Pharmocogenetics

Question 1

potential causes of variability in drug effects

Answer 1

-Pathogenesis and the severity of the disease being treated
-Drug interactions from concomitant treatment (plasma protein binding, metabolism)
-Individual’s age, gender, lifestyle (including environmental factors), behaviour, nutritional state, renal and liver function, and concomitatnt illnesses
-Genetic variation

Question 2

What can allele differences affect

Answer 2

Pharmokinetic factors
-ADME
Pharmacodynamic factors
-Target proteins
-Downstream messengers

Question 3

Phase 1 metabolism (Oxidation)

Answer 3

Oxidation by CYP450s
over 1000 CYP450 enzymes identified (57 active enzymes in human).
Expressed mainly in the liver
Multiple alleles with different frequencies in different ethnic groups

Question 4

P450 enzyme function

Answer 4

P450 enzymes oxidise drugs or other xenobiotics in order to:
-Increase polarity and enhance excretion (decrease resorption in distal nephron)
-Convert to substrate for phase 2 metabolism

Question 5

Important CYP450s in drug metabolism

Answer 5

-CYP3A4 (most important: 50%)
-CYP2D6 (next in line: 20%)
-CYP2C9 and 2C19 (next (15%))

Question 6

Phase II metabolism

Answer 6

Known as conjunction
-substrate is phase I reaction product or other endogenous compound (eg. steroid hormones)
-Conjugation of highly polar glucuronide enhances water solubility/decreases lipid solubility and thereby promotes excretion
-Fewer genes and functional variants than P450s

Question 7

Most relevant variations in pharmacogenetics

Answer 7

-Insertions/deletions (small and large)
-Single nucleotide polymorphisms (SNPs)

Question 8

SNPs

Answer 8

The most commonly occuring genetic difference
they are single base pair positions in genomic DNA at which different sequence alternatives (alleles) exist wherein the least frequent allele has an abundance of 1% or greater

Question 9

SNP rate and size

Answer 9

Estimated to occur throughout genome at a rate of between 3 and 6 per 1000 base pairs
There are expected to be a total of 10-20M SNPs in human population

Question 10

Pharmacogenetics

Answer 10

The effects of an individual’s genotype on the pharmacokinetics and pharmacodynamics of drug action

Question 11

Warfarin function

Answer 11

Warfarin inhibits vitamin K reductase which is the enzyme responsible for recycling oxidated vitamin K back into the system. For this reason, drugs in this class are referred to as Vitamin K antagonists

Question 12

Warfarin history and prescription

Answer 12

Discovered 60 years ago and one of the most widely prescribed drugs in the world
Intended to prevent and treat thromboembolisms
-Anticoagulant
-1,2,2.5,3-6,7.5 and 10 mg tablet strengths

Question 13

Safety of Warfarin

Answer 13

-Major risk is bleeding: frequent and severe
-1.2-7 major bleeding episodes per 100 patients
-Responsible for 1 in 10 hospital admissions

Question 14

DNA testing for Warfarin sensitivity

Answer 14

FDA clinical Pharmacology Subcommittee of the Advisory Committee for Pharmaceutical Sciences recommends testing for variations in CYP2C9 and VKORC1

Question 15

Warfarin Metabolism based off genes

Answer 15

-Two polymorphic genes, CYP2C9 and VKORC1 affect warfarin metabolism and response
-Allelelic frequencies of these two genes are usually associated with ethnicity
-Overdose can result in bleeding which can be fatal
-Underdose can result in thrombosis which can be fatal

Question 16

Population differences in warfarin dose

Answer 16

-European-mean~ 5mg/d
-African-American-higher~6.0-7.0mg/d
-Asian-lower~3.0-3.5mg/d

Question 17

Haplotype contributing to racial variability in warfarin dosing

Answer 17

VKORC1 haplotypes

Question 18

VKORC1

Answer 18

Vitamin K epOxide Reductase Complex subunit 1

Question 19

VKORC1 variants effect

Answer 19

The polymorphisms may explain up to 25% of patient variability in response to warfarin. Patients with VKORC1 polymorphisms are at risk for exaggerated anticoagulant response

Question 20

CYP2C9 variant effect

Answer 20

Variants take more time to achieve stable dosing and are associated with an increased risk of bleeding events.
Low CYP2C9 activity results in higher plasma levels of warfarin so the patient is at risk for bleeding.
Contributes 10% dose variation especially in Caucasians

Question 21

Warfarin Sensitivity Test

Answer 21

It determines presence of specific variations of CYP2C9 and VKORC1 genes
CYP2C9 is involved in warfarin metabolism and VKORC1 influences warfarin’s anticoagulation effect through vitamin K

Question 22

Differences between types of drugs and metaboliser phenotype

Answer 22

Question 23

How does Pharmacogenomics determine therapeutic course

Answer 23

It uses panels of polymorphisms to calculate the relative risk-benefit ratio of a particular therapeutic course for an individual patient