A clinicians guides to pharmacokinetics Flashcards
How do you know how much drug to give a patient?
- read the bottle!
What do clinicians need to do when determining dose?
Options:
- Read label
- Read modifications in research papers
- individualize treatments
How does dose connect to effect?
- dose not proportional to effect!
**More is not better! Will get closer to toxic effect
-need to take into account the dose giving 50% of effect, and then dose giving maximum effect
Therapeutic window
-need to be within the window between min therapeutic dose and min toxic dose
-windows can be large or small
Therapeutic range
plasma concentration range in a population likely to produce a desired effect
Pharmacokinetics
-study of how drugs go in and out of body and there they go when inside the body
-includes mathematical models (includes logs)
Problems with pharmacokinetics
-drug testing on blood which is not where all drugs work; drugs go to tissues
>plasma vs tissue drug concentration
-drug testing conducted on small group of similar individuals
-drug use is not always systemic (eg. ears, wounds)
Pharmacokinetics drug testing
-measured using blood plasma
HOWEVER most drugs don’t effect/work in the blood
-also often compared to bacterial research which is not the same as when it is within the body
-difficult to study how drugs impact the tissues where they are acting because would need to kill animals at different time intervals
Drug use that isn’t systemic
-skin
-ears
-inhaled
-intra-mammary
-intra uterine
-wounds
**often not entering the blood
Difficult to extrapolate plasma kinetics
-most studies conducted on small groups or similar animals (ex. young males)
-but many factors can impact effect including age, gender, sex, body type, breed, pregnancy, lactation, genetics
Plasma vs. tissue drug concentration
- drugs acting in a tissue may stay in lung for much longer COMPARED to drug concentrations in the blood which may drop off quite quickly
Drug levels in fat
-Compare skinny vs fat individuals
>lots of drugs will accumulate within the fatty tissue and will slowly leak back into the blood
>with skinny individuals, drug would not get stuck in fat reservoir and would be cleared from body faster
1st order elimination
Rate of elimination is proportional to amount of drug remaining (curved line)
-Max concentration in blood at time zero (Cmax)
-Half life: period where half the drug is left
-Area under the curve (AUC): measure of drug and drug time in the body
Where would a toxic effect occur with a drug?
Would occur around Cmax (at start of giving dose)
**some drugs need to be given slowly to ensure that concentration does not spike too high too fast
Half lives
-pharmacokineticists usually stop at 7x half lives because at that point drug concentration is basically at zero
IV dose infusion at a constant rate
-The concentration will rise logarithmically to reach a steady state
>always drug leaving the blood
>eventually drug will reach steady state equilibrium (occurs at 4 half lives)
**final concentration is related to the rate of infusion
Loading dose
-used when you need to get to steady state faster (related to dose half life)
>rapid iv bolus followed by sustained infusion
Loading dose= desired concentration X volume of distribution
Volume of distribution
=total dose of drug/Cmax= L/kg
-how many L/kg body weight is dissolved in blood
*high VD (more than 1)= drug left the blood
Drug infusion when not IV
-drug must be absorbed into the blood
-give drug at time zero, it is usually absorbed quite quickly
>Cmax will not be right at Tmax
What factors effect drug distribution when drug not given as IV?
-absorption phase- how long it gets into blood
-bioavailability- how much makes it into the blood for use
-sustained release- clearance will stay the same no matter what route. But if it takes awhile to get into the blood, means less time for use
Bioavailability
-calculated using: AUCoral/AUCiv
-the amount of drug that gets to the blood/available for use
Speed of drug availability
1.IV
2. IM
3. SQ
4. Oral
5. Rectal
Sustained release
-Use slow release products
>Can attach drug to molecule such as a salt. The salt can help ensure the drug stays longer at site of administration and can allow for a sustained release
ex.procaine penicillin in large animal
Flip-flop kinetics
-describes the situation where a depot injection is slowly absorbed over time
>like an infusion
**absorption rate determines the elimination rate
Repeated dosing resulting in accumulation
-Give dose day after day, more frequently than its half life then the drug will accumulate in the body
**still a steady state because min and max are the same every time
ex. phenobarbital- will build up over time slowly so that it reaches therapeutic level
Repeated dosing after the half life
Will result in Cmax of single dose being close to Cmax at steady state. Will not get accumulation
Difference between Cmax and Cmin are very different
Repeated dosing at half life
Allows for drug to be within the therapeutic window
What can you use pharmacokinetics info for?
Changing dose regimens
1. different routes result in different bioavailability
2. Change of drug clearance:
> Renal or hepatic disease, enzyme inhibition= decrease dose
>increased clearance due to enzyme induction= increase dose
3. Therapeutic drug monitoring- based on therapeutic drug window and differing metabolism for certain individuals eg phenobarb
Drug development
1. Drug formation
Does pharmacokinetics tell you which drug is better?
No
-don’t look at safety or efficacy. Need to use PK and PD together
Clinical limitations of PK data
- Volume of distribution is just a ratio
>more drug in tissues or less drug in plasma BUT don’t know what tissue drug is in. High VD just tells us that drug is not in blood! - Elimination half-life
>longer does not make it better
>just influences dosing intervals - Plasma drug concentrations are used
>may not be as relevant as tissue drug concentrations - PK/PD models can’t predict efficacy or safety
>just a predictive method; may not correlate to clinic
