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
CYP2C19 polymorphism:
**Poor metabolizer phenotype**
* Population incidence: **3–20%**
* homozygous poor
* primarily **2 variant alleles**
26
What classes of drugs do CYP2C19 affect?
* **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
CYP2C9 polymorphism:
**Poor metabolizer phenotype**
* 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
CYP2C9 polymorphism:
Warfarin
* 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
Vitamin K Receptor (VKORC1) Polymorphism:
**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
Vitamin K Receptor (VKORC1) Polymorphism:
**Haplotypes & Clades**
**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
How does VKORC1 gene expression correlate to dose?
* **gene expression:** B/B \> B/A \> A/A
* **warfarin dose:** B/B \> B/A \> A/A
32
Pseudocholinesterase Polymorphism:
* **Variant response to succinylcholine**
* depolarizing muscle relaxant
* Due to **reduced activity variants of pseudocholinesterase**
* butyrylcholinesterase in
plasma and liver
* **30–90%** decrease in cholinesterase activity
* 1–6% of population (ethnic variation)
* Rare silent variants
33
How does TPMT Polymorphism present?
* Presents as **increased risk for life-threatening bone marrow suppression** in cancer patients treated with **thiopurine drugs**
* **6-mercaptopurine, 6-MP**
34
Describe the variants in TPMT polymorphism?
* 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
**_TPMT genotype (alleles):_**
1. normal/normal
2. normal/slow
3. slow/slow
**_Resulting phenotype:_**
1. **Normal risk** of marrow suppression from 6-MP
2. **Elevated risk** of marrow suppression from 6-MP
3. **High risk** of marrow suppression from 6-MP
36
**P-glycoprotein (Pgp or MDR-1):**
ATP-binding protein that **effluxes drugs from the gastrointestinal mucosa**
37
What happens with a **P-glycoprotein (Pgp)** polymorphism?
* 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
Parameters that increase the clinical significance of genetic polymorphisms:
1. When the drugs are **used relatively frequently** (on a population basis)
2. The **pathway affected** by the polymorphism must be the **predominant** one
3. If the parent drug and the metabolite are equally active, metabolic genetic polymorphisms will NOT likely alter efficacy/toxicity.
4. Polymorphisms are more important for drugs with a **relatively narrow therapeutic ****window**
5. Polymorphisms are more important when the drug’s **side effects are potentially serious**
39
Describe's codeine's narrow therapeutic window:
* **CYP2D6 activates a portion of codeine to morphine**
* Poor metabolizers will not get expected therapeutic benefit from codeine
* Tylenol #3 with codeine:
* codeine → morphine
1. **CYP2D6 Poor metabolizer:**
* CODEINE → morphine
* no benefit
2. **CYP2D6 Ultrafast metabolizer:**
* codeine → MORPHINE
* morphine side effects
PDA Block 1
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