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Genetics > L30 Pharmacogenetics > Flashcards

L30 Pharmacogenetics Flashcards

1
Q

What is the range of variations in drug responses?

A
  • severe adverse effects

- lack to therapeutic activity

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2
Q

what are the factors that can influence the drug response phenotype?

A
  • age
  • gender
  • disease
  • genetic variation!
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3
Q

define pharmacogenomics?

A

study of the role of inheritance in variation in drug responses

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4
Q

why is pharmacogenomics important to study?

A

because adverse drug reactions are a major cause of morbidity and mortality

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5
Q

what are the 3 types of genetic variation that can influence pharmacotherapy?

A
  1. variation in proteins involved in drug metabolism/transport
  2. variation in drug targets (pharmacodynamic variation)
  3. variation in proteins associated with unique (idiosyncratic) adverse drug effects
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6
Q

what does absorption, distribution and elimination (what the body does to the drug) define?

A

pharmacokinetics

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7
Q

what describes what the drug does to the body?

A

pharmcodynamics

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8
Q

what is the most common factor responsible for pharmacogenetic variation in drug responses?

A

genetic variation in enzymes that catalyze drug metabolism

*most enzymes in drug metabolism are POLYMORPHIC!

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9
Q

give 4 examples of the polymorphic drug metabolizing enzymes?

A
  • butyrylcholinesterase (pseudocholinesterase) (BChE)
  • N-acetyltransferase 2 (NAT 2)
  • cytochrome P450 2D6 (CYP2D6)
  • thiopurine S-methyltransferase (TPMT)
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10
Q

what type of drug is succinycholine?

A

depolarizing neuromuscular blocker

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11
Q

what is the function of succinylcholine?

  • what receptor does it bind to?
  • what NT does it act like?
  • what does it cause to happen on the end plate?
A
  • binds to nicotinic receptors
  • acts like ACh
  • depolarizes the end plate
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12
Q

what is the major difference between ACh and succinylcholine?

A

succinylcholine is not metabolized at the synapse effectively like ACh (using AChE)

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13
Q

what type of onset and duration does succinyl choline have?

A

fast onset

short duration

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14
Q

what breaks down and metabolizes succinylcholine?

A

plasma butyrylcholinesterase

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15
Q

what happens with genetic variation in butyrylcholinesterase?

  • main problem
  • result
  • cause (what is the defected gene)
  • how it is transmitted?
A
  • decreased rate of metabolism of succinyl choline
  • prolonged paralysis
  • defect in BCHE gene
  • autosomal recessive trait
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16
Q

what does N-acetyltransferase 2 (NAT 2) catalyze?

A

ACETYLATION of isoniazid (for TB) and other drugs

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17
Q

what are the 2 classes of patients tc with isoniazid?

A
  • slow acetylators
  • fast acetylators

*The rate is inherited!

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18
Q

will slow acetylators have high or love blood levels of drug?

A

high because they metabolize the drug SLOWER

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19
Q

will fast acetylators have high or low blood levels of drug?

A

low because they metabolism the drug FASTER

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20
Q

slow acetylators of isoniazid are ____ for an autosomal recessive allele of the enzyme with lower activity levels

A

homozygous

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21
Q

what acetylators are more prone to toxicity of drugs that are metabolized by acetylation? Why

A

slow acetylators are prone to toxicity of drugs because they take a long time to metabolize the drugs so the levels are going to rise int he blood and can create serious adverse effects on the pt.

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22
Q

____ may cause neuropathy and hepatotoxicity

A

isoniazid

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23
Q

______ and _____ may cause SLE

A

hydralazine and procainadmide

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24
Q

_____ may cause hypersensitivity reactions, hemolytic anemia, SLE

A

sulfonamides

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25
Q

what drugs were used when studying the CYP2D6 polymorphism?

A

antihypertensive - debrisoquine

oxytotic - sparteine

26
Q

if the ratio of decrisoquine/4-hydroxydebrisoquine metabolic ratio is high, what does that indicate?

A

poor metabolizer

27
Q

if the ratio of decrisoquine/4-hydroxydebrisoquine metabolic ratio is low, what does that indicate?

A

ultrarapid metabolizer

28
Q

poor metabolizers are _____ for the recessive alleles coding for enzymes with low activity

A

homozygous

29
Q

extensive metabolizers (normal) are ______ or _____ for the “wild type” allele

A

homozygous

heterogygous

30
Q

some ultra rapid metabolizers can have ______ copies of the CYP2D6 gene

A

multiple (up to 13)

31
Q

inter individual differences are important with CYP2D6 because they metabolize many commonly prescribes drugs like…

A
  • beta blockers
  • antipsychotic
  • opiods
  • antidepressants
32
Q

what drug is ineffective in poor metabolizers and why?

A

codeine

requires CYP2D6-catalyzed conversion from codeine to morphine

33
Q

what metabolizers can overdose with standard doses of codeine and suffer from respiratory depression or arrest?

A

ultrarapid metabolizers

34
Q

what does TPMT catalyze?

A

S-methylation of the anticancer thiopurines (6 mercaptopurine and azathioprine)

35
Q

____ of the anticancer thiopurine inactivates them!

A

methylation

36
Q

thiopurines have a ________therapeutic index and some pts may suffer from life-threatening _____

A

narrow

myelosuppression

37
Q

about 1/300 individuals are ____ for a polymorphism that leads to LOW TPMT activity

A

homozygous

38
Q

the individuals who are homozygous for low TPMT activity have an increased risk for ____ when treated with standard doses of thiopurine drugs , so these pts have to be tx with _____ of the standard dose

A

myelosuppression

1/10

39
Q

why does warfarin make dosing problematic?

  • therapeutic window
  • variability
A

because it has a narrow therapeutic winnow and

wide inter individual variability

40
Q

what does under-anticoagulation result in

A

thrombosis

41
Q

what does over-anticoagulation result in

A

bleeding episodes

42
Q

warfarin

  • what type of mixture?
  • what are the 2 types?
  • are they both metabolized by the same enzyme?`
A
  • racemic
  • S-warfarin***** (3-5x more potent) and R warfarin
  • stereoismoers are metabolized by DIFFERENT enzymes
43
Q

which gene is most involved in the metabolism of S-warfarin?

A

CYP2C9 - VERY polymorphic!

44
Q

pts who carry the variant alleles require ____ doses of warfarin to achieve an anticoagulant effect and they also have an increased risk for ____ during warfarin therapy

A

decreased

increased

45
Q

what is the molecular target for warfarin?

A

vitamin K epoxide reductase

46
Q

the gene that encodes the enzyme for vitamin K epoxide reductase complex 1 (VKORC1) how a number of _____

A

polymorphisms

47
Q

what do idiosyncratic drug reactions result from? what is a classic example?

A

interactions between the drug and a unique aspect of the physiology of the individual patient

deficiency of G6PD

48
Q

what is the normal function of G6PD

A

protects RBCs from oxidative injury

49
Q

what does diminished G6PD impair?

A
  • cell can’t form NADPH which is important for the maintenance of the reduced glutathione pool
  • this results in a decrease in the cellular detoxification of free radicals and peroxides formed within the cell
50
Q

what is the most common G6PD polymorphism? how much enzyme function is reduced with this polymorphism?

A

G6PD A

causes a 90-95% reduction of the enzyme function

51
Q

what are some other drugs that can cause oxidative stress on RBCs?

A
  • sulfonamides
  • antimalarials
  • chloramphenicol
52
Q

what happens if a pt with G6PD deficiency is exposed to

  • sulfonamides
  • antimalarials
  • chloramphenicol
  • FLAVA beans
A

may develop hemolytic anemia

53
Q

Describe malignant hyperthermia

A

-potentially fatal genetic disorder of skeletal muscle

54
Q

how is malignant hyperthermia triggered?

A

by volatile inhalation anesthetics (halothane) and depolarizing skeletal muscle relaxants (succinylcholine)

55
Q

how is malignant hyperthermia transmitted?

A

autosomal dominant - but its rare

56
Q

what is one of the main causes of death due to anesthesia?

A

malignant hyperthermia

57
Q

what are the sx/s of malignant hyperthermia syndrome?

A
  • tachycardia
  • hypertension
  • severe muscle rigidity
  • hyperthermia
  • hyperkalemia
  • acidosis
58
Q

what is the cellular mechanism behind malignant hyperthermia?

  • altered control of what?
  • defected gene?
A

altered control of Ca2+ release from the SR

defect in the ryanodine receptor gene (RYR1)

59
Q

what is the most reliable test to establish susceptibility to malignant hyperthermia?

A

the Caffeine-Halothane muscle contracture test

60
Q

how was drug genetic variation measured then and now?

A

then - urinary excretion levels
now - DNA -based tests
—Amplichip CYP450 tests

61
Q

what can the AmpliChip CYP450 test determine?

A

CYP2D6 and CYP2C19 genotypes

Genetics (15 decks)

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