Receptor and other drug targets pharmacogenetics Flashcards
What are the main targets for drug action?
Receptors, Enzymes, Ion channels, Transporters
What is typically affected by polymorphisms related to receptors?
Function of receptor or level of expression
What is the basic structure of G-coupled protein receptors?
7 transmembrane proteins
Which region is important in coupling to G-proteins in G-coupled protein receptors?
Linker region between transmembrane domains 5 and 6
Is it usually possible to study phenotype in receptor gene polymorphisms like in CYP genes?
No, it’s not usually possible
What methods are used to discover polymorphisms in receptor genes?
Scanning of genes by sequencing or other appropriate methods
What are common approaches to study receptor polymorphisms?
- Coding sequence studies
- Upstream polymorphism studies
Which receptors are important drug targets related to adrenoreceptors?
Beta 1 and Beta 2 receptors
What is the product of the B2-adrenegic receptor gene?
ADRB2 gene
How many known polymorphisms are in the coding region of the B2-adrenegic receptor?
9 known polymorphisms
What is the first coding region polymorphism identified in the B2-adrenegic receptor?
Arg16Gly
What effect does the Arg16Gly polymorphism have on agonist binding?
Gly16 variant enhances down-regulation compared to Arg16
What is the effect of the Arg16 form of ADRB2 on short-acting beta agonists?
Associated with increased agonist induced down-regulation
Did studies show a difference in response to long-acting beta agonists based on codon 16 genotype?
No, studies failed to show any difference
What is the significance of the polymorphism at amino acid 16 in B2 adrenergic receptor?
It is the ligand binding site, outside the cell
What haplotypes are associated with B2 adrenergic receptor?
- Ca (Caucasian)
- A (African American)
- As (Asian)
- H-L (Hispanic-Latino)
What was the outcome of the study by Connie et al, 2000 regarding B2AR?
Identified 13 SNPs in a continuous region of B2AR
What are the main types of adrenoreceptors in the heart?
B1 receptors
What is the common polymorphism in the ADRB1 gene?
G389A
What is the frequency of the Gly and Arg variants in the ADRB1 gene?
- Glycine variant: 0.26
- Arginine variant: 0.74
What is the target enzyme for coumarin anticoagulants including warfarin?
Vitamin-K epoxide reductase (VKOR)
What is the gene that encodes VKOR?
VKORC1
What percentage of inter-individual variation in coumarin anticoagulant dose do VKORC1 and CYP2C9 account for?
Up to 40%
What are the two polymorphisms identified in VKORC1?
- G-1639A
- C1173T
What does the presence of the G-1639A polymorphism indicate about VKORC1 expression?
Lower VKORC1 expression
What is the common cause of warfarin resistance?
Mutations in the coding region of VKORC1
What is the role of HMG-CoA reductase?
Converts HMG-CoA into mevalonic acid, the rate limiting step for cholesterol biosynthesis
What is the effect of polymorphisms in the HMGCR gene?
Associated with decreased response to statin treatment
What defect is present in cystic fibrosis patients?
Defect in the CFTR gene which codes for an ion channel
What drug targets the G551D gating defect in cystic fibrosis?
Ivacaftor
What was the improvement in lung function after 48 weeks of Ivacaftor treatment?
Improved by 11%
What percentage of cases is D involved in?
Approx. 5% of cases only
What is the gating defect in the context of D?
The channel no longer responds to the ligand
What drug targets the G551D gating defect?
Ivacaftor
What effect does Ivacaftor have on sweat chloride levels after 48 weeks?
Significantly reduced
By what percentage did lung function (FEV1.0) improve after Ivacaftor treatment?
11%
What is the percentage decrease in pulmonary exacerbations observed with Ivacaftor?
55% decrease
What is the cost of Ivacaftor per patient per year?
£150,000
For which patients is Ivacaftor approved by the EMA?
Patients over 6 years old with G551D or R117H allele
What did a patient quote about the effectiveness of Ivacaftor?
‘It’s like someone else’s lungs are inside of me’
What is the target mutation of the drug Orkambi?
Common F508del mutation
What two components make up Orkambi?
Ivacaftor plus lumacaftor
What does lumacaftor help with in Orkambi?
Movement of CFTR to plasma membrane
What is the newest drug that targets F508del more efficiently than Orkambi?
Symkevi
What components does Symkevi consist of?
Ivacaftor, tezacaftor, and elexacaftor
