Pharm Test 1 Flashcards
What is a big reason why people react differently to drug and drug regimens?
Genetics
A Person who is hyporeactive is someone who
does not respond well to a drug or drug regimen
A Person who is hyperreactive is someone who
Overresponds to a drug or drug regimen
Different genes are turned on at
different ages (pre-puberty vs post-puberty)
What is “personalized pharmacology”?
Specific genetic testing, looking for polymorphisms, in order to predict whether a drug or regimen will be beneficial.
What is polymorphisms?
Changes in genes that are going to affect how you metabolize a particular drug
Usually we do DNA tests to
Explain a certain reaction vs. to predict.
What is the goal of personalized medicine?
Right dose
Right drug
Right indication
Right patient
Right time
How many bases are in the human genome?
6.4 Billion
Half of our genes come from our
mother and the other half from our father
How many different genes do we have?
30,000
What percent of our genes code for protein?
1-2%
What explains all of the differences that we see in the people around us?
the 0.1% difference in all our genes
What does SNP stand for?
single nucleotide polymorphisms
What are SNPs?
A single nucleotide that explains all the differences that we see.
What is a Losi?
the location of where a gene is on a chromosone
What is an allele?
an alternate version of the gene at the same loci (like 1 from mom and 1 from dad)
a variant from the wild type
Every 3 base pairs in the DNA codes for
one amino acid in a protein
What is a silent mutation?
A polymorphism that doesn’t change the protein and is not detectable unless you do DNA testing
What is a non-synonymous SNP?
A polymorphism that does change the protein and can therefore have a significant effect, although not always.
What does PM stand for?
Poor metabolizer
In a person who has the gene that inactivates CYPC219, how will Plavix work on them?
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
Describe a poor metabolizer
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
A person who is a poor metabolizer takes a prodrug that requires metabolism to work. What is the result?
poor efficacy and possible accumulation of prodrug.
A person who is a poor metabolizer takes an active drug that is inactivated by metabolism. What is the result?
Good efficacy and possible accumulation of the active drug which can produce adverse reactions.
This pt. might require a lower dose
What is an example of a prodrug that needs to be metabolized to work?
codeine-> morphine
What is an example of an active drug that is inactivated by metabolism?
Omeprazole
A person who is an ultra-rapid metabolizer takes a prodrug that requires metabolism to work. What is the result?
good efficacy and rapid effect
A person who is an ultra-rapid metabolizer takes an active drug that is inactivated by metabolism. What is the result?
poor efficacy and needs a greater dose of slow release formulation
Why?
They get rid of the drug very quickly
Delete
Me
Delete
Me
What do we look at for personalized drugs in the field of Hematology/Oncology?
the Tumor’s genetics.
What percent does hematology/oncology represent on the graph that describes which fields run genetic testing?
38%
What is a purine?
Adenine and guanines
What does incorporating a purine analog into a cancer cell do?
it stops the DNA from forming, essentially blocking a rapidly dividing cell from dividing.
What are examples of diseases that purine analogs treat?
What do all of these have in common?
Lymphoblastic leukemia
autoimmune disease
inflammatory bowel disease
after transplant
They all involve rapidly dividing cells
How can purine analogs be toxic?
They suppress the immune system
What is 6-Methyl mercaptopurine?
a degradation product of of 6-mercaptopurine
What is the enzyme that 6mercaptopurine relies on to degrade it?
TPMT
If a patient is TPMT deficient, what happens?
they can build up toxins very quickly
What defines a person as a Type 1 when it comes to 6mercaptopurine?
They have 2 alleles that include the TPMT gene
What is TPMT?
Thiopurine Methyltransferase
What defines a person as a poor metabolizer when it comes to 6mercaptopurine?
They have 1 alleles that include the TPMT gene, and the other does not, a SNP. This is also called heterozygous.
What determines if someone is an ultra-poor metabolizer of 6mercaptopurine?
When someone inherits 2 of the genes without TPMT
What do we do for poor metabolizers?
We adjust the dose, or change the drug altogether.
What was warfarin used for in the past?
Rat Poison
Why does warfarin have significant problems for humans?
- 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
Warfarin is metabolized by what?
CPY2C9
What is Warfarin made of?
A racemic mixture of R and S warfarin
S Warfarin has a ________ X potency of R
7-10
Are R and S Warfarin metabolized in the same way?
No, they use different enzymes. This can be bad because you may only have genes that work on one or the other
Genetic testing allows for what?
a more rapid determination of stable therapeutic dose
a better prediction of dose
This reduces between 4500-22000 serious bleeding evens annually.
Patient’s who carry at least one copy of such a variant allele (as CYP2C92 and CYP2C93) have
reduced metabolism leading to higher warfarin concentrations
= more likely to bleed out
how many new breast cancer cases are diagnosed each year in the USA?
200,000
New testing can better predict _________
recurrence and potential benefit from treatments
What feeds breast cancer cells?
Estrogen
Progesterone
What are the markers that we follow in breast cancer?
Estrogen Receptors (ER)
Progesterone Receptors (PR)
HER2
Normal cells have one copy of the HER2 on each
chromosome 17
In 15-20% of breast cancers, HER2 is how much more amplified?
2-20X
What does having HER2, and the proteins that produce HER2, being amplified do?
The proteins surround the surface of the cell and respond to growth factors. This growth factor is going to cause proliferation.
What is one type of treatment for Breast cancer?
estrogen deprivation
Where are estrogen, progesterone, and HER2 receptors found?
on the surface of the cell wall
What do HER2 positive cancers respond to?
Herceptin. Have to be DNA tested before taking
What it the other name for Herceptin?
Trastuzumab
How does Herceptin/Trastuzumab work?
Binds to the HER2 receptors that are overproduced, and stop the signaling of growth factor receptors.
What are special carriers?
molecules bind to the drug and move move across barriers
Facilitated diffusion moves down
the concentration gradient
Active transport requires
ATP/ energy
What is the primary function of special carriers?
Transport endogenous substances and some xenobiotics
Where are special carriers found?
Intestine
liver
kidney
Blood Brain Barrier
Blood Placenta Barrier
Blood Testes Barrier
How many genes write for transporters?
7%
What does SLC stand for?
solute carrier protein
What percent of membrane proteins are transporters?
15-30%
What are the passive transporters talked about in pharm?
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
What is the single most important active transporter?
Na+/K+ pump
What are drug efflux transporters?
Transporters that bind and either push drugs into the cell or back out of the cell?
Why did we come up with the term multidrug resistant cancer?
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
If one drug was being “pumped out” of the cancer cells, what other drugs were being affected too?
Drugs of the same class because they have a similar mechanism of action
Termed “broad substrate specificity”
Most of the efflux transporters require what?
ATP
what is the progression of names for binding sites that resist or pump back out medications?
Multi Drug Resistant MDR
Multidrug Resistant Protein
ATP Binding cassette ABC
What is a nucleotide binding domain?
a nucleotide is binding to them (an ATP)
How many ABC families are there?
- A-G with over 50 different subfamilies
Where is the apical surface?
The side that faces the organ
Where is the basal surface?
The side that faces the blood
What are the major efflux transporters?
BCG
What are other names for ABCB1?
P-Glycoprotein
MDR1
What kind of specificity does ABCB1 have?
broad
Where are ABCB1’s found?
Wide distribution including the
GI
Liver
Kidney
Testes
Critical in the BBB
What drugs are examples of ABCB1 inhibitors?
How effect does this have?
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
What is a drug that is usually transported by ABCB1?
Digoxin
Where in the body is ABCB1 important in?
The gut
Why do people take quinidine with loperamide?
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.
Besides ABCB1, what are other ABC transporters?
ABCC
ABCG2
ABCC is:
largest class, ubiquitous (many proteins, but doesn’t transport as many drugs as ABCB1
Mainly for antineoplastic efflux.
ABCG2 is used for:
A breast cancer resistant protein (BCRP)
antineoplastics, toxins, food-borne carcinogens
folate transport
Non-ABC Drug efflux transporter:
SLC21
Do not have ATP binding cassettes
so are largely passive and work with gradients
What does OATP stand for?
Organic anion-transporter proteins
vast majority of the transporters on the cell wall of the intestine are oriented to _____
push drugs into the intestine
vast majority of the transporters on the cell wall of the placenta are oriented to _____
push drugs back into the blood
vast majority of the transporters on the cell wall of the liver are oriented to _____
push drugs into the liver
vast majority of the transporters on the cell wall of the blood-cerebrospinal fluid are oriented to _____
mostly push drugs back into the blood but some -cains can make it through
vast majority of the transporters on the cell wall of the brain are oriented to _____
push drugs back into the blood
vast majority of the transporters on the cell wall of the kidney are oriented to _____
Push drugs into the kidney
What are the 3 reasons that it is difficult to get across the BBB?
ABC transporters
Vascular epithelium-tight junctions(no leaky capillaries)
Other cells that surround the brain vascular space
-astrocyte
-podocyte
What are examples of glia cells? In pharm
astrocytes
podocytes
what are the types of things that can cross the BBB and cross through selective active efflux transporters
small lipophilic molecules
O2
CO2
ethanol
nicotine
What are carrier protein-mediated things that get into the BBB?
Glucose
amino acids
nucleotide
What are very large molecules that require receptor mediated endocytosis?
Insulin
Transferrin
IgG
How does albumin histone get into the BBB?
through adsorptive endocytosis.
Cell swallows it and spits it out on the other side.
How does the brain get the things that it needs?
Lipophilic pathways
Carrier protein mediated pathways
receptor mediated endocytosis
Absorptive endocytosis
The blood-CSF barrier has less _____
eflux
some drugs given here can reach the brain but so far not many antineoplastic drugs
Where are most of the transporters located in the GI tract?
On the apical surface of the cells on the microvili
What are microvili?
Finger like projections that increase cell surface area
Which transporter is most common in the GI tract?
ABCG2 (BCRP)
ABCC (MRPs)
How is Acetaminophen metabolized?
Glucuronidation in the liver
How does Acetaminophen metabolism work?
- Take oral Acetaminophen
- Goes through the intestines to be absorbed into the GI tract and go to the liver
- Liver has CYP450 and phase 2 metabolism
- Glucuronidation attaches a glucose molecule to the drug making it a non-toxic glucuronide
- Some goes to the brain, the pieces with glucose stuck to it get put into bile and excreted through the feces
Where are most drugs headed after the liver?
Blood
Bile
The liver facilitates what?
xenobiotic metabolism with excrection into the bile
Why can nicotine and alcohol cross over into the placenta?
They are very lipophilic
What upregulates efflux transporters?
PXRs
Steroids
Xenobiotics
Why do PXRs, steroids, and xenobiotics increase the amount of transporters on the cell?
Because the cell doesn’t want it and so increases transporters to keep them out of the cell.
What is released by the blood vessels in the pulmonary circulation that decreases pulmonary htn by relaxing smooth muscle?
Endothelen
CYP2D6 catalyzes metabolism of
beta-blockers
class 1C antiarrhythmic
Analgesics
Various antidepressants
5HT3 inhibitors
