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Pharmacology Test 4 > Pharmacogenomics 2 > Flashcards

Pharmacogenomics 2 Flashcards

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1
Q

The rate of warfarin metabolism(phenotype) is dependent on what genotype?

A

CYP2C9

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2
Q

Which enzyme is special in that sometimes it has deleted polymorphisms and sometimes it has duplicated polymorphisms?

A

CYP2D6

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3
Q

Why do we genotype people?

A

To ensure efficacy

To prevent toxicity

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4
Q

Why is it important to genotype the tumor?

A

Because the tumor may have different genes then the rest of the body.

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5
Q

When are polymorphisms in genes coding for drug metabolizing enzymes important?

A

When metabolism is the major route for elimination or termination of drug action.
When the drug requires metabolic activation (Plavix)
When an altered metabolic pathway or parent compounds cause toxicity or side effects.

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6
Q

What is the biggest factor responsible for variation in drug response?

A

Inherited variation

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7
Q

What are the first poor metabolizers discovered?

A

Butyrylcholinesterase (BChE)

N-acetyltransferase 2 (NAT2)

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8
Q

What are the iconic second generation poor metabolizers?

A

CYP2D6

thiopurine S-methyltransferase (TPMT)

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9
Q

What are examples of variant drug metabolizing enzymes?

A 
butyrylcholinesterase (BChE)
N-Acetyltransferase 2 (NAT2)
CYP2D6
CYP2C9
CYP2C19
UDP-Glucuronosyl-transferase (UGT1A1)
Thiopurine Methyltransferase (TPMT)
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10
Q

What does the enzyme butyrylcholinesterase (BChE) do?

A

Hydrolyzes the short acting muscle relaxant succinylcholine (anesthetic). The enzyme is required for degradation of succinylcholine.

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11
Q

What are the butyrylcholinesterase (BChE) phenotypes?

A 
Extensive metabolizers (wild type)
Slow metabolizers (frequency 1:3000)
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12
Q

What does the enzyme N-acetyltransferase 2 (NAT2) do?

A

Its a genetically polymorphic phase II enzyme that catalyzes the acetylation of isoniazid (treats tuberculosis).

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13
Q

What are the N-acetyltransferase 2 (NAT2) phenotypes?

A 
Fast acetylators (wild type)
Slow acetylators (variant)
Middle Easterners are 80% slow
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14
Q

What selective toxicity do slow acetylators of the NAT2 enzyme have?

A

Procainamide-induced lupus erythematosis

Isoniazid-induced peripheral nerve damage

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15
Q

What selective toxicity do fast acetylators of the NAT2 enzyme have?

A

Isoniazid induced hepatotoxicity

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16
Q

Which enzyme polymorphism contributes to a large number of medications (15-25%) and may have gene deletions or copy number variants?

A

CYP2D6
CYP2D65 deletion
CYP2D62xN copy number variant

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17
Q

The CYP2D6*2xN phenotype is?

A

Ultrarapid metabolizers

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18
Q

The CYP2D6*5 phenotype is?

A

Poor metabolizers

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19
Q

Which ethnic frequency for the CYP2D6 phenotype is important?

A

Ethiopians are 13-29% ultrarapid metabolizers

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20
Q

What is the clinical significance of the poor metabolizer phenotype of the CYP2D6?

A

Adverse drug effects when treated with standard doses

Therapeutic failure for drugs that need to be activated by 2D6

21
Q

What is the clinical significance of the ultra rapid metabolizer phenotype of the CYP2D6?

A

May need super-doses

Could “overdose” UM on drugs that must be activated such as Codeine

22
Q

What are some of the narrow therapeutic index drugs metabolized by CYP2C9?

A

Warfarin
Tolbutamide
Phenytoin
Glipizide

23
Q

What are some inhibitors of the CYP2C9?

A 
Phenylbutazone
Sulfinpyrazone
Amiodarone
Miconazole
Fluconazole
24
Q

What are the most common variants of CYP2C9?

A

CYP2C9*2 (20% activity)

CYP2C9*3 (5% activity)

25
Q

Which ethnic frequency for the CYP2C9 phenotype is important?

A

Causcasians are 30% low activity variant
African Americans are categorized for 1-3% low activity but this is not true. It happens much more often so new studies need to be done.
East Asians are 0%

26
Q

Which variant has a 90% reduction in S-warfarin clearance?

A

homozygous CYP2C9*3

27
Q

What are the substrates of CYP2C19?

A

PPIs, fluoxetine, sertraline, and diazepam

28
Q

What are the phenotypes of the CYP2C19 variants?

A

Extensive metabolizers

Poor metabolizers

29
Q

Which ethnic frequency for the CYP2C19 phenotype is important?

A

East Asians are 25% poor metabolizers

30
Q

What is the clinical significance of CYP2C19 variants?

A

SSRIs - increased adverse drug reactions
Diazepam - increased sedation
PPI’s - increased ulcer healing (they don’t clear the drug)

31
Q

What does the UDP-Glucuronosyl-transferase (UGT1A1) usually do?

A

It is located in the promoter region and transcribes an enzyme that usually clears the SN38 metabolite created by irinotecan (cancer treatment).

32
Q

What is the variant for UDP-Glucuronosyl-transferase (UGT1A1) and what does it do?

A

It is a promoter region variant that decreases the transcription rate and causes lower Glucuronidation activity. This causes an increase in the SN-38 metabolite created by Irinotecan and therefore causes bone marrow suppression.

33
Q

What does the TPMT variant do?

A

It causes 6-MP(cancer) and Azathioprine(immunosuppressant) to not be cleared and therefore causes bone marrow suppression.

34
Q

What was the first drug that must be genotyped?

A

Mercaptopurine(6-MP) for the TPMT*3A SNP

35
Q

Which TPMT variants have significantly reduced activity?

A

TPMT*3A

TPMT*3C(East Asians)

36
Q

What are the phenotypes for TPMT variants?

A

Extensive
Intermediate
Poor
(Measure the enzyme activity in RBCs)

37
Q

Why is genetic testing fro the TPMT variant important?

A

Because 100% of homozygous deficient patients will need dose reduction (tolerate less than 10%) and 35% of heterozygotes need dose decrease.

38
Q

Which transporter is encoded by the ABCB1 gene?

A

P-gp

39
Q

What drugs does P-gp affect?

A

Digoxin, cyclosporine and tacrolimus, and antiretroviral protease inhibitors.

40
Q

Why is P-gp expression clinically important?

A

Reduced expression - supratherapeutic levels

Increased expression - sub therapeutic expression

41
Q

Where do the common P-gp variants occur?

A 
12 (C1236T)
21 (G2677T)
26 (C3435T)
21 and 26 are associated with intestinal expression, digoxin plasma concentration
26 - protease inhibitors.
42
Q

What are the important variations in drug targets?

A 
B1 Receptor
B2 Receptor
Epideraml Growth Factor Receptor
5-Lipoxygenase
Angiotensin-Converting Enzyme
43
Q

What variants in the B1 receptor are important and what do they affect?

A

Ser49Gly
Arg389Gly
less response to metoprolol (beta blockers)

44
Q

What variants in the B2 receptor are important and what do they affect?

A

Coding block region, codon Arg16Gly
Coding block region, codon 27
Upstream in promoter region
may causes less response to asthma medications

45
Q

What variants in the Epidermal Growth Factor Receptor (EGFR) are important and what do they affect?

A

HER1
ErbB1
They are over expressed in tumors so geftinib will genotype for it and will respond.

46
Q

What variants in the 5-Lipoxygenase are important and what do they affect?

A

5 repeat alleles in the promoter region of gene ALOX5 that increase expression of 5-lipoxygenase. Will not affect the severity of asthma but indications that subjects with at least one copy will respond to the drug.

47
Q

A poor metabolizer doesn’t need to cause a disease to influence the treatment for that disease. T/F

A

True

48
Q

What variants in the angiotensin-converting enzyme (ACE) are important and what do they affect?

A

poor metabolizer insertion/deletion in intron 16 resulting in prescence of 287-base pair fragment
small study says it may cause cough whereas larger study didn’t find correlation.
Possibly angioedema - needs more studies

49
Q

What can affect the efficacy of warfarin?

A

Poor metabolizers of the CYP2C9*2 or *3

Ineffective reductase of the Vitamin K epoxide reductase (decreased target enzyme)

Pharmacology Test 4 (5 decks)

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