Genetic Variations

Question 1

Pharmacokinetics:

Answer 1

what the body does to a drug

• refers to the movement of drug into, through, and out of the body
• time course of its absorption, bioavailability, distribution, metabolism, and excretion.

Question 2

Pharmacodyamics:

Answer 2

what a drug does to the body

• involves receptor binding, post-receptor effects, and chemical interactions.
• helps explain the relationship between the dose and response, ie, the drug’s effects.

Question 3

Pharmacogenetics:

Answer 3

• study of inherited differences (variation) in drug metabolism and response.

Question 4

Pharmacogenetics can influence:

Answer 4

pharmacodynamics and pharmacokinetics

Question 5

Pharmacogenomics:

Answer 5

• A ‘genomic’ approach to pharmacogenetics – using genomic wide association studies to assess the impact of SNPs on the impact of drug therapy.

Question 6

Prothrombin time (PT):

Answer 6

• a blood test that measures how long it takes blood to clot.
  
  • normal is 11-13.5 seconds

Question 7

Drug sensitivity:

Answer 7

• need less of a drug to be within the therapeutic window

Question 8

Drug tolerance:

Answer 8

• need more of a drug to be within the therapeutic window.

Question 9

Cytochrome p450s are:

Answer 9

• heme-containing proteins expressed primarily in the liver.

Question 10

Cytochrome p450s are responsible for:

Answer 10

• detoxifying and exporting both endogenous and external/foreign chemical compounds.
• activating some drugs

Question 11

How do cytochrome p450s function?

Answer 11

• Accept electrons from donors such as NADPH to catalyze a number of different reactions.
  
  • most important: the addition of oxygen to carbon, nitrogen or sulfur atoms.
• drug binds to heme group, flap closes, reaction occurs and the drug is reduced

Question 12

How many cytochrome p450s are there?

Answer 12

56

each encoded by a different gene

Question 13

What do cytochrome p450s do to drugs?

Answer 13

• reduces them.
• adds an oxygen to hydrophobic groups of the drug to increase the drug’s solubility and expedite its clearance from the body

Question 14

Phase I of drug metabolism:

Answer 14

• addition of a hydroxyl group to a drug
• carried out by CYPs

Question 15

Phase II of drug metabolism:

Answer 15

• carried out by enzymes other than CYPs
• functionalization of the hydroxyl group, increasing drug solubility, allowing it to be excreted.

Question 16

How many families of CYPs are there?

Answer 16

20

Question 17

Tylenol (acetaminophen) is primarily broken down by what CYP?

Answer 17

• CYP3A4 converts acetaminophen to a toxic form
• liver then further modifies drug and excretes it
• if you take too much acetaminophen, the liver cannot keep up with formation of the toxic drug, and irreversible liver damage occurs

Question 18

Do individual CYPs only react with one specific substrate?

Answer 18

No.

• CYPs interact with a lot of different substrates - fairly promiscuous.
• CYP flap opens, and whatever drug fits into the heme pocket will be reduced once the flap closes.

Question 19

Warfarin/coumadin is used to:

Answer 19

• prevent abnormal blood clotting:
  
  • thrombosis
  • embolism in cases of heart valve prosthesis
  • recurrent stroke
  • deep vein thrombosis
  • pulmonary embolism

Question 20

How does warfarin function in the body?

Answer 20

• Impairs synthesis of vitamin K dependent clotting factors
• Inhibits vitamin K reductase – key enzyme in vitamin K recycling.

Question 21

S-warfarin is primarily modified by what CYP?

Answer 21

• CYP2C9
  
  • hydroxylates S-Warfarin, making it more soluble and able to be excreted

Question 22

What can happen if there is a mutation in CYP2C9 that decreases its activity?

Answer 22

• CYP2C9 will not be able to hydroxylate S-Warfarin.
  
  • S-Warfarin will stay in body longer, have a longer effect on the body.
  • patient will be more sensitive to drug.

Question 23

What can happen if there is a mutation in CYP2C9 that increases its activity?

Answer 23

• CYP2C9 will hydroxylate S-Warfarin faster.
  
  • S-Warfarin will be excreted faster
  • patient will be more tolerant to drug.

Question 24

Is there a standard of cytochrome p450 across individuals?

Answer 24

• no
  
  • each of us have a unique spectrum of cytochrome p450 activity.
  • we have multiple CYPs to modify each drug we ingest.

Question 25

Is CYP2C9 interaction with warfarin considered pharmacokinetics or pharmacodynamics?

Answer 25

pharmacokinetics

“what the body does to a drug”

Question 26

CYP variants can be classified as:

Answer 26

• poor, normal, or ultrafast metabolizers

Question 27

What kind of metabolizer is this?

Answer 27

• sawtooth curve = normal metabolizer
• patient stays within the therapeutic window when given normal dosage of the drug.

Question 28

What kind of metabolizer is this?

Answer 28

• step-wise curve = abnormal metabolizer
  
  • drug is accumulating in body
  • poor metabolizer
  • patient will be more sensitive to drug; will require a lower dose to stay within the therapeutic window

Question 29

What will a change in pharmacokinetics do to the curve in this graph?

Answer 29

• the shape of the curve will change
  
  • if the drug is metabolized and excreted faster, the curves will become more steep

Question 30

What will a change in pharmacodynamics do to the curve in this graph?

Answer 30

• pharcodynamics will affect the drug at the site of action; therapeutic (blue) window will move around.

Question 31

Mutations in what CYP2C9 alleles make patients more sensitive to warfarin?

Answer 31

• allele 2
  
  • reduced affinity of CYP2C9 for warfarin
• allele 3
  
  • altered substrate specificity

Question 32

What is one way you can treat a warfarin overdose?

Answer 32

• give a bolus of vitamin K to outcompete warfarin binding to CYPs.
  
  • vitamin K is the natural ligand of CYPs for blood clotting.

Question 33

What genotypes tend to have the largest therapeutic window for a drug?

Answer 33

wild-type

Question 34

What genotypes tend to have an intermediate therapeutic window for a drug?

Answer 34

heterozygous

(one allele is mutated)

Question 35

What genotypes tend to have the smallest therapeutic window for a drug?

Answer 35

homozygous

(both alleles mutated)

Question 36

What is the target of warfarin?

Answer 36

• vitamin K epoxide reductase (VKORC1)

Question 37

Inhibition of VKORC1 (vitamin K epoxide reductase) by warfarin:

Answer 37

• prevents regeneration of reduced vitamin K, which is necessary for carboxylation/activation of coagulation factors.
• vitamin K remains oxidized

Question 38

If a mutation in an enzyme increases the affinity of that enzyme for the drug, will the patient be more sensitive or tolerant to the drug?

Answer 38

• more sensitive
• need less drug to have the same therapeutic effect

Question 39

If a mutation in an enzyme decreases the affinity of that enzyme for the drug, will the patient be more sensitive or tolerant to the drug?

Answer 39

• patient will be more tolerant
  
  • will need more drug to have the same therapeutic effect

Question 40

Is the VKORC1 (vitamin K epoxide reductase) interaction with warfarin considered a component of pharmacodynamics or pharmacokinetics?

Answer 40

• pharmacodynamics
  
  • “what the drug does to the body”
  • this is the site of drug activity; warfarin inhibits VKORC1