drug genetics

Question 1

pharmacogenetics definition

Answer 1

genetically controlled variations in drug response

genetic factors that alter an individual’s drug response to a drug (genetic polymorphisms, less common genetic variants)

Question 2

genetic differences can significantly alter

Answer 2

• dose response relationships (positively or negatively)
• drug clearance and pharmacokinetics
• susceptibility to toxic effects
• adverse drug reaction (idiosyncratic)

differences are not apparent until they are exposed to a particular drug

Question 3

Genotype vs phenotypw

Answer 3

an individuals composition at the gene level, the specific genes they have

Phenotype: an individuals expression of their genotype, the observable physical or biochemical characteristics

Question 4

genetic polymorphism

Answer 4

mendelian trait that exists in the population in at least 2 phenotypes neither of which is rare

Question 5

single nucleotide polymorphism

Answer 5

SNP- a change in 1 single base pair in DNA sequence that differs from the wild type or predominant sequence

may/not result in altered phenotype

Question 6

haplotype

Answer 6

refers to closely linked genetic markers (or SNPs) present on one chromosome which tend to be inherited together often within a gene or closely linked genes
a way of grouping people according to the pattern of SNPs they have, the combo of these snps dictates the phenotype

could be a single gene or could be distant genes or chromosomes (not a haplotype)

Question 7

types of inheritance

Answer 7

autosomal codominance: each allele contributes to phenotype

Autosomal recessive: wild type allele has predominant effect, it takes 2 recessive alleles to see the recessive effect

autosomal dominant: a single allele predominates over alleles

X-linked inheritance- genes are inherited on X chromosome all males will express these traits

Question 8

mendelian inheritance

Answer 8

homozygous and heterozygous alleles

Question 9

NAT-2 polymorphism

Answer 9

increased neurologic side effects with isoniazid
N-acetyltransferase-2 detoxifies isoniazid
autosomal recessive trait (slow)
the dominant is fast

can use caffeine metabolism

50% are heterozygous

Question 10

CYP2D6 polymorphism

Answer 10

deprisoquine effect, escessive hypotension, poor metabolizer, activates codeine to morphine

Genotypic frequency ~ 30%, heterozygotes within low normal range

Poor metabolizer phenotype frequency (2 copies, overall 2-10% of patients)

gene duplication of normal allele= ultrafast metabolizers1-30% of patients

B blockers, antiarrhythmics, neuroleptics, antidepressents- specifically tricyclic antidepressents

poor metabolizers: increased side effects
ultrafast metabolizers: degrade too quickly no benefit

Question 11

CYP2C19 polymorphism

Answer 11

3-20% population are homozygous poor metabolizers

Proton pump inhibitors (omeprazole)
Anticonvulsants (phenytoin)
Anti platelet (clopidogrel)

poor metabolizers have higher drug levels which correlate with increased gastric pH and higher cure rates for GERD

Clopidogrel inhibits platelet aggregation, and is activated by CYP2C19, those with even one slow allele can have a 53% increase in seerious CV outcomes (MI stroke)

omeprazole + clopidogrel are both CYP2C19 substrates- competitive inhibition- dont give together

Question 12

CYP2C9

Answer 12

poor metabolizer phenotype (*2 and *3 are the low activity alleles)
*1 is wildtype

occur in 31% of pts

Warfarin- risk of bleeding/hemorrhage

When blood levels are too high causes serious bleeding events, when blood levels are too low causes intravascular clotting including stroke

S-warfarin is cleared almost exclusively by CYP2CP, polymorphism reduce warfarin clearance, increase warfarin half-life, require lower maintanence dose, increased risk of adverse outcomes–(increased anticoagulation/bleeding)

NO ULTRAFAST

Question 13

vitamin K receptor (VKORC1)

Answer 13

key protein needed to modify some clotting factors to mature forms

Warfarin, a vitK antagonist, inhibits the activity of this complex

CYP2C9

HAPLOTYPES:
H1 and H2: low dose, Clade A
H7-9: high dose, Clade B

A clade common in Asians, B in Africans

Question 14

pseudocholinesterase polymorphism

Answer 14

variant response to succinylcholine

Surgical skeletal muscle relaxant whose effect should stop after 5 minutes, atypical pts experience apnea and paralyis for 2-3 hours

30-90% decrease in cholinesterase activity, multiple genetic variants each with different levels of decreased activity

present in 1-6% of population

Question 15

TPMT polymorphism

Answer 15

increased risk for life threatening bone marrow suppression in cancer pts treated with mercaptopurine

variants have a decreased activity of thiopurine methyltransferase (TPMT)

.3% of population has the 2 alleles SNPS

Question 16

Genotype vs phenotype for TPMT

Answer 16

normal/normal: normal risk of marrow suppression from 6-MP
normal/slow: increased risk of marrow suppression from 6-MP
slow/slow: high risk of marrow suppression from 6MP

Question 17

SCO1B1 OATp1B1

Answer 17

role in the liver
an organic anion transporter
important for the uptake of some hydrophilic drugs and endogenous compounds into the liver

statins are used to decrease cholesterol, skeletal muscle toxicity is a side effect, with SCO1B1 low activity variants get elevated blood levels of statin, specifically simvastatin

elevated levels of simvastatin= increased risk of myopathy

low expression in the C allele in 8-28 % of patients

autosomal codominance

other drugs that interact with OAT1B1 have the potential to affect statin levels and make things worse for low activity pts

Question 18

polymorphisms and therapeutic windows

Answer 18

polymorphisms have greater significance for drugs with a relatively narrow therapeutic window