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Flashcards in Lec Pharmacogenetics Deck (17):
1

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

Single Nucleotide Polymorphisms

2

What is an SNP

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

3

CYP2D6 Mutation

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

4

CYP2C19 Polymorphisms

- 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

5

CYP2C9 polymorphism

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

6

Procainamide

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)

7

What drugs are metabolized by NAT2?

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

8

Isoniazid metabolism

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

9

Pseudocholineterase polymorphism

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

10

What are "fast acetylators" at risk for?

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

11

TPMT

Thiopurine Methyl Transferase

12

What does TPMT do?

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

Also metabolizes Azathioprine, an immunosuppressant

13

TPMT Polymorphism

Build up in life threatening 6-thioguanine nucleotides = myelosupression

14

MDR-1

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.

15

MDR-1 SNP Reactions

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

16

Beta-2-Adrenergic Receptor (ADRB2) polymorphism

Rapid desensitization by agonist in veins but increased bronchodilator response

17

5-LOX Polymorphism

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

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