A Clinicians Guide to Pharmacokinetics Flashcards
What is C”max”?
maximum plasma concentration
What is AUC?
area under plasma concentration vs time curve from time of inj to the limit of quantification of the assay
What is t”max”?
time point @ which C”max” is reached
What is T”1/2”?
plasma half-life of drug
What is t”+0.2”?
time plasma concentrations remain above 0.2 micrograms/mL
how does clinical pharmacokinetics work?
- drug companies work out dosage regime (costs millions of dollars)
- research paper will suggest modifications
- individualizing treatment for specific patient requires that you have an understanding of the basics
What do you know about pharmacodynamics so far?
Dose is not proportional to effect!
What is the therapeutic window?
range btwn minimum EFFECTIVE & minimum TOXIC plasma concentrations in an INDIVIDUAL
(you will not know what these numbers will be)
What is the therapeutic range?
plasma concentration range in POPULATION likely to produce a desired effect
What is pharmacokinetics the study of ?
how drugs get into & out of the body & where they go when they are in the body
why do we need mathematical models?
to develop dosing regimes
What are 2 problems associated with pharmacokinetics?
- math involves logs
- studies are mainly done on blood (plasma) - & most drugs dont work in the blood
what are the clinical limitations of pharmacokinetic data?
- PK data is based on plasma drug concentrations, which may not be as relevant as tissue drug concentrations (ex: UTI)
- PK/PD models
- PK values may be model dependent
- often highly variable btwn studies
- numbers are NOT absolute
Where else can you use drugs that is not in the bloodstream?
Not all drug use is systemic
1. skin
2. ears
3. inhaled
4. intra-mammary
5. intra uterine
6. wounds
what is the problem of extrapolating plasma kinetics?
- most studies are done on sm grps of similar animals & dont account for effects of: age, gender, sex, body type, breed, pregnancy, lactation, &/or genetics
also 2. plasma vs tissue drug concentrations may vary or some drugs get sequestered in fat
How does first order drug elimination work?
- rate of elimination is proportional to amt of drug remaining
- constant PROPORTION of drug is eliminated per unit time
- this results in curved line when plotted on LINEAR/linear graph
- (straight line when plotted on LOG/linear graph)
- most drugs follow 1st order kinetics (@ label doses)!
why do pharmacokineticists tend to stop at 7 half lives?
only 0.8 % of drug remaining
How do you know if graph is linear/linear or log/linear?
look at y axis scale!
what is K”el”?
elimination rate constant; slope of line of LOG/linear graph
what happens if you infuse a drug at a constant rate?
- concentration will rise logarithmically to reach a steady state
- final concentration is related to rate of infusion
How long does it take to reach steady state?
7 half-lives
How do you get a drug concentration to steady state faster?
w/ a loading dose (rapid IV bolus followed by a sustained infusion)
How to calculate a loading dose?
Vol of distribution - total dose of drug/ C”max” = L/Kg (how many L of water per kg of body weight is drug dissolved in?)
What does calculating the volume of distribution give you an idea of ?
how drug distributes in body
- blood only 0.08
- body water 0.6
- highly fat soluble drugs 200!
What does volume of distribution greater than 100 mean?
drug has gone out of blood
How to roughly calculate a loading dose?
loading dose = desired concentration X volume of distribution
How else can drugs be given other than IV?
IM, SC, oral, rectally, nasally, trans-dermal, vaginally
If you are giving a drug any way other than IV, what has to happen?
drug has to be absorbed into the plasma
Why does route of administration matter?
- absorption phase
- bioavailability
- sustained release
What is bioavailability?
how much drug gets into blood & system
how to calculate bioavailability?
area under the curve oral / area under curve IV
What is flip-flop kinetics?
- describes situation where “depot” injection is slowly absorbed over time (bit like an infusion)
- elimination rate is controlled by absorption rate (rate that it is coming in is controlling rate @ which is is released from blood)
What kind of meds have flip-flop kinetics?
long acting meds
What happens when dosage interval is shorter than the half-life?
concentration will slowly increase over time (drug accumulation - C”max” at steady state is much higher than C”max” after a single dose); there is minimal fluctuations btwn C”max” & C”min”; missing 1 dose has minimal impact on [plasma]; loading dose may be useful to reach desired [plasma] more quickly
What happens when dosage interval is equal to the half-life?
will get a little accumulation but much more variation; as long as the drug stays above the therapeutic margin you are good
What happens when dosage interval is longer than the half-life?
not much difference btwn C”max” @ steady state & C”max” of single dose (little drug accumulation); marked fluctuations in drug concentration btwn C”max” & C”min” (ex: b/c penicillin is super safe you can give a massive dose and let it drop & repeat); missing dose greatly affects concentration; minimal lag time to achieve desired concentration in body (no loading dose needed)
What does little T (tau) mean?
dosing interval
When can you make changes to a dosing schedule?
need to be v cautious; only if you have scientific paper to support you
What can vet’s do with PK info?
adjust dose regimens
How can vets adjust dose regimens?
- change dose
- w/ diff route of administration (using relative bioavailability)
- w/ likely changes in drug clearance
> renal or hepatic disease, enzyme inhibition: decrease dose
> increased clearance due to enzyme induction: increase dose - change dose interval
- based on therapeutic drug monitoring
> calc T”1/2elim”
> useful: phenobarb or KBr therapy
> not so much: theophylline, aminoglycosides, cyclosporine, etc.
- based on likely changes in drug clearance
> ex: renal or hepatic failure
What else can PK info be used for?
drug development:
- drug formulation optimized based on PK & PD data
- correlation btwn PK/PD & clinical efficacy, but only if PK & PD data are well known (even then there is wide PK variability btwn animals & PD outcomes are not uniform)
What can you not used PK for?
Knowing which drug is better
- PK parameters do NOT indicate safety or efficacy
- PK-PD together improves predictions about clinical efficacy/safety, but correlation isnt necessarily that strong!
What are the clinical limitations of PK data?
- vol of distribution is just a ratio!
- elimination half-life
- PK data is based on plasma drug concentrations
- PK/PD models
explain how PK data is limited by volume of distribution:
higher volume of distribution means there is more drug in the tissue OR less drug in the plasma, but we dont know which tissues the drug might be in; higher V”D” does not mean the drug works better
explain how PK data is limited by elimination half-life:
- longer half-life doesnt mean better, it may influence the dosing interval but that is it!
- the elimination half-life from tissues may not appear to match the elimination half-life from plasma -> means that withdrawal periods cannot be accurately estimated from plasma half-life
explain how PK data is limited by PK data being based on plasma drug concentrations:
these may not be as relevant as tissue drug concentrations; ex: UTIs: are treated by therapeutic urine! drug has already left the body & kidneys are just used to distribute drug (could get same effect from using a catheter)
explain how PK data is limited by using PK/PD models to predict efficacy:
PK models may be model-dependent; they are often highly variable btwn studies & #s are not absolute, PK/PD models are PREDICTIVE only and their predictions may not always correlate w/ clinical results
