Pharmacogenetics Flashcards
Pharmacogenetics is
the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity.
Pharmacogenomics, the genomic approach to _______, is concerned with _______
genomic approach to pharmacogenetics;
the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy.
Pharmacokinetics:
the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites.
Pharmacodynamics:
the response of the drug binding to its targets and downstream targets, such as receptors, enzymes, or metabolic pathways
pharmacokinetics is concerned with _______ and pharmacodynamics is concerned with _______
- whether or how much drug reaches the target(s)
- what happens when the drug successfully reaches its target
both phenomenon occur simultaneously in the race between drug effect (_______) and removal (_______).
dynamics
kinetics
two basic ways that drugs are metabolized through biotransformations:
- Phase I (simplified): attach a polar group onto the compound to make it more soluble; usually a hydroxylation step
- Phase II (simplified): attach a sugar/acetyl group to detoxify the drug and make it easier to excrete
The cytochrome P450 (CYP450) genes encode important enzymes that are
very active in the liver and to a lesser extent in the epithelium of the small intestine
CYP450 genes
- The CYP families
- CYP3A4
- There is wide genetic polymorphic variation with phenotypic consequences in the CYP families of genes, which is why they are so important to prescribing physicians.
CYP families
The CYP families (CYP1, CYP2, CYP3) are particularly active including six genes (CYP1A1, CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4) that are involved in the Phase I metabolism of ~90% of all commonly used medications, and CYP3A4 itself takes part in the metabolism of over 40% of all drugs used in clinical medicine.
While most CYP genes are important in the rate of inactivation of a drug, in some cases the CYP gene(s) is required to activate a drug. The classic example of this is _______ activity being necessary to convert codeine (inactive, almost no analgesic effect) to morphine (active with a potent analgesic effect).
CYP2D6
Frameshift
alter reading frame –> NO ACTIVITY
Splicing
skip exons and/or alter reading frame –> NO ACTIVITY
Missense
alter protein function –> usually REDUCED ACTIVITY
Copy number alleles
increased gene copy alleles –> INCREASED (‘ULTRAFAST)
Based on the combinations (since individuals have 2 alleles in their genotypes) have 3 major phenotypes: _______, _______, and _______
normal, poor (includes null alleles), and ultrarapid/ultrafast
drinking grapefruit juice while taking felodipine for hypertension can lead to significant hypotension due to
- significant hypotension
- potentiation of the felodipine effect since CYP3A activity is reduced and metabolism/elimination of felodipine is similarly slowed
Dosage of the immunosuppressive drug _______ (used in kidney transplants for instance) must be reduced by 75% to avoid toxicity when the antifungal _______ is added to treat a fungal infection
cyclosporine
ketoconazole
ketoconazole temporarily inhibits _______ which leads to raised levels of _______ which can be _______.
CYP3A metabolism
cyclosporine
neprotoxic
Renal transplant patient who is exposed to tuberculosis and requires rifampin prophylaxis: In this case, the dose of cyclosporine must be _______ since rifampin is a _______ and leads to more _______
- increased
- CYP3 inducer
- more rapid metabolism and elimination of cyclosporine
CYP3A
Cyclosporine (substrate),
ketoconazole (inhibitor), rifampin (inducer), grapefruit juice (inhibitor) [here more relevance of environmental factors than specific genotypes]
CYP2D6
tricyclic antidepressants, quinidine, fluozetine, paroxetine and codeine-remember CPY2D6 is needed to activate codeine into morphine
CYP2C9 + VKORC1
warfarin (blood thinner)
NAT
Isoniazid for TB
TPMT
6-mercaptopurine/6-thiguanine and childhood ALL (leukemia)
***often presented as the classic example of a pharmocogenetic mechanism that can be fatal if ignored
G6PD
X linked enzyme
Chemolytic anemia after sulfa drugs or maybe dapsone