Pharmacogenetics Flashcards
1
Q
What is pharmacogenetics?
A
- genetically controlled variations in drug response
- genetic factors that alter an individual’s drug response to a drug
- genetic polymorphisms
- less common genetic variants
2
Q
State the importance in recognizing genetic differences in individuals:
A
- Genetic differences can cause significant differences in the dose of a drug required to achieve the desired effect.
- Genetic differences in drug metabolism can significantly alter drug clearance and pharmacokinetics.
- Genetic differences can alter susceptibility to toxic effects of drugs and other chemicals.
- Genetic differences can cause or exacerbate adverse drug reactions, some of which used to be called “idiosyncratic”.
- These patients do not become apparent until they are exposed to a particular chemicalor drug.
3
Q
Genetic locus:
A
chromosomal location at which two alleles are possible
4
Q
Genotype:
A
- an individual’s **composition at the gene level **
- i.e. the specific genes they have
5
Q
Phenotype:
A
an individual’s expression of their genotype
6
Q
Genetic polymorphism:
A
- Mendelian trait that exists in the population in at least two phenotypes neither of which is rare
- i.e. at least one variant that represents greater than 1% of total pool
7
Q
Allele:
A
- an alternative form of a gene
- one of the different forms of a gene that can exist at a single locus
8
Q
Single nucleotide polymorphism (SNP):
A
- a change in one single base pair in the DNA sequence that differs from the “wild type” or predominant sequence
- may or may not result in an altered phenotype
- 99% do not change the phenotype
- most common polymorphism
9
Q
How do we categorize individuals based off of SNPs?
A
- Haplotypes
- Halotypes
10
Q
Haplotype:
A
- refers to closely linked genetic markers on a chromosome that tend to be inherited together
- often within a gene or closely linked genes
11
Q
Halotypes:
A
- refers to a cluster of SNPs that occur together in an individual (andare of interest to a phenotype)
- useful for categorizing individuals to understand how clusters of SNPs can contribute to phenotype
-
multiple SNPs may be:
- in a single gene (similar to a haplotype)
- multifactorial, multiple genes not necessarily inherited as a unit
12
Q
Types of inheritance:
A
- Autosomal co-dominance: each allele contributes to phenotype
- Autosomal recessive: wild-type allele has predominant effect; it takes two recessive alleles to see the effect
- Autosomal dominant: a single allele predominates over the presence of other possible alleles
- X-linked inheritance: genes inherited on X chromosome; all males will express these traits (males are hemizygous)
13
Q
Hardy Weinberg equilibrium:
A
- In populations with random mating and no selection pressure, the incidence of the various genotypes can be determined mathematically
- This description is the Hardy Weinberg formula:
1 = (p+q)2=p2 +2pq +q2
where:
- p = proportion of wild type alleles
- 2pq = frequency of heterozygote
- q = proportion of variant alleles
- p2 = frequency of homozygous WT
- q2 = frequency of homozygous variant
- If frequencies of observed phenotypes fit the equation, a variant is said to be
consistent with Mendelian inheritance
14
Q
homozygous:
A
have 2 identical alleles
- e.g. AA or aa
15
Q
Pharmacogenetics versus pharmacogenomics:
A
- Pharmacogenetics: variation at selected loci
- Pharmacogenomics: whole genome variation
16
Q
What are some potential genetic polymorphic impacts on drug efficacy & toxicity:
A
- Polymorphisms which could impact pharmacokinetics:
- Transporters (uptake, distribution)
- Plasma protein binding
- Metabolism
- Excretion
- Polymorphisms which could impact pharmacodynamics:
- Receptors
- Ion channels
- Enzymes
- Signaling events
17
Q
NAT-2 polymorphism:
A
Initial observations
- Increased neurologic side effects in some patients were correlated with increased plasma concentrations of isoniazid
- Plasma half-life phenotype in population identified two groups, and implicated a difference in elimination/metabolism
- Subsequently established that genetic differences in NAT-2 explain “fast” versus “slow” acetylators
- autosomal recessive trait
18
Q
____________ responsible for metabolism of the anti-tuberculosis drug isoniazid
A
- N-acetyltransferase-2 (NAT-2)
19
Q
Other drugs influenced by N-acetylation phenotype:
A
- hydralazine
- nitrazepam
- procainamide
- phenelzine
- dapsone
- clonazepam
- sulfonamides
- others
20
Q
Slow acetylator phenotype has been associated with:
A
- increased incidence of neuropathy due to isoniazid
- arylamine-associated bladder cancer
- hypersensitivity to sulfonamides
- higher incidence of lupus erythematosus with long-term hydralazine therapy
21
Q
CYP2D6 Polymorphism:
A
- First identified from those that suffered severe hypotension following administration of the anti-hypertensive debrisoquine
- Severe hypotension associated with increased debrisoquine concentrations, and decreased metabolism of debrisoquine
- Subsequently linked to “poor metabolizer” variants of CYP2D6
22
Q
Poor metabolizer variants of CYP2D6:
A
- CYP2D6 variant alleles
- Autosomal gene
- >75 variants identified
- Frequency of poor metabolizer allele and phenotype:
- Mutant allele frequency about 30%
-
Poor metabolizer phenotype frequency:
- 2–10% of population
- (ethnic variation)
23
Q
Ultrafast CYP2D6 metabolizers
A
- CYP2D6 gene duplication (up to 13 copies) of the normal allele
- Incidence among different ethnic groups (varies from 1–30%)
- Clinical trials of nortriptyline clearance in patients show much more rapid drug clearance in those with multiple copies of functional CYP2D6
24
Q
Why are CYP2D6 polymorphisms important?
A
- CYP2D6 metabolizes about 25% of metabolized prescription drugs, including:
- β-blockers
- antiarrhythmics
- antidepressants
- neuroleptics
- some opiates
- others
25
Q
CYP2C19 polymorphism:
Poor metabolizer phenotype
A
- Population incidence: 3–20%
- homozygous poor
- primarily 2 variant alleles
26
Q
What classes of drugs do CYP2C19 affect?
A
-
anti-convulsants (e.g. mephenytoin, phenytoin):
- Increased drug levels and side effects
-
proton pump inhibitors (e.g. omeprazole, lansoprazole)
- higher drug levels, higher gastric pH, and better control of GERD
-
anti-platelet drugs (e.g. clopidogrel)
- clopidogrel is activated by CYP2C19
- those with even one slow allele have less active drug and >50% increase in M.I. and stroke
-
omeprazole decreases the activation of clopidogrel and increases the risk for:
- serious cardiovascular events, even in those with a normal genotype
- anti-depressants (e.g. amitriptyline)
- anti-cancer (e.g. cyclophosphamide)
- hormones (e.g. progesterone)
27
Q
CYP2C9 polymorphism:
Poor metabolizer phenotype
A
- 2 predominant variants (CYP2C9*2 and CYP2C9*3)
- alleles in up to 31% of patients
- Several substrates including some drugs with a narrow therapeutic window, e.g.
- phenytoin (anticonvulsant)
- tolbutamide (type 2 diabetes)
28
Q
CYP2C9 polymorphism:
Warfarin
A
- S-warfarin cleared almost entirely by CYP2C9
- *3 allele has a much larger impact on warfarin clearance and dosing than *2
-
*2 and *3 alleles:
- decrease warfarin clearance
- increase warfarin half-life
- increased risk of serious bleeding
- need lower maintenance doses
29
Q
Vitamin K Receptor (VKORC1) Polymorphism:
A
VKORC1:
- Subunit of the vitamin K epoxide reductase complex
- Warfarin, a vitamin K antagonist, inhibits the activity of this complex
- Haplotypes and clades predict successful warfarin dose
30
Q
Vitamin K Receptor (VKORC1) Polymorphism:
Haplotypes & Clades
A
10 common SNPs:
-
A clade:
- haplotypes H1 and H2 require lower warfarin doses
- associated with lower expression of VKORC1
-
B clade:
- haplotypes H7, H8, H9 require higher warfarin doses
- associated with higher expression of VKORC1
31
Q
How does VKORC1 gene expression correlate to dose?
A
- gene expression: B/B > B/A > A/A
- warfarin dose: B/B > B/A > A/A
32
Q
Pseudocholinesterase Polymorphism:
A
-
Variant response to succinylcholine
- depolarizing muscle relaxant
- Due to reduced activity variants of pseudocholinesterase
- butyrylcholinesterase in
plasma and liver
- butyrylcholinesterase in
- 30–90% decrease in cholinesterase activity
- 1–6% of population (ethnic variation)
- Rare silent variants
33
Q
How does TPMT Polymorphism present?
A
- Presents as increased risk for life-threatening bone marrow suppression in cancer patients treated with thiopurine drugs
- 6-mercaptopurine, 6-MP
34
Q
Describe the variants in TPMT polymorphism?
A
- Due to variants with decreased activity of thiopurine methyltransferase (TPMT)
- Low activity allele has 2 SNPs in the TPMT gene
-
TPMT allele frequency:
- 0.3% are homozygous for low activity allele
- 11% heterozygous
- DNA testing recommended by FDA
35
Q
TPMT genotype (alleles):
- normal/normal
- normal/slow
- slow/slow
A
Resulting phenotype:
- Normal risk of marrow suppression from 6-MP
- Elevated risk of marrow suppression from 6-MP
- High risk of marrow suppression from 6-MP
36
Q
P-glycoprotein (Pgp or MDR-1):
A
ATP-binding protein that effluxes drugs from the gastrointestinal mucosa
37
Q
What happens with a P-glycoprotein (Pgp) polymorphism?
A
- result in increased net uptake of the cardiac glycoside digoxin
- decreased levels of Pgp protein
- low expression alleles found in 16–57% of patients
- Pgp polymorphisms affect other drugs also
38
Q
Parameters that increase the clinical significance of genetic polymorphisms:
A
- When the drugs are used relatively frequently (on a population basis)
- The pathway affected by the polymorphism must be the predominant one
- If the parent drug and the metabolite are equally active, metabolic genetic polymorphisms will NOT likely alter efficacy/toxicity.
- Polymorphisms are more important for drugs with a **relatively narrow therapeutic **window
- Polymorphisms are more important when the drug’s side effects are potentially serious
39
Q
Describe’s codeine’s narrow therapeutic window:
A
-
CYP2D6 activates a portion of codeine to morphine
- Poor metabolizers will not get expected therapeutic benefit from codeine
- Tylenol #3 with codeine:
- codeine → morphine
-
CYP2D6 Poor metabolizer:
- CODEINE → morphine
- no benefit
-
CYP2D6 Ultrafast metabolizer:
- codeine → MORPHINE
- morphine side effects
