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Genetics > Pharmacogenomics > Flashcards

Pharmacogenomics Flashcards

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1
Q

factors that influence drug response phenotype

A

age, gender, disease, genetic variation

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2
Q

study of the role of inheritance in variation in drug response

A

pharmacogenomics

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3
Q

why is pharmacogenomics important

A

adverse drug reactions are major cause of morbidity and mortality

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4
Q

average interindividual difference in terms of base pairs

A

3 million bp

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5
Q

used to optimize drug efficacy and reduce adverse effects

A

knowledge of patient’s DNA sequence

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6
Q

three types of genetic variation that can influence pharmacotherapy

A

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.

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7
Q

most common factor responsible for pharmacogenetic variation in drug responses

A

genetic variation in enzymes that catalyze drug metabolism

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8
Q

do major enzymes in drug metabolism show polymorphism

A

yeah

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9
Q

drugs used during surgery to cause skeletal muscle paralysis

A

neuromuscular blockers such as succinylcholine

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10
Q

4 main enzymes that exhibit polymorphism

A
  • Butyrylcholinesterase (Pseudocholinesterase) (BChE)
  • N-acetyltransferase 2 (NAT2)
  • Cytochrome P450 2D6 (CYP2D6)
  • Thiopurine S-methyltransferase (TPMT)
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11
Q

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

A

rapid hydrolysis by plasma butyrylcholinesterase

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12
Q

onset of neuromuscular blockade

A

quickly ~1 min

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13
Q

what happens with patients who have a genetic variation in butyrylcholinesterase

A

decreased metabolism of succinylcholine leading to prolonged muscular paralysis

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14
Q

inheritance pattern of butyrylcholineterase

A

autosomal recessive

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15
Q

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

A

dibucaine

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16
Q

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

A

N-acetyltransferase 2 (NAT2)

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17
Q

what are slow and fast acetylators (of NAT2)

A

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

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

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18
Q

inheritance pattern of NAT2 polymorphism

A

autosomal recessve

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19
Q

slow acetylators (of NAT2) are more prone to what

A

toxic effects of drugs that are metabolized by acetylation

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20
Q

isoniazid can cause what?

A

neuropathy and hepatotoxicity

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21
Q

Hydralazine and procainamide may cause what

A

systemic lupus erythematosus

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22
Q

Sulfonamides may cause what

A

hypersensitivity reactions, hemolytic anemia, and systemic lupus erythematosus

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23
Q

CYP2D6 is a member of what family

A

CYP450

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24
Q

CYP2D6 metabolizes what types of drugs

A

antidepressants, antiarrhythmics, and analgesics.

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25
Q

two important drugs used to talk about CYP2D6

A

antihypertensive debrisoquine and the oxytotic agent sparteine

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26
Q

extensive metabolizes of CYP2D6 have what genotype

A

heterozygous or homozygous for the wild type allele

27
Q

main reason people can be ultra rapid metabolizers by CYP2D6

A

they have multiple copies of the CYP2D6 gene up to 13

28
Q

why is codeine ineffective in poor metabolizers by CYP2D6

A

it requires CYP2D6 catalyzed conversion to morphine

29
Q

when do people suffer adverse effects to metoprolol

A

if they are poor metabolizers of CYP2D6

30
Q

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

A

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

31
Q

Thiopurine S methyltransferase (TPMT) catalyzes what reaction

A

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

32
Q

problem with TPMT polymorphism

A

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

33
Q

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

A

10%

34
Q

oral anticoagulant

A

warfarin

35
Q

does warfarin have a big therapeutic window

A

nah

36
Q

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

A

under - thrombosis

over - bleeding episodes

37
Q

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

A

a racemic mixture

38
Q

which form of warfarin is more potent

A

S-warfarin by 3-5 times

39
Q

which one of the racemic mixture of warfarin metabolizes more warfarin

A

R-warfarin

40
Q

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

A

decreased, hemmorhage

41
Q

multiple gene that affect both pharmacokinetics and pharmacodynamics of a drug

A

warfarin

42
Q

molecular target for warfarin

A

Vitamin K epoxide reductase (inhibits its)

43
Q

what does Vitamin K epoxide reductase do?

A

reduces Vitamin K and brings it back to its active form:

Vitamin K epoxide –> reduced Vitamin K

44
Q

what does reduced Vitamin K do?

A

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

45
Q

gene that encodes vitamin k epoxide reductase

A

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

46
Q

interindividual variability is huge which what drug

A

warfarin

47
Q

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

A

S-warfarin - uses CYP2C9 and makes 6-hydroxywarfarin and 7-hydroxywarfarin

R-warfarin - make metabolites using CYP1A1, CYP1A2, CYP3A4

48
Q

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

A

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

49
Q

example of idiosyncratic drug effect

A

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

50
Q

what does G6PD do

A

prevents red blood cells from oxidative damage

51
Q

what happens when G6PD deficiency

A

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

52
Q

drugs that cause oxidative stress

A

sulfonamides, antimalarials, chloramphenicol

53
Q

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

A

hemolytic anemia (also be caused by fava beans)

54
Q

inheritance of malignant hyperthermia

A

autosomal dominant

55
Q

malignant hyperthermia is the main cause of death due to?

A

anesthesia

56
Q

symptoms of malignant hyperthermia

A

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

57
Q

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

A

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

58
Q

ryanodine receptors are located between what?

A

SR and DHPR protein (senses voltage in plasma protein)

59
Q

what happens when abnormal RYR1 receptor

A

unregulated release of calcium –> acute hyperthermia crisis

60
Q

used to establish susceptibility to malignant hypethermia

A

caffeine halothane muscle contracture test

61
Q

results of increased calcium intracellularly

A
  • 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.
62
Q

how does the caffeine halothane muscle contracture test work

A
  • 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
63
Q

used to figure out genotype for CYP2D6

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

Genetics (19 decks)

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