Genomic Medicine

Question 1

What are the goals of pharmacology

Answer 1

The ability to administer the right kind of drug in the right patient at the right amount

Question 2

Explain pharmacokinetics and pharmacodynamics

Answer 2

Kinetics is what we do to the drug, rate of absorption of the drug and the rate at which it gets to the site of action,

Dynamics is what the drug does to us, its effects and side effects both

Question 3

What must be true for an effective drug, 4 things

Answer 3

1. Has to reach its site of action
2. Has to be in active form
3. Has to be in sufficient concentration
4. Has to stay there for sufficient time

All of these concepts lie under the concept of pharmacokinetics

Question 4

How does the pharmacokinetics and pharmacodynamics interact in terms of administering the drug, there are 4

Answer 4

ADME
Absorption
Distribution within the body
Metabolism
Excretion

Question 5

What enzyme metabolizes most of the drugs

Answer 5

CYP450, it is a family of enzymes

Question 6

Where are they found

Answer 6

In the liver, primarily

Question 7

Differentiate between pharamcogenetics and pharmacogenomics

Answer 7

Pharmacogenomics is searching the entire genome to identify target genes that can be potentially be used for site of action for a drug and help us in developing more drugs

Pharmacogenetics is the genetic heritability that an individual has that determines how that individual responds to a drug

Question 8

What is debrisoquine

Answer 8

Anti hypertensive

Question 9

What enzyme metabolizes debrizoquine

Answer 9

CYP2D6

Question 10

What are the classes of people that have different functional polymorphism that codes for this enzyme

Answer 10

Extensive metabolizers are those people that fall in the middle and are classified as normal metabolizers of debrizoquine

Poor metabolizers have lower functioning CYP2D6 and then we have ultra rapid metabolizers that have high functioning CYP2D6

Question 11

How does the mutations affect this enzyme

Answer 11

Most mutations causes loss of function. Gene duplication, having more genes for this enzyme causes people to become ultra fast metabolizers

Question 12

Does environmental factors affect drug metabolism

Answer 12

Yes

Question 13

What example did he give us regarding this

Answer 13

Usually when you administer a drug you see a peak concentration of it in the blood in about an hour. However people with charcoal broiled beef diet can have increase in the transcription of the CYP450 drugs that increase their metabolism power by 50 or 100 folds so the max concentration seen in the blood after an hour decreases.

Charcoal broiled beef diet has transcription factors that directly go in to the liver and increases transcription of CYP450, or somehow they cause an increase in transcription and translation of these enzymes

Question 14

What is this process called

Answer 14

Induction

Question 15

What does induction do for the therapeutic concentration

Answer 15

We need higher doses of the drugs

Question 16

What is the drug Terfenadine

Answer 16

It is an anti histaminase

Question 17

How does it act in our body

Answer 17

It is broken down by CYP3A4 to Fexofenadine (Allegra) which is the active component that helps with allergies

Question 18

What potential problems can we run into if we use this drug with other drugs

Answer 18

Terfenadine is frequently taken with erythromycin. Erythromycin competes for CYP3A4 and it has a higher affinity for it. Terfenadine is then not broken down into its active form called Fexofenadine and hence it doesnt help people with their allergy problems.

This can cause some patients to take more terfenadine. In dangerously high concentrations and when not broken down into its active form, terfenodine can cause arrhythmia as it interacts with the calcium channel in cardiomyocytes.

Question 19

Contrast the effects and mechanism of debrizoquine and terfenadine. Know how they act in a fundamentally different way

Answer 19

The fundamental difference is in the pharmacokinetics and pharmacodynamics. Pharmacokinetics is always simple, more CYP450 results in less concentration of the drug in the blood and vice versa.

For pharmacodynamics, it gets tricky, for debrizoquine it is straighforward as the parent drug is the active form, so the more the parent drug the more therapeutic effect we see. But for terfenadine it is different as the parent drug is not the active therapeutic agent

Question 20

Are there polymorphism that are present more in certain ethnic populations

Answer 20

Yes but since the different ethnicities of people live together, the ethnic distinction for these polymorphism is getting less and less distinct

Question 21

What are phase I and phase II enzymes

Answer 21

Phase 1 is direct breakdown of drugs by CYP450 or other enzymes. Phase 1 does redox reactions and hydrolytic reactions. The by product of those reactions are reactive oxygen species.

Phase II is adding a conjugate to the drug so that it can be either excreted by the body by making it water soluble or rendering it in its inactive form