Lecture 4 - Drug Individualization Flashcards
what is a gene
segment of dna that contains information for encoding a protein
what are SNPs
single nucleotide polymorphism
eg rs10516526
what is allele
different DNA sequence at a locus
eg rs10516526 G
what is a genotype
pair of alleles at particular locus
eg rs10516526 GG, GA or AA
what is a phenotype
the observable property of an organism; a trait such as height, weight, medical codition etc
what is haplotype
a set of dna variations, or polymorphisms, that tend to be inherited together
all genotype in a chromosome
what is variability (Sir william osler)
the law of life, and as no two faces are the same, so no two bodies are alike, and no two individuals react alike and behave alike under the abnormal conditions which we know as disease
what is diversity
factors that make individuals or subgroups of a population different from the rest
describe possible different respones of same drug
drug toxic bit beneficial
drug toxic but not beneficial
drug not toxic and not beneficial
drug not toxic and beneficial
factors of environment that can affect patient drug response
-diet (drug-food interaction)
-lifestyle (“don’t do this”, eat with or without food, keep med cold or a certain temp)
-socioeconomics
-others
factors of biology that can affect patient drug response
age, sex, others
genetic factors that can affect patient drug response
we don’t know these factors unless we ASK the patient
dosage statistics
means and medians derived from clinical trial
- relatively homogenous populations
- caucasian, adult, no co morbidities, middle of the curve
(this is why it is not always right for the whole population)
pharmacological outcomes based on statistics
derived from clinical trials
altered if post marketing surveillance data indicate a need
what to remember about the results on pharmacological statistics
remember: many patients recieve inappropriate drugs or dosage of drugs because they are not “middle of the curve”
what is pharmacogenomics
the study of how genes affect a persons response to drugs
what are the goals of pharmacogenomics
getting the right dose of the right drug to the right patient at the right time
enhances drug efficacy and reduces drug toxicity
identify the genetic variations and what can be affected
enzyme, transporter, receptor, disease
silent:no functional effect
( can have changes in the gene but nothing actually shows)
how does genetic variation of a drug relate to population
some drugs are more effective in a certain group
(some drugs can be racially exclusive)
how are genetic variations relavent to a drug
-affect PK or PD
-resulted in drug efficacy, toxicity, or drug dosing
- has no effect
how are genetic variations relevant to a disease
- increase or decrease drug susceptibility or condition
-utility as a screening or diagnostic tool
how are PGX and metabolism classified
phase I and phase II reactions
modifications and examples of of phase I reaction
types of modifications:
- oxidation
- hydroxylation
- reduction
- hydrolysis
Examples:
- P450 CYPs
modifications and examples of phase II reaction
modifications: conjugation
examples
- UGT: glucuronidation (adding glucaronic acid to large molecule to increase- easily soluble in blood water)
- NAT: acetylation (reduces polarity)
- MT: methylation (inactivated process)
- GST: gluthione conjugation
SULT: sulphation
types of genetic variations and enzymatic activity ( phenotypes)
extensive metabolizers, poor metabolizer, intermediate metabolizer, ultra rapid metabolizer
what is an extensive metabolizer
(EM or WT)
- individuals who are homozygous for the two alleles coding for “normal” enzyme function
(“normal” is middle of everyone)
what is a poor metabolizer
PM
- individuals who are homozygous with two variant alleles resting in inactive or absent enzymes
(cant metabolize- reduced or none)
*has certain enzymes
what is an intermediate metabolizer
IM
those who are heterozygous manifest phenotype with reduced function of the heterozygous EM
(low but not too low)
single gene copy of metabolic enzyme CYP2D6 in an individual will lead to what phenotypes
unstable enzyme formation and decreased metabolism of the parents drug
normal metabolism of the parent drug
altered metabolism and this formation of other metabolites
what is an ultra rapid metabolizer
UM
- resulted from gene duplication or multiplication
Facts about PGx of metabolizing enzymes
*1 is normal- functioning enzyme, person able to metabolize well
*2, 3+ is not normal and requires to be looked into
if a person has a gene deletion, they have no mRNA to make a specific enzyme and therefore will not have the enzyme to break down specific drug so… you wont give the person that drug because if with the gene for it they don’t have the enzyme to metabolize it
( if a person has *2N you need to determine if its n=toxic or not- they have two copies of the same gene meaning ultra metabolism so you may want to decrease the dose or not use a drug
what does a gene deletion do to metabolism
creates no mRNA so no specific enzyme is produced leading to inability to metabolize
what can a single gene copy lead to
could have mRNA that doesn’t code for a protein- leading to no metabolism
could have a unstable enzyme made by mRNA- leading to decreased metabolism of parent drug
could have- normal enzyme made leading to normal metabolism of parent drug
could have altered substrate specificity leading to other metabolites
what does ABC stand for
ATP binding cascade
ABC-> MDRI gene pathway
(more common- and you want to know this before prescribing a drug)
ABC—–> ABCB——> MDR1——> reduced expression——–>higher drug plasma level (eg digoxin) ——-> C1236T, C3435T, G2677T/A
( so with digoxin, the levels in the plasma rise to more than what you think you are prescribing)
what does MDR1 mean, what is the meaning if you are positive
Multidrug Resistance 1
it is drug sensitivity as a result of a genetic variant that can cause severe or life threatening complications after taking particular medication and specific doses
Lesson from tamoxifen patient case (efficacy)
(example in breast tissue)
- it is metabolized before it can act
- enzyme TAM can act then CYP2D6 enzyme acts (hydrolyzes) and turn it into its active form of endoxifen ( or CY first then different enzyme works to demethylate)
- drug must be demethylated (by other enzymes working behind CYP2D6), and hydrolyzed (CYP2D6) before it is in its active form
-CYP2D6- common to be mutated in people (CYP2C9 is the mutation)
ER antagonist and Breast Cancer Efficacy
overall recurrence rate
- EM: 14.9%
-IM 20.9%
***- PM 29%
All cause mortality rates
-EM:14.9%
-IM: 18%
***- PM: 22.8%
alternative treatments for breast cancer
aromatase inhibitors
- blocks aromatase enzyme (converts androgen into estrogen)
- anastrazole
- letrozole
Warfarin case of efficacy and toxicity
initial dose:
- initial dose (2-10mg) based on medical need and factors that will alter the PK or PD of warfarin like OTC products, green leafy, cranberry juice, etc (must check with patient)
maintenance dose:
adjust the maintenance dose by X% up or down based on INR (internationalized normalized ratio- how fast it takes blood to clot based on blood test): caution about factors that will alter the PK and PD of warfarin, OTC products, green leafy, cranberry juice, etc
Warfarin and genetic variations
S-warfarin is more potent than R- warfarin (more active in stopping coagulation)
VKOR enzyme is a vitamin K opoxide reductase that reduced vitamin K is needed to start the pathway (factors that work together for blood clotting) and then will stay in the bod as the active form
activation = coagulation
–>warfarin blocks the VKOR enzyme from activating these factors that cause coagulation
what is AA
more sensitive- should recieve lower dose
what is G/G
least active, least sensitive, needs more dose
what is P2C9
poor metabolizer
Ranges of expected maintenance of coumadin based on CYP2C9 and VKORC1 genotypes
( so these are the pathways that activate warfarin then block the pathway enzyme that causes coagulation)
GG allele- needs 5-7mg if 1/1 or 1/2
but if patient is 2/3 they can only handle 3-4 mg
or 3/3 ( worst) then they can only handle .5-2 mg so if they are given the “normal” dose they will have excessive bleeding which is not what we want
Irinotecan genetic variant and effect
(example of PGX application)
Medication = Irinotecan
Genetic variant/marker = UGT1A1*28
Effect = Neutropenia
Codeine (prodrug) genetic variant and effect
(example of PGX application)
Medication= Codeine (prodrug)
Genetic Variant/Marker = CYP2D6
Effect =
PM- no analgesic effect
UM- respiratory depression
the genetic marker demethylates and removes hydroxylate making it into morphine essentially
difference between codeine (prodrug) and morphine
codeine is prodrug of morhpine-
codeine ha a hydroxyl group on aromatic ring
morphine has a hydroxyl by itself
clopidogrel (prodrug) variant and effect
Medication= clopidogrel (prodrug)
Genetic variant/ marker = CYP2C19 (low C19 means no activation so no drug activity)
Effect= PM- no drug activity
What does transcription?
Process by which information from DNA strand, is coupled into a new mRNA molecule
what is translation?
Process by which a cell makes proteins, using the genetic information carried in mRNA
