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[Ther 201] 2nd Exam Transes > Pharmacogenetics (Nerissa Dando, MD) > Flashcards

Pharmacogenetics (Nerissa Dando, MD) Flashcards

1
Q

What is the goal for non-responders? Toxic responders?

A

Drug efficacy; drug safety

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2
Q

What are the three possible effects of drug administration?

A

Therapeutic effect
Adverse effect
Lethal effect

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3
Q

Describe: Succinylcholine

A 
Anesthetic agent (muscle relaxant)
ADR: overparalysis
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4
Q

What type of drug is primaquine?

A

Antimalarial

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5
Q

What type of drug is isoniazid (INH)?

A

Anti-tuberculosis

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6
Q

Intake of primaquine causes ADRs among African-Americans where they develop (1) which leads to (2).

A

(1) G6PD deficiency

(2) hemolytic anemia

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7
Q

Who developed the concept of chemical sensitivity?

A

Archibald Garrod

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8
Q

Define: Alcaptonuria

A

Excretion of homogenateisic acid in urine due to congenital absence of homogentisate 1,2 dioxygenase.

No breakdown of phenylalanine and tyrosine.

Urine is dark.

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9
Q

Enumerate Mendel’s Four Principles of Inheritance

A
  1. Genes come in pairs.
  2. Dominance and recessiveness
  3. Principle of segregation
  4. Principle of independent assortment
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10
Q

How many possible codons are there?

A

64

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11
Q

What is the sequence of the start codon? Stop codons?

A

Start codon - AUG

Stop codons - UAA, UAG, UGA

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12
Q

Enumerate the basic patterns of inheritance

A

Autosomal Dominant
Autosomal Recessive
X-linked
Mitochondrial Inheritance

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13
Q

Give examples of X-linked diseases

A

G6PD deficiency
Pyridoxine sensitive anemia
Vasopressin resistance

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14
Q

T/F: Mitochondrial inheritance is secondary to exposure to aminoglycosides like streptomycin, gentamycin and amikacin.

A

True

i.e. aminoglycoside-induced deafness

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15
Q

What are the factors affecting drug sensitivity?

A

Genetics
Disease
Age
Drug related factors

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16
Q

Which groups of patients are most sensitive to the effects of drugs?

A

Geriatric
Preterm
Chronically Ill

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17
Q

What drug related factors affect drug sensitivity?

A

Pharmaceutical formulation
Route of administration
Drug interaction
Environmental factors

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18
Q

Enumerate extrinsic factors affecting drug sensitivity

A

Drug-food interaction (grapefruit juice, alcohol & histamine cause sedation)
Environmental chemicals
Vices

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19
Q

Enumerate intrinsic factors affecting drug sensitivity

A

Physiological and pathophysiological attributes of a person (age, gender, weight, etc.)
Patient characteristics

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20
Q

Define: Gene

A

Unit of heredity on a chromosome

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21
Q

Define: Alleles

A

Alternative forms of genes that occur in pairs

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22
Q

It includes all alleles present in the cell whether dominant or recessive, expressed or not.

A

Genotype

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23
Q

Physical manifestation of a trait

A

Phenotype

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24
Q

What method can predict whether an individual is a candidate for polymerphic metabolism?

A

Molecular Genotyping

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25
Q

What methods are commonly employed in molecular genotyping?

A

Polymerase chain reaction (PCR)

Restriction fragment length polymorphism mapping (RFLM)

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26
Q

Method accomplished by administering a probe to an individual followed by analysis of metabolites in blood or urine

A

Phenotyping

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27
Q

What anti-hypertensive drug is used to identify the activity of CYP450?

A

Drebisoquine

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28
Q

Enumerate the three potential applications of molecular genotyping in drug development

A
  1. Determine safety and efficacy of investigational new drug prior to approval
  2. Protect patients against ADRs by identifying poor metabolisers
  3. Establish an individual’s genetic predisposition to disease
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29
Q

Define: Monogenic

A

Due to allelic variation at a single gene

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30
Q

Define: Polygenic

A

Due to variations at two or more genes

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31
Q

What describes frequently occurring monogenic variants occurring at a frequency > 1%?

A

Polymorphic

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32
Q

What are the most common polymorphisms?

A

Single nucleotide polymorphisms (SNPs)

Copy number variations (CNVs)

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33
Q

What are less common polymorphisms?

A

Insertions

Deletions

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34
Q

What are the two types of gross rearrangements?

A

Inversions

Translocations

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35
Q

These are implicated in human diseases (i.e. cancer and Alzheimer’s) but most have no known clinical effects.

A

Single Nucleotide Polymorphisms

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36
Q

What are the different types of SNPs?

A

Missense
Nonsense
Frameshift by addition
Frameshift by deletion

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37
Q

How many SNPs have been identified in the human genome?

A

2 million

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38
Q

T/F: A polymorphic distribution follows a normal distribution.

A

False

70 - 90% of them are found in extremes.

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39
Q

Enumerate the project goals of the Human Genome Project

A
  1. Identify all 30,000 genes in human DNA
  2. Determine sequences of 3 billion base pairs
  3. Store the information
  4. Improve tools for data analysis
  5. Transfer technologies to private sector
  6. Address ELSI (ethical, legal and social issues) that may arise
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40
Q

When was a working draft of the human genome completed?

A

June 2000

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41
Q

When were analysis of the working draft published?

A

February 2001

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42
Q

T/F: To be important, SNPs must affect either function or amount of a protein.

A

True

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43
Q

What are the possible effects of genetic polymorphisms?

A
  1. Pharmacokinetic (enzymes, transporters and binding proteins)
  2. Pharmacodynamic (target proteins, receptors and ion channels)
  3. Idiosyncratic Responses (no explanation)
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44
Q

Refers to genetic loci in which variants occur with a frequency of 1 - 2%

A

Genetic Polymorphism

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45
Q

Twin and family studies enable discrimination of?

A

Various modes of genetic transmission

Dominance-recessivity relationships

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46
Q

T/F: Pharmacogenomics is a subset of pharmacogenetics.

A

False

It’s the other way around.

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47
Q

Define: Pharmacogenomics

A

Study of variations of DNA AND RNA characteristics related to drug response

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48
Q

Define: Pharmacogenetics

A

Study of genetically controlled variations in DNA sequence related to drug response

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49
Q

According to pharmacogenomics, what is the key to creating personalised drugs with greater efficacy and safety?

A

Understanding an individual’s genetic make-up

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50
Q

Define: Poor Metabolizers

A

Slower-than-usual metabolism leading to toxicity

May be due to liver or kidney failure

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51
Q

Define: Ultra-rapid Metabolizers

A

Observed therapeutic failure

Variability in drug target genes

52
Q

T/F: There is poor efficacy of prodrugs in slow metabolizers and ADR risk in ultra-rapid metabolizers.

A

True

53
Q

Give examples of prodrugs.

A

Codeine
Tamoxifen
Clopidogrel

54
Q

What is seen in CYP2D6 poor metabolises of debrisoquine?

A

Marked hypotension

Note: This is not an ADR.

55
Q

What group has the largest incidence of G6PD deficiency?

A

Indians-Parsees

56
Q

T/F: Newborn screening cannot detect G6PD deficiency.

A

False

57
Q

Enumerate the drugs demonstrated to precipitate haemolytic anemia in G6PD deficients

A 
Acetanilide
Methylene blue
Nalidixic acid
Naphthalene
Sulfapyridine
Sulfanilamide
Sulfamethixazole
Primaquine
Sulfacetamide
Nitrofurantoin
Nitrates
58
Q

Example of an unusual drug response is malignant hyperthermia following the use of what?

A

Halothane (anaesthetic agent)

59
Q

What is the classic presentation of malignant hyperthermia?

A 
Rapid rise in body temperature
Muscle rigidity
Tachycardia
Rhabdomyolysis
Severe acidosis
Hyperkalemia
60
Q

What is the antidote for malignant hyperthermia?

A

L.V. dantrolene

61
Q

What causes malignant hyperthermia?

A

Mutations in the ryanodine receptor

62
Q

In cases of Warfarin resistance, by how much does the dose need to be increased?

A

7 - 20 times recommended therapeutic dose

63
Q

In cases of folate resistance, by how much does the dose need to be increased?

A

40 - 1000 times daily recommended dose

64
Q

T/F: Fast acetylators are susceptible to phenytoin toxicity when phenytoin and isoniazid are given together.

A

False

Slow acetylators!

65
Q

T/F: Individualizing therapy is important for drugs with a wide therapeutic range.

A

False

Narrow!

66
Q

Increased risk of cancer is associated with polymorphisms in what genes?

A

CYP (2A1, 1A2 and 2E1)
Glutathione transferases (GSMT1, GSTT1)
Epoxide hydrolase
NAT2 - N-acetyl transferase 2

67
Q

T/F: Drug clearance typically removes drugs via enzymatic transformation into more hydrophobic metabolites.

A

False

Hydrophilic!

68
Q

T/F: Cytochrome P450 enzymes are responsible for Phase II oxidative metabolism of steroid hormones, xenobiotics and carcinogens.

A

False

Phase I oxidative metabolism!

69
Q

What CYPs are important for Phase I?

A

CYP3A4, CYP2C19 and CYP2D6

70
Q

What enzymes are important for Phase II?

A

TPMT, NAT1 & NAT2

71
Q

What are the mechanisms of variation in drug response?

A
  1. Modification of absorption of xenobiotic
  2. Modified metabolism resulting in modification of rate, pattern of elimination, detoxification or activation of a given xenobiotic
  3. Modification in the abundance, affinity or function of a target enzyme or receptor
72
Q

What factors influence absorption of the xenobiotic?

A
  1. Rapid metabolizer
  2. Decreased abundance of transport protein
  3. Enhanced excretion by multi-drug resistance protein
73
Q

T/F: When the main metabolic pathway leading to a harmless metabolite is blocked, parent drug could accumulate and cause toxicity.

A

True

74
Q

T/F: Deficiency of methemoglobin reductase is inherited as an autosomal recessive trait.

A

True

75
Q

T/F: Methemoglobin reductase homozygotes are predisposed to develop methemoglobinemia when exposed to nitrates and other stress.

A

False

Heterozygotes!

76
Q

Give an example of a modification in the abundance, affinity or function of a target enzyme or receptor.

A
  1. Silent variants of serum cholinesterase associated with succinylcholine
  2. Poor metaboliser variants of CYP2D6 and CYP2C19
77
Q

Describe the metabolism of ethanol by the body

A

Ethanol -> acetaldehyde (by ADH) -> acetate (by ALDH)

78
Q

T/F: The rate of ethanol metabolism of genetically controlled.

A

True

79
Q

T/F: Atypical ADH exhibits higher catalytic activity and typically contains a variant alpha 2 subunit.

A

False

Variant beta 2 subunit!

80
Q

What ethnic group has the largest distribution of atypical ADH?

A

Swiss (20%)

81
Q

How does the atypical B2 subunit of alcohol dehydrogenase differ from the typical?

A

CGC to CAC transition resulting in an Arg47His substutition

82
Q

What does the atypical ADH subunit mutation cause?

A

Higher ethanol Vmax

Higher Km for the homozygous B2B2

83
Q

What are the three genotypes for aldehyde dehydrogenase?

A
  1. Homozygote normal
  2. Heterozygote
  3. Deficient homozygote
84
Q

What causes the “flush” and feelings of discomfort associated with ethanol intake?

A

Acetaldehyde accumulation

85
Q

Describe: cyclophosphamide polymorphic biotransformation

A

Antineoplastic agents that cause cystitis

86
Q

Familial pyrimidinemia and pyridinuria are associated with what?

A

5-fluorouracil induced toxicity

87
Q

Major toxic manifestation of 5FU in DPD occurs in what tissue?

A

Bone marrow

88
Q

What are the two phenotypes for mephenytoin hydroxylation polymorphism?

A
  1. Poor metaboliser

2. Extensive metabolizer

89
Q

Mephenytoin hydroxylation is mediated by what enzyme?

A

CYP2C19

90
Q

What are the types of parathion poisoning and paraoxon polymorphism?

A

PON1 & PON2

91
Q

What causes the hydrolysis of succinylcholine?

A

Pseudocholinesterase

92
Q

How do you document pseudocholinesterase deficiency?

A

History taking

Unexpected persistent respiratory paralysis for a prolonged period of time

93
Q

Enumerate a few examples of choline ester compounds

A

Succinylcholine
Mivacarium
Cocaine

94
Q

Atypical plasma cholinesterase causes (1) that lasts (2)

A

(1) paralysis
(2) 2 - 6 mins

Note: Patients deficient in the enzyme experience 1-hour long paralysis episodes.

95
Q

How many % of succinylcholine is inactivated by normal functioning pseudocholinesterase?

A

90 - 95%

96
Q

T/F: Flaccid paralysis of skeletal muscle develops within 1 minute of succinylcholine binding

A

True

97
Q

What is the cause of pseudocholinesterase deficiency?

A

Abnormal alleles that code for the enzyme

98
Q

Where is the gene coding for pseudocholinesterase located?

A

E1 locus on the long arm of chromosome 3

99
Q

How many % of the population carries one or more of the atypical gene alleles for pseudocholinesterase gene?

A

4%

100
Q

How is the dibucaine-resistant genetic variant form of pseudocholinesterase detected?

A

Percent inhibition of hydrolysis of benzyl choline caused by addition of dibucaine (dibucaine number)

101
Q

What is the DN value for normal homozygotes? for the atypical dibucaine resistant genotype?

A

80%; 20%

102
Q

How is the fluoride-resistant pseudocholinesterase enzyme variant detected?

A

Percent inhibition of benzyl choline hydrolysis when fluoride is added to assay

103
Q

What is the FN value for normal homozygotes? for the atypical homozygotes?

A

60%; 36%

104
Q

What is the most severe form of atypical pseudocholinesterase?

A

Silent form

105
Q

T/F: Only 1 in 100,000 individuals are homozygous for the silent Es genotype with no detectable pseudocholinesterase enzyme activity.

A

True

106
Q

What causes the silent Es genotypes?

A

Gene mutations by frameshift or stop codon

107
Q

What is the cause of fish odor syndrome?

A

Excessive excretion of trimethylaminuria (TMA) in urine, sweat and breath

108
Q

What is the prodrug used to check the activity of CYP2D6?

A

Debrisoquine

109
Q

T/F: If you give a patient debrisoquine and there is marked hypotension, the phenotypic presentation is ultra rapid metabolism.

A

False

Poor metabolism!

110
Q

What are drugs that can cause increased toxicity in ultra rapid metabolizers?

A

Codeine-narcotic and opioid

111
Q

What are drugs with an extremely narrow therapeutic index?

A

Antiarrythmitics
Antidepressants
Antipsychotics

112
Q

What are the two N-acetyltransferase isozymes?

A

NAT1 and NAT2

113
Q

T/F: Filipinos are fast acetylators.

A

True

114
Q

NAT2 allele polymorphism produces what phenotypes?

A

Rapid acetylator
Intermediate acetylator
Slow acetylator

115
Q

T/F: Due to NAT2 polymorphism, there is a higher incidence and/or severity of adverse drug reactions to isoniazid, hydrazine, procainamide and sulfamethaxazole.

A

True

116
Q

NAT2 activates and deactivates many of the (1) and (2) amine carcinogens.

A

(1) Aromatic

(2) Heterocyclic

117
Q

T/F: There is no association between acetylation polymorphism and urinary bladder & colorectal cancers.

A

False

There is!

118
Q

Slow acetylators have an 8-fold higher risk of what compared to fast acetylators?

A

Cancer

119
Q

Rapid acetylators are at increased risk of what from acetylation of heterocyclic amines found in cooked meats?

A

Colon cancer

120
Q

Where has human NAT2 been localised?

A

Short arm of chromosome 8

121
Q

What allele is associated with rapid acetylators?

A

NAT2*4

122
Q

What alleles are associated with poor acetylators?

A

NAT25B, NAT26A and NAT2*14A

123
Q

What complications does thiopurinemethyltransferase (TPMT) polymorphism cause?

A

Severe coma or depression after giving certain anti-cancer drugs

In AFL, patients may develop myosuppression

124
Q

Patients with TPMT polymorphism will experience toxicity after administration of what?

A

6-mercaptopurine

125
Q

T/F: TPMT is found in patients with acute lymphoblastic leukaemia.

A

True

126
Q

With pharmacogenetics, we aim for (1) and (2).

A

(1) efficacy

(2) safety

[Ther 201] 2nd Exam Transes (5 decks)

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