Personalized Medicine Lecture Sep 16

Question 1

How many people in the US die from med side effects annually

Answer 1

100,000

Question 2

What are some factors that may influence how a person responds to medication?

Answer 2

Weight
Diet
Food in stomach
Fatigue
Age
Sun exposure
Physical condition / lack of exercise
Drug interactions (i.e., Cross reactivity, synergism)
Genetic make-up
Comorbidities

Question 3

What are the three main cateogories of drug reactions?

Answer 3

1. drug metabolizing enzymes influence pharmacokinetics (poor clearance of drugs may increase to toxic levels–thiopurine A-methyltransferase)
2. drug transports (influence pharmacodynamics- can the drug enter cells?)
3. Human Leukocyte Antigen - drug sensitivities may look like an allergy

Question 4

What are 5 goals of personalized medicine?

Answer 4

1. safer drugs with reduction of side effects
2. increased drug effectiveness
3. alternative drugs for standard treatments
4. Dosages based on an indivual’s genetics (their ability to metabolize drugs)
5. Reduce cost (by skipping ineffective treatments)

Question 5

What is warfarin for? Who gets it?

Answer 5

Warfarin is used to prevent blood clots from forming or growing larger in your blood and blood vessels.

Prescribed for people with / who:

• certain types of irregular heartbeat,
• prosthetic (replacement or mechanical) heart valves
• have suffered a heart attack

Question 6

What food will interfere with the drug’s anticoagulant functions?

Why?

Answer 6

vitamin K in anything like kale, spinach, brussel spourts, parlsy, collard greens, char, green tea

Vitamin K is a natural blood clotting factor, so it will reverse the blood thinning effects of warfarin

Also avoid cranberry juice and alcohol

alcohol will increase its blood thinning effects because it will affect the metabolism of the drug

Question 7

What are the two main genes of interest that are involved in warfarin sensitivity?

Answer 7

vitamin K epoxide reductase (VKORC1)

cytochorme p450 2C9

(VKORC1 has a greater impact)

Question 8

How does ethnicity factor in to warfarin sensitivity?

Answer 8

people of east asian decent require on average a 30-40% lower warfarin dose than those of european descent because variants of VKORC1 associated with greater warfarin sensitiity are more common in Asians than europeans

But DO NOT ASSUME - you need to do the genetic test

Question 9

What is a single nucleotide polymorphism?

Are they always considered mutations?

Answer 9

A SNP is a gene variant where one nucleotide is different than the wildtype.

This isn’t always considered a “mutation”–often they simply confer normal variation in the gene pool

They occur naturally and may not even alter the encoded protein’s function

Question 10

What are three ways to detect a SNP?

Which one is used clinically right now?

Answer 10

Deep Sequencing (sequences all of the genetic material in a sample and gives frequencies of nucleotides in a strand–provides massive amounts of data)

Exon trapping (this is in the lab only)

Direct sequencing (this is similar to deep sequencing where it counts how often a nucleotide is read, but it focuses on a single strand of the genome)

Direct sequencing is what occurs clinically right now, but deep sequencing is rapidly increasing as deep sequencers are becoming more affordable

Question 11

WHen you’re looking at a direct sequence of a tumor, what type of sample must be used?

Answer 11

You have to use a microdissected sample because you’re interested in any mutations that may have occured in the tumor cells.

Testing an undissected sample won’t show hardly any mutations because it’s done with cells that are not necessarily cancerous

For an undissected sample for show a mutation, the mutation would have had to be present from the beginning of development, and tumors aren’t like that

Question 12

What is pharmacogenetics?

Answer 12

the study of how an indiviual’s genetic inheritance affects the body’s response to drugs

• decoding drug responsiveness
• minimize side effects
• maximize effectivenes

Question 13

Personalized medicine is much more prevalent now than was expected 5 years ago. What is largley playing a role in that?

Answer 13

The reduction in cost.

Right now the cheapest genome sequencing costs $99.

Question 14

What are the cytochrome p450 enzymes important for?

Answer 14

They metabolize about half of all medications we use.

The drugs may need to be metabolized to an active form

OR

they may need to be metabolized to an inactive form, otherwise they’ll build up and become toxic

Question 15

WHat is CYP3A4?

Answer 15

It is in the superfamily of cytochrome p450 enymes

THe enzyme is the cytochrome P-450 3A4

It’s expressed in the liver and intestines and has an ESSENTIAL role in detoxification.

If we don’t have this one, we’re dead.

Question 16

What enzyme is required for the metabolism of codeine to morphine?

Answer 16

2D6

Question 17

What genetic factor effects the bioavailability of codeine?

Answer 17

The balance of 3A4 to 2D6.

If you have too much 3A4, codein does not metabolize to morphine, it’s converted to norcodeine, which is not useful for the body.

Question 18

What are the 3 types of metabolizers in terms of codeine?

Answer 18

A poor metabolizer cannot metabolize codeine because they don’t have enough 2D6. The 3A4 metabolizes the codeine to norcodeine which doesn’t do anything.

An extensive metabolizer metabolizes codeine to morphine and has benefit from the drug.

Ultrarapid metabolizers have too much 2D6 in comparison to 3A4, so the codeine is metabolized to morphine so fast that the body can’t gain any benefit.

Question 19

In general, what happens in someone who is a poor metabolizer?

Answer 19

THey have a genetic predisoposition or polymorphism that blocks the metabolism of certain drugs.

This may mean they dont gain any benefit form the drug

OR

They OD at much lower doses than normal

Question 20

What medication can inhibit codeine metabolism? How?

Answer 20

Quinidine (for arrythmias or malaria) reduces the 2D6 levels, so the codeine isn’t metabolized to morphine appropriately

Question 21

What effect will drinking grapefruit juice have on codein metabolism?

Answer 21

Grapefruit juice will reduce the 3A4

You may gain some benefit at first, but as the 3A4 decreases, 2D6 activity will be higher in comparison and may result in ultra rapid metabolism of codeine

Question 22

Describe the role of targeted therapy involving treament for cancers with abnormal activity of the epidermal growth factor receptor?

Answer 22

When the EGFR receptor binds EGF, it will activate one of two cascades: the apoptotic pathway through PI3K or the proliferative pathways through Ras/Raf pathway.

In the treatment of cancer, the drug blocks the proliferative pathway, thus leaving the apoptotic pathway as the only option.

HOWEVER! This only worked in 10% of people who received the drug, and it was later discovered that it was only effective in patients with mutations in EGFR.

Question 23

Why did the patients who responded to the EGFR drug eventually develop resistance to the drug?

Answer 23

Only the cancer cells with the EGFR mutation were susceptible to the drug, so after the drug killed off those cancer cell, the cancer cells with out the mutation were able to proliferate and take over.