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PharmD Program Semester 2 > Principles of Drug Action Pharmacogenomics > Flashcards

Principles of Drug Action Pharmacogenomics Flashcards

1
Q

What is pharmacogenomics?

A

Study of how an individual’s genes influence effects of drugs on that individual’s health

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2
Q

Why Study PGx?

A

Reduces adverse drug events

Reduces health care costs

Improves health care outcomes

Stakeholders demand use of PGx

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3
Q

Adverse Drug Reaction Statistics

A

82% of adults take at least one medication

29% take five or more

Over 700k ER visits, 120k hospitalizations, and 100k deaths per year

3.5 billion dollars per year of extra medical costs

~40% of costs of ambulatory ADEs estimated to be preventable

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4
Q

Most common ADR culprits

A

Anticoagulants

Antidiabetics

Antiepilectics

Opioids

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5
Q

Stakeholder interest in PGx is increasing rapidly

A

FDA issued guidance

Over 300 drugs with genomic biomarkers in labels

Over 25% prescriptions for drugs with genomic bio markers (2006)

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6
Q

Human Genome Project overview of facts and figures

A

3.2 billion nucleotides

<2% genome constitutes genes

Many repeated sequences

Many movable elements

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7
Q

Genomic Similarities and Differences

A

Our genomes are 99.9% the same, but with .1% of difference between them

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8
Q

Types of DNA sequence variations

A

Chromosome number variations

Gene copy number variations

Insertion of nucleotides

Deletion of nucleotides

Single nucleotide polymorphisms (SNPs)

SNPs are most common (>98%)

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9
Q

Genetics and genetic medicine: Central assumptions

A

Variation is essential for survival

Some variation may be disadvantageous

Some variation may be advantageous

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10
Q

Genetics and genetic medicine

A

Goal of health care provider: Use genetic information to find point of entry in this pathway to provide best benefit or cure

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11
Q

Chromosomes and Genomes

A

Diploid cells have double chromosome number (2n) and are vegetative

Haploid cells have half the number of chromosomes (n) and are used for reproduction.

Mutations in these two cells can cause genetic, physiological, and sometimes physical defects

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12
Q

Karyotyping

A

A technique to display chromosomes

Normally, somatic human cells have 23 pairs of chromosomes

1-22 are called autosomes

Pair 23 is called sex chromosome and is designated XX or XY

Maintaining the number and integrity of chromosomes is vital for all organisms

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13
Q

Genes and chromosomes

A

Vegetative cells have double chromosome number (2N or 2n). These are also called diploid cells

Reproductive cells or gametes have half the number of chromosomes as that of vegetative cells. These are called haloid cells.

Any deviation from 2N or N in respective cells results in genetic, physiological, and sometimes even physical defects

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14
Q

Change in chromosome number/size causes disability/disease examples

A

Trisomy21: extra copy of chromosome 21: Down syndrome

Trisomy13: Severe retardation, death

Trisomy18: Microcephaly

Trisomy X: Behavioral defects

XXY: Sterility, gynecomastia

XYY: Hyperactivity

Translocation: Physical transfer of part of one chromosome to another

Translocations often cause schizophrenia, bipolar disorders, and some cancers

Technological advances are uncovering many newer health conditions due to translocations

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15
Q

Eukaryotic genetic material has specific structural organization based on size, list from smallest to largest

A

Naked DNA (2 nm)
Nucleosome cores (10 nm)
Folded nucleosomes (30 nm)
Chromosome loops (300 nm)
Folded chromosome (700 nm)
Mitotic chromosome (1400 nm)

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16
Q

DNA supercoiling

A

Coiling and compaction is an intrinsic property of cellular DNA

All cellular DNA is reversibly supercoiled to various degrees

Cellular proteins affect degree of coiling and compaction

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17
Q

Topoisomerases

A

Cut and relax supercoiled DNA

Type 1 does one strand, Type 2 does both

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18
Q

Topoisomerases as therapeutic agents

A

Camptothecin: Gastric, colon, lung, and ovarian cancer

Etoposide: Testicular, lung, and cancer; leukemias, sarcomas

Doxorubicin: Ostogenic sarcomas, Hodgkin’s and non-Hodgkin’s lymphoma

Daunorubicin: Leukemia

Teniposide: Acute lymphoblastic leukemia

Moxifloxacin: Used against pathogens resistant to other antibiotics

Ciprofloxacin: Used against pathogens resistant to other antibiotics and anthrax

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19
Q

Chromatin Structure

A

Mass of nucleic acids and proteins in the nucleus of eukaryotic cells is chromatin

It undergoes physiochemical changes depending on cell physiology

Euchromatin, the diffused, open structure represents active genes

Heterochromatin represents inactive genes

Sperm chromatin structure has been used as a diagnostic tool in male infertility tests

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20
Q

Nucleosome and some of the properties

A

DNA and tightly bound proteins from nucleosomes

Histones are small proteins with high basic amino acid content

Five major classes of histones in eukaryotes: H1, H2A, H2B, H3, and H4

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21
Q

Nucleosome

A

The fundamental organizational unit of chromatin

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22
Q

Chromatin and Nucleosome binding

A

Each nucleosome contains about 200 bp DNA wrapped around a protein core of eight histones

The nucleosomal beads are connected by linker DNA

Histone H1 binds the linker DNA

Nucleosomes pack into reversible higher ordered structures as per cell physiology

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23
Q

Chromatin and therapeutic applications

A

Dynamic nature of chromatin structure governs its function

Chromatin structure regulates DNA replication

Chromatin structure regulates expression, amplification, and silencing of genes as well as other DNA metabolic pathways

Enzymes/proteins involved in these pathways are excellent tolls for diagnostic/therapeutic applications

Histone Deacetylase: Cancer treatment

Poly-ADP-Ribose polymerase: Cancer treatment, heart disease

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24
Q

Eukaryotic genome

A

Most eukaryotic non-gene DNA is repetitive, about half of which is derived from transposable elements

TEs may move around in the genome and cause mutation

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25
Q

Four major elements of eukaryotic chromosomes

A
  1. Ends of a chromosome are called telomeres. They have a unique function during DNA replication
  2. Centromeres have highly repetitive DNA. It is critical in cell division
  3. Some repeated sequences and multiple origins of replication are also present across the length of a chromosome
  4. Unique DNA sequences which form genes are present along the length of a chromosome.
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26
Q

Gene and the relationship with a trait

A

Genetically, a gene is the basic unit of inheritance, responsible for determining a trait in an organism

Biochemically, a gene contains all genetic information necessary and sufficient for producing a functional polypeptide or RNA molecule

This gene product contributes to the trait of an organism

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27
Q

Structure of an eukaryotic gene

A

Structure and function of most eukaryotic genes are very complex

Promoters regulate expression of genes

Intron or intervening sequences do not code for proteins

Exons code for part or all of a specific protein or RNA product

Splicing removes intronic RNA, joins exonic RNA and makes mature messages

28
Q

Eukaryotic gene and the relation with a trait

A

Gene DNA –> RNA –> Protein –> Trait –> RNA

A trait may be represented by one or more genes

29
Q

Regulation of translation: Alternative splicing

A

Alternative splicing of tropomyosin mRNA results in multiple tissue specific isoforms of the protein

Examples of splicing patterns:
Exon skipping
Alternative 5’ and 3’ splice site
Mutually exclusive exons
Intron retention
Alternative first or last exons

30
Q

Alternative splicing defects

A

Amyotrophic lateral sclerosis

Calcium-activated K+ channel in the inner ear hair

Muscular dystrophy

Dementia

31
Q

Muscular Dystrophy

A

Skeletal muscle atrophy

X-linked, affects 1 in 5000 male newborns

Defects in dystrophin, >7000 variants known

Different forms or subtypes of MD

Duchenne muscular dystrophy is most common

32
Q

DMD genetics

A

Largest gene in humans (79 exons, large introns)

Encodes largest human protein, dystrophin

Multiple — produced by — splicing

Mutations known to affect splicing
Duchenne MD: — protein, — phenotype

Becker MD: — protein, — phenotype

33
Q

Gene

A

Basic unit of DNA; final product may be protein or RNA

34
Q

Allele

A

Alternative form of a gene; in a population, there may be more than one allele of a gene

35
Q

Dominant

A

Only one copy is needed to exhibit the phenotype

36
Q

Recessive

A

Two copies needed of a gene are required to exhibit a trait

37
Q

Homozygous

A

Indicates presence of two alleles, which are exact copies of each other, in the same individual organism

38
Q

Heterozygous

A

Two different alleles of a gene in the same individual organism

39
Q

Genotype

A

Description of the genetic composition of a specific trait

40
Q

Mutation

A

Any physical or chemical change in the genetic material of an organism

May occur anywhere in the genome of an organism

May occur anytime in the life cycle of an organism

May be beneficial or detrimental to the organism

Hereditary mutations are transmitted to offspring

Somatic mutations are not transmitted to offspring

Genetically, a mutation must be heritable

Clinically, a mutation must not be heritable

41
Q

Phenotype

A

Description of a morphological, physiological, biochemical, pharmacological, or clinical presentation of a trait. Some phenotypes are visible and others not.

42
Q

Exceptions to Mendelian genetics

A

Primarily observed in case of dominant gene disorders

Increasing disease severity

Early onset of disease

Possible mechanism: Triplet repeat expansion

43
Q

Antisense Oligonucleotides as Drugs

A

Single stranded oligonucleotides

Complimentary to target pre-RNA or mRNA

Modulate translation and increase/decrease of protein levels

44
Q

What is a pedigree chart?

A

Study of inheritance of a trait in several generations of genetically related individuals provides valuable information.

45
Q

Examples of dominant gene disorders

A

Huntington disease: 1/10,000
Gene: HTT

Retinitis pigmentosa: 1/4,000
Gene: RHO

Polycystic kidney disease: 1/1,000
Gene: PKD1 and 2

Familial hypercholesterolemia: 1/500
Gene: APOB and LDLR

46
Q

Examples of recessive gene disorders

A

Cystic fibrosis: 1/2,500
Gene: CFTR

Phenylketonuria: 1/10,000
Gene: PAH

Retinitis pigmentosa: 1/4,000
Gene: USH2A

Gaucher disease, Type 1: 1/50,000
Gene: GBA

Beta thalassemia: 1/20,000
Gene: Beta globin

Alpha 1-antitrypsin deficiency: 1/3,500
Gene: SERPINA1

47
Q

Hemochromatosis

A

Caused by mutation in HEF gene

Inherited as an autosomal recessive trait

1/10 individuals are carriers

<1% homozygotes actually develop clinical hemochromatosis

1/250-400 individuals may manifest disease

Causes increased gastrointestinal iron absorption and complications

48
Q

Non-genetic factors often influence genetic disorders

A

Age

Environment

Diet

Socioeconomic conditions

49
Q

Functional effects of genetic variations

A

Genetic variations may affect function

Decrease of a function

Lead to a new function for the gene/product

(gain of function) variations

50
Q

Nucleotide sequence of a hypothetical gene from your DNA

A

DNA sequence variations that occur when a single nucleotide in the genome sequence is altered with another common nucleotide

51
Q

Variation is the rule

A
52
Q

SNP types

A

Synonymous: GAA to GAG (Leucine to Leucine)

Non-synonymous: TCA to TCT (Serine to Arginine)

Nonsense: Stops translation of codon

53
Q

Single nucleotide polymorphism

A

DNA sequence variations that occur when a single nucleotide in the genome sequence is altered

Account for >97% of all genetic variation in humans

SNPs frequency in human genome ~1/100 nucleotides

Majority occur in non-coding region of the DNA

Only about ~70,000 occur in coding region

Each human SNP has a unique ID or reference SNP number

54
Q

Types of SNPs

A

Intergenic: Between gene (Majority)

Intragenic: Inside gene (Fewer)

Within non-coding region
Within transcribed region
Within introns or exons
Within untranslated or translated region

55
Q

Genetic variations may vary across races

A

Cosmopolitan polymorphisms
- More frequent
- Across all populations

Race specific polymorphisms
- Less frequent
- Limited to specific race

56
Q

What are SNPs good for?

A
  1. Drug response prediction
  2. Drug reaction prediction
  3. Disease detection
  4. Disease predisposition prediction
57
Q

Pharmacogenomic Traits

A

A — trait associated with drugs

Biochemical —
— (e.g. blood pressure)
Clinical (Tumor size or drug sensitivity)
—genic (simple) vs. —genic (complex)

58
Q

Drug metabolism rates vary in a population, what are the groups?

A

Poor metabolizers

Intermediate metabolizers

Extensive metabolizers

Ultrarapid metabolizers

59
Q

CYP2D6 substrates and inhibitors

A

ADHD: Atomoxetine

Antianginal: Flecainide, mexiletine, and propafenone

Antidepressant: Mianserin

Antihistamines: Chlorpheniramine

Antipsychotics: Chlorpromazine, risperidone, thioridazine, zucloperthixol, and perphenazine

Beta blockers: Carvedilol

Muscarinic antagonists: Tolterodine

60
Q

Pathways of codeine metabolism

A

Codeine -UGT287-> Codeine-6-glucoronide –> Excretion via bile

Codeine -CYP2D6-> Morphine -UGT287-> Morphine-6-glucoronide –> Morphine-3-glucoronide –> Excretion via bile

61
Q

Foundations of Health Care Ethics

A

Right to autonomy: Individual right to make decisions

Beneficence: Acting for the patient’s best interest

Non-maleficence: Doing no harm to the patient

Justice: Fairness and equity among all patients

62
Q

GINA 2008 Strengths

A

Prohibits insurance providers from denying health insurance to you or requiring a genetic test

Employers prohibited from using genetic information for hiring/firing or requesting genetic information on employees

Medicare prohibited from asking individuals to take genetic test

63
Q

GINA 2008 Limitations

A

Genetic discrimination in life, long-term, or disability insurance by creditors

Medical underwriting based on an individuals current health status

Does not mandate coverage for any specific test or treatment

Does not prohibit insurers from obtaining and using genetic test results in payment decisions

Does not apply to US armed forces, veterans, Indian health service, or employers with less than 15 people

64
Q

Genetic exceptionalism at the State Level

A

Many states require consent to perform, obtain, and disclose genetic information

Some states define genetic information as personal property

Several legislations under consideration at federal/state level

65
Q

Intellectual Property Issues and potential solutions

A

Who owns my DNA?
What will they do with it?

Tighter regulations
Consumer education

PharmD Program Semester 2 (14 decks)

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