A clinicians guides to pharmacokinetics

Question 1

How do you know how much drug to give a patient?

Answer 1

• read the bottle!

Question 2

What do clinicians need to do when determining dose?

Answer 2

Options:

1. Read label
2. Read modifications in research papers
3. individualize treatments

Question 3

How does dose connect to effect?

Answer 3

• 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

Question 4

Therapeutic window

Answer 4

-need to be within the window between min therapeutic dose and min toxic dose

-windows can be large or small

Question 5

Therapeutic range

Answer 5

plasma concentration range in a population likely to produce a desired effect

Question 6

Pharmacokinetics

Answer 6

-study of how drugs go in and out of body and there they go when inside the body

-includes mathematical models (includes logs)

Question 7

Problems with pharmacokinetics

Answer 7

-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)

Question 8

Pharmacokinetics drug testing

Answer 8

-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

Question 9

Drug use that isn’t systemic

Answer 9

-skin
-ears
-inhaled
-intra-mammary
-intra uterine
-wounds

**often not entering the blood

Question 10

Difficult to extrapolate plasma kinetics

Answer 10

-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

Question 11

Plasma vs. tissue drug concentration

Answer 11

• 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

Question 12

Drug levels in fat

Answer 12

-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

Question 13

1st order elimination

Answer 13

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

Question 14

Where would a toxic effect occur with a drug?

Answer 14

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

Question 15

Half lives

Answer 15

-pharmacokineticists usually stop at 7x half lives because at that point drug concentration is basically at zero

Question 16

IV dose infusion at a constant rate

Answer 16

-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

Question 17

Loading dose

Answer 17

-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

Question 18

Volume of distribution

Answer 18

=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

Question 19

Drug infusion when not IV

Answer 19

-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

Question 20

What factors effect drug distribution when drug not given as IV?

Answer 20

-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

Question 21

Bioavailability

Answer 21

-calculated using: AUCoral/AUCiv

-the amount of drug that gets to the blood/available for use

Question 22

Speed of drug availability

Answer 22

1.IV
2. IM
3. SQ
4. Oral
5. Rectal

Question 23

Sustained release

Answer 23

-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

Question 24

Flip-flop kinetics

Answer 24

-describes the situation where a depot injection is slowly absorbed over time
>like an infusion

**absorption rate determines the elimination rate

Question 25

Repeated dosing resulting in accumulation

Answer 25

-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

Question 26

Repeated dosing after the half life

Answer 26

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

Question 27

Repeated dosing at half life

Answer 27

Allows for drug to be within the therapeutic window

Question 28

What can you use pharmacokinetics info for?

Answer 28

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

Question 29

Does pharmacokinetics tell you which drug is better?

Answer 29

No
-don’t look at safety or efficacy. Need to use PK and PD together

Question 30

Clinical limitations of PK data

Answer 30

1. 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!
2. Elimination half-life
   >longer does not make it better
   >just influences dosing intervals
3. Plasma drug concentrations are used
   >may not be as relevant as tissue drug concentrations
4. PK/PD models can’t predict efficacy or safety
   >just a predictive method; may not correlate to clinic