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Pharmacokinetics > Pharmacogenetic > Flashcards

Pharmacogenetic Flashcards

1
Q

What was pythagoras contribution to pharmacogenetics?

A
  1. Ingestion of fave bean is potentially fatal reaction but was attributed to Glucose-6-Phosphate Dehydrogenase deficiency affecting glutathione metabolism in patients with hemolytic anemia
  2. First observation
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2
Q

Describe observation of suxmethonium?

A
  1. Metabolized by pseudocholinesterase
  2. Prolonged apnea was caused by the drug in some patients who later were found to have an atypical genetic variant for the enzyme?
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3
Q

Who was Friedrich Vogel?

A

First coined the term “pharmacogenetics” and defined it as the study of the role of genetics in the drug response

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4
Q

When was the human genome project created?

A

On February 15, 2001, the human genome draft produced by the public consortium was published in the journal ‘Nature’.

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5
Q

What were the findings of the human genome project?

A
  1. Composed of 3 billion pairs of nucleotide bases
  2. 20000 -25000 protein coding genes
  3. All human beings share 99.9% similarity at the DNA level, only 0.1% of genetic variation (difference) exist
  4. Most common genetic variation is SNPs
  5. 10 million SNPs in the human genome
  6. SNps are located in the DNA genes
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6
Q

What is a genome?

A

An organism’s complete set of genetic instructions

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7
Q

What is the study of genomes?

A

Genomics

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8
Q

What is pharmacogenetics?

A

Studies the effect of single genes on drug response

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9
Q

What is pharmacogenomics?

A

Looks at the influences of multiple genes on drug response

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10
Q

What is the main concept of central dogma?

A

DNA does not code for proteins directly but rather acts through intermediary RNA molecules

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11
Q

What is dogma?

A

A set of beliefs

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12
Q

What is transcription?

A

The process of making RNA strand from DNA template

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13
Q

What is translation?

A

The synthesis of polypeptides under the direction of mRNA molecule

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14
Q

What is a gene?

A

The basic physical unit of inheritance, the blueprint of life

Contains the info needed to specify traits

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15
Q

What is a locus?

A

The physical position of a gene along a chromosome

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16
Q

What is DNA?

A

Molecule that carries genetic instructions

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17
Q

What are DNA strands comprised of?

A

Base (sugar-deoxyribose) and phosphate groups

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18
Q

What are the 4 bases of DNA?

A

Adenine, cytosine, guanine, and thymine

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19
Q

What are the DNA pairings?

A

A-T, C-G

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20
Q

What is a chromosome?

A

Tightly packed structure of DNA and proteins in the nucleus of a cell

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21
Q

How many pairs of chromosomes do humans have?

A

23, parent contributes one chromosome to each pair

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22
Q

What is an allele?

A

One of 2 versions of a gene inherited from each parent

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23
Q

What are homozygous alleles?

A

2 alleles are the same

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24
Q

What are heterozygous alleles?

A

Two alleles are different

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25
Q

What is a genotype?

A

2 alleles inherited for a particular gene

Genetic contribution to the phenotype

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26
Q

What is a phenotype?

A

Observable traits

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27
Q

What are haplotypes?

A

Set of genes or DNA variations that tend to be inherited together from the same parent

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28
Q

What is genetic/DNA sequencing?

A

Process of working out the exact order of bases in a DNA molecule

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29
Q

What are the regions of a gene?

A
  1. Regulatory region
  2. Coding region
  3. Noncoding region
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30
Q

What is a promoter?

A

Regulatory region where transcription of gene is initiated

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31
Q

What is an exon?

A

The portion of a gene that codes for amino acids

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32
Q

What is an intron?

A

Non-coding regions of an RNA transcript that is eliminated by splicing before translation

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33
Q

What are genetic variations?

A

Refers to differences in gene sequences between individuals or populations

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34
Q

What is the source of genetic variation?

A

Mutation

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35
Q

What is a mutation?

A

Change in DNA sequence

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36
Q

What can cause mutations?

A
  1. DNA copying mistakes during cell division,
  2. exposure to ionizing radiation or chemicals
  3. infection by viruses
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37
Q

What is polymorphism?

A

A certain mutation occurs in 1% or more frequencies in a given population

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38
Q

What is the result of polymorphism?

A

Functional or non-functional gene products

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39
Q

What are common genetic polymorphisms?

A
  1. Single nucleotide polymorphisms (SNPs) -> substitution -> most common
  2. Insertion/deletion (Indels) polymorphisms
  3. Duplication/repeat polymorphisms
  4. Copy-number variations (CNVs)
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40
Q

What are snips (SNPs)?

A

Represent more than 90% of all human genetic variations

Involve variation of a single base pair substitution

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41
Q

What is insertion?

A

Involves the addition of genetic material

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42
Q

What is deletion?

A

Involves the loss of genetic material

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43
Q

What is duplication?

A

Involves the production of one or more copies of a gene

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44
Q

What is copy number variations (CNVs)?

A

The number of copies of a particular gene varies from one individual to the next

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45
Q

What is ultra-rapid metabolizers (UM)?

A

Individuals with high enzyme activity. They may have more than two functional alleles of the enzyme in question.

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46
Q

What are extensive metabolizers (EM)?

A

Individuals with at least one or two normal functional alleles of the enzyme in question.

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47
Q

What is intermediate metabolizers (IM)?

A

Individuals with (two reduced functional alleles of the enzyme in question or one non-functional allele and the other allele with reduced function.

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48
Q

What is poor metabolizers (PM)?

A

Individuals with significantly reduced or no enzyme activity. They may have two non-functional alleles of the enzyme in question.

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49
Q

What enzyme is associated with expressors and non?

A

CYP3A5

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50
Q

What is the enzyme associated with slow and fast acetylators?

A

NAT2

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51
Q

How do genetic variations change the the structure of target proteins?

A

Alters the function of protein or rate and kinetic constants of an enzyme

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52
Q

What type of polymorphism occurs that affect ADME?

A

Polymorphisms of drug-metabolizing enzymes and drug transporter proteins

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53
Q

What type of polymorphism occurs that affect target protein function and drug-target interaction affecting pharmacodynamics?

A

Polymorphisms in genes encoding drug targets [receptors, enzymes, ion-channels, etc]

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54
Q

What is the major determinant of drug clearance?

A

Metabolism

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55
Q

What are the phases of drug metabolism?

A
  1. Oxidation mainly mediated by CYP450 enzymes
  2. Conjugation reactions, mediated by N-acetyl-transferase (NAT), UGTs
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56
Q

How many CYP450 enzymes are active in humans?

A

57

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57
Q

Where are CYP450 mainly expressed in?

A

Liver

58
Q

What reactions do CYP450 catalyze?

A

Catalyzes the mono-oxygenation of lipophilic drugs to produce metabolites with increased water solubility or for further metabolism by other phase 2 enzymes

59
Q

How is CYP2D6*5 labeled?

A

CYP: Superfamily
2: Family
D: subfamily
6: isform
*5: variant allele

60
Q

What is CYP2D61/1?

A

Wild type homozygous

61
Q

What is CYP2D61/5?

A

Heterozygous

62
Q

What is CYP2D65/5?

A

Mutan homozygous

63
Q

How much of drugs are metabolized by CYP2D6?

A

25%

64
Q

What are type of drugs are metabolized by CYP2D6?

A
  1. Antipsychotic
  2. Antiarrythmic
  3. Tricyclic antidepressants
  4. B-antagonists
  5. Opoids
  6. Estrogen receptor antagonist
65
Q

What are antipsychotics the are metabolized by CYP2D6?

A

Haloperidol, clozapine, risperidone

66
Q

What are antiarrhythmics the are metabolized by CYP2D6?

A

Flecainide and perphenazine

67
Q

What are tricyclic antidepressants the are metabolized by CYP2D6?

A

Imipramine, clomipramine, nortriptyline, amitriptyline

68
Q

What are b-antagonists the are metabolized by CYP2D6?

A

Metoprolol, propranolol, bupranolol, carvedilol

69
Q

What are opioids the are metabolized by CYP2D6?

A

codeine and tramadol

70
Q

What are estrogen receptor antagonist the are metabolized by CYP2D6?

A

tamoxifen

71
Q

What are the most common CYP2D6 variants?

A

1, 2, 3, 4, 5, 6, 10, 17, 41

72
Q

Why is CYP2D6 polymorphism important?

A
  1. Poor metabolizers exhibit a higher incidence of undesirable life effects
  2. Ultra-rapid metabolizers experience diminished response to these drugs
73
Q

Why is CYP2D6 polymorphism important?

A
  1. Poor metabolizers exhibit a higher incidence of undesirable life effects
  2. Ultra-rapid metabolizers experience diminished response to these drugs

CYP2D6 - Tamoxifen (Antitumor) -> active metabolite
CYP2D6 - Codeine -> morphine -> higher concentration of morphine

74
Q

How much of drugs are metabolized by CYP2C9? And what are they?

A

15-20%

  1. Anticoagulants
  2. Antihypertensive
  3. Diuretic
  4. Antidiabetics
  5. Anticonvulsant
  6. NSAIDS
75
Q

What are anticoagulants metabolized by CYP2C9?

A

Warfarin (narrow TI)

76
Q

What are antihypertensive metabolized by CYP2C9?

A

Losartan

77
Q

What are diuretic metabolized by CYP2C9?

A

Torasemide

78
Q

What are antidiabetic metabolized by CYP2C9?

A

Tolbutamide, glipizide

79
Q

What are anticonvulsant metabolized by CYP2C9?

A

Phenytoin (narrow TI)

80
Q

What are NSAIDs metabolized by CYP2C9?

A

Ibuprofen, diclofenac, piroxicam, tenoxicam, mefanamic acid

81
Q

What CYP2C9 variants are common in white people?

A

2, 3

82
Q

What CYP2C9 variants are common in black people?

A

5, 6, 8, 11

83
Q

What can you say about people with CYPC9*2 and 3?

A

poor metabolizers of S-Warfarin

84
Q

What do you do with people who are poor metabolizers of warfarin?

A
  1. Dose adjustment required due to toxicity
  2. CYP2C9 genotyping prior to warfarin initiation approved by the FDA and improves the safety profile
85
Q

What drugs are metabolized by CYP2C19?

A
  1. Anti platelet
  2. Anti ulcers
  3. Anti convulsant
  4. Anti malarial
  5. Anxiolytics
  6. Antidepressants
86
Q

What are antiplatelets metabolized by CYP2C19?

A

Clopidogrel

87
Q

What are anti-ulcers metabolized by CYP2C19?

A

Omeprazole

88
Q

What are anti0convulsant metabolized by CYP2C19?

A

Pheytoin

89
Q

What are anti-malarial metabolized by CYP2C19?

A

Proguanil -> Cycloguanil (active)

90
Q

What are anxiolytics metabolized by CYP2C19?

A

Diazepam

91
Q

What are antidepressants metabolized by CYP2C19?

A

Citalopram, Imipramine, amitriptyline, clomipramine

92
Q

What are the CYP2C19 variants?

A

2, 3, 17

93
Q

What is the function of CYP2C19*17?

A

Leads to increased CYP2C19 activity -> rapid clearance of substrate drugs causing a lack of response PPI and antidepressants

94
Q

What are the overlapping expressions of CYP3A4 and 5?

A
  1. Responsible for the metabolism of >50% of drugs
  2. CYP3A5 more polymorphic than CYP3A4
  3. CYP3A5 (*3, *5, *6 & *7)
95
Q

What is the most common alleles variant?

A

CYP3A5*3

96
Q

What are drugs that are metabolized CYP1A2?

A

Coffee, theophylline, estrogen, clozapine, olanzapine

97
Q

What are drugs that are metabolized CYP2A6?

A

Nicotine

98
Q

What are drugs that are metabolized by CYP2B6?

A

Bupropion, efavirenz, nevirapine, cyclophosphamide

99
Q

What are the phase 2 metabolizing enzymes?

A
  1. UDP-glucuronosyltransferases (UGTs)
  2. N-acetyltransferases (NATs)
  3. Thiopurine S-methyltransferase (TPMT)
100
Q

What is the result of a defective UGT1A1 gene?

A

Hypebilirubinemia

101
Q

What the function of UGT1A1?

A

Major role in the glucuronidation of bilirubin

102
Q

What is UGT1A1*28?

A
  1. promoter region causes a thymine-adenine (TA) repeat sequence polymorphism  A(TA)7TAA in place of the wild-type A(TA)6TAA :-
  2. This polymorphism causes ↓ transcription rate ofUGT1A1gene
103
Q

What is the clinical significance of UGT1A1?

A
  1. Susceptible toIrinotecantoxicity (used as the second-line therapy in the treatment of colorectal cancer.)
  2. FDA recommends a dose reduction
  3. ↑ susceptibility to drug-induced hyperbilirubinemia.
104
Q

What are examples drugs that are metabolized by UGT2B7?

A

Opiods, NSAIDS, antiepileptics, cancer drugs, antiretrovirarls, and lypolipidemic agents

105
Q

What is the common variant of UGT2B7

A

2

106
Q

What is the clinical significance of UGT2B7?

A
  1. Diclofenac (NSAID)  undergoes extensive glucuronidation by UGT2B7
  2. Reduced-activity ofthe enzyme in individuals with UGT2B7*2  predispose to ↑ risk of hepatotoxicity from reactivediclofenac.
107
Q

What does NAT2 do?

A

Is a phase-2 metabolic enzyme that conjugates with acetyl-groups

108
Q

What is acetylation important for?

A
  1. Isoniazide
  2. Hydralazine
  3. Procainamide
  4. Nitrazepam
  5. Sulfonamides
  6. Dapsone
  7. Phenelezine
  8. Zonisamide
  9. amifampridine
109
Q

What encodes NAT2?

A

NAT 2 gene

110
Q

What are the SNPs in NAT2 responsible for?

A

Fast and slow acetylator phenotypes

111
Q

What is the clinical significance of NAT2?

A

FDA recommends genetic based dosing of AMifampridine (K+ channel blocker)

112
Q

What is TPMT?

A
  1. TPMT gene encodes enzyme
  2. Genetic polymorphisms on this gene affect the function of TPMT enzyme.
113
Q

What are the TPMT variations?

A

2, 3A, 3B, and 3C

114
Q

What is the clinical significance of TPMT?

A

A decreased TPMT activity is associated with thiopurine-related toxicity mainly bone marrow suppression.

115
Q

What are the drug metabolized by TPMT?

A

Drugs: Anticancer/immunosuppressive thiopurine derivative agents:
Azathioprine, 6-Mercaptopurine [6-MP], 6-thioguanine [6TGN]

116
Q

What is the most frequent TPMT allele in Caucasians?

A

3A

117
Q

What is the most frequent TPMT allele in Asian and africans?

A

3C

118
Q

What is the most frequent TPMT allele in South american and middle eastern?

A

2

119
Q

How do drug transporters mediate ADME?

A

Regulates the influx and efflux of drugs

120
Q

What do variations in genes coding transporter proteins lead to?

A

Variability

121
Q

How many ABC families are there

A

A-G

122
Q

What is ABCB1 (MDR1)?

A
  1. Encodes PgP. most studied
  2. Limits intestine absorption, mediates exclusion of drugs from entry to brain by BBB.
    Highly polymorphic
123
Q

What are example drugs for ABCB1?

A

Anticancer drugs, Digoxin, Immunosuppressive agents, Glucocorticoids, and Protease inhibitors.

124
Q

What is the most common ABC variant?

A

ABCB1 3435 C< T

125
Q

What is ABCG2?

A
  1. (Breast cancer resistance protein - BCRP)
  2. Transports – Chemotherapeutic agents, Antivirals, Antibiotics.
    3.Important in the intestinal absorption and biliary excretion
126
Q

What are example drugs for ABCG2?

A

– Rosuvastatin, Allopurinol.

127
Q

What is an example of efflux transporters?

A

ATP-Binding Cassette (ABC)

128
Q

What is an example of influx transporters?

A

Organic Anion Transport Polypeptides (OATPs) or Solute carrier organic anion transporters (SLCO).

129
Q

What is the function of OATPs?

A
  1. Mediate uptake of a broad range of drugs into cells.
  2. Expressed in a variety of different tissues: Intestine, liver, kidney and brain.
130
Q

What are the drugs for OATPs?

A

Statins, Cardiac glycosides, Methotrexate and Rifampicin.

131
Q

What are the variants of OATPs?

A

1B1, 1A2, 1B3, 2B1

132
Q

What is the clinical significance for OATPs?

A
  1. All statins are transported from circulation to liver by OATP1B1:
  2. ↓ transporter activity due to SNPs (SLCO1B1*1b, SLCO1B1 *5)  statin induced myopathy
133
Q

What are the Pharmacodynamic Consequences of VKORC1?

A

Major gene influencing pharmacodynamics warfarin.

134
Q

What are the Pharmacodynamic Consequences of HMG-CR?

A

Statin responsiveness at lowering LDL cholestrol

135
Q

What are the Pharmacodynamic Consequences of ADRB2?

A

Altered response to b-agonists

136
Q

What are the Pharmacodynamic Consequences of ACE?

A

Altered response to ACE inhibitors for treating hypertension

137
Q

What are the Pharmacodynamic Consequences of Dopamine D2 receptor gene?

A

Altered response to antipsychotic medicatiosn

138
Q

What are HLAs?

A

The genetic region of the MHC

139
Q

Where are HLAs found?

A

Group of genes located at 6p21

140
Q

What are HLAs are associated with?

A

drug induced hypersensitivity reactions such as Stevens-Johnson Syndrome (SJS) & drug-induced liver injury (DILI).

141
Q

What are example drugs that are associated with HLAs?

A

Antiepileptic drugs (Carbamazepine, Phenytoin) & Antiretroviral drug (Abacavir)

Pharmacokinetics (29 decks)

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