Pharmacogenomics

Question 1

Pharmacogenetics is the study of how the genetic make up of a person affects their ____ to a drug

Answer 1

Response

Question 2

The goal of pharmacogenetics is to combine pharmacology and genetics to increase ____ and _____ of drug therapy

Answer 2

Efficacy and safety

Question 3

Pharmacogenetics creates the foundation for _____ drug therapies

Answer 3

Individualized

Question 4

We can look at the metabolic pathway for drug metabolism and compare the ____ ____ in the individual to make better choices for dosing or drug selection

Answer 4

Genetic variations

Question 5

The human genome is made up of ___ billion nucleotides with 25,000 genes that encode 100,000 proteins

Answer 5

3

Question 6

The average difference between 2 people is ___ ___ base pairs

Answer 6

3 million

Question 7

Most of these differences that exist between people are ____ ___ ___

Answer 7

Single nucleotide polymorphisms (SNPs)

Question 8

If these SNP differences affect pathways for drug metabolism, it can have major impacts on the results of ___ ____

Answer 8

Drug therapy

Question 9

Enzyme variations, or _____, are common in drug metabolism

Answer 9

Polymorphisms

Question 10

Polymorphisms can affect phase 1 (____/____) and phase 2 (_____) of drug metabolism (remember that drugs don’t always follow the phases)

Answer 10

Oxidation/reduction; conjugation

Question 11

We can use genetic information to guide therapy by identifying patients by their ___ ____

Answer 11

Metabolic pathways

Question 12

If someone has slow (poor) metabolic pathways, they have ____ varients (one on each chromosome) and loss of enzyme function

Answer 12

2

Question 13

If someone has intermediate metabolic pathways, they have ___ variant (one chromosome affected) and a reduction of enzyme function

Answer 13

1

Question 14

____ metabolic pathways are normal

Answer 14

Extensive

Question 15

____ have fast (ultra-rapid) metabolic pathways, and can have more than 10 copies of metabolizing enzyme

Answer 15

Acetylators

Question 16

What are some key drugs metabolized by the 2D6 pathway of the CYP450?

Answer 16

-Opioids: hydrocodone, codeine, tramadol
-Beta-blockers: carvedilol, metoprolol, timolol, propranolol
-Oncology: tamoxifen, doxorubicine
-SSRIs: fluoxetine, paroxetine, sertraline
-SNRIs: duloxetine, venlafaxine
-Antiarrhythmics: flecainide, quinidine

Question 17

What are some key drugs metabolized by the 2C9 pathway of CYP450?

Answer 17

-Hypoglycemics: glipizide, glimepiride, glyburide
-Anticoagulants: S-warfarin
-ARBs: losartan, ibesartan
-Statins: fluvastatin, rosuvastatin
-NSAIDs: celecoxib, diclofenac, meloxican, IBU, naproxen

Question 18

What are some key drugs metabolized by the 3A4 pathway of CYP450?

Answer 18

-Statins: atorvastatin, lovastatin, simvastatin
-Opioids: fentanyl, methadone, oxycodone, buprenorphine
-Sedatives/hypnotics: zolpidem, eszopiclone
-Benzodiazepines: alprazolam, midazolam
-Antiarrhythmic: amiodarone
-Cardio: amlodipine, diltiazem, nifedipine, verpamil

Question 19

The frequency distribution of the metabolic ratio for the CYP450 2D6 pathway catalyzes the metabolism of ___ to form its 4-hydroxyl metabolite

Answer 19

Debrisoquine

Question 20

Most subjects metabolized debrisoquine extensively, while some subjects metabolize the compound ____ or ____

Answer 20

Faster or slower

Question 21

The Ampli Chip CYP450 array can be used to determine variant _____ for cytochrome P450 genes that influence drug metabolism

Answer 21

Genotypes

Question 22

The majority of people are ____ metabolizers

Answer 22

Extensive

Question 23

Are poor metabolizers or ultra-metabolizers more common?

Answer 23

Poor

Question 24

We would not use the Ampli Chip on everyone because we know that most people are ____ metabolizers

Answer 24

Extensive

Question 25

Ultra-rapid metabolizers will have ___ of a therapeutic response because the drug will not achieve a steady state

Answer 25

Less

Question 26

Poor metabolizers are going to have the opposite effect because the drug will accumulate ____ than expected, have higher concentrations, and have adverse effects much faster

Answer 26

Faster

Question 27

_____ is metabolized by two cytochrome P450 pathways to form the active metabolites 4-hydroxytamoxifen and endoxifen, which are further metabolized by sulfotransferase 1A1

Answer 27

Sulfotransferase

Question 28

____-____ curves show the influence of CYP2D6 'metabolizer' status on the survival of women with ER+ breast cancer who were treated with tamoxifen

Answer 28

Kaplan-Meier

Question 29

Patients who were extensive metabolizers of tamoxifen had _____ relapse-free survival and disease-free survival relative to intermediate and poor metabolizers

Answer 29

Improved

Question 30

Vitamin ___ is a required cofactor for the post-translational y-carboxylation of glutamate that resides in certain clotting factor precursors

Answer 30

K

Question 31

Vitamin K is oxidized to the inactive ____ as a consequence of the carboxylation reaction

Answer 31

Epoxide

Question 32

The enzyme vitamin K epoxide reductase (VKORC1) converts the inactive epoxide to the ____, reduced form of vitamin K

Answer 32

Active

Question 33

____ acts as an anticoagulant by inhibiting VKORC1 and thereby preventing the regeneration of reduced vitamin K

Answer 33

Warfarin

Question 34

S-Warfarin is ___ times more potent than R

Answer 34

4

Question 35

People respond very differently to warfarin because S-Warfarin (the more potent isomer) needs CYP 2C9 to be metabolized but if you have problems with your 2C9 metabolism, this isomer _____ quickly

Answer 35

Accumulates

Question 36

What are some possibilities for using genetics in pharmacology?

Answer 36

-Increase the accuracy of drug dosing for an individual -Reduce side effects and adverse effects -Choose a more appropriate drug therapy without failing other therapies first -Development of new drugs to work through more selective pathways increasing effectiveness yet decreasing risk -Studies can be done on groups that have ADRs to see if there is a variant correlation

Question 37

Barriers to genetic testing:

Answer 37

-Cost (insurance now starting to pay for testing; competition bringing costs down) -FDA backing (only 2D6 and TMPT valid biomarkers; holding more hearings on other pathways) -Ethical issues of having genetic info available and stereotyping

Question 38

We need to realize that while the majority of patients respond normally to drugs, what we often see as adverse effects may be due to ____ varients that could be identified and adjustments made before the adverse effect

Answer 38

Metabolic

Question 39

As costs drop and insurers and regulating bodies gain evidence and support for genetic testing, we will continue to see more changes to initial drug ____ and ____

Answer 39

Choices and doses