Lec Pharmacogenetics

Question 1

What’s the most common cause of genetic variation in drug response?

Answer 1

Single Nucleotide Polymorphisms

Question 2

What is an SNP

Answer 2

Single BP change that alters the coding sequence of a particular gene

Question 3

CYP2D6 Mutation

Answer 3

Derisoquin-sparteine polymorphism - Changes response to certain drugs (codeine, oxycodone, antidepressants and B blockers)

Question 4

CYP2C19 Polymorphisms

Answer 4

• Inactivate enzymes
• Higher in Asians and African Americans
• Leads to Loss of Function:
  1. Increase efficacy of Proton Pump Inhibitors
  2. Leads to loss of inhibition of platelet activity by clopidogrel

Question 5

CYP2C9 polymorphism

Answer 5

Reduced activity which slows down metabolism
- Sensitivity to Warfarin is reduced due to SNP in Viamin K epoxide reductase gene (VKORC1) (recylces Vitamin K and affects sensitivity to Warfarin).

Higher dose of Warfarin may be needed, need to do INR to measure prothrombin time for clotting

Question 6

Procainamide

Answer 6

Antiarrhythmic Drug - If NAT2 doesn’t work right procainamide is metabolized by FMO instead to become a toxic compound that may even trigger Lupus (drug-induced lupus)

Question 7

What drugs are metabolized by NAT2?

Answer 7

1. Isoniazid
2. Procainamide
3. Caffeine
4. Dapsone
5. Hydralazine
6. Histamine

Question 8

Isoniazid metabolism

Answer 8

Normally not toxic, with mutation of NAT2 you get production of a neurotoxic compound

Question 9

Pseudocholineterase polymorphism

Answer 9

Anesthesia lasts longer due to extension of duration of action for succinylcholine

Question 10

What are “fast acetylators” at risk for?

Answer 10

Colon cancer as a result of increase metabolism of pro-carcinogens

Question 11

TPMT

Answer 11

Thiopurine Methyl Transferase

Question 12

What does TPMT do?

Answer 12

Methylates 6-thioguanine nucleotides to inactivate them. Activity can be measured in RBC assays.

Also metabolizes Azathioprine, an immunosuppressant

Question 13

TPMT Polymorphism

Answer 13

Build up in life threatening 6-thioguanine nucleotides = myelosupression

Question 14

MDR-1

Answer 14

Large gene, also called P-glycoprotein. Produces a membrane pump that facilitates the efflux of metabolites and drugs from cells. Also forms part of the blood brain barrier.

Question 15

MDR-1 SNP Reactions

Answer 15

1. Silent SNP - Reduces the level of expression of the protein in the duodenum, causing lower plasma levels of anti-retroviral drugs and increased recovery of CD4 cell counts
2. Second SNP - Causes a substitution that enhances MDR-1 function

Question 16

Beta-2-Adrenergic Receptor (ADRB2) polymorphism

Answer 16

Rapid desensitization by agonist in veins but increased bronchodilator response

Question 17

5-LOX Polymorphism

Answer 17

Arachidonate 5-Lipoxygenase polymorphism - Impaired Function - reduced incidence of asthma