Pharmacokinetics -> lecture 2 Flashcards
Why do we use models of bodies in drug production?
Allows predictions of drug activity on body e.g. how does drug act, what is the drugs active duration etc.
What is the single compartment model and what is it showing?
- The body is one bucket with opening at top and outflow at bottom.
- Full drug dose is added at once, enters bucket w/o absorption etc, is eliminated.
What is the apparent volume of distribution (Vd)?
Total amount of drug in body compared to plasma concentration.
Vd = amount of drug in body/plasma drug concentration.
What is the Vd an indicator of?
Indicates extravascular distribution.
Why is Vd called the apparent volume?
It may not be a real number, e.g. if Vd was 300l then that’s larger than avg vol of a human.
What would a high Vd indicate?
There is a large distribution of plasma into different sites i.e. more drug leaves the plasma and goes into other body compartments.
How to include elimination in simple model to calculate drug extraction ratio?
- Blood will take drug into eliminator.
- Blood will then flow away from eliminator.
- Calculate the amount of drug extracted.
What is drug elimination also called?
Clearance
How to calculate clearance?
Clearance = rate of elimination/conc of input.
What are the units/inference of clearance?
How much of a set volume of plasma is cleared per unit time.
Vol/unit time.
How to measure clearance clinically?
Best way = creatinine clearance:
- Look at how much creatinine is cleared.
- Renal clearance correlated with clearance of creatinine.
Clinically done via:
- Single blood sample.
- Measuring urine collection over 24 hours.
What is creatinine and how to measure it’s clearance?
- Product of the breakdown of creatine phosphate in muscle.
Measuring creatinine clearance for men:
Creatinine clearance = ((1.23(140-age))*weight)/serum creatinine.
How does clearance differ with age?
Decreases with age.
What precautions are needed due to age-related decreased clearance?
- Pay attention to drug half-lives, don’t want drug accumulation.
What are the features of first order drug elimination?
- Most common.
- Exponential decay.
- Rate of elimination is proportional to drug conc. (more drug = faster removal).
- Constant half-lives.
What is the elimination rate constant ?
Kel => proportion of drug eliminated per unit time.
What is the association with elimination constant and Vd?
Kel = rate of elimination/amount of drug left. = clearance/Vd.
On a natural log (concentration)-time graph what does the slope represent?
- The negative elimination constant (-Kel)
What is a drug half-life?
- Time taken for [drug] to halve.
How many half lives roughly for avg drug to decay?
~5 half-lives.
How does half-life differ with the elimination constant?
Different Kel = different half-lives.
What are the half-lives of drugs used for in clinical settings?
- Used to set dosing intervals i.e. one hl then another dose etc.
How do drug kinetics differ if distribution is added to the model?
- More drug causes more rapid distribution.
- Still a first order reaction.
- Measure distribution via Kd.
What happens if absorption is added to single compartment model?
- Still a first order reaction.
- Rate of absorption proportional to unabsorbed drug.
- Measure absorbance via Ka
How to calculate absorption from the area under curve?
- AUC = dose/clearance
- i.e. g/(l/time)
How can bioavailability be measured using the area under curve?
Bioavailability = AUC (in dosage form)/AUC (via IV injection)
What is a loading dose?
- Top up drug dose to keep drug within therapeutic window.
How are loading doses done?
- Continuous IV injections.
What are the advantages of loading doses?
- Good for drugs with narrow therapeutic windows.
- Stop toxicity due to too quick drug presentation |(immune, hypotensive, vein damage).
What are the key features of a zero-order elimination?
- Elimination rate isn’t proportional to drug conc. (the drug is removed at same rate no matter the conc).
- Half-lives depend on [drug].
Why do half-lives depend on [drug] for zero-orders reactions?
Using enzyme e.g. alcohol:
- Enzymes work at constant rate.
- HL depends on starting conc, higher conc = more saturated enzymes.
Key differences between first and zero order elimination:
1st order:
- Amount of drug eliminated per unit time is proportional to [drug].
- A constant proportion of total drug is eliminated per unit time.
0 order:
- Constant amount of drug is eliminated per unit time.
When would drug doses need to vary?
Mainly due to differing ages (neonates, elderly)
Why are doses changed with neonates and elderly groups?
Neonates:
- Lower body vol.
- Higher water %
Elderly:
- Higher fat %
- Lower body weight.
What are the effects of low and high age on drug dose?
- Less plasma-drug binding = lower levels of albumin.
- Less clearance = lower renal function.
- Lower metabolism.
What is therapeutic drug monitoring?
- Monitor + measure conc of drug in body + determine effective dosage times etc.
How to do therapeutic drug monitoring ?
- Measure drug in blood, urine or saliva (if unbound).
- Aim to avoid toxicity in patient.
For different drugs when is monitoring important?
- Antibiotics = measuring peak drug conc important to not be too high.
- Anticonvulsants = measuring trough drug conc, don’t want them to get too low + cause seizures.
- Want to measure time above threshold value measuring minimum inhibitory conc i.e. what’s the lowest conc of drug to produce max response.
- Measure overall drug exposure in anticancer drugs etc.
When is urine sampling used + why?
- Instead of blood sampling.
- Useful for drugs w partial/full elimination into urine.
As urine volume is variable it’s not using drug conc (which doesn’t mean anything) + can express drug quantity as absolute amount.
How to urine sample?
- Look at cumulative amount btwn two time points.
OR - Look at amount excreted per interval btwn urine collections.
