Pharmacogenetics Flashcards

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1
Q

Pharmacogenetics is

A

the study of differences in drug response due to allelic variation in genes affecting drug metabolism, efficacy, and toxicity.

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2
Q

Pharmacogenomics, the genomic approach to _______, is concerned with _______

A

genomic approach to pharmacogenetics;

the assessment of common genetic variants in the aggregate for their impact on the outcome of drug therapy.

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3
Q

Pharmacokinetics:

A

the rate at which the body absorbs, transports, metabolizes, or excretes drugs or their metabolites.

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4
Q

Pharmacodynamics:

A

the response of the drug binding to its targets and downstream targets, such as receptors, enzymes, or metabolic pathways

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5
Q

pharmacokinetics is concerned with _______ and pharmacodynamics is concerned with _______

A
  • whether or how much drug reaches the target(s)

- what happens when the drug successfully reaches its target

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6
Q

both phenomenon occur simultaneously in the race between drug effect (_______) and removal (_______).

A

dynamics

kinetics

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7
Q

two basic ways that drugs are metabolized through biotransformations:

A
  • 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
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8
Q

The cytochrome P450 (CYP450) genes encode important enzymes that are

A

very active in the liver and to a lesser extent in the epithelium of the small intestine

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9
Q

CYP450 genes

A
  • 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.
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10
Q

CYP families

A

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.

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11
Q

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).

A

CYP2D6

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12
Q

Frameshift

A

alter reading frame –> NO ACTIVITY

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13
Q

Splicing

A

skip exons and/or alter reading frame –> NO ACTIVITY

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14
Q

Missense

A

alter protein function –> usually REDUCED ACTIVITY

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15
Q

Copy number alleles

A

increased gene copy alleles –> INCREASED (‘ULTRAFAST)

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16
Q

Based on the combinations (since individuals have 2 alleles in their genotypes) have 3 major phenotypes: _______, _______, and _______

A

normal, poor (includes null alleles), and ultrarapid/ultrafast

17
Q

drinking grapefruit juice while taking felodipine for hypertension can lead to significant hypotension due to

A
  • significant hypotension
  • potentiation of the felodipine effect since CYP3A activity is reduced and metabolism/elimination of felodipine is similarly slowed
18
Q

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

A

cyclosporine

ketoconazole

19
Q

ketoconazole temporarily inhibits _______ which leads to raised levels of _______ which can be _______.

A

CYP3A metabolism
cyclosporine
neprotoxic

20
Q

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 _______

A
  • increased
  • CYP3 inducer
  • more rapid metabolism and elimination of cyclosporine
21
Q

CYP3A

A

Cyclosporine (substrate),
ketoconazole (inhibitor), rifampin (inducer), grapefruit juice (inhibitor) [here more relevance of environmental factors than specific genotypes]

22
Q

CYP2D6

A

tricyclic antidepressants, quinidine, fluozetine, paroxetine and codeine-remember CPY2D6 is needed to activate codeine into morphine

23
Q

CYP2C9 + VKORC1

A

warfarin (blood thinner)

24
Q

NAT

A

Isoniazid for TB

25
Q

TPMT

A

6-mercaptopurine/6-thiguanine and childhood ALL (leukemia)

***often presented as the classic example of a pharmocogenetic mechanism that can be fatal if ignored

26
Q

G6PD

A

X linked enzyme

Chemolytic anemia after sulfa drugs or maybe dapsone