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Pharm > Chapter 5: Pharmacogenomics and Drug Transporters > Flashcards

Chapter 5: Pharmacogenomics and Drug Transporters Flashcards

Test 1

1
Q

Define pharmacogenomics and its importance in personalized medicine

A

The study of how an individual’s genetic makeup affects their response to drugs.

It is important for personalized medicine because it allows for predicting drug efficacy and toxicity based on a patient’s genetic profile.

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2
Q

What does idiosyncratic mean?

A

Unusual drug response

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3
Q

Name and describe three drugs that may require dosage adjustments in specific genetic populations, the enzyme or mutation responsible, and the type of testing done to determine susceptible populations.

A
  1. Herceptin which blocks the Her2 receptor on cancer cells
    -Her2
    -Required Biopsy to see if cancer is HER2-positive (over expressing Her2)
  2. Warfarin which is metabolized by CYP2C9
    -CYP2C9
    -Recommended genetic testing for dose adjustments based on CYP2C9 genetic variants
  3. Codeine - Dosage adjustments based on CYP2D6 genetic variants, which affect conversion of codeine to the active metabolite morphine.
    required prior to 6MP administration
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4
Q

How many gene bases do we have?

A

3.2 billion base PAIRS

6.4 billion bases with both strands

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5
Q

_____% of DNA codes for protein

A

1-2%

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6
Q

_____ % of us have the same DNA

A

99.9

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7
Q

How many genes do we have?

A

30,000

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8
Q

How many Single base pairs variants (Single nucleotide polymorphism or SNP) do we have?

A

More than 1 million

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9
Q

What is an locus/loci?

A

Exact location on a chromosome

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10
Q

What are alleles?

A

An alternate form of a gene at the same loci

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11
Q

What is a silent mutation?

A

The different allele doesnt change the amino acid and is not even detectable unless theres a DNA scan.

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12
Q

What does PM stand for?

A

Poor Metabolizer

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13
Q

Prodrug + poor metabolizer =

A

Drug cannot be activated that well. Wont reach its full efficacy
Accumulation of prodrug because not being metabolized (Not being activated nor excreted)

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14
Q

Active drug + poor metabolizer =

A

High efficacy
Stays in the system longer
Not being metabolized fast therefore not being inactivated fast and not excreting fast (stays in system longer)
May need lower dose and/or longer intervals so wont have toxic levels

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15
Q

Prodrug + ultarapid metabolizer =

A

Works fast, high efficacy

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16
Q

Active drug + ultrarapid. metabolizer =

A

Inactivated quick
Cant even reach its full efficacy because its metabolized and inactivated/excreted so quick

Needs greater dose or slow release

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17
Q

CYP2D6

A

Absent in 7% of Caucasians

Hyperactive in 30% of East Africans

Catalyzes metabolism: Betablockers, Class 1C antiarrhythimcs, Analgesics, Various antidepressants/physchotics

5HT3 inhibitor

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18
Q

What activates Codeine?

A

CYP2D6

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19
Q

What inactivates Codeine

A

CYP3A4 to Norcodeine

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20
Q

What is warfarin metabolized by?

A

CYP2C9

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21
Q

Describe Warfarin

A

Metabolized by CYP2C9
Racemic mixture of R- and S- Warfarin
S- warfarin 7-10x more potent

22
Q

What happens if you carry a variant allele of CYP2C9 while taking warfarin?

A

Reduced metabolism of warfarin leading to higher concentrations of warfarin therefore higher risk of bleeding.

23
Q

What causes breast cancer?

A

Overproducing Estrogen and Progesterone receptors

24
Q

What type of treatment is included in breast cancer?

A

Estrogen deprivation

25
Q

HER2+ cancers respond to what drug?

A

Herceptin

26
Q

What is required before starting Herceptin?

A

Biopsy with genetic testing to determine is the tumor is overproducing th HER2 gene

27
Q

Describe the role of drug transporters in the cell

A

Primary function is to transport endogenous substances

Drug transporters play a role in moving or preventing drugs and other substances across cell membranes, facilitating both influx and efflux.

28
Q

Active Transport Requires____

A

ATP

29
Q

Facilitated diffusion requires a ______

A

Concentration Gradient

30
Q

What are the special carriers?

A

Active transport and facilitated diffusion

31
Q

What are 4 specialized barriers?

A

Blood-brain
Blood-placenta
Blood-testes
Blood-ovarian

32
Q

What does xenobiotic mean?

A

Something thats been introduced into the body

33
Q

Define the role of drug efflux transporters

A

Drug efflux transporters, such as the ATP-binding cassette (ABC) transporters, actively pump drugs out of cells, reducing intracellular drug concentrations.

This can cause drug resistance.

34
Q

70% of genes are _______

A

Transporters

35
Q

What are 3 types of passive transporters?

A

Coupled
Exchanger
Passive

36
Q

What is a coupled transporter?

A

It takes 2 things simultaneously through a “sim porter” or coupled transporter

Ex) SGLT

37
Q

Passive transport _____ require ATP

A

does not

38
Q

What is an Exchanger transporter?

A

1 thing goes out and another goes in. Important in the heart.

Ex) NCX

39
Q

What is the most important active transporter?

A

Na/K ATPase

40
Q

List the most important ABC transporters and differences in their drug affinity

A

***ABCB1 (broadest substrate specificity including antineoplastics, HIV protease inhibitors antibiotics, antidepressants, antiepileptics, and opioids). They also have a wide distribution in the body (GI, kidney, liver, testes) and are critical to the maintenance of the blood-brain barrier (BBB)

  • Remember quinidine, cyclosporine A, and Ritonavir are competitive inhibitors to ABCB1
  • Digoxin is transported by ABCB1 and, if inhibited, ABCB1 won’t remove as much resulting in toxic plasma levels.
  • Loperamide typically has no CNS effects but if ABCB1 is inhibited, systemic absorption can occur resulting in CNS effects like respiratory suppression***
  • ABCC - Largest class; ubiquitous; antineoplastics drug
  • ABCG2 is known as the breast cancer resistance protein (BCRP) (antineoplastics, toxins, food-born carcinogens)
  • Also, an efflux transporter of folate
41
Q

ABC transporter require_____

A

ATP

ATP binding cassette transporters

42
Q

Describe an ABC transporter?

A

Transmembrane spanning domains and NBD (Nucleotide binding domains) intracellularlly.

The ATP binds at The C-terminus NBD and then the drug can be pumped out or in to the cell (this depends on the location and orientation of the receptor)

43
Q

What separates the gut from the blood?

A

The basal membrane (closest to blood) and the apical surface (closest to gut)

44
Q

Analyze the anatomic differences between drug transporters in different organs and their overall effects

A

Drug transporters are differentially expressed in organs like the intestine, liver, kidney, and blood-brain barrier. This affects drug absorption, distribution, metabolism, and elimination

45
Q

List the components of the intact blood-brain barrier

A

-The intact blood-brain barrier consists of the vascular endothelium with tight junctions, astrocytes, and podocytes; which together restrict the entry of most drugs into the brain. It has many efflux transporters so even when a drug is allowed in, it may be immediately pumped back out before its effects are seen

-Tight junctions and adherens junction complexes

46
Q

Where does the ABCB1 mostly sit?

A

On the Apical surface

47
Q

Why cant some drugs be taken orally?

A

Some drugs if taken orally will just get pumped back out by an efflux transporter

48
Q

Where are drugs entered and filtered into the kidney?

A

The Glomerulus

49
Q

Where are most of the transporters on the BBB?

A

The vascular epithelium

50
Q

Delineate the pathway of Tylenol in the gut before and after biotransformation

A
51
Q

Describe the transporters for the Blood-CSF barrier

A

On the Pia matter and ependymal cells

Less efflux

Not effective for antineoplastics

52
Q
A

Pharm (5 decks)

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