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Pharm S1 > Lecture 4 - Drug Individualization > Flashcards

Lecture 4 - Drug Individualization Flashcards

1
Q

what is a gene

A

segment of dna that contains information for encoding a protein

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2
Q

what are SNPs

A

single nucleotide polymorphism

eg rs10516526

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3
Q

what is allele

A

different DNA sequence at a locus

eg rs10516526 G

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4
Q

what is a genotype

A

pair of alleles at particular locus

eg rs10516526 GG, GA or AA

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5
Q

what is a phenotype

A

the observable property of an organism; a trait such as height, weight, medical codition etc

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6
Q

what is haplotype

A

a set of dna variations, or polymorphisms, that tend to be inherited together

all genotype in a chromosome

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7
Q

what is variability (Sir william osler)

A

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

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8
Q

what is diversity

A

factors that make individuals or subgroups of a population different from the rest

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9
Q

describe possible different respones of same drug

A

drug toxic bit beneficial
drug toxic but not beneficial
drug not toxic and not beneficial
drug not toxic and beneficial

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10
Q

factors of environment that can affect patient drug response

A

-diet (drug-food interaction)
-lifestyle (“don’t do this”, eat with or without food, keep med cold or a certain temp)
-socioeconomics
-others

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11
Q

factors of biology that can affect patient drug response

A

age, sex, others

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12
Q

genetic factors that can affect patient drug response

A

we don’t know these factors unless we ASK the patient

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13
Q

dosage statistics

A

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)

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14
Q

pharmacological outcomes based on statistics

A

derived from clinical trials
altered if post marketing surveillance data indicate a need

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15
Q

what to remember about the results on pharmacological statistics

A

remember: many patients recieve inappropriate drugs or dosage of drugs because they are not “middle of the curve”

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16
Q

what is pharmacogenomics

A

the study of how genes affect a persons response to drugs

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17
Q

what are the goals of pharmacogenomics

A

getting the right dose of the right drug to the right patient at the right time

enhances drug efficacy and reduces drug toxicity

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18
Q

identify the genetic variations and what can be affected

A

enzyme, transporter, receptor, disease

silent:no functional effect
( can have changes in the gene but nothing actually shows)

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19
Q

how does genetic variation of a drug relate to population

A

some drugs are more effective in a certain group
(some drugs can be racially exclusive)

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20
Q

how are genetic variations relavent to a drug

A

-affect PK or PD
-resulted in drug efficacy, toxicity, or drug dosing
- has no effect

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21
Q

how are genetic variations relevant to a disease

A
  • increase or decrease drug susceptibility or condition
    -utility as a screening or diagnostic tool
22
Q

how are PGX and metabolism classified

A

phase I and phase II reactions

23
Q

modifications and examples of of phase I reaction

A

types of modifications:
- oxidation
- hydroxylation
- reduction
- hydrolysis

Examples:
- P450 CYPs

24
Q

modifications and examples of phase II reaction

A

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

25
Q

types of genetic variations and enzymatic activity ( phenotypes)

A

extensive metabolizers, poor metabolizer, intermediate metabolizer, ultra rapid metabolizer

26
Q

what is an extensive metabolizer

A

(EM or WT)
- individuals who are homozygous for the two alleles coding for “normal” enzyme function
(“normal” is middle of everyone)

27
Q

what is a poor metabolizer

A

PM
- individuals who are homozygous with two variant alleles resting in inactive or absent enzymes

(cant metabolize- reduced or none)
*has certain enzymes

28
Q

what is an intermediate metabolizer

A

IM
those who are heterozygous manifest phenotype with reduced function of the heterozygous EM
(low but not too low)

29
Q

single gene copy of metabolic enzyme CYP2D6 in an individual will lead to what phenotypes

A

unstable enzyme formation and decreased metabolism of the parents drug

normal metabolism of the parent drug

altered metabolism and this formation of other metabolites

30
Q

what is an ultra rapid metabolizer

A

UM
- resulted from gene duplication or multiplication

31
Q

Facts about PGx of metabolizing enzymes

A

*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

32
Q

what does a gene deletion do to metabolism

A

creates no mRNA so no specific enzyme is produced leading to inability to metabolize

33
Q

what can a single gene copy lead to

A

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

34
Q

what does ABC stand for

A

ATP binding cascade

35
Q

ABC-> MDRI gene pathway

A

(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)

36
Q

what does MDR1 mean, what is the meaning if you are positive

A

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

37
Q

Lesson from tamoxifen patient case (efficacy)

A

(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)

38
Q

ER antagonist and Breast Cancer Efficacy

A

overall recurrence rate
- EM: 14.9%
-IM 20.9%
***- PM 29%

All cause mortality rates
-EM:14.9%
-IM: 18%
***- PM: 22.8%

39
Q

alternative treatments for breast cancer

A

aromatase inhibitors
- blocks aromatase enzyme (converts androgen into estrogen)
- anastrazole
- letrozole

40
Q

Warfarin case of efficacy and toxicity

A

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

41
Q

Warfarin and genetic variations

A

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

42
Q

what is AA

A

more sensitive- should recieve lower dose

43
Q

what is G/G

A

least active, least sensitive, needs more dose

44
Q

what is P2C9

A

poor metabolizer

45
Q

Ranges of expected maintenance of coumadin based on CYP2C9 and VKORC1 genotypes

A

( 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

46
Q

Irinotecan genetic variant and effect

A

(example of PGX application)

Medication = Irinotecan
Genetic variant/marker = UGT1A1*28
Effect = Neutropenia

47
Q

Codeine (prodrug) genetic variant and effect

A

(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

48
Q

difference between codeine (prodrug) and morphine

A

codeine is prodrug of morhpine-

codeine ha a hydroxyl group on aromatic ring
morphine has a hydroxyl by itself

49
Q

clopidogrel (prodrug) variant and effect

A

Medication= clopidogrel (prodrug)
Genetic variant/ marker = CYP2C19 (low C19 means no activation so no drug activity)
Effect= PM- no drug activity

50
Q

What does transcription?

A

Process by which information from DNA strand, is coupled into a new mRNA molecule

51
Q

what is translation?

A

Process by which a cell makes proteins, using the genetic information carried in mRNA

Pharm S1 (18 decks)

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