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

Principles of Drug Action Pharmacogenomics Flashcards

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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
Four major elements of eukaryotic chromosomes
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.
26
Gene and the relationship with a trait
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
27
Structure of an eukaryotic gene
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
Eukaryotic gene and the relation with a trait
Gene DNA --> RNA --> Protein --> Trait --> RNA A trait may be represented by one or more genes
29
Regulation of translation: Alternative splicing
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
Alternative splicing defects
Amyotrophic lateral sclerosis Calcium-activated K+ channel in the inner ear hair Muscular dystrophy Dementia
31
Muscular Dystrophy
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
DMD genetics
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
Gene
Basic unit of DNA; final product may be protein or RNA
34
Allele
Alternative form of a gene; in a population, there may be more than one allele of a gene
35
Dominant
Only one copy is needed to exhibit the phenotype
36
Recessive
Two copies needed of a gene are required to exhibit a trait
37
Homozygous
Indicates presence of two alleles, which are exact copies of each other, in the same individual organism
38
Heterozygous
Two different alleles of a gene in the same individual organism
39
Genotype
Description of the genetic composition of a specific trait
40
Mutation
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
Phenotype
Description of a morphological, physiological, biochemical, pharmacological, or clinical presentation of a trait. Some phenotypes are visible and others not.
42
Exceptions to Mendelian genetics
Primarily observed in case of dominant gene disorders Increasing disease severity Early onset of disease Possible mechanism: Triplet repeat expansion
43
Antisense Oligonucleotides as Drugs
Single stranded oligonucleotides Complimentary to target pre-RNA or mRNA Modulate translation and increase/decrease of protein levels
44
What is a pedigree chart?
Study of inheritance of a trait in several generations of genetically related individuals provides valuable information.
45
Examples of dominant gene disorders
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
Examples of recessive gene disorders
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
Hemochromatosis
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
Non-genetic factors often influence genetic disorders
Age Environment Diet Socioeconomic conditions
49
Functional effects of genetic variations
Genetic variations may affect function Decrease of a function Lead to a new function for the gene/product (gain of function) variations
50
Nucleotide sequence of a hypothetical gene from your DNA
DNA sequence variations that occur when a single nucleotide in the genome sequence is altered with another common nucleotide
51
Variation is the rule
52
SNP types
Synonymous: GAA to GAG (Leucine to Leucine) Non-synonymous: TCA to TCT (Serine to Arginine) Nonsense: Stops translation of codon
53
Single nucleotide polymorphism
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
Types of SNPs
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
Genetic variations may vary across races
Cosmopolitan polymorphisms - More frequent - Across all populations Race specific polymorphisms - Less frequent - Limited to specific race
56
What are SNPs good for?
1. Drug response prediction 2. Drug reaction prediction 3. Disease detection 4. Disease predisposition prediction
57
Pharmacogenomic Traits
A --- trait associated with drugs Biochemical --- --- (e.g. blood pressure) Clinical (Tumor size or drug sensitivity) ---genic (simple) vs. ---genic (complex)
58
Drug metabolism rates vary in a population, what are the groups?
Poor metabolizers Intermediate metabolizers Extensive metabolizers Ultrarapid metabolizers
59
CYP2D6 substrates and inhibitors
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
Pathways of codeine metabolism
Codeine -UGT287-> Codeine-6-glucoronide --> Excretion via bile Codeine -CYP2D6-> Morphine -UGT287-> Morphine-6-glucoronide --> Morphine-3-glucoronide --> Excretion via bile
61
Foundations of Health Care Ethics
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
GINA 2008 Strengths
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
GINA 2008 Limitations
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
Genetic exceptionalism at the State Level
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
Intellectual Property Issues and potential solutions
Who owns my DNA? What will they do with it? Tighter regulations Consumer education

PharmD Program Semester 2 (14 decks)

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