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E'Pharmacology Test 1 Fall '24 > 9/09 Class 5 > Flashcards

9/09 Class 5 Flashcards

1
Q

What is a big reason why people react differently to drug and drug regimens?

A

Genetics (idiosyncratic)

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2
Q

A Person who is hyporeactive is someone who

A

does not respond well to a drug or drug regimen

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3
Q

A Person who is hyperreactive is someone who

A

Overresponds to a drug or drug regimen

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4
Q

Different genes are turned on at

A

different ages (pre-puberty vs post-puberty)

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5
Q

What is “personalized pharmacology”?

A

Specific genetic testing, looking for polymorphisms, in order to predict whether a drug or regimen will be beneficial.

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6
Q

What is polymorphisms?

A

Changes in genes that are going to affect how you metabolize a particular drug

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7
Q

Pharmacogenomics helps _________, ___________ and __________

A

predict (normal dose, reduced increased and alternative therapy) , explain and treat

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8
Q

Usually we do DNA tests to

A

Explain a certain reaction vs. to predict.

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9
Q

What is the goal of personalized medicine?

A

Right dose
Right drug
Right indication
Right patient
Right time

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10
Q

How many bases are in the human genome?

A

6.4 Billion

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11
Q

Half of our genes come from our

A

mother and the other half from our father

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12
Q

How many different genes do we have?

A

30,000

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13
Q

What percent of our genes code for protein?

A

only 1-2%

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14
Q

What explains all of the differences that we see in the people around us?

A

the 0.1% difference in all our genes

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15
Q

What does SNP stand for?

A

single nucleotide polymorphisms

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16
Q

What are SNPs?

A

A single nucleotide that explains all the differences that we see.

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17
Q

What is a Loci?

A

the location of where a gene is on a chromosome (Chromosome 7, P arm, Q-arm, etc)

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18
Q

What is an allele?

A

an alternate version of the gene at the same loci (like 1 from mom and 1 from dad)
a variant from the wild type

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19
Q

Every 3 base pairs in the DNA codes for

A

one amino acid in a protein

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20
Q

What is a silent mutation?

A

A polymorphism that doesn’t change the protein and is not detectable unless you do DNA testing

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21
Q

What is a non-synonymous SNP?

A

A polymorphism that does change the protein and can therefore have a significant effect, although not always.

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22
Q

In a person who has the gene that inactivates CYPC219, how will Plavix work on them?

A

It is metabolized by multiple enzymes, so the patient can still take Plavix, but the result may be less than it would be in a person who didn’t have this gene

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23
Q

Describe a poor metabolizer

A

A person who has a gene that decreases the effect of a certain enzyme. The enzyme is still working, but the it works at a slower rate.
A person with this gene who takes an active drug that is metabolized by this enzyme will see the active effects of this drug for much longer

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24
Q

A person who is a poor metabolizer takes a prodrug that requires metabolism to work. What is the result?

A

poor efficacy and possible accumulation of prodrug.

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25
Q

A person who is a poor metabolizer takes an active drug that is inactivated by metabolism. What is the result?

A

Good efficacy and possible accumulation of the active drug which can produce adverse reactions.

This pt. might require a lower dose

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26
Q

What is an example of an active drug that is inactivated by metabolism?

A

Omeprazole

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27
Q

A person who is an ultra-rapid metabolizer takes a prodrug that requires metabolism to work. What is the result?

A

good efficacy and rapid effect

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28
Q

A person who is an ultra-rapid metabolizer takes an active drug that is inactivated by metabolism. What is the result?

A

poor efficacy and needs a greater dose of slow release formulation

Why?
They get rid of the drug very quickly

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29
Q

What do we look at for personalized drugs in the field of Hematology/Oncology?

A

the Tumor’s genetics.

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30
Q

What percent does hematology/oncology represent on the graph that describes which fields run genetic testing?

A

38%

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31
Q

What is a purine?

A

Adenine and guanines

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32
Q

What does incorporating a purine analog into a cancer cell do?

A

it stops the DNA from forming, essentially blocking a rapidly dividing cell from dividing.

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33
Q

What are examples of diseases that purine analogs treat?
What do all of these have in common?

A

Lymphoblastic leukemia
autoimmune disease (overproduction of B and T cells)
inflammatory bowel disease
after transplant

They all involve rapidly dividing cells

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34
Q

How can purine analogs be toxic?

A

They suppress the immune system

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35
Q

What is 6-Methyl mercaptopurine?

A

a degradation product of of 6-mercaptopurine

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36
Q

What is the enzyme that 6mercaptopurine relies on to degrade it?

A

TPMT

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37
Q

If a patient is TPMT deficient, what happens?

A

they can build up toxins very quickly (dosing is personalized)

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38
Q

What defines a person as a Type 1 when it comes to 6mercaptopurine?

A

They have 2 alleles that include the TPMT gene

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39
Q

What is TPMT?

A

Thiopurine Methyltransferase

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40
Q

What defines a person as a poor metabolizer when it comes to 6mercaptopurine?

A

They have 1 alleles that include the TPMT gene, and the other does not, a SNP. This is also called heterozygous.

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41
Q

What determines if someone is an ultra-poor metabolizer of 6mercaptopurine?

A

When someone inherits 2 of the genes without TPMT. They wont know until they take 6MP (Adjust dose as needed)

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42
Q

What do we do for poor metabolizers?

A

We adjust the dose, or change the drug altogether.

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43
Q

What was warfarin used for in the past?

A

Rat Poison

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44
Q

Why does warfarin have significant problems for humans?

A
  • Ranks #1 in total mentions of deaths for drugs causing adverse evens
  • ranks among the top drugs associated hospital ER visits for bleeding
  • overall frequency of major bleeding range from 2%-16%
  • Minor bleeding even rates as high as 29% per year
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45
Q

Warfarin is metabolized by what?

A

CPY2C9

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46
Q

What is Warfarin made of?

A

A racemic mixture of R and S warfarin

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47
Q

S Warfarin has a ________ X potency of R

A

7-10 (S-CYP2C9.. R-CYP2C19)

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48
Q

Are R and S Warfarin metabolized in the same way?

A

No, they use different enzymes. This can be bad because you may only have genes that work on one or the other

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49
Q

Genetic testing allows for what? (recommended, not required)

A

a more rapid determination of stable therapeutic dose
a better prediction of dose
This reduces between 4500-22000 serious bleeding evens annually.

50
Q

Patient’s who carry at least one copy of such a variant allele (as CYP2C92 and CYP2C93) have

A

reduced metabolism leading to higher warfarin concentrations

= more likely to bleed out

51
Q

how many new breast cancer cases are diagnosed each year in the USA?

A

200,000

52
Q

New testing can better predict _________

A

recurrence and potential benefit from treatments

53
Q

What feeds breast cancer cells?

A

Estrogen
Progesterone

54
Q

What are the markers that we follow in breast cancer?

A

Estrogen Receptors (ER)
Progesterone Receptors (PR)
HER2

55
Q

Normal cells have one copy of the HER2 on each

A

chromosome 17

56
Q

In 15-20% of breast cancers, HER2 is how much more amplified?

A

2-20X

57
Q

What does having HER2, and the proteins that produce HER2, being amplified do?

A

The proteins surround the surface of the cell and respond to growth factors. This growth factor is going to cause proliferation.

58
Q

What is one type of treatment for Breast cancer?

A

estrogen deprivation (estrogen therapy for menopause is bad)

59
Q

Where are estrogen, progesterone, and HER2 receptors found?

A

on the surface of the cell wall

60
Q

What do HER2 positive cancers respond to?

A

Herceptin. Have to be DNA tested before taking

61
Q

What it the other name for Herceptin?

A

Trastuzumab

62
Q

ER and Tumors respond to ___________ or ____________-

A

tamoxifen; aromatase inhibitors

63
Q

How does Herceptin/Trastuzumab work?

A

Binds to the HER2 receptors that are overproduced, and stop the signaling of growth factor receptors.

64
Q

What are special carriers?

A

molecules bind to the drug and move move across barriers ( if not too small or goes through ion channel)
Can be on mitochondria and vesicles as well

65
Q

What is the primary function of special carriers?

A

Transport endogenous substances and some xenobiotics

66
Q

Where are special carriers found?

A

Intestine
liver
kidney
Blood Brain Barrier
Blood Placenta Barrier
Blood Testes Barrier

67
Q

How many genes write for transporters?

A

7%

68
Q

What does SLC stand for?

A

solute carrier protein

69
Q

What percent of membrane proteins are transporters?

A

15-30%

70
Q

What are the passive transporters talked about in pharm?

A

coupling transporter (Na+/Glucose)
Exchanger (1 thing goes out another goes in. NCX in the heart)
K+ through simple diffusion down the concentration and electrical gradient

71
Q

What is the single most important active transporter?

A

Na+/K+ pump

72
Q

What are drug efflux transporters?

A

Transporters that bind and either push drugs into the cell or back out of the cell?
Cancer cells adapt/mutate to push cancer drug out of cell

73
Q

Why did we come up with the term multidrug resistant cancer?

A

Because patient’s were being given cancer treatments and it would work for a while then stop, given another drug and same thing.

It turns out this was happening because the drug efflux pumps were increasing over time in response to these drugs

74
Q

If one drug was being “pumped out” of the cancer cells, what other drugs were being affected too?

A

Drugs of the same class because they have a similar mechanism of action
Termed “broad substrate specificity”

75
Q

Most of the efflux transporters require what?

A

ATP

76
Q

what is the progression of names for binding sites that resist or pump back out medications?

A

Multi Drug Resistant MDR
Multidrug Resistant Protein
ATP Binding cassette ABC

77
Q

What is a nucleotide binding domain?

A

a nucleotide is binding to them (an ATP)

78
Q

How many ABC families are there?

A
  1. A-G with over 50 different genes (subfamilies)
79
Q

ABCA1 Cholesterol efflux

A

Regulates cholesterol within cell (low-brings in. High-takes it out)

80
Q

Where is the apical surface?

A

The side that faces the organ (gut)

81
Q

Where is the basal surface?

A

The side that faces the blood

82
Q

What are the major efflux transporters?

A

BCG
ABC B
ABC C
ABC G

83
Q

What are other names for ABCB1?

A

P-Glycoprotein
MDR1

84
Q

What kind of specificity does ABCB1 have?

A

broad

85
Q

Where are ABCB1’s found?

A

Wide distribution including the
GI
Liver
Kidney
Testes
Critical in the BBB

86
Q

What drugs are examples of ABCB1 inhibitors?
How effect does this have?

A

Cyclosporine A
Quinidine
Ritonavir
These drugs basically turn off the ABC1 transporter, which can lead to other drugs that typically get thrown by this transporter building up to toxic levels

87
Q

What is a drug that is usually transported by ABCB1?

A

Digoxin

88
Q

Where in the body is ABCB1 important in?

A

The gut

89
Q

Why do people take quinidine with loperamide?

A

To get high off of the loperamide (opioid).
The quinidine blocks ABCB1 transporter from getting rid of the loperamide through the intestine.
This can lead to respiratory suppression.

90
Q

Besides ABCB1, what are other ABC transporters?

A

ABCC
ABCG2

91
Q

ABCC is:

A

largest class, ubiquitous (many proteins, but doesn’t transport as many drugs as ABCB1

Mainly for antineoplastic efflux.

92
Q

ABCG2 is used for:

A

A breast cancer resistant protein (BCRP)
antineoplastics, toxins, food-borne carcinogens
folate transport

93
Q

Non-ABC Drug efflux transporter:

A

SLC21
Do not have ATP binding cassettes
so are largely passive and work with gradients

94
Q

What does OATP stand for?

A

Organic anion-transporter proteins

95
Q

vast majority of the transporters on the cell wall of the intestine are oriented to _____

A

push drugs into the intestine

96
Q

vast majority of the transporters on the cell wall of the placenta are oriented to _____

A

push drugs back into the blood

97
Q

vast majority of the transporters on the cell wall of the liver are oriented to _____

A

push drugs into the liver

98
Q

vast majority of the transporters on the cell wall of the blood-cerebrospinal fluid are oriented to _____

A

mostly push drugs back into the blood but some -cains can make it through

99
Q

vast majority of the transporters on the cell wall of the brain are oriented to _____

A

push drugs back into the blood

100
Q

vast majority of the transporters on the cell wall of the kidney are oriented to _____

A

Push drugs into the kidney

101
Q

What are the 3 reasons that it is difficult to get across the BBB?

A

ABC transporters
Vascular epithelium-tight junctions(no leaky capillaries)
Other cells that surround the brain vascular space
-astrocyte
-podocyte

102
Q

What are Glia cells?

A

astrocytes
podocytes

Create TIGHT junctions in BBB

103
Q

what are the types of things that can cross the BBB and cross through selective active efflux transporters

A

small lipophilic molecules
O2
CO2
ethanol
nicotine

104
Q

What are carrier protein-mediated things that get into the BBB?

A

Glucose
amino acids
nucleotide

105
Q

What are very large molecules that require receptor mediated endocytosis?

A

Insulin
Transferrin
IgG

106
Q

How does albumin histone get into the BBB?

A

through adsorptive endocytosis.
Cell swallows it and spits it out on the other side.

107
Q

How does the brain get the things that it needs?

A

Through
Carrier protein mediated pathways
receptor mediated endocytosis
receptor mediated endocytosis

108
Q

The blood-CSF barrier has less _____

A

eflux
some drugs given here can reach the brain but so far not many antineoplastic drugs

109
Q

Where are most of the transporters located in the GI tract?

A

On the apical surface of the cells on the microvili

110
Q

What are microvili?

A

Finger like projections that increase cell surface area

111
Q

Which transporter is most common in the GI tract?

A

ABCG2 (BCRP)
ABCC (MRPs)

112
Q

How is Acetaminophen metabolized?

A

Glucuronidation in the liver

113
Q

How does Acetaminophen metabolism work?

A
  1. Take oral Acetaminophen
  2. Goes through the intestines to be absorbed into the GI tract and go to the liver
  3. Liver has CYP450 and phase 2 metabolism
  4. Glucuronidation attaches a glucose molecule to the drug making it a non-toxic glucuronide
  5. Some goes to the brain, the pieces with glucose stuck to it get put into bile and excreted through the feces
114
Q

Where are most drugs headed after the liver?

A

Blood
Liver
Bile

115
Q

The liver facilitates what?

A

xenobiotic metabolism with excrection into the bile

116
Q

Why can nicotine and alcohol cross over into the placenta?

A

They are very lipophilic

117
Q

What upregulates efflux transporters?

A

PXRs
Steroids
Xenobiotics

118
Q

Why do PXRs, steroids, and xenobiotics increase the amount of transporters on the cell?

A

Because the cell doesn’t want it and so increases transporters to keep them out of the cell.

119
Q

What is released by the blood vessels in the pulmonary circulation that decreases pulmonary htn by relaxing smooth muscle?

A

Endothelen

120
Q

CYP2D6 catalyzes metabolism of

A

beta-blockers
class 1C antiarrhythmic
Analgesics
Various antidepressants
5HT3 inhibitors

E'Pharmacology Test 1 Fall '24 (5 decks)

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