Select Topics Flashcards by Michellea Russell

What is pharmacogenetics?

The individual impact on drug efficacy and toxicity. Genetics dictate enzyme differences across and within species.

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What are the observable differences in human pharmacogenetics?

Enzyme effectiveness
DDIs
Drug toxicity

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What are DMEs exhibiting polymorphisms?

CYP2D6
CYP2C9
CYP2C19
UDP-Glucuronosyl Transferase (UGT 1A1)
NAT2
Thipurine S-MEthyltransferase (TPMT)

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What is the consequence of being a CYP2C19 poor metabolizer in the different subpopulations when Mephenytoin is given?

3 Phenotypes(EM, IM, PM)
3-5% Caucasians
12-23% Asians
3% African Americans
are poor metabolizers and thus have sedation when given Mephenytoin.

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What subpopulations does CYP2D6 have?

PM-poor metabolizers
IM-intermediate metabolizers
EM-extensive metabolizers
UM-ultra-rapid metabolizers

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What phenotypic subpopulations does NAT2 have?

Rapid acetylators (Eskimos)
Slow acetylators (Egyptians)
affects Isoniazid

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What are NAT2 slow acetylators associated with?

10-20% decrease in enzyme amounts in liver cytosol and decrease in NAT2 enzyme activity.

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When was the Human Genome Project Established?

1990

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When was the emergence of pharmacogenomics?

1995

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What is pharmacogenomics?

It involves the genome-wide anaylsis of genetic determinants of drug efficacy and toxicity.
Requires genetic profiling and advocates genetically guided therapy.
Used in chemotherapy.

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What is the ultimate goal of pharmacogenomics?

Tailored, personalized, individualized drug therapy.

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What is polymorphism?

Variations in DNA nucleotide sequences

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What are the types of polymorphism?

Single nucleotide (A,T,C,G) polymorphism (SNP)
>1 nucleotide changes
Entire gene insertion
Entire gene deletion
Extra gene copies

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What are the effects of polymorphism?

Lead to disease
Alter protein function (DME)
Ultimately drug therapeutic efficacy is impacted.

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Which enzyme has 80 plus different alleles?

CYP2D6

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What is important about CYP2D6*5?

It has deleted nucleotide base pairs in the 2D6 gene
Not a SNP
Results in loss of CYP2D6 function which makes it a poor metabolizer phenotype.

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What drugs does CYP2D6*5 affect?

Metoprolol, SSRIs, codeine, atomoxetine, tamoxifen, etc. (MS.CAT)

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What is important about TPMT*3?

Thiopurine methyltransferase (TPMT)
A SNP(single nucleotide polymorphism)
Results in decreased TPMT activity.

What drugs does TPMT*3 affect?

Azathiprine, 6-mercaptopurine which causes fatal myelosuppression

Genetic testing is suggested because of what polymorphic DMEs?

2C19, 2C9, 2D6, TPMT

What drugs should genetic testing be suggested for?

Warfarin
Atomoxetine
6MP or Azathioprine
Tamoxifen

What enzyme should be tested before being given Warfarin?

CYP2C9

What enzyme should be tested before being given Atomoxetine and Tomoxifen?

CYP2D6

What enzyme should be tested before being given 6MP or Azathioprine?

TPMT

What consequences are from PMs(poor metabolizer)?

Toxicity

What consequences are from UMs(ultra metabolizers)?

Therapeutic failure

What is metabolomics?

Identification of small molecule metabolites in body fluids to create unique 'fingerprints'

Endogenous metabolites (lipids, etc.) are under tight ______ _____.

Endogenous metabolites are under tight homeostatic control.

What can metabolomics identify?

disease markers | metabolism phenotypes

What enzyme activities are low in children?

``` CYP450 1st pass effect low for 1A2, 2C9, & 3A4 MAOB & EHs ADH NAT AA (perhaps due to low glycine) SULT (almost mature) DME activity increase with age but can be compromised in malnourished children. ```

What affects pregnancy drug metabolism?

Estrogen, progesterone, placental growth, hormones, prolactin, etc.

What enzyme changes occur in pregnancy?

CYP1A2 activity decreases CYP2D6 & CYP3A activities increases UGT1A1/4 & other UGTs activities increase NAT2 activity decreases.

What enzymes are involved in alcohol metabolism?

Alcohol dehydrogenase Catalase CYP450 or Microsomal Ethanol Oxidizing System (MEOS)

What is important about Ethylene Glycol and Diethylene Glycol?

Sweet & odor-less liquids Metabolized by ALDH, ADH to toxic metabolites Metabolic acidosis Accidental and intentional poisonings

Obesity causes what type of enzyme activities?

Decreased CYP450 activities (3A4 &2E1) | Increased Phase II conjugations (UGT, SULT, GST, AA) causes shorter duration of action.

What bodily functions are affected by obesity?

Cardiac output & liver blood flow increase in obesity. | Altered enterohepatic recirculation.

Obesity causes a disruption of drug metabolism and transport which....

causes reduced efficacy or increased toxicity.

What are antioxidant enzymes?

superoxide anion, peroxyl, hydroxyl, alkoxyl, hydroperoxyl, lipid peroxyl, nitric oxide, nitrogen dioxide, hydrogen peroxide, peroxynitrate, peroxynitrite, hypochlorous acid.

What is Xanthine Oxidase?

Metabolizes purines and pyrimidines.

What drugs does Xanthine oxidase affect?

Thiopurines &methylxanthines

Where are the highest XO levels?

liver and intestines

What is the rare disease that causes no XO?

Xanthinuria

Males or Females have more Xanthine oxidase?

Males

What is the main indication of XO inhibitors is?

Hyperuricemia & Gout(precipitation of Na Urate crystals in various tissues)