Pharm: Pharmacogenomics Flashcards
What is pharmacogenetics?
study of relationship between individual gene variants (allelism) and variations in drug effects
focus is on pharmacological responses in an individual and their modification by genetic influences
What is pharmacogenomics?
study of relationship between variants in a large collection of genes, up to the whole genome, and variations in drug effects
focus is on pharmacological responses across populations and the genetic basis for the differences between individuals
What is the goal of pharmacogenomics?
to customize drug prescriptions to an individual’s genotype
What are the basic concepts and levels of regulation of pharmacogenomics?
genetic background influences response to drugs
drug metabolism: mainly p450 enzymes but others
receptors: germline alterations (ryanodine receptor) vs somatic alterations (in cancer)
influences on efficacy and toxicity
designer drugs and individualized medicine
drugs bind to proteins to elicit their effects
regulation variation
What are the basics of drug metabolism?
phase I = hydroxlation (involves addition or unmasking of polar functional groups)
phase II = glucoronidation (conjugation)
p450s - phase I
renders hydrophobic drugs hydrophilic
What are the basic characteristics of cytochrome p450s?
50 kDal hemeproteins - axial cysteine ligand to heme gives unique chemistry
monooxygenation of hydrophobic compounds at chemically unreactive sites
two classes: class I = prokaryotes, mitochondria, class II = smooth ER (site of most drug metabolism)
eukaryotic are all membrane bound (57 in human genome) - no selection pressure against null alleles or altered activity
CYP1, CYP2, CYP3 families perform most metabolism
What are association studies?
correlations between specific genotypes (esp single nucleotide polymorphisms in key genes - allelism) and phenotypes
association b/w candidate genes and certain phenotypes
association b/w SNPs and certain phenotypes
For which p450s is allelism important?
CYP2D6 (46 alleles*), CYP2C9, CYP2C19
little CYP3A4 allelism
What types of allelism can be seen in p450s?
copy number variations
changes in coding sequence
deletions or stop codons
intergenic or intronic (may affect gene expression and splicing)
What is malignant hyperthermia?
AD, predisposition of clinically inconspicuous individuals to respond w uncontrollable skeletal muscle hypermetabolism upon exposure to volatile anesthetics (halothane, etc) or polarizing muscle relaxants (succinylcholine)
target is ryanodine receptor
What are symptoms of malignant hyperthermia?
greatly increased whole body metabolism muscle rigidity (increased Ca levels in skeletal muscle cells due to release from SR) high fever tachy acidosis (stimulation of glycolysis)
What is the antidote drug for malignant hyperthermia?
dantrolene sodium - blocks ongoing release of calcium from SR
What is a global approach to designer drugs?
determine individual’s response to particular drug family using pharmacogenomic approaches
select drug that gives best response or avoid drugs that give worst response
What is a target-based approach to designer drugs?
design or select drugs to reverse deleterious effects of mutations in an expressed gene product
large amount of structural info about target protein usually required for rational design
high throughput screening needed when less structural info is known
What is an example of a rational design approach to creating designer drugs?
can a receptor mutation that destroys ligand binding be compensated for by altering the structure of the ligand?
