Pharmacokinetics Flashcards
(179 cards)
1
Q
What are G-protein coupled receptors? How do they work?
A
In the off state, the 3 part (alpha, beta, gamma) of the GPCR is bound to GDP. Once the ligand binds the receptor, the actual g proteins move to the ‘on’ state. The alpha subunit will slowly hydrolyzes GTP to revert the GPCR back to the off state.
2
Q
What is pharmacokinetics?
A
How drugs are administered, distributed, metabolized, and excreted.
3
Q
Describe the central hypothesis of drug therapeutics based on the graph.
A
This graph describes the concentration of the drug in the blood. At the time of ingestion, the concentration is zero until it reaches its peak effect. Blood concentration then decreases until the drug is fully metabolized and excreted. The duration of action of the drug is the line under the peak effect at the therapeutic level.
4
Q
What are the two types of drug administration?
A
Enteral and parenteral administration. (also have insufflation which is nasal admin)
5
Q
What is enteral administration?
A
Oral admin
6
Q
What is parenteral administration?
A
Everything else except oral admin. Includes injections, patches, lotions, sprays, suppositories, etc.
7
Q
What is the most common route of drug administration?
A
Oral
8
Q
How does the speed of absorption compare between oral and injected drugs?
A
Injected drug increases the concentration of that drug much faster than oral drugs.
9
Q
How are the absorption and distribution of a drug measured?
A
Bioavailability
10
Q
What is bioavailability?
A
Measures the plasma drug concentration after oral or IV administration dose over time.
11
Q
Describe bioavailability in terms of the graph.
A
The area under the curve for oral admin is divided by IV dose.
12
Q
The bioavailability of itraconazole is 55% because it is very lipophilic. A formulation of itraconazole and cyclodextrin increased its bioavailability by 30%. How would the curves change for a cyclodextrin formulation?
A
The area under the oral curve would increase.
13
Q
The bioavailability of itraconazole is 55% because it is very lipophilic. A formulation of itraconazole and cyclodextrin increased its bioavailability by 30%. Antacids interfere with drug uptake. How would the curves change for someone taking an antacid?
A
The curves would be smaller.
14
Q
Where does most drug absorption take place?
A
From the gut, most absorption takes place in the stomach and GIT.
15
Q
What are formulations?
A
These can include acid-resistant formulations that protect drugs from breakdown and absorption in the stomach until they enter GIT. Intestines are better for absorption anyways due to there large surface area.
16
Q
How does pH affect drug absorption for acidic drugs?
A
When an acidic drug enters the acidic stomach, the drug is neutralized. This allows the drug to cross the stomach lining and enter the bloodstream. Once in the bloodstream, the drug becomes charged again and cannot return to the stomach.
17
Q
What is an example of a weak acid drug?
A
Aspirin. This is a weak acid that is neutralized by the acid stomach. It crosses the stomach lining and enters the blood stream, where it turns acidic again and cannot re-enter the stomach.
18
Q
How does pH affect drug uptake for basic drugs?
A
Most drugs are weak bases. In the stomach’s acidic environment, they are in their ionized form and cannot cross the epithelial lining of the stomach. However, when weak bases enter a neutral/ alkaline (pH greater than 7) environment like the intestines, the weak base is neutralized and then absorbed.
19
Q
How would an antiacid affect the uptake of a basic drug in the gut?
A
The drug could be neutralized in the stomach due to its lower acidity (more basic) and absorbed there, instead of being absorbed in GIT.
20
Q
To summarize, acidic drugs are taken up by the _________ and basic drugs are taken up by the ___________.
A
Stomach; small intestine
21
Q
Many drugs are basic. If someone overdoses on a weakly basic drug like amphetamine, what is the best way to prevent absorption and increase secretion?
A
Lower the pH with a weak acid like ammonium chloride. Lowering the pH will make the stomach acidic and not neutralize the drug for absorption. Lowering the pH in the intestines will also make it more difficult for the basic drug to be absorbed.
22
Q
When drugs are taken orally, how do they eventually enter the bloodstream?
A
Drugs are absorbed through the gut wall and then transported to the liver via the portal vein.
23
Q
What is first-pass metabolism?
A
This occurs in the liver. It is when drugs are chemically modified.
24
Q
What are the two body compartments that drugs can be distributed into?
A
Central compartment and peripheal compartment.
25
What is included in the central compartment?
Includes highly vascularized organs like the heart, liver, kidneys, lungs, and blood.
26
What is included in the peripheal compartment?
Includes less vascularized organs like fat, muscle, and cerebrospinal fluid.
27
If a drug is injected with the concentration profile shown in the graph, which compartment does it target?
This represents the curve for entrance into the peripheral compartment.
28
Draw a curve if the drug enters the other compartment.
29
Which compartment is being targeted with Diphenhydramine used as a sleep aid?
Peripheral (CNS)
30
Which compartment is being targetted with Sertraline when used for depression and anxiety?
Peripheral (CNS) but has effects in central
31
Which compartment is being targeted with Aspirin when used to treat inflammation?
Central
32
What is the volume of distribution?
This is the dose of a drug needed to achieve a given concentration. However, it is not a measurement of volume. It reflects the localization of the drug in the plasma versus tissues and free versus bound.
33
What is the loading dose equation?
Vd= X/C0
Vd, volume of distribution
X, the total amount of drug in the body
C0, plasma concentration of drug at time 0
34
If you apply 50mg and the concentration is 10 mg/L, what is the Vd?
Vd= 50mg/10mg/L= 5L
35
If you apply 50mg and the concentration is 0.5mg/L, what is the Vd?
Vd= 50mg/0.5 mg/L= 100L
36
When the plasma concentration of the drug is __________, the volume of distribution will be __________. When the plasma concentration is HIGH, the volume of distribution will be LOW.
LOW; HIGH
37
A high volume of distribution means that a drug enters the tissues very ________.
Readily
38
Erythromycin has one basic center with a Vd of 0.95 L/kg and a half-life of 2 hours. Its sister drug, Azithromycin, had two basic centers with a Vd of 33L/Kg and a half-life of 69 hours. How do these basic centres affect drug uptake across a lipid membrane?
Basic groups allow the outer negative portion of the drug to be attracted to the charge of the plasma membrane for longer. This allows the drug to move through the cell and out the other side of the plasma membrane where it leaves circulation and enters the peripheral compartment. Overall, basic centers allow easier movement across the plasma membrane.
39
Some drugs may have the same volume of distribution but distribute ___________ due to solubility.
Differently
40
What is the blood-brain barrier (BBB)?
These are tiny junctions in the blood vessels of the brain. They are made of zipper-like proteins. Some drugs can make it through this junction, while others cannot. Drugs can also accumulate in different spots in the brain due to their chemical properties.
41
What is Parkinson's Disease?
This is a disease in which the neurons in the brain stop producing the monoamine dopamine.
42
How can Parkinson's Disease be treated?
We need to get dopamine into the brain, but it will not cross the blood-brain barrier. To get dopamine into the brain, the proform of dopamine called Levodopa is given. Levodopa can cross the blood-brain barrier. This enzyme, called levodopa decarboxylase, converts levodopa to dopamine in the bloodstream. An inhibitor of this enzyme is given to stop that conversion and is called Carbidopa.
43
What is Levodopa?
Prodrug form of dopamine used to treat Parkinson's Disease.
44
What is Carbidopa?
A levodopa decarboxylase inhibitor.
45
When given Levodopa alone, where does most of the drug end up?
In the plasma where it gets broken down to dopamine by the enzyme levodopa decarboxylase.
46
When given Levodopa, how does its uptake change when also given carbidopa?
Carbidopa stops the levodopa (LD) breakdown, which allows LD to cross the blood-brain barrier.
47
What is the combined form of carbidopa and levodopa together called?
Sinemet
48
Most drugs in the plasma end up binding to ___________.
Proteins
49
What type of proteins do acidic drugs and hydrophobic drugs typically bind to?
Albumin
50
What types of protein do basic drugs typically bind to?
Acid glycoproteins
51
What types of proteins do lipophilic drugs bind to?
Lipoproteins
52
When a drug is bound to a protein, it is ______ functional.
Not
53
Why does Albumin bind to several different types of drugs?
Albumin is readily available in the bloodstream. Whenever it sees drugs floating free throughout the circulation, it will bind them and move them around.
54
Is albumin or acid glycoprotein more abundant in the body?
Albumin is much more abundant.
55
Acid glycoproteins bind basic drugs. They can ________ transport drugs across plasma membranes.
Directly
56
Why do we even care about protein binding?
Well, basic drugs have a higher volume of distribution (Vd) because they interact with negatively charged phospholipids on cells.
57
Why would lower protein binding and increased membrane binding increase the volume of distribution (Vd)?
Lower protein binding means it is not floating around in circulation as much and wants to bind to its protein of activation. This allows the drug to leave circulation more readily and enter the peripheral tissues leading to a higher Vd.
58
Why would higher protein binding and decreased membrane binding decrease the volume of distribution?
Higher protein binding keeps the drug in plasma circulation, meaning it has a difficult time leaving the central compartment and entering the peripheral compartment.
59
Lipophilic (fat-loving) drugs tend to cross membranes and _______ the circulation. While less lipophilic drugs tend to _________ in circulation.
Leave; stay
60
How do drugs get into cells?
They can get in through various ways like paracellular transport, diffusion, facilitated diffusion, and more. Some drugs resemble natural metabolites that the cell would want and bring them in accordingly. Specifically discussed in class the organic anion transporting proteins (OATS).
61
What are organic anion-transporting proteins (OATS)?
Groups of proteins that move acidic drugs into the urine. Substrates that move through these include NSAIDS, cancer drugs, antivirals, and more.
62
How do drugs get out of a cell?
P-glycoprotein transports large classes of drugs out of the cell.
63
How was the p-glycoprotein discovered?
Patient with cancer given Doxorubicin. This drug diffused across the cancer plasma membrane, where it was effluxed from cells via the P-glycoprotein. Cancer cells that express a lot of P-glycoprotein cannot be treated with Doxorubicin.
64
After absorption and distribution of a drug throughout the body, what happens?
The drug starts to be metabolized. Active drugs could be converted to another active form or inactivated. Inactive prodrugs could be activated. Or non-secretable forms of a drug can be converted to secretable forms.
65
On a basic level, what is the goal of drug metabolism?
To turn the lipophilic drugs we start with into hydrophilic drugs so the kidneys can excrete it.
66
What are the two phases of drug/prodrug metabolism?
Phase 1- small chemical groups added
Phase 2- large chemical groups added
67
What are some examples of Phase 1 metabolism enzymes and reactions?
Oxidation by P-450 enzymes, reduction, and hydrolysis.
68
What are some examples of Phase 2 metabolism enzymes and reactions?
Addition of glucoronidate, sulfates, alkylates, glutathione, and more.
69
During Phase 1 metabolism, the majority of drugs are modified by _____________.
P-450 enzyme
70
Why is the P-450 enzyme named the way it is?
P-450 is a protein class with a heme group at its center with iron. This gives the proteins brown color. The color brown is then absorbed at a wavelength of 450 nm.
71
Describe the cytochrome P-450 reaction and how it becomes activated.
Inactive Ferric (Fe3+) P450 is oxidized by P450 reductase to active Ferrous (Fe2+) P450. Active P450 can now oxidize substrates.
72
What are some common things that are oxidized by the active P-450 enzyme?
Estrogen is cleared this way. Lipids and cholesterol as well. However, P-450 proteins drive the synthesis of almost all steroid hormones like cortisol, testosterone, etc.
73
There are a lot of P-450 enzyme inhibitors out there. What happens if someone accidentally takes a P-450 enzyme inhibitor while taking a drug that can only be metabolized by the P-450 enzyme?
That drug would stay in the body in an unmetabolized form. The longer a drug stays in circulation, there is a larger chance of side effects from that drug to occur.
74
How would Warfarin (P450 substrate) levels change if someone ingested it with grapefruit juice (P450 enzyme inhibitor)?
The warfarin would not be metabolized and would stay in its unmetabolized form in the body.
75
What are two types of drugs that induce the P-450 system?
Ethanol and antibiotics.
76
What could happen if someone takes St. John's wort (P450 inducer) with a blood pressure medication like Warfarin?
The drug could be quickly metabolized and inactivated, so the effects of the drug are not seen in the body.
77
Fentanyl is metabolized by a P450 enzyme called CYP3A4 into an inactive form called norfentanyl. If someone were given cimetidine (P450 inhibitor) while also given fentanyl, what would happen?
Cimetidine would stop the P450 enzyme from breaking down fentanyl. This allows active fentanyl to bind and produce effects throughout the whole body. This can cause an overdose and can be very dangerous.
78
Would a combination of fentanyl plus cimetidine increase or decrease norfentanyl levels?
This would decrease the levels of norfentanyl.
79
What are some examples of drugs that are metabolized by Phase 2 metabolism through the addition of large chemical groups like glutathiones and acetyl groups?
Aspirin, lidocaine, and acetaminophen
80
Explain the metabolism of Diazepam?
Diazepam is originally modified by the P450 enzyme CYP3A4. This converts diazepam to desmethyldiazepam. Two other smaller metabolites produced include Oxazepam and Tetrazepam. Phase 2 of this metabolism attaches multiple hydroxyl groups onto these to make them more hydrophilic so they can then be excreted into the urine.
81
People who are ________ metabolizers need _______ drug. However, poor metabolizer need less of a drug.
Fast; more
82
Hydrophilic drugs are typically excreted via the kidneys. Hydrophobic drugs are excreted via the liver. When a drug is non-polar, the _______ may modify the drug to become polarized so it can excreted by the _________.
Liver: Kidneys
83
What are the three different ways that drugs are excreted from the body?
1. Through the GIT and the drug is not absorbed at all
2. Cleared by liver by being incorporated into bile to be excreted
3. Excretion as urine from the kidneys
84
Everyday, the kidneys filter ______ L of plasma while only ______ L of urine is released.
180; 1.5
85
What is glomerular filtration rate?
Measurement of albumin levels in the urine. Protein in urine is bad so any detection of albumin is a sign of kidney damage.
86
Can a drug bound to an acid glycoprotein be filtered by the kidneys?
No, the kidneys cannot and should not be filtering any proteins in a healthy individual.
87
How is the half-life of a drug determined?
By using the graph that compared time versus the log concentration of the drug, the slope of the line is called the elimination rate constant (Ke).
88
What is clearance?
The volume of plasma from which a drug is cleared in a unit of time (mL/min). Clearance is heavily dependent on a drug's volume of distribution and half-life.
89
What is the equation for clearance?
Clearance (ml/min) = Ke (min-1) x Vd (ml)
If the Ke for a drug was 0.7/T1/2 the equation would look the following picture.
90
If drugs A and B have a similar Vd, but A has a longer half-life, how does the clearance of A compare to B?
If A has a long half-life, the clearance rate would be smaller than that of drug B. This can be supported by using the clearance equation. The larger the half-life the smaller the clearance rate will be.
91
If a drug had a high volume of distribution, why would it have a longer half-life?
A higher volume of distribution means it leave circulation and enters the peripheral more readily. It then needs to come back into circulation for it to be cleared. This takes time so a longer half-life is needed.
92
If the clearance of a drug increased, how would that affect its half-life?
Higher clearance rates produce a decreased half-life. This makes sense because if the body is clearing it at a high rate, it must not last long in the body.
93
Consider two drugs that have the same rate of clearance, but their concentration profiles look like the following diagram. Which curve best represents a drug with the large Vd? What about the larger clearance?
Drug A has the larger volume of distribution. Drug B has a larger clearance.
94
Which statement best represents the relationship between the uptake of a drug and tissue pH?
A weak base crosses the plasma membrane efficiently at a higher pH.
95
Which of the following answers reflects the pharmacokinetic properties of diazepam?
Diazepam has active metabolites and a long half-life.
96
Which of the following is an example of a drug with an enteral route of administration?
A pill of diphenhydramine taken for allergies.
97
A weak acid shown in the graph along with the ionization state of the drug. Is this drug absorbed in the stomach or small intestines?
Absorbed in the stomach due to the low initial pH.
98
If the pH were elevated based on with graph with the use of an antacid, would absorption increase or decrease?
Absorption of the drug through the stomach would decrease due to increased pH levels.
99
The plasma concentration over time for a drug that can be injected or given orally is seen in the graph. The drug container has a big warning that states do not take with a meal. This is because food interferes with the absorbance of this drug. But someone takes it with a meal anyways. How would the curve appear for the orally administered drug when taken incorrectly with a meal?
Since the drug was taken with a meal against medical advice, the absorption of the drug taken orally will be decreased. This means graphically, the area under the green curve will decrease.
100
The plasma concentration over time for a drug that can be injected or given orally is seen in the graph. The drug container has a big warning that states do not take with a meal. This is because food interferes with the absorbance of this drug. But someone takes it with a meal anyways. How would the shape of the curve change if the person had a genetic change to a hyper-active allele of the main enzyme that metabolizes the drug?
With a hyper active allele of the enzyme that metabolizes this drug, it means the drug will leave the body quickly. Graphically, this would represent the lower height (due to food ingestion) with tail end of curve cut off.
101
If you apply 200 mg of a drug orally, and the volume of distribution is 1000L, what is the drug's plasma concentration?
C0=X/Vd
200mg/1000L= 0.2mg/L
102
Which of the following statements about the blood brain barrier (BBB) is true?
The BBB is a series of cell-cell tight junctions formed by proteins.
103
You and your colleagues have discovered a new drug, sharpinib and you want to know more about its metabolism. You inject a rat with it and find that sharpinib is secreted in the hydroxylated form in urine. The hydroxylated from diminishes when you co-administer ketoconazole, a protease inhibitor like grapefruit juice. What can you conclude about sharpinib metabolism?
Sharpinib is likely a cytochrome P450 substrate.
104
A widely used antihistamine called loratadine is excreted after being conjugated to a chemical called glucuronic acid. What is the name of this chemical modification process?
Phase 2 metabolism.
105
You read about a place where people are taking a very dangerous drug recreationally. In addition to producing a high, the drug fen suppresses breathing. Fen is modified to the metabolite norfen, which is inactive. It turns out that people taking another drug call DI at the same time as fen are suffering respiratory failure. They also have decreased levels of norfen. What is the most likely explanation for the respiratory failure?
DI is likely a P450 inhibitor, stopping the metabolism of active fen to inactive norfen. This causes constant levels of fen in the body that will continue binding to receptors and induce respiratory failure.
106
Based on the graph, what is the time point called that is pointed out?
The half-life
107
Based on the following graph describing the ability to reach a steady state concentration in the body, why is the concentration higher at the second dose point?
The second dose was given after 1 half-life has passed for the same drug given at the first dose. This will build up from the current concentration in the blood.
108
Based on the graph, what would happen if someone lets a drug fully metabolize before giving another dose in relation to reaching steady state concentration?
They would not reach the therapeutic level needed to produce a response. They would likely believe the medication does not work.
109
How does the line change for reaching a steady state concentration between oral administration and intravenous administration?
Intravenous starts high and exponentially decreases. Orally administered drugs start low, enter blood stream, reach their max concentration, and then comes back down.
110
Based on the following graph, why does the concentration of the drug not keep rising?
The body begins to adapt to the drug.
111
How would someone reach a steady state concentration of a drug more quickly?
Through the use of a loading dose.
112
What is a loading dose?
The is a single dose that is much higher than the standard dose given.
113
How is the loading dose calculated?
Loading Dose (Dl) = Volume of distribution x steady-state concentration (Css).
114
If the volume of distribution is high, why do you need a higher loading dose?
A high volume of distribution means a drug leaves the circulation and enters the peripheral compartments very readily. If a drug leaves the plasma quickly, you will need more of the drug initially to increase plasma concentration levels.
115
For ibuprofen, a typical plasma concentration is 50 microg/mL (5000 microg/L) and has a Vd of 0.1 L/Kg (10L for this person). What is the loading dose of this drug?
Dl= (5000 micrograms/L) x (10L)= 50,000 micrograms/ 50 milligrams.
116
What is the equation used to determine the initial dose of a drug?
X= Vd x Css
Css, plasma concentration at steady state
X, amount of drug applied in dose
117
Once the steady state of a drug is reached, how is the maintenance dose of that drug determined so a person can stay at the correct therapeutic drug level concentration?
K0= Css x CL, units of mL/min
K0, rate at which drug is administered
Css, plasma concentration at steady state
CL, clearance rate
118
To maintain a steady-state concentration of a drug with a high clearance, would the dose rate be higher or lower?
Based on the equation for maintenance dose rate, a drug with a higher clearance will need a higher dose rate. This also makes sense because a drug that leaves the body at a faster rate will need more of the drug to keep it at proper theraptic levels.
119
What is clearance rate most dependent on?
Kidney Health
120
When attempting to reach a stead-state concentration of a drug, the way we administer is dependent on ____________________. However when we reach steady-state and are trying to maintain this concentration, the way we administer is dependent on ______________.
Volume of distribution; clearance
121
Norepinephrine is a _____________. It is released from vesicle into synaptic cleft where it binds to its receptor. It is reuptook back into the synapse with the NE transporter where the monoamine oxidase enzyme breaks it down.
Monoamine
122
The ____________ enzyme keeps NE levels low in the cytoplasm while the _____________ keeps NE levels low in the synapse to prevent over stimulation to adrenergic receptors.
Monoamine oxidase; NE transporter
123
What is the drug Amphetamine?
Ampethamine resembles both dopamine and norepinephrine. This drug is taken up by the NE transporter where it is stored in the vesicles with NE and dopamine. Once drug is in the vesicle, the pH of it changes. This reverses the system and forces the release of NE and dopamine into the synapse. This promotes excitation.
124
What does increased norepinephrine stimulation cause in the body?
Elevates blood pressure, nervousness, and decreases appetite.
125
What are the side-effects of stimulants like amphetamines and methylphenidate?
Increase in blood pressure and heart rate, growth retardation, appetite suppression, anxiety, insomnia, restlessness, psychosis, and headache.
126
Why are amphetamines linked to addiction?
This drug acts on dopamine just like it acts on norepinephrine. When the excess release of dopamine happens, this promotes the pleasure center leading to addiction.
127
Methylphenidate is ______ efficacious and better tolerated, while amphetamine is ______ efficacious and less well tolerated.
Less; more
128
What are the D and L conformations of amphetamines?
D is the more potent isomer form. D and L conformations are enantiomers of eachother.
129
What is the drug Concerta?
This is a slow release methylphenidate. IT has small holes in it that allow water to enter to create osmotic pressure that slowly pushes the drug out. The goal of this drug is to decrease the side effects and addiction risk.
130
What is the drug Vyvanse?
This is an Amphetamine prodrug. Amphetamine is linked to the amino acid lysine. This makes the drug more hydrophobic so it can cross plasma membranes easily. Once in the blood stream, proteins in red blood cells break the bond and release the active form of amphetamine. This form is resistant to crushing so less potential for abuse.
131
How are amphetamines metabolized?
They are metabolized by P450 enzymes called Cyp2D6. It is then excreted by the kidneys.
132
What is the drug Solriamfetol (Sunosi)?
This is a norepinephrine and dopamine reuptake inhibitor. It keeps those with sleep apnea away during the day.
133
Two people are depicted taking Fluoxetine. Does the person represented by the red line have a hyper and hypo- active variant of the P450 enzyme that metabolizes this drug?
The person represented by the red line has a hypo active P450 enzyme because the concentration is continually decreasing and there is no metabolism of the drug occuring.
134
Imagine blue lines represents a drug with a Vd of 100. What would the line look like with a similar drug of Vd 10?
A lower Vd means a shorter half-life so the greater that slope of the blue lines.
135
Imagine blue lines represents a drug with a Vd of 100. What would the line look like with a similar drug of Vd 10?
A lower Vd means a shorter half-life so the greater that slope of the blue lines.
136
What is Rheumatoid Arthritis?
Inflammation and pain in the joints are caused by immune cells attacking synovial joints.
137
What are the two types of immune responses?
Innate immune system and adaptive immune system.
138
What is the innate immune system?
Nonspecific immune cells attacking invading cells.
139
What is the adaptive immune system?
Adaptive specific antibodies and T-cells that target pathogens. Target for drugs.
140
What is the difference between Immune-suppressed and hyper-immune?
Immune-suppressed is when a virus attacks the immune system, and it can no longer produce an adequate immune system. Hyper-immune is when the immune system starts to attacks its own body.
141
Immune cell precursors came from what?
Come from hemopoietic stem cells in the bone marrow.
142
What are the two main types of immune cells, and where do they come from?
1. T cells differentiate in the Thymus
2. B cells differentiate in bones cells
143
What is Sjogren's Syndrome?
This is a comorbidity associated with Rheumatoid Arthritis when immune cells attack the secretory tear cells in the eyes.
144
The first line of defence against RA is to inhibit gene expression associated with inflammation. This can be treated through the use of ____________.
Aspirin
145
Why is Aspirin not always a good option as treatment for RA?
It can cause GI bleeding.
146
The second line of defence against RA is the use of _________________.
Corticosteroids, specifically Prednisone.
147
How do corticosteroids bind to their receptor?
Cortisol is a steroid hormone. It binds to the glucocorticoid receptor in the cytoplasm. Once the substrate binds to the receptor and moves to the nucleus where is can alter transcription.
148
Where is cortisol naturally produced in the body?
The adrenal glands ontop of the kidney.
149
What is the main function of cortisol?
In this sense, cortisol inhibits inflammatory cytokines through its receptor.
150
What are the key inflammatory cytokines?
IL-1, IL-6, and TNF-alpha
151
What is the mechanism of action of Prednisone?
Prednisone is a prodrug that is converted to prednisolone, which then binds to the glucocorticoid receptors. The receptor then moves to nucleus to alter transcription.
152
What are the long-term adverse effects of corticosteroid use?
There are many side effects due to steroid receptors being all over the body. Main side effects include an increased risk of infection, poor wound healing, and psychological problems like psychosis.
153
Prednisone is typically given as a taper-down method while other drug therapies begin. What is the taper-down method?
Start with a high dose and decrease as days go on until you are taking none of it.
154
The 3rd line of defence for RA is the use of disease-modifying drugs like _____________.
Methotrexate
155
What is proliferation in the sense of B cells?
When B cells bind to an antigen, it provides a growth signal to other B cells to proliferate.
156
What is the action of Methotrexate?
Methotrexate resembles folic acid. The drug will inhibit Dihydrofolate Reductase (DHFR), which blocks the synthesis of tetrahydrofolate (THF). THF is a cofactor then needed to make dTMP. THF is then needed to make purines and pyrimidines to be used a nucleotides.
Blocks NTP synthesis which is basically DNA synthesis in a basic sense.
157
What are the side effects of Methotrexate?
It takes 1-2 months to work. Side effects include GIT distress due to constant GIT cell turnover that is being inhibited.
158
Methotrexate is cross-linked with polyglutamate derivatives inside the cell. These derivatives are highly active against DHFR. The cross-linked version of Methotrexate _________ in the cell while the parents compound does not.
Stays
159
Methotrexate accumulates in body cavities with other drugs like salicylate and phenytoin. Methotrexate is an acid that builds up in the peritoneal cavity. These drugs can ____________ methotrexate from its normal binding proteins and cause increased toxicity.
Displace
160
What would happen if you gave sulfonamides to a patient that had recently received methotrexate?
These sulfonamides could displace the methotrexate from different body cavities causing increased concentration and leading to increased toxicity.
161
The 4th level of therapy used for RA includes biological agents like __________________.
Monoclonal antibodies
162
What is one of the main inflammatory cytokines TNF-alpha do?
Tumor necrosis factor-alpha is a cytokine and fever inducer. Induced in healthy immune responses. TNF-alpha forms a little pyramid.
163
What is the mechanism of action for TNF-alpha?
TNF binds to the TNFR1 receptor, where it triggers several signalling pathways. It triggers the NF-kB pathway, which increases inflammatory signalling and triggers JNK pathway.
164
What is Adalimumab? (humira)
A monoclonal antibody binds to the TNF-alpha and neutralizes it.
165
Why is TNF-directed therapy an improvement over methotrexate?
TNF-directed therapy is a monoclonal antibody, so it is very specific to that one substrate. Methotrexate inhibits the production of nucleotides by inhibiting the enzyme DHFR which means all cells turning over will not have access to new building machinery.
166
How long would someone take a drug like Adalimumab?
Likely their whole life.
167
How are antibodies cleared from the body?
They are cleared via the reticuloendothelial system in which phagocytic cells engulf them. The kidneys do not excrete them.
168
About how long do antibodies stay in the body?
3-12 days
169
How often is the drug Adalimumab given?
Subcutaneously every 2 weeks.
170
What are JAK kinases?
When cytokines bind to their receptor, kinase binds to the receptor inside the cell. Janus Kinases have two kinase domains. Since cytokine receptors have no activity, they rely on JAK kinases to relay their signal once cytokine is bound.
171
How does inhibiting JAK kinase help inactivate the immune response?
For example, the cytokine IFN-gamma boosts immune responses to infection but too much of this can cause the immune system to attack the body. Inhibiting the JAK kinase will stop this signalling from happening.
172
What is the drug Tofacitinib (Xeljanz)?
A specific inhibitor of the JAK3, blocking the activity of multiple cytokines. It also acts on JAK1 and JAK2 but with less inhibition.
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How is Tofacitinib taken and how quickly does it work?
Taken in pill form and works within 3 day to 2 weeks.
174
Why is there an increased risk of upper respiratory infections due to Tofacitinib?
We have suppressed the immune system and the airways are exposed to the most bacteria a lot.
175
Why is there an increased risk of upper respiratory infections due to Tofacitinib?
We have suppressed the immune system and the airways are exposed to the most bacteria a lot.
176
Which accurately represents drug filtration by the kidneys?
Plasma drug levels rely on a balance of kidney filtration and reabsorption. (no, drug levels in urine do NOT increase with protein binding. No, drugs metabolized by P450 protein do not remain in circulation longer than the parent drug. No, not all filtered liquid from the kidney is excreted directly as urine)
177
A drug for psoriasis was used clinically for years and was found to be excreted in the urine in the unmodified form. A new form of the drug has similar protein binding and volume of distribution but undergoes extensive and rapid phase one and phase two modification. Which of the following would you predict to be a feature of the new drug?
The new drug will have a shorter half-life (?)
178
A cancer drug erlotinib has a clearance of 4 L/hour. The volume of distribution is 233L. What is the estimated half-life?
T1/2= (0.7)(233L)/ 4L/hr
179
A drug for psoriasis was used clinically for years and was found to be excreted in the urine in the unmodified form. A new form of the drug has similar protein binding and volume of distribution but undergoes extensive and rapid phase one and phase two modification. Which of the following would you predict to be a feature of the new drug?
