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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
What is a genotype?
2 alleles inherited for a particular gene Genetic contribution to the phenotype
26
What is a phenotype?
Observable traits
27
What are haplotypes?
Set of genes or DNA variations that tend to be inherited together from the same parent
28
What is genetic/DNA sequencing?
Process of working out the exact order of bases in a DNA molecule
29
What are the regions of a gene?
1. Regulatory region 2. Coding region 3. Noncoding region
30
What is a promoter?
Regulatory region where transcription of gene is initiated
31
What is an exon?
The portion of a gene that codes for amino acids
32
What is an intron?
Non-coding regions of an RNA transcript that is eliminated by splicing before translation
33
What are genetic variations?
Refers to differences in gene sequences between individuals or populations
34
What is the source of genetic variation?
Mutation
35
What is a mutation?
Change in DNA sequence
36
What can cause mutations?
1. DNA copying mistakes during cell division, 2. exposure to ionizing radiation or chemicals 3. infection by viruses
37
What is polymorphism?
A certain mutation occurs in 1% or more frequencies in a given population
38
What is the result of polymorphism?
Functional or non-functional gene products
39
What are common genetic polymorphisms?
1. Single nucleotide polymorphisms (SNPs) -> substitution -> most common 2. Insertion/deletion (Indels) polymorphisms 3. Duplication/repeat polymorphisms 4. Copy-number variations (CNVs)
40
What are snips (SNPs)?
Represent more than 90% of all human genetic variations Involve variation of a single base pair substitution
41
What is insertion?
Involves the addition of genetic material
42
What is deletion?
Involves the loss of genetic material
43
What is duplication?
Involves the production of one or more copies of a gene
44
What is copy number variations (CNVs)?
The number of copies of a particular gene varies from one individual to the next
45
What is ultra-rapid metabolizers (UM)?
Individuals with high enzyme activity. They may have more than two functional alleles of the enzyme in question.
46
What are extensive metabolizers (EM)?
Individuals with at least one or two normal functional alleles of the enzyme in question.
47
What is intermediate metabolizers (IM)?
Individuals with (two reduced functional alleles of the enzyme in question or one non-functional allele and the other allele with reduced function.
48
What is poor metabolizers (PM)?
Individuals with significantly reduced or no enzyme activity. They may have two non-functional alleles of the enzyme in question.
49
What enzyme is associated with expressors and non?
CYP3A5
50
What is the enzyme associated with slow and fast acetylators?
NAT2
51
How do genetic variations change the the structure of target proteins?
Alters the function of protein or rate and kinetic constants of an enzyme
52
What type of polymorphism occurs that affect ADME?
Polymorphisms of drug-metabolizing enzymes and drug transporter proteins
53
What type of polymorphism occurs that affect target protein function and drug-target interaction affecting pharmacodynamics?
Polymorphisms in genes encoding drug targets [receptors, enzymes, ion-channels, etc]
54
What is the major determinant of drug clearance?
Metabolism
55
What are the phases of drug metabolism?
1. Oxidation mainly mediated by CYP450 enzymes 2. Conjugation reactions, mediated by N-acetyl-transferase (NAT), UGTs
56
How many CYP450 enzymes are active in humans?
57
57
Where are CYP450 mainly expressed in?
Liver
58
What reactions do CYP450 catalyze?
Catalyzes the mono-oxygenation of lipophilic drugs to produce metabolites with increased water solubility or for further metabolism by other phase 2 enzymes
59
How is CYP2D6*5 labeled?
CYP: Superfamily 2: Family D: subfamily 6: isform *5: variant allele
60
What is CYP2D6*1/*1?
Wild type homozygous
61
What is CYP2D6*1/*5?
Heterozygous
62
What is CYP2D6*5/*5?
Mutan homozygous
63
How much of drugs are metabolized by CYP2D6?
25%
64
What are type of drugs are metabolized by CYP2D6?
1. Antipsychotic 2. Antiarrythmic 3. Tricyclic antidepressants 4. B-antagonists 5. Opoids 6. Estrogen receptor antagonist
65
What are antipsychotics the are metabolized by CYP2D6?
Haloperidol, clozapine, risperidone
66
What are antiarrhythmics the are metabolized by CYP2D6?
Flecainide and perphenazine
67
What are tricyclic antidepressants the are metabolized by CYP2D6?
Imipramine, clomipramine, nortriptyline, amitriptyline
68
What are b-antagonists the are metabolized by CYP2D6?
Metoprolol, propranolol, bupranolol, carvedilol
69
What are opioids the are metabolized by CYP2D6?
codeine and tramadol
70
What are estrogen receptor antagonist the are metabolized by CYP2D6?
tamoxifen
71
What are the most common CYP2D6 variants?
1, 2, 3, 4, 5, 6, 10, 17, 41
72
Why is CYP2D6 polymorphism important?
1. Poor metabolizers exhibit a higher incidence of undesirable life effects 2. Ultra-rapid metabolizers experience diminished response to these drugs
73
Why is CYP2D6 polymorphism important?
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
How much of drugs are metabolized by CYP2C9? And what are they?
15-20% 1. Anticoagulants 2. Antihypertensive 3. Diuretic 4. Antidiabetics 5. Anticonvulsant 6. NSAIDS
75
What are anticoagulants metabolized by CYP2C9?
Warfarin (narrow TI)
76
What are antihypertensive metabolized by CYP2C9?
Losartan
77
What are diuretic metabolized by CYP2C9?
Torasemide
78
What are antidiabetic metabolized by CYP2C9?
Tolbutamide, glipizide
79
What are anticonvulsant metabolized by CYP2C9?
Phenytoin (narrow TI)
80
What are NSAIDs metabolized by CYP2C9?
Ibuprofen, diclofenac, piroxicam, tenoxicam, mefanamic acid
81
What CYP2C9 variants are common in white people?
2, 3
82
What CYP2C9 variants are common in black people?
5, 6, 8, 11
83
What can you say about people with CYPC9*2 and 3?
poor metabolizers of S-Warfarin
84
What do you do with people who are poor metabolizers of warfarin?
1. Dose adjustment required due to toxicity 2. CYP2C9 genotyping prior to warfarin initiation approved by the FDA and improves the safety profile
85
What drugs are metabolized by CYP2C19?
1. Anti platelet 2. Anti ulcers 3. Anti convulsant 4. Anti malarial 5. Anxiolytics 6. Antidepressants
86
What are antiplatelets metabolized by CYP2C19?
Clopidogrel
87
What are anti-ulcers metabolized by CYP2C19?
Omeprazole
88
What are anti0convulsant metabolized by CYP2C19?
Pheytoin
89
What are anti-malarial metabolized by CYP2C19?
Proguanil -> Cycloguanil (active)
90
What are anxiolytics metabolized by CYP2C19?
Diazepam
91
What are antidepressants metabolized by CYP2C19?
Citalopram, Imipramine, amitriptyline, clomipramine
92
What are the CYP2C19 variants?
2, 3, 17
93
What is the function of CYP2C19*17?
Leads to increased CYP2C19 activity -> rapid clearance of substrate drugs causing a lack of response PPI and antidepressants
94
What are the overlapping expressions of CYP3A4 and 5?
1. Responsible for the metabolism of >50% of drugs 2. CYP3A5 more polymorphic than CYP3A4 3. CYP3A5 (*3, *5, *6 & *7)
95
What is the most common alleles variant?
CYP3A5*3
96
What are drugs that are metabolized CYP1A2?
Coffee, theophylline, estrogen, clozapine, olanzapine
97
What are drugs that are metabolized CYP2A6?
Nicotine
98
What are drugs that are metabolized by CYP2B6?
Bupropion, efavirenz, nevirapine, cyclophosphamide
99
What are the phase 2 metabolizing enzymes?
1. UDP-glucuronosyltransferases (UGTs) 2. N-acetyltransferases (NATs) 3. Thiopurine S-methyltransferase (TPMT)
100
What is the result of a defective UGT1A1 gene?
Hypebilirubinemia
101
What the function of UGT1A1?
Major role in the glucuronidation of bilirubin
102
What is UGT1A1*28?
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 of UGT1A1 gene
103
What is the clinical significance of UGT1A1?
1. Susceptible to Irinotecan toxicity (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
What are examples drugs that are metabolized by UGT2B7?
Opiods, NSAIDS, antiepileptics, cancer drugs, antiretrovirarls, and lypolipidemic agents
105
What is the common variant of UGT2B7
2
106
What is the clinical significance of UGT2B7?
1. Diclofenac (NSAID)  undergoes extensive glucuronidation by UGT2B7 2. Reduced-activity of the enzyme in individuals with UGT2B7*2  predispose to ↑ risk of hepatotoxicity from reactive diclofenac.  
107
What does NAT2 do?
Is a phase-2 metabolic enzyme that conjugates with acetyl-groups
108
What is acetylation important for?
1. Isoniazide 2. Hydralazine 3. Procainamide 4. Nitrazepam 5. Sulfonamides 6. Dapsone 7. Phenelezine 8. Zonisamide 9. amifampridine
109
What encodes NAT2?
NAT 2 gene
110
What are the SNPs in NAT2 responsible for?
Fast and slow acetylator phenotypes
111
What is the clinical significance of NAT2?
FDA recommends genetic based dosing of AMifampridine (K+ channel blocker)
112
What is TPMT?
1. TPMT gene encodes enzyme 2. Genetic polymorphisms on this gene affect the function of TPMT enzyme.
113
What are the TPMT variations?
2, 3A, 3B, and 3C
114
What is the clinical significance of TPMT?
A decreased TPMT activity is associated with thiopurine-related toxicity mainly bone marrow suppression.
115
What are the drug metabolized by TPMT?
Drugs: Anticancer/immunosuppressive thiopurine derivative agents: Azathioprine, 6-Mercaptopurine [6-MP], 6-thioguanine [6TGN]
116
What is the most frequent TPMT allele in Caucasians?
3A
117
What is the most frequent TPMT allele in Asian and africans?
3C
118
What is the most frequent TPMT allele in South american and middle eastern?
2
119
How do drug transporters mediate ADME?
Regulates the influx and efflux of drugs
120
What do variations in genes coding transporter proteins lead to?
Variability
121
How many ABC families are there
A-G
122
What is ABCB1 (MDR1)?
1. Encodes PgP. most studied 2. Limits intestine absorption, mediates exclusion of drugs from entry to brain by BBB. Highly polymorphic
123
What are example drugs for ABCB1?
Anticancer drugs, Digoxin, Immunosuppressive agents, Glucocorticoids, and Protease inhibitors.
124
What is the most common ABC variant?
ABCB1 3435 C< T
125
What is ABCG2?
1. (Breast cancer resistance protein - BCRP) 2. Transports – Chemotherapeutic agents, Antivirals, Antibiotics. 3.Important in the intestinal absorption and biliary excretion
126
What are example drugs for ABCG2?
– Rosuvastatin, Allopurinol.
127
What is an example of efflux transporters?
ATP-Binding Cassette (ABC)
128
What is an example of influx transporters?
Organic Anion Transport Polypeptides (OATPs) or Solute carrier organic anion transporters (SLCO).
129
What is the function of OATPs?
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
What are the drugs for OATPs?
Statins, Cardiac glycosides, Methotrexate and Rifampicin.
131
What are the variants of OATPs?
1B1, 1A2, 1B3, 2B1
132
What is the clinical significance for OATPs?
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
What are the Pharmacodynamic Consequences of VKORC1?
Major gene influencing pharmacodynamics warfarin.
134
What are the Pharmacodynamic Consequences of HMG-CR?
Statin responsiveness at lowering LDL cholestrol
135
What are the Pharmacodynamic Consequences of ADRB2?
Altered response to b-agonists
136
What are the Pharmacodynamic Consequences of ACE?
Altered response to ACE inhibitors for treating hypertension
137
What are the Pharmacodynamic Consequences of Dopamine D2 receptor gene?
Altered response to antipsychotic medicatiosn
138
What are HLAs?
The genetic region of the MHC
139
Where are HLAs found?
Group of genes located at 6p21
140
What are HLAs are associated with?
drug induced hypersensitivity reactions such as Stevens-Johnson Syndrome (SJS) & drug-induced liver injury (DILI).
141
What are example drugs that are associated with HLAs?
Antiepileptic drugs (Carbamazepine, Phenytoin) & Antiretroviral drug (Abacavir)

Pharmacokinetics (29 decks)

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