Lecture 13 + 14 (Cut off for Exam 1) Flashcards Preview

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1
Q

Pharmacogenomics

A

Science of how genetic variants affect drug action.

Contributes to PK parameters

2
Q

Clinical Consequences (4)

A
  1. Therapeutic failure (not active)
  2. Increase adverse side effects
  3. Increased toxicity
  4. Fatal adverse reactions
3
Q

GINA

A
  • designed to prohibit improper use of genetic info by insurance employment
  • Prohibits denial or coverage or higher rates based on genetic predispositions
  • Bars employers from firing, hiring, promoting, etc. based on genetic information
4
Q

Human Genome Basics

A
  • 3 billion base pairs (haploid), 6 billion (diploid)
  • Approximately 23,000 genes
  • Extensive interindividual variation genomic structure
  • 99.9% genetically identical between two people, difference in ~1 per 1,000 base pairs
  • Bases = integral part of DNA
5
Q

Genes

A

Sequence of DNA that codes cellular functional units (proteins), multiple gene on each DNA segment. Genes are the exception to the rule though, the majority of DNA isn’t genes.

6
Q

Things to Know

A
  • Basic components of gene structure (introns, exons, coding regions, etc.)
  • Know how this connects to the central dogma of biology
7
Q

Types of Genetic Variations

A
  1. Single Nucleotide Polymorphisms (SNPs)
  2. Insertions (Indels)
  3. Deletions (Indels)
  4. Copy Number Variations
    * *NOT MUTATIONS**
8
Q

Alleles

A
  • Genetic variant form of a gene
  • Different alleles may be responsible for different in observable phenotypic traits, but also different in response to drug
  • MAF - Minor Allele Frequency, an allele occurs in population in reference to most common allele
  • Often alleles that are investigated are SNPs
9
Q

SNPs

A
  • Genetic variation that arises when single nucleotide in DNA is different
  • Can happen ANYWHERE in DNA (not just coding regions)
10
Q

Possible SNP Consequences

A

Coding Region:

  • Decrease in protein (enzyme) activity compared to common variant
  • Increase in enzyme activity
  • No change (synonymous SNP)
  • *Functional assay needed to identify the effect**

Non-coding Region:

  • Decrease in gene expression and therefore decrease in enzyme activity
  • Increase in gene expression and therefore increase in enzyme activity
  • Increase in the number of copies of an enzyme that leads to increased activity (and vice versa)
11
Q

Association Studies (2)

A
  1. Candidate Gene Approach

2. GWAS

12
Q

Candidate Gene Approach

A
  • Hypothesis Driven
  • Pharmacist can participate
  • Identify drug response to observable trait
13
Q

3 Candidate Gene Categories

A
  1. Direct Drug Response
  2. Signal Transduction Proteins
  3. Downstream Proteins
14
Q

GWAS

A
  • Alternate approach to Candidate Gene
  • Designed to identify genetic association to an observable response by examining genetic variations across an entire genome
  • Doesn’t rely on pharmacology knowledge and isn’t hypothesis driven
  • Very successful results
  • Includes group with the observable trait and a control group (group without the observable trait)
15
Q

3 Major Divisions of Pharmacogenomics

A
  1. PK - action of body on drug (ADME)
  2. PD - action of drug on body
  3. Non-PK/PD - adverse reactions
16
Q

PIEU

A
Variations of Metabolism
P - Poor Metabolizers
I - Intermediate Metabolizers
E - Extensive Metabolizers
U - Ultrarapid Metabolizers
17
Q

P

A
  • Two variant alleles

- No enzyme activity

18
Q

I

A
  • One reduced activity allele

- One null allele

19
Q

E

A
  • At least one normal allele

- “Average”

20
Q

U

A
  • Multiple functional alleles

- Excess enzymatic activity

21
Q

Warfarin

A
  • Can be excreted by CYP2C9
  • Acts on Vitamin K epoxide reductase
  • Stops activation of clotting factors
22
Q

CYP2C9*2 and *3

A
  • Two non-synonymous SNPs (PK)

- Decrease activity of CYP2C9 to 60-70% (2) or 5% (3)

23
Q

Drug Target Pharmacogenomics

A

-Newer area
-Any protein involved in drug action is a target
-Seeks to identify how variability in targets affects drugs
-Polymorphisms clearly contribute to the drug response
-Use candidate gene and genomic screens to identify
EX: VKORC1 (PD) in Warfarin activity

24
Q

Haplotypes

A

Cluster of tightly linked genes on a chromosome that are likely to be inherited together.

25
Q

Mercaptopurine + TPMT

A
  • 6MP is used to treat pediatric leukemias
  • TPMT deficiency is inherited
  • Polymorphs in TPMT result in decreased activity
  • TPMT inactivates 6MP so that its toxic metabolites are cleared
  • 6MP’s toxic metabolites can cause myelosuppresion and hepatotoxicity
  • This deficiency means you can use smaller doses of the medication to get the same efficacy
26
Q

Irinotecan + UGT1A1

A
  • Campotothein class of topoisomerase inhibitors
  • Fight against malignancies like rectal and lung cancers
  • Metabolized by carboxylesterases and then UGT1A1 to be excreted
27
Q

UGT1A1*28

A
  • Polymorphisms in UGT1A1 lead to decreased levels of the enzyme
  • Causes the toxic, active metabolite SN-28 to not clear which can cause Gilbert’s Syndrome
28
Q

Non-PD/PK Examples

A
  1. HLA-B*5701 + Abacavir

2. HLA-B1502 + HLA-A3101

29
Q

HLA-B*5701 + Abacavir

A
  • Presence of allele could cause Abacavir-induced hypersensitivity reaction, could lead to death
  • Fever, rash, GI & respiratory symptoms and malaise
30
Q

HLA-B1502 + HLA-A3101

A
  • Carbamazepines & Phenytoins could lead to cutaneous adverse reaction
  • Also Stevens-Johnson Syndrome