Lec Pharmacogenetics Flashcards

1
Q

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

A

Single Nucleotide Polymorphisms

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2
Q

What is an SNP

A

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

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3
Q

CYP2D6 Mutation

A

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

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4
Q

CYP2C19 Polymorphisms

A
  • 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
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5
Q

CYP2C9 polymorphism

A

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

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6
Q

Procainamide

A

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)

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7
Q

What drugs are metabolized by NAT2?

A
  1. Isoniazid
  2. Procainamide
  3. Caffeine
  4. Dapsone
  5. Hydralazine
  6. Histamine
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8
Q

Isoniazid metabolism

A

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

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9
Q

Pseudocholineterase polymorphism

A

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

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10
Q

What are “fast acetylators” at risk for?

A

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

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11
Q

TPMT

A

Thiopurine Methyl Transferase

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12
Q

What does TPMT do?

A

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

Also metabolizes Azathioprine, an immunosuppressant

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13
Q

TPMT Polymorphism

A

Build up in life threatening 6-thioguanine nucleotides = myelosupression

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14
Q

MDR-1

A

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.

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15
Q

MDR-1 SNP Reactions

A
  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
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16
Q

Beta-2-Adrenergic Receptor (ADRB2) polymorphism

A

Rapid desensitization by agonist in veins but increased bronchodilator response

17
Q

5-LOX Polymorphism

A

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