VOC - Pharmacogenomics

Question 1

What does pharmacogenomics study?

Answer 1

How genetic determinants and variability affect how a drug works

Question 2

What are the four patient groups based on drug toxicity and benefit?

Answer 2

• Drug TOXIC but beneficial.
• Drug TOXIC but NOT beneficial.
• Drug NOT toxic and beneficial.
• Drug NOT toxic and NOT beneficial

Question 3

Name the four components of Pharmacokinetics and Pharmacodynamics

Answer 3

Pharmacokinetics (organism on drug)

• Absorption
• Distribution
• Metabolism
• Excretion

Pharmacodynamics (drug on organism)

• Receptors
• Ion channels
• Enzymes
• Immune system

Question 4

What are the consequences of too quick drug metabolism?
What are the consequences of too slow drug metabolism?

Answer 4

• No drug response at usual dosage
• Excessively high drug levels at usual dosage, leading to a higher risk of adverse drug reactions (ADRs)

Question 5

What are some features of the Succinylcholine (Suxamethonium) neuromuscular junction block?

Answer 5

• Short-lived drug used as muscle relaxant to immobilize in surgery

Short-lived (thus controlled by its breakdown by serum cholinesterase)

• 1:3000 have a genetically altered enzyme that has reduced activity
• The homozygous and heterozygous unaffected copy of gene enzyme activity

The individuals carrying two copies of the modified gene have adverse reaction. Sustained neuromuscular junction muscle block

Question 6

How does Coding SNP, Exonic deletion, Gene duplication and Deletion/inactivation of transcription factor binding site affect the transcribed mRNA?

Answer 6

• Coding SNP alters transcription mRNA
• Exonic deletion shortens transcription mRNA
• Gene duplication produces double transcription mRNA
• Deletion/inactivation of transcription factor binding site produces no transcription mRNA

Question 7

What is Cytochrome P450’s role in drug metabolism?

Answer 7

• Essentially detoxifies oxidation reactions (other physiological functions).
• Transform drug structure to increase elimination.
• Transform drug structure to inactivate or reduce potency.
• Transform drug structure to increase potency relative to the parent (pro-drug activation).
• Transform drug structure to generate toxic intermediate.

Question 8

How does genetic variation in Cytochrome P450 affect drug metabolism?

Answer 8

Gene deletion

• No mRNA → No enzyme → No metabolism

Single gene copy

• → Unstable enzyme → Decreases metabolism of parent drug
• → Normal enzyme → Normal metabolism of parent drug
• → Altered substrate specificity → Other metabolites

Gene duplication/multiplication

• → Higher enzyme levels → Increased metabolism of parent drug

Question 9

What are some features of the CYP2D6 gene

Answer 9

Sits on chromosome 22

Gene itself is made of 9 exons and 8 introns

• 100 genetic variants across the gene

Selectively metabolises tricyclic antidepressants

Effective on beta adrenergic receptor blockers, antiarrhythmic drugs.

> 10 fold variability in plasma concentrations.

Question 10

What are Ultrarapid metabolizers and what is the issue with them aswell as how this can be resolved?

Answer 10

UM have very reduced levels of active drug

• Problem if there is a narrow therapeutic window. PM excess

Increases pro-drug metabolism e.g. codeine to morphine:

• Latter more potent and CYP2D6 effects analgesia PM don’t use/UM overdose

Question 11

Describe the modified signalling in the Arg389Gly Beta 1 receptor

Answer 11

P49 SNP exists at N-terminus

P389 SNP exists at C-terminus

Both SNP exist outside of agonist binding sites

• No dramatic change in agonist binding

However G-protein coupled reaction is affected downstream

SNP lowers potency and efficacy of beta receptor

Question 12

What drugs are used after a heart attack and in hypertension? Arg389 or Gly389?

Answer 12

Beta blockers

• Compare Arg 389 and Gly 389 cohorts there is a benefit to Arg 389

This outcome only seen if the comparison is made between treated and untreated