Pharmacokinetics Flashcards
What are G-protein coupled receptors? How do they work?
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.
What is pharmacokinetics?
How drugs are administered, distributed, metabolized, and excreted.
Describe the central hypothesis of drug therapeutics based on the graph.
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.
What are the two types of drug administration?
Enteral and parenteral administration. (also have insufflation which is nasal admin)
What is enteral administration?
Oral admin
What is parenteral administration?
Everything else except oral admin. Includes injections, patches, lotions, sprays, suppositories, etc.
What is the most common route of drug administration?
Oral
How does the speed of absorption compare between oral and injected drugs?
Injected drug increases the concentration of that drug much faster than oral drugs.
How are the absorption and distribution of a drug measured?
Bioavailability
What is bioavailability?
Measures the plasma drug concentration after oral or IV administration dose over time.
Describe bioavailability in terms of the graph.
The area under the curve for oral admin is divided by IV dose.
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?
The area under the oral curve would increase.
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?
The curves would be smaller.
Where does most drug absorption take place?
From the gut, most absorption takes place in the stomach and GIT.
What are formulations?
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.
How does pH affect drug absorption for acidic drugs?
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.
What is an example of a weak acid drug?
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.
How does pH affect drug uptake for basic drugs?
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.
How would an antiacid affect the uptake of a basic drug in the gut?
The drug could be neutralized in the stomach due to its lower acidity (more basic) and absorbed there, instead of being absorbed in GIT.
To summarize, acidic drugs are taken up by the _________ and basic drugs are taken up by the ___________.
Stomach; small intestine
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?
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.
When drugs are taken orally, how do they eventually enter the bloodstream?
Drugs are absorbed through the gut wall and then transported to the liver via the portal vein.
What is first-pass metabolism?
This occurs in the liver. It is when drugs are chemically modified.
What are the two body compartments that drugs can be distributed into?
Central compartment and peripheal compartment.
What is included in the central compartment?
Includes highly vascularized organs like the heart, liver, kidneys, lungs, and blood.
What is included in the peripheal compartment?
Includes less vascularized organs like fat, muscle, and cerebrospinal fluid.
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.
Draw a curve if the drug enters the other compartment.
Which compartment is being targeted with Diphenhydramine used as a sleep aid?
Peripheral (CNS)
Which compartment is being targetted with Sertraline when used for depression and anxiety?
Peripheral (CNS) but has effects in central
Which compartment is being targeted with Aspirin when used to treat inflammation?
Central
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.
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
If you apply 50mg and the concentration is 10 mg/L, what is the Vd?
Vd= 50mg/10mg/L= 5L
If you apply 50mg and the concentration is 0.5mg/L, what is the Vd?
Vd= 50mg/0.5 mg/L= 100L
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
A high volume of distribution means that a drug enters the tissues very ________.
Readily
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.
Some drugs may have the same volume of distribution but distribute ___________ due to solubility.
Differently
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.
What is Parkinson’s Disease?
This is a disease in which the neurons in the brain stop producing the monoamine dopamine.
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.
What is Levodopa?
Prodrug form of dopamine used to treat Parkinson’s Disease.
What is Carbidopa?
A levodopa decarboxylase inhibitor.
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.
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.
What is the combined form of carbidopa and levodopa together called?
Sinemet
Most drugs in the plasma end up binding to ___________.
Proteins
What type of proteins do acidic drugs and hydrophobic drugs typically bind to?
Albumin
What types of protein do basic drugs typically bind to?
Acid glycoproteins
What types of proteins do lipophilic drugs bind to?
Lipoproteins
When a drug is bound to a protein, it is ______ functional.
Not
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.
Is albumin or acid glycoprotein more abundant in the body?
Albumin is much more abundant.
Acid glycoproteins bind basic drugs. They can ________ transport drugs across plasma membranes.
Directly
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.
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.
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.
Lipophilic (fat-loving) drugs tend to cross membranes and _______ the circulation. While less lipophilic drugs tend to _________ in circulation.
Leave; stay
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).
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.
How do drugs get out of a cell?
P-glycoprotein transports large classes of drugs out of the cell.
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.
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.
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.
What are the two phases of drug/prodrug metabolism?
Phase 1- small chemical groups added
Phase 2- large chemical groups added
What are some examples of Phase 1 metabolism enzymes and reactions?
Oxidation by P-450 enzymes, reduction, and hydrolysis.
What are some examples of Phase 2 metabolism enzymes and reactions?
Addition of glucoronidate, sulfates, alkylates, glutathione, and more.
During Phase 1 metabolism, the majority of drugs are modified by _____________.
P-450 enzyme
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.
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.
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).
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.
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.
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.
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.
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.
Based on the graph, what is the time point called that is pointed out?
The half-life
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.
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.
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.
Based on the following graph, why does the concentration of the drug not keep rising?
The body begins to adapt to the drug.
What is a loading dose?
The is a single dose that is much higher than the standard dose given.
How is the loading dose calculated?
Loading Dose (Dl) = Volume of distribution x steady-state concentration (Css).
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
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.
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.
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.
