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Pharm 2 > Test 5: Pharmacogenomics > Flashcards

Test 5: Pharmacogenomics Flashcards

1
Q

What is Pharmacogenetics?

A

The study of variations in human genes that are responsible for different responses to drug therapy.
-Variation of a single gene (!) or relatively few genes influencing a drug’s response
-Seeks to correlate phenotypic biomarkers with responses

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2
Q

What is Pharmacogenomics?

A

Involves identifying drug response markers at the level of disease, drug metabolism, or drug target.
-Encompasses the genome (all genes - whole genetic makeup)
-Involves DNA sequencing and gene mapping to identify genetic basis for variations in drug efficacy, metabolism, and transport
-Study of how chromosomal variations effect drug response

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3
Q

What is DNA?

A

-Main constituent of chromosomes
-Carrier of genetic information

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4
Q

What is an Allele?

A

2 or more forms of a gene that occupy a specific position on a specific chromosome

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5
Q

What is Allele Frequency?

A

The fraction or percentage of times a specific allele is observed in proportion to the total of all possible alleles that could occur at a specific location on a chromosome.

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6
Q

What is a Chromosome?

A

DNA containing structure that contains all or most of the genes of an organism
-largest is number 1

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7
Q

What is a Gene?

A

A sequence of DNA that occupies a specific position on the chromosome & determines a particular characteristic in an organism.
-Length of DNA that codes for a specific protein

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8
Q

What is Genotype?

A

-A representation of an organism’s genetic makeup or the particular set of genes that the organism possesses
-Ex: BB, Bb, or bb

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9
Q

What is Heterozygous?

A

Having two different alleles for the same trait

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10
Q

What is Homozygous?

A

Having an identical allele for a single trait

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11
Q

What is Phenotype?

A

The observable physical or biochemical characteristics of the organism’s genetic makeup
-Ex: Brown or blue eyes

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12
Q

What is Polymorphism?

A

A specific genetic alteration; occurs in more than 1% of the population.
-Any genetic variation in the DNA sequence (occur anywhere on the genome)
-Can be used interchangeably with variant

Variations in DNA sequence that occur in at least 1% of population

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13
Q

What is a Single Nucleotide Polymorphism (SNP)?

A

The most common type of genetic or allelic variation.
-Pair based substitutions that occur in the genome
-1 nucleotide is exchanged for another in a given position; occur anywhere on the genome
-A.k.a. Point Mutation

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14
Q

Genes specify the _____. Alleles specify ________. (Blue Box)

A

Genes specify the trait. Alleles specify what form the gene takes.

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15
Q

What does PM, IM, EM, and UM stand for?

A

Poor, intermediate, extensive, or ultra-rapid metabolizer phenotype

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16
Q

Polymorphisms are variations in the _____ sequence that occur in at least _____% of the population (Blue Box!)

A

Polymorphisms are variations in the DNA sequence that occur in at least 1% of the population.

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17
Q

What are the 3 areas of variations with Polymorphisms?

A

1) Drug-metabolizing enzymes
2) Enzyme receptor genes
3) Drug transporter genes

18
Q

What are the allele activity scores?

A

-Range 0 > 3
-0 = PM
-0.5 = IM
-1.0 = normal fxn
-1.0-2.0 = EM
-> 2 = UM

19
Q

What is the function of Phase 1 Drug Metabolizing Enzymes?

A

-CYP450 enzymes, biotransformation of over 75% of prescription drugs
-Clinical Ex: CYP2D6 – responsible for O-demethylation of Codeine to Morphine

20
Q

What would the effect of PM, IM, EM, and UM due to drug-metabolizing enzymes polymorphisms?

A

-PM: insufficient analgesia
-IM: insufficient analgesia
-EM: desired effect
-UM: increased adverse effects

21
Q

What is the recommended dosing adjustments for PM, IM, EM, and UM due to drug-metabolizing enzymes polymorphisms?

A

PM: alternative agent
IM: standard dose
EM: standard dose
UM: alternative agent

22
Q

What is the function of Phase 2 enzymes?

A

-Conjugation (enhance elimination of endo/exogenous substances)
-Clinical Ex: UGT1A1 – responsible for clearance of Irinotecan
-Conjugates glucuronic acid into lipophilic molecules
-UGT1A1 *6 & *28 decreases the clearance

23
Q

What are the effects of Phase 2 enzyme polymorphism?

A

-Can diminish drug elimination
-Can increase risk for toxicities

Individuals homozygous for UGT1A1*28 have 60-70% increased levels of circulating unconjugated bilirubin due to a 30% reduction in UGT1A1 activity

24
Q

What are the effects from genetic differences in transporter genes?

A

-Alter drug disposition and response
-May increase risk for toxicities
-Mediate selective uptake and efflux of endogenous compounds
-Important role in determining plasma and tissue concentrations

25
Q

What is the clinical example associated with drug transporter genes polymorphism?

A

-OATP1B1 transporter. Fxn:
Hepatic uptake of weakly acidic drugs and endogenous compounds (statins, methotrexate, bilirubin)
-Rs4149056 variant associated with Simvastatin-induced myopathy

26
Q

What are the example polymorphism of enzyme receptor genes?

A

Polymorphism of HLA genes:
-HLA-B, HLA-DQ, HLA-DR

27
Q

What is the outcome of HLA-B polymorphism?

A

-Associated with Steven-Johnson Syndrome
-Toxic epidermal necrosis
-Drug-induced liver injury

28
Q

What drugs are associated with hypersensitivity reactions with polymorphism of HLA genes?

A

Drug induced: Allopurinol, Carbamazepine, Abacavir, Flucloxacillin

29
Q

Describe genetic variations and NMB agents.

A

-Succs and atypical pseudocholinesterase: Due to point mutations on chromosome 3
-Most common variants: A variant (Asp70Gly), K variant (Ala539Thr)
-Most severe variants: silent! (esp if homozygous)
-Outcome of heterozygous polymorphism: prolong relaxation 3-8 times longer (30-80 minutes)
-Outcome of homozygous polymorphism: prolong relaxation up to 60 times longer (paralysis up to 8 hours, little to no pseudocholinesterase activity)

30
Q

What can occur with polymorphism to CYP2D6 as an UM?

A

Higher risk for life threatening side effects

31
Q

What can occur with polymorphism to CYP2D6 as an PM?

A

Mostly free of any adverse effects

32
Q

What is the Opioid receptor gene and the implications of polymorphism?

A

-OPRM1 gene
-Specific polymorphism R gene name: OPRM1 GG genotypes

This polymorphism Implication:
-Requires 93% higher morphine doses as compared to the OPRM1 AA genotype (codes for the MOR)

33
Q

What is the opioid transporter and the implications of polymorphism?

A

P-glycoprotein
-effect opioid variability on respiratory depression, associated with higher methadone doses in methadone therapy heroin addicts

34
Q

MH is due to mutation of what receptor?

A

RYR1 gene

35
Q

What is the physiology of MH?

A

-Substitution of Cys for Arg614
-Increased calcium and hypermetabolic state

36
Q

What are known inherited disorders that are associated with MH?

A

Central core disease (muscle weakness), Myotonic muscular dystrophy, Centronuclear myopathy, King-Denborough syndrome

37
Q

What are 3 receptor types involved in PONV?

A
  1. 5HT3
  2. D2
  3. MOR
38
Q

What polymorphisms are associated with thrombotic outcomes after cardiac surgery (CVA, PE, coronary graft thrombosis)?

A

Associated with elevated fibrinogen levels:
-Fibrinogen b-chain 455 G/A,
-Fibrinogen b-chain 854 G/A
-Fibrinogen b-chain Bcl1,

-Consistently associated with arterial thrombotic disease
-Risk factor for ischemic stroke, MI and PVD
-No recommendation for screening due to the lack of evidence to indicate any prognostic or therapeutic consequence within the general population

39
Q

Atrial fibrillation is associated with polymorphism of:

A

IL-6 (!)
ACE
ApOE

40
Q

What are suggested treatments post-CABG to prevent A Fib?

A

-Beta-blockers
-ACE-inhibitors
-NSAIDs

Pharm 2 (40 decks)

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