Pharmacogenomics

Question 1

factors that influence drug response phenotype

Answer 1

age, gender, disease, genetic variation

Question 2

study of the role of inheritance in variation in drug response

Answer 2

pharmacogenomics

Question 3

why is pharmacogenomics important

Answer 3

adverse drug reactions are major cause of morbidity and mortality

Question 4

average interindividual difference in terms of base pairs

Answer 4

3 million bp

Question 5

used to optimize drug efficacy and reduce adverse effects

Answer 5

knowledge of patient’s DNA sequence

Question 6

three types of genetic variation that can influence pharmacotherapy

Answer 6

pharmacokinetic variation (variations in proteins involved in drug metabolism or transport)

pharmacodynamic variation (variation in drug target)

variation in proteins associated with idiosyncratic adverse drug effects.

Question 7

most common factor responsible for pharmacogenetic variation in drug responses

Answer 7

genetic variation in enzymes that catalyze drug metabolism

Question 8

do major enzymes in drug metabolism show polymorphism

Answer 8

yeah

Question 9

drugs used during surgery to cause skeletal muscle paralysis

Answer 9

neuromuscular blockers such as succinylcholine

Question 10

4 main enzymes that exhibit polymorphism

Answer 10

• Butyrylcholinesterase (Pseudocholinesterase) (BChE)
• N-acetyltransferase 2 (NAT2)
• Cytochrome P450 2D6 (CYP2D6)
• Thiopurine S-methyltransferase (TPMT)

Question 11

why is the duration of succinylcholine (neuromuscular blockade) so short between 5-10 mins

Answer 11

rapid hydrolysis by plasma butyrylcholinesterase

Question 12

onset of neuromuscular blockade

Answer 12

quickly ~1 min

Question 13

what happens with patients who have a genetic variation in butyrylcholinesterase

Answer 13

decreased metabolism of succinylcholine leading to prolonged muscular paralysis

Question 14

inheritance pattern of butyrylcholineterase

Answer 14

autosomal recessive

Question 15

good at inhibiting normal butyrylcholinesterase (bad at inhibiting its polymorphic variation)

Answer 15

dibucaine

Question 16

catalyzes the acetylation of isoniazid and other drugs (include sulfonamide, hydralazine, procainamide)

Answer 16

N-acetyltransferase 2 (NAT2)

Question 17

what are slow and fast acetylators (of NAT2)

Answer 17

slow acetylators - catalyze isoniazid slowly and have high blood drug levels

fast acetylators - catalyze isoniazid rapidly and have low blood drug levels

Question 18

inheritance pattern of NAT2 polymorphism

Answer 18

autosomal recessve

Question 19

slow acetylators (of NAT2) are more prone to what

Answer 19

toxic effects of drugs that are metabolized by acetylation

Question 20

isoniazid can cause what?

Answer 20

neuropathy and hepatotoxicity

Question 21

Hydralazine and procainamide may cause what

Answer 21

systemic lupus erythematosus

Question 22

Sulfonamides may cause what

Answer 22

hypersensitivity reactions, hemolytic anemia, and systemic lupus erythematosus

Question 23

CYP2D6 is a member of what family

Answer 23

CYP450

Question 24

CYP2D6 metabolizes what types of drugs

Answer 24

antidepressants, antiarrhythmics, and analgesics.

Question 25

two important drugs used to talk about CYP2D6

Answer 25

antihypertensive debrisoquine and the oxytotic agent sparteine

Question 26

extensive metabolizes of CYP2D6 have what genotype

Answer 26

heterozygous or homozygous for the wild type allele

Question 27

main reason people can be ultra rapid metabolizers by CYP2D6

Answer 27

they have multiple copies of the CYP2D6 gene up to 13

Question 28

why is codeine ineffective in poor metabolizers by CYP2D6

Answer 28

it requires CYP2D6 catalyzed conversion to morphine

Question 29

when do people suffer adverse effects to metoprolol

Answer 29

if they are poor metabolizers of CYP2D6

Question 30

way to overcome ultra rapid metabolizers of codeine by CYP2D6 and its disadvantage

Answer 30

you can overcome by giving higher doses but can overdose on codeine (respiratory depression or arrest)

Question 31

Thiopurine S methyltransferase (TPMT) catalyzes what reaction

Answer 31

S-methylation of the anticancer thiopurines, 6-mercaptopurine and azathioprine

Question 32

problem with TPMT polymorphism

Answer 32

thiopurines have short therapeutic window so if not quickly methylated, it can be life threatening and lead to myelosuppression

Question 33

patients with low TPMT levels have to treated with what percentage of standard dose

Answer 33

10%

Question 34

oral anticoagulant

Answer 34

warfarin

Question 35

does warfarin have a big therapeutic window

Answer 35

nah

Question 36

under anti-coagulation and over anti-coagulation can result it

Answer 36

under - thrombosis | over - bleeding episodes

Question 37

there is an S-warfarin and and R-warfarin meaning that warfarin is?

Answer 37

a racemic mixture

Question 38

which form of warfarin is more potent

Answer 38

S-warfarin by 3-5 times

Question 39

which one of the racemic mixture of warfarin metabolizes more warfarin

Answer 39

R-warfarin

Question 40

patients with CYP2C9 have variant alleles that have lower activity hence requiring ______ dose of warfarin to achieve therapeutic effect and have increased risk for _______ during warfarin therapy

Answer 40

decreased, hemmorhage

Question 41

multiple gene that affect both pharmacokinetics and pharmacodynamics of a drug

Answer 41

warfarin

Question 42

molecular target for warfarin

Answer 42

Vitamin K epoxide reductase (inhibits its)

Question 43

what does Vitamin K epoxide reductase do?

Answer 43

reduces Vitamin K and brings it back to its active form: | Vitamin K epoxide --> reduced Vitamin K

Question 44

what does reduced Vitamin K do?

Answer 44

provides carboxyl group for clotting factor precursor, glutamic acid, (using gamma glutamyl carboxylase) to become clotting factor, carboxy glutamic acid

Question 45

gene that encodes vitamin k epoxide reductase

Answer 45

vitamin k epoxide reductase complex 1 (VKORC1) <---has polymorphism

Question 46

interindividual variability is huge which what drug

Answer 46

warfarin

Question 47

difference between using R-warfarin and S-warfarin on vitamin K epoxide reductase

Answer 47

S-warfarin - uses CYP2C9 and makes 6-hydroxywarfarin and 7-hydroxywarfarin R-warfarin - make metabolites using CYP1A1, CYP1A2, CYP3A4

Question 48

what causes idiosyncratic (pertaining to an individual) drug effects?

Answer 48

interaction between drug and unique aspect of physiology pertaining to the particular individual

Question 49

example of idiosyncratic drug effect

Answer 49

glucose 6 phosphate dehydrogenase deficiency (G6PD deficiency), malignant hyperthermia

Question 50

what does G6PD do

Answer 50

prevents red blood cells from oxidative damage

Question 51

what happens when G6PD deficiency

Answer 51

electrons not provided to NADP+ to form NADPH hence reduction in glutathione pool to reduce peroxide to water

Question 52

drugs that cause oxidative stress

Answer 52

sulfonamides, antimalarials, chloramphenicol

Question 53

what happens when exposed to sulfonamides, antimalarials, and chloramphenicol and person has G6PD deficiency

Answer 53

hemolytic anemia (also be caused by fava beans)

Question 54

inheritance of malignant hyperthermia

Answer 54

autosomal dominant

Question 55

malignant hyperthermia is the main cause of death due to?

Answer 55

anesthesia

Question 56

symptoms of malignant hyperthermia

Answer 56

tachycardia, hypertension, severe muscle rigidity, hyperthermia, hyperkalemia, acidosis, death

Question 57

malignant hyperthermia is caused by a defect in ____________ resulting in ________

Answer 57

ryanodine receptor gene (RYR1), altered control of calcium release from SR

Question 58

ryanodine receptors are located between what?

Answer 58

SR and DHPR protein (senses voltage in plasma protein)

Question 59

what happens when abnormal RYR1 receptor

Answer 59

unregulated release of calcium --> acute hyperthermia crisis

Question 60

used to establish susceptibility to malignant hypethermia

Answer 60

caffeine halothane muscle contracture test

Question 61

results of increased calcium intracellularly

Answer 61

* the increased Ca2+ concentration causes sustained muscle contraction which generates heat * accelerated levels of aerobic metabolism produce CO2 and deplete O2 and ATP * a switch to anaerobic metabolism worsens acidosis with the production of lactate * energy stores get depleted * muscle fibers die leading to hyperkalemia and myoglobinuria.

Question 62

how does the caffeine halothane muscle contracture test work

Answer 62

- piece of muscle taken from thigh and several strips of muscle prepared - strip placed in a physiological bath and it is attached to an electrical stimulator that produces a twitch every ten seconds then strength of contraction is measured - halothane is added and normal muscle would not move from its baseline by more than 0.5g

Question 63

used to figure out genotype for CYP2D6

Answer 63

- from phenotype - urinary excretion of metabolite of drug - DNA based tests - AmpliChip CYP450 Test (uses microarrays - also determines CYP2C19 genotype)