Pharmacogenetics Flashcards
Definition
The study of how variations in the human genome affect the response to medications
Tailoring treatments to unique genetic profiles
“personalized” or “individualized” medicine
Implications for drug development/discovery
Variations secondary to polymorphisms (Difference in DNA sequence among individuals that may underlie differences in health. Genetic variations occurring in more than 1% of a population would be considered useful polymorphisms for genetic linkage analysis.)
Factors Involved in Response to Drug
Intrinsic factors: age, gender, race/ethnicity, disease states, organ dysfunction and genetics
Physiological changes: pregnancy, lactation, aging
Extrinsic factors: smoking, diet, concomitant medications, exercise
Basis for Pharmacgenetics
Genetic variation Sequencing of the human genome (2003) Some things we learned: 3.2 billion base pairs 30,000 genes (estimated) 1% contained in exons 24% in introns 75% is intergenic
All human beings share ~ 99.9% DNA sequence
diversity at the genetic level is encoded by 0.1% variation in our DNA
Variability in Drug Metabolizing Enzymes
Degree of enzyme activities are different between individuals
Polymorphisms occur in transporters and receptors cause variability in drug response
Polymorphic metabolizing enzymes that can be clinically significant are CYP2C9, CYP2C19, & CYP2D6
Major CYP450 Enzymes Involved in Drug Metabolism
CYP2D6- metabolizes over 100 drugs- is on Chromosome 22
CYP2C19- metabolizes drugs such as Plavix and PPIs
CYP3A4- metabolizes many drugs but no genetic polymorphisms (metabolizes antifungals)
CYP2D6
On Chromosome 22 & metabolizes over 100 drugs
Beta blockers- metoprolol & propranolol
Antiarrythmics
Antidepressants- amitriptyline, clomipramine, desipramine, fluoxetine, fluvoxamine, imipramine, nortryptaline, paroxetine
Neuroleptics- haloperidol, reserpine, thoridazine
Others- codiene, dextramethophan, tramadol
CYP2D6 Polymorphisms
Approximately 100 polymorphisms known (genotype)
Four phenotype subpopulations of metabolizers
Poor metabolizers
Intermediate metabolizers
Extensive metabolizers
Ultrarapid metabolizers
Variations according to ethnic background
Absent in 7% of Caucasians, 1-2% of non-Caucasians
Hyperactive in up to 30% of east Africans (Ethiopians)
Inhibited by:
Fluoxetine
Haloperidol
Paroxetine
Quinidine
Amiodarone
Prodrug
Prodrug: A precursor (forerunner) of a drug. A prodrug must undergo chemical conversion by metabolic processes before becoming an active pharmacological agent.
An inactive precursor of a drug, converted into its active form in the body by normal metabolic processes.
Codiene is a prodrug for morphine
Concerns with Prodrugs and CYP2D6 Phenotypes
Consequences of variants for prodrugs that need to be converted to active drugs
PM: no active drug (select a different drug)
IM: less active drug- approximately 20% lower concentrations of morphine than in EM
UM: more active drug- up to 800% higher concentrations of morphine than in EM(dramatic decrease in dose or different drug)
Codeine concerns with CYP2D6 Phenotypes
Limited evidence suggests that individuals who are UR metabolizers may convert codiene to its active metabolite, morphine, more rapidly & completely than others
In nursing moms, this metabolite can results in higher than expected serum & breast milk morphine levels
In a nursing mom known to be or suspected to be an UR consider other options for pain relief or persistent cough
Implications for geriatric pts prescribed medications containing codiene for pain relief??
But who pays for these tests???
Limitations to Using Pharmacogenetics
Cost
Potential emotional and financial liability associated with genetic information
Availability and timeliness of genetic testing
CYP2C9
Metabolizes 90% of active drug
Variants in this enzyme associated with increased sensitivity to warfarin
Variances in VKORC1 (Vit. K reductase) gene also associated with altered response
CYP2C9 Phenotypes
2 common variants- seen in 20-40 % of Caucasians, <10% of Asians and African Americans- reduces enzyme activity
Variances are associated with lower mean doses of warfarin, longer times to stabilization of INR & higher risk for bleeding events
85% Caucasians and 99% Asians considered PM
FDA Label Revisions
2 million pts start warfarin annually
Label (changed in 2007) now provides information regrading altered metabolism in CYP2C9 & VKORC1 genetic variances
However- genetic testing for this is $200-$500
New oral anticoags ready for launch
(120 drugs had genetic information in drug inserts)
Plavix and Pharmacogenetics
Is a prodrug and metabolized by CYP2C19
Has shown evidence that there are polymorphisms by the metabolism
Possible drug interactions with PPIs?
Omeprazole is a 2C19 inhibitor as we think others are- if pt needs a PPI then Protonix is probably best choice
