Pharmacogenetics - Lecture 7

Question 1

What is the purpose of pharmacogenetics?

Answer 1

Attempt to understand the genetic basis for why some patients respond well to drugs and others don’t, or why patients suffer adverse effects from drugs and others don’t

Question 2

What does the FDA demand regarding drugs and certain subgroups?

Answer 2

If evidence to support the safety and effectiveness of a drug in subgroups of the population exists, labeling must describe the evidence and identify the tests for selection and monitoring of patients

Question 3

Suppose there is a drug where 50% of people have a positive result, 50% don’t, and 50% of people have adverse effects, and 50% don’t…how many patients can receive benefit?

Answer 3

25% - if you have a clinical trial using random populations

Question 4

If clinical trials pre-screen populations before a clinical trials…how many people receive benefit?

Answer 4

100%?

Question 5

Genotype

Answer 5

Part of the DNA sequence which determines specific characteristics

Question 6

Phenotype

Answer 6

Observable character traits

Question 7

Monogenic phenotypes

Answer 7

Result from variations of a single gene

Question 8

Polygenic phenotypes

Answer 8

Results from variations in multiple genes

Question 9

How can genotype variations produce phenotypic differences in pharmacokinetics?

Answer 9

Usually result in differences in drug metabolism

Question 10

How can genotype variations produce phenotypic differences in pharmacodynamics?

Answer 10

Usually result in differences in drug targets or downstream elements

Question 11

How can effects of polymorphisms of drug-metabolizing enzymes effect plasma concentrations?

Answer 11

Wild/Wild = patients will have plasma concentrations that are not lethal
Wild/Variant = patients will have plasma concentrations creep to the level of toxicity - the drug is being metabolized slower
Variant/Variant = patients will have plasma concentrations that are at toxic levels - drugs are being metabolized very slowly

Question 12

What enzyme metabolizes about 25% of all drugs?

Answer 12

CYP2D6

Question 13

CYP2D6

Answer 13

A Cytochrome P450 enzyme that oxidizes many drugs and environmental agents
Removes methyl groups from oxygen (O-de-methylation) in the liver to make them more soluble and therefore excretable

Question 14

Why might someone with a Cytochrom P450 deficiency have adverse effects to drugs?

Answer 14

Because they could have lower levels of CYP2D6, and drugs (such as cevimeline) would reach higher conventrations in the tissues, and stick around longer than it should

Question 15

What should you do with a patient that has never taken cevimeline?

Answer 15

It’s an agonist to treat dry mouth and is metabolised by CYP2D6
Since CYP2D6 metabolizes so many drugs, take a detailed medical history, make sure they’re not deficient

Question 16

What can happen to CYP2D6 deficient patients taking Tamoxifen?

Answer 16

They have poorer outcomes when treated for breast cancer with Tamoxifen

Question 17

What can happen to patients with a CYP2D6 deficiency taking Codeine?

Answer 17

Codeine will be ineffective with poor metabolizers (10% of pop.)
Cyp2D6 ultra metabolizers can experience severe abdominal pain

Question 18

What can happen to people with a CYP2C9 deficiency taking warfarin?

Answer 18

They can have serious bleeding complications

Question 19

What does the Ryanodine receptor do?

Answer 19

Mediates the Ca-mediated-Ca-release from the SR
There have been 29 mutant alleles identified for this receptor
Mutations can lead to malignant hyperthermia