Term
| What is Pharmacokinetic "disposition"? |
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Definition
The combination of Distribution and Elimination (consisting of metabolism and excretion).
Everything AFTER Absorption |
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Term
| Describe the basic concept of volume distribution (Vd) of drugs |
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Definition
Vd is a calculated, reproducable and clinically-useful value, that IS NOT LITERAL
1) Body acts like well-stirred beaker, and
[Drug]= amount added/volume of beaker
2) Take a blood sample and measure [drug] and divide the amount added by that concentration to get a volume. |
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Term
| What does the concept of "Loading Dose" have to due with volume of distribution in pharmacokinetics? |
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Definition
1) LD is an amount of drug given to achieve a target [Drug]p
LD X B (bioavailability) = Atarget
so LD= (Vd x [D]p)/B- the DETERMINANTS of loading dose
** IF given IV, LD= Atarget** |
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Term
| What are the determinants of loading dose? |
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Definition
LD= Atarget/B= (Vd x [D]p)/B
- Volume of distribution
- Plasma drug concentration
- Bioavailability
So, if you increase plasma protein binding, for example, you by definition, decrease Vd |
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Term
| What is the difference between one-compartment and two-compartment behavior in relation to volume of distribution |
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Definition
1) One-compartment involves a fast equilibration of drug to compartments (beaker of fixed size)
2) Two-compartment involves an initial restriction to certain compartments, followed by a slow equilibration to other compartments over time (beaker gets bigger over time). |
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Term
| Explain why you would use Vd (initial) vs. Vd (final) when calculating loading dose |
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Definition
For a 2-compartment system:
LD= (Vd X [D]p)/B
1) Use final when concern is therapeutic response
2) Use initial when concern is toxicity |
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Term
| What is the quantitate definition of Drug Clearance (Cl)? |
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Definition
** Major determinant of [D]p at steady state (when input=output)
Cl= Rate of elimination/[D]p (volume/time)
Usually constant over wide range of [D]p, since drugs are usually eliminated by 1st order kinetics |
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Term
| Distinguish between Maintenance dosage (MD), Dosing interval (DI) and Bioavailability (B) |
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Definition
MD= amount of drug taken at regular intervals
DI= time between MDs
B= Fraction administered that is absorbed into systemic circulation
Since [D]ss= R0/Cl, R0= [D]ss x Cl= (B X MD)/ DI
[D]ss= (B x MD)/ (DI x Cl) |
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Term
What conceptual point is drawn from the fact that
[D]p ss= (B X MD)/ DI X Cl |
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Definition
Plasma drug concentration at steady state depends on RATIO of MD to DI, and not on their absolute values.
Remember, [D]p determines therapeutic response AND toxicity |
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Term
| What might the effect of a renal disease that decreases glomerular filtration and tubular secretion of a drug be on Rate of elimination? |
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Definition
Such a disease would reduce renal clearance (Clr)
Since Clr= R/[D]p, this would also decrease the rate of elimination |
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Term
| What is the quantitative definition of Therapeutic ratio (TR)? |
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Definition
| (Highest [D]p that is safe/ Lowest [D]p effective) |
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Term
| What is the steady state time for both 1 and 2 compartment systems? |
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Definition
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Term
| What are the 5 basic steps involved in designing a dosage regimen? |
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Definition
1) Define PK (patient is best, but may settle for population)
- Vd, [D]t, B, Cl
2) Decide whether LD is required, and if so, calculate it (can you wait 4x t1/2 to obtain [D]pSS?)
remember, LD= At/b= (Vd x [D]t)/B
3) Calculate MD/DI ratio
- MD/DI= ([D]p X Cl)/B
4) Determine DI (interplay between therapeutic ratio and t 1/2)
- DImax= 1.44 x t 1/2 x ln(TR)
5) Determine MD
- Use ratio and DImax
- MD= (MD/DI) x DI |
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Term
| What factors increase/decrease hepatic clearance? |
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Definition
Remember, [D]ss is major determinant of TR and toxicity and it equals Ro/Cl. Clearance determines these factors too!
1) Decrease
- Liver failure
- Genetic variation in drug-metabolizing enzymes
- Ionization of drugs which limits penetration
- Competition between drugs
2) Increase
- Induction of liver enzymes
- Genetic variation in drug-metabolizing enzymes |
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Term
| What are the major determinants of half-life? |
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Definition
Vd and Cl
t1/2= (0.693 x Vd)/ Cl
If you increase Vd, you increase half-life
If you increase Cl (which is Ro/[D]ss), you decrease half-life) |
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Term
| What are the 3 meanings of tss? |
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Definition
tss= 4 X t 1/2
1) TIme to get from 0 to an initial [D]ss
2) Time to get to a new [D]ss once dosage is altered
3) Time to get to [D]ss=0, once treatment is stopped |
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Term
| What are the 4 major determinants of Volume of distribution? |
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Definition
1) Body compartments
2) Tissue binding (increase leads to increase in Vd)
3) Plasma binding (increase leads to decreases in Vd)
4) Fat distribution (increase leads to increase in Vd) |
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Term
| What happens to drug clearance if the [D]p increases? |
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Definition
clearance decreases
Cl= Ro/[D]p |
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Term
| How should you adjust an MD if the bioavailability of your drug decreases? |
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Definition
MD:DI= ([D]ss x Cl)/B
So if bioavailability decreases, your MD:DI ratio will increase |
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Term
| How does half-life change with liver disease? |
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Definition
Liver disease will decreases Cl from the liver and t1/2= 0.693 x Vd/Cl. If Clearance decreases, half-life will increase
You may need to give a loading dose, since tss will get really large! |
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Term
| IF the therapeutic ratio of drug B is greater than drug A, but both drugs have the same half life, how will their dosing be effected? |
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Definition
Since DImax= 1.44 X t1/2 X ln(TR), a larger TR means that there will be a larger DImax, so the drug can be taken less often.
Since [D]ss is determined by the MD:DI RATIO, the MD will also have to be greater to achieve the same plasma drug concentration |
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