorphism in specific genes can lead to
difference in response to drugs
what is an allele
an alternative form at a genetic locus on a single chromosome
for loci in most of the genome, a human has – chromosomes which carry –
2
carry the same alleles or 2 different alleles
what is a genotype
alleles present in an individual
cystic fibrosis genotype
deletion of nucleotides encoding phenylalanine in CFTR gene
what is a phenotype
physical manifestation of the genotype
cystic fibrosis phenotype
chronic respiratory infection, mucus build-up, fat maldigestion
what are potential uses of genomics for therapy
- Individualized gene therapy for preventive/treatment measures (future)
- Identify genes conveying risk for development of chronic disease; implement preventive measures (future)
- Understand disease pathophysiology; identify new diagnostic or therapeutic targets (ongoing)
- Improve the drug development process (ongoing)
- Improve the clinical risk/benefit profile of therapeutic agents (here and now)
- Direct drug therapy and dose (here and now)
genetically polymorphic P450s are associated with what
changes in drug effects
59% of commonly prescribed drugs are metabolized by enzymes with
polymorphic alleles
metabolizer classifications
- poor metabolizer
- intermediate metabolizer
- extensive metabolizer
- ultra-rapid metabolizer
poor metabolizer
has 2 defective alleles and lacks functional enzyme
intermediate metabolizer
- heterozygous for one functional and one deficient allele
- has 2 partially defective alleles that cause reduced metabolism
extensive metabolizer
- 2 normal alleles
- often majority of population
- “normal” metabolizers
ultra-rapid metabolizer
-duplicated or multiduplicated functional alleles with extremely high metabolic capacity
conversion of codeine to morphine is partially dependent on
CYP2D6
function if CYP2D6
genotype partially determines analgesic effect of codeine
poor metabolizers (PM) have low
CYP2D6 activity and do not efficiently convert codeine into morphine
ultra-rapid metabolizers (UM) have high
CYP2D6 activity and rapidly convert codeine into morphine
what is warfarin
inhibits synthesis of vit K dependent clotting factors
what are the polymorphic genes affecting warfarin metabolism
CYP2C9
VKORC1
allelic frequencies are usually associated with
ethnicity
see diagrams: slide 22-23
see diagram: slide 22-23
> 50% of the variability in the warfarin dose may be explained by
polymorphism in CYP2C9 and VKORC1
the maintenance warfarin dose can estimated from
clinical and pharmacogenetic factors that can be obtained at the the time of warfarin initiation
what are carbamazepine ADRs
dangerous or even fatal skin reactions caused by carbamazepine therapy
carbamazepine ADRs are more common in patients with
a particular human leukocyte antigen (HLA) allele, HLA-B*1502
allele HLA-B*1502 occurs mostly in patents with ancestry across broad areas of
Asia, including South Asian Indians
see slides 26-27
see slides 26-27
examples of pharmacogenomic information supplied and test recommended
- mercaptopurine (TPMT deficiency)
- irinotecan (UGT1A1*28 allele)
- atomoxetine (CYP2D6 variants)
- tamoxifen (CYP2D6 variants)
tumor tissue tested for
somatic mutation before prescribing selected drugs
tumor therapy: pharmacogenomic information supplied and test recommended examples
cetuximab (EGFR expression)
trastuzumab (Her2/neu overexpression)
see slide 30
see slide 30
FDA list of approved biomarkers
- drug exposure and clinical response variability
- risk for adverse events
- genotype-specific dosing
- mechanisms of drug action
- polymorphic drug target and disposition genes
