Csf Test 1 Kuma

Front 1

What is Pharmacokinetics?

Back 1

1. PK is the description of changes in drug concentrations over time.
2. Drug concentrations in plasma is the most common context, although PK can be described in any tissue or fluid.
3. PK is also described as the study of “ADME”: the absorption, distribution, metabolism and excretion of drugs.

Front 2

How much drug should be given?

Back 2

Assumes that the responses to a drug, both therapeutically desirable as well as toxic, are functions of the size of the dose

Front 3

How often should a drug be given?

Back 3

Assumes that the effect of a drug declines with time following a single dose, and that repeated dosing is required to maintain the desired response

Front 4

Basic assumption

Back 4

The magnitude of drug effect is assumed to be a function of the concentration of the drug at its site of action

Front 5

Objective of drug therapy

Back 5

Maintain an adequate concentration of drug at its site of action for the required duration of therapy

Front 6

The purpose of pharmacokinetics

Back 6

1. Characterize the rates of absorption, distribution, metabolism, and excretion of drugs within a biological system using mathematical representations and parameters.
2. Analyze drug concentrations or amounts using mathematical representations, and to use these mathematical parameters to construct appropriate dosage regimens which will maintain desired drug concentrations of drugs at their sites of action for the required duration of therapy.

Front 7

The potential advantages of determining the pharmacokinetic characteristics of drugs include:

Back 7

1. Distinction can be made between the pharmacokinetic and pharmacodynamic causes of an unusual or unexpected response to a drug.
2. Information about the pharmacokinetics of one drug can help to predict the pharmacokinetics of another.
3. Understanding the pharmacokinetics of a drug helps to explain, and indeed often dictates, the manner of the drug’s use.
4. Knowledge of the pharmacokinetics of a drugs aids the clinician in optimizing the dosage regimen for an individual patient, and also aids in predicting what will happen if the dosage regimen is changed in some way.

Front 8

The Therapeutic Window

Back 8

If it is assumed that the magnitude of drug effect is a function of drug concentration at the site of action, drug therapy generally fails for one of two reasons:
1. Therapy is ineffective because concentrations are too low.
2. Unacceptable toxicity is present because concentrations are too high.
Between the upper and lower limits of drug concentration lies the region of desirable concentrations; this region is referred to as the therapeutic “window” or “range” or “index”.

Front 9

Where are drug concentrations measured?

Back 9

Drug concentrations are rarely able to be measured directly at the site of action  concentrations in blood, plasma or serum are usually used
It must be inferred that measured concentrations are directly related to drug concentrations at the site of infection
“Optimal” concentrations are those that achieve and maintain measured concentrations within the predetermined therapeutic range

Front 10

Common misconceptions regarding the therapeutic range:

Back 10

Therapeutic ranges are always derived from carefully controlled clinical studies.
Concentrations within the therapeutic range invariable result in a favorable clinical response.
In reality, therapeutic ranges are based on probabilities of achieving desired responses to drug therapy.

Front 11

What are therapeutic ranges based on?

Back 11

probabilities because there is a lot of variabilty

Front 12

Pharmacokinetic Variability

Back 12

Dosage regimens (dose and frequency) are determined by both the width of the therapeutic range and the ADME characteristics of the drug in the body
Patient variability in drug ADME offers a challenge to the clinical use of drugs:
Age
Weight
Obesity
Type and severity of underlying disease(s)
Genetic phenotypes
Concurrently administered drugs
Environmental factors

Front 13

What is the result of PK variability?

Back 13

Pharmacokinetic variability results in “standard” dosing regimens (based on population pharmacokinetics) being effective for some patients and ineffective or unacceptably toxic for others

Front 14

Ability to individulize a drug is the basis of?

Back 14

Ability to individualize drug therapy/dosage forms the basis of “clinical pharmacokinetics”
Also known as “applied pharmacokinetics” or “therapeutic drug monitoring” (TDM)
Objective is to individualize therapy to achieve the best possible outcomes for each patient
What’s this patient doing PK-wise that may impact the success of therapy?
How can we account for potential PK differences in order to optimize therapy in this patient?

Front 15

Clinical Pharmacokinetics

Back 15

Clinical PK can improve the probability of producing favorable response and/or avoiding unacceptable toxicities
Clinical PK cannot be used independently of good clinical, patient-oriented pharmacy practice
“Favorable” concentrations are only intermediate therapeutic objectives and can never replace clinical response as the ultimate measure of the success of drug therapy

Front 16

Clinical Pharmacokinetics focuses on

Back 16

1. Relatively well-defined therapeutic range
2. Narrow therapeutic range and potential for significant toxicities at dosages close to those required for efficacy
3. High potential for significant variability within individual patients

Front 17

Pharmacokinetics: Drug Concentrations

Back 17

Protein binding in plasma is common, typically to albumin and alpha-1-acid-glycoprotein (AAG)
Drug concentrations in plasma (or serum) represent “total concentrations” (bound plus unbound drug), or Ct
The unbound “free” concentration, Cu, is the pharmacologically “active” concentration
The free fraction (fu) = unbound concentration (Cu) divided by the total concentration (Ct)
fu = Cu / Ct
Cu = Ct x fu

Front 18

What is Pharmacodynamics?

Back 18

Pharmacodynamics = relationship between drug concentration and drug effect

Pharmacodynamics of a given drug are intimately related to the PK properties

Front 19

Intensity of Drug Effects (Emax principles)

Back 19

1. Intensity of drug response is a function of drug exposure (dependent on PK properties)
2. Maximal magnitude of effect is the Emax (The law of diminishing returns with increasing doses)
3. Drug exposure at which there is a 50% maximal response is called the EC50
Measure of drug potency
4. There is often a linear relationship between ~20% and 80% maximal response

Front 20

chronic dosing typically includes a __________ dose and a _______ time

Back 20

fixed
fixed

Front 21

If all of the dosing regimens have the same total daily dose how is the Css ave affected?

Back 21

The Css will be the same, but the Cmin and Cmax will differ

Front 22

Css ave=

Back 22

[(dose*F*S)/tau]/CL

Front 23

how many half lives does it take to reach SS?

Back 23

5

Front 24

how is maintence dose is calculated?

Back 24

dose= (Css * CL* tau)/F*S

if teh target concentration is the Css (not Cmax or min)

Front 25

What are the 3 main parts for a chronic dosing profile?

Back 25

SS Cmax, SS Cmin
A time to rise to SS
1st dose Cmax and Cmin

Front 26

Accumulation factor ratio def:

Back 26

determins the fold accumulation at SS compared with the first dose for a given interval tau

Front 27

The accumulation factor can be used for SS calculations for:

Back 27

1. Bolus
2. Short infusion

Front 28

acumulation factor=

Back 28

1/ 1-e^-ke*tau

where 1-e^-ke*tau is the fraction lost in the first dose interval between 0-1

e^-ke*tau is the fraction remaining in the dose

Reciprocal of the fraction would be the amount of the drug gained

Front 29

Accumulation ratio depends on...

Back 29

depends on the dose interval, tau and the elimation rate constant ke

the SS Cmax equals the single dose Cmax multiplied by the accumulation factor

Front 30

Cmax for bolus dose =
(single dose)

Back 30

(dose*F*S)/Vd

Front 31

Cmin for bolus dose =
(single dose)

Back 31

Cmax * e^-ke(tau)

Front 32

C max (Nth dose)=
(bolus)

Back 32

Cmaxss*(1-e^-ke(N)(tau)

analogous to:
Ct=Css*(1-e^-ke*t)

Front 33

Cmaxss=
(bolus)

Back 33

Cmax (single dose)/ 1-e^ke*tau

Front 34

Cminss=
(bolus)

Back 34

Cmaxss*e^-ke*tau

Front 35

Cmax(pre-ss)=
(bolus)

Back 35

Cmaxss*(1-e^-ke(N)(tau)

N=# of doses

Front 36

when do you use short infusion equations?

Back 36

when you have to account for drug lost during administration

when the half life is NOT 6 times or more than the administration time

Front 37

when do you use bolus equations?

Back 37

when the half life is 6 times greater then the administration time

Front 38

Cmax for short infusion=
(single dose)

Back 38

(dose/t-in/CL)*(1-e^-ke*t-in)

Front 39

Cmin for short infusion=
(single dose)

Back 39

Cmax (single dose)* e^-ke*(tau-t-in)

Front 40

Cmaxss for short infusion =

Back 40

Cmax (single dose)/1-e^(ke*tau)

Front 41

Cminss for short infusion=

Back 41

Cmaxss*e^-ke(tau-t-in)

Front 42

Cmax(pre-ss)=
Short infusion

Back 42

Cmaxss*(1-e^-ke(N)(tau)

Front 43

Flat pk profile

Back 43

Little fluctuation in the dose interval

drugs with long half lives will have little fluctuation therefore have a flat pk profile

Front 44

When is a drug considered to have a flat pk profile?

Back 44

when 1/2 life is 3 times or more greater than tau

Front 45

when you have a flat pk profile what is the relationship between Cmax, Cmin, and Css?

Back 45

They are realatively equal
Cmax, Cmin, Css= ((dose*F*S)/tau)/CL
or
Cmax, Cmin, Css=Ro/CL

Front 46

Finding tau for bolus equations

Back 46

tau=[ln Cmax/cmin]/ke

Front 47

finding tau for short infusion equations

Back 47

tau-t-in= [ln Cmax/Cmin)/ke

Front 48

What is the first consideration for designing a dosing interval when you have Cmax and Cmin targets?

Back 48

find tau

Front 49

What is the second consideration for designing a dosing intercal when you have Cmax and Cmin targets?

Back 49

after finding tau find the dose that will achive Cmaxss

Cmaxss= [(dose*F*S/Vd)]/(1-e^-ke*tau)
Cminss=Cmaxss*e^-ke*tau

Front 50

when is a loading dose useful

Back 50

when drugs have an accumulation factor > 3 and when we don't want to wait to get to ss

Administration of an initial loading dose allowd rapid attainment of effective (therapeutic) drug concentrations

Front 51

what dose an accumulation factor of 1 indicate

Back 51

SS is achieved after a single dose therefore a loading dose would not have much of an impact

Front 52

loading dose calculation (3 of them)

Back 52

1. loading dose= desired C * Vd

2. Loading dose =(desired C- C on board) *Vd

3. loading dose= maintenace dose * accumulation factor

Front 53

assumptions for predicting SS pk for the first dose

Back 53

assume linear pharmacokinetics (CL and V, T 1/2) are constant from the first dose to SS

Front 54

In what situations are the pk profiles not linear

Back 54

saturable elimination
auto-induction of metabolism

Front 55

If the drug does not have a linear pk profile is it correct to predict concentrations from the ss equations

Back 55

no, because the values would not be correct ke would be changing

Front 56

Given linear pk first dose AUC (0-infinite)=

Back 56

SS dose AUC(0-tau)

Front 57

what factor does not affect accumulation ratio?

Back 57

dose

Front 58

what 3 factors affect accumulation ratio

Back 58

CL
Vd
tau

Front 59

units of CL

Back 59

measured as volume of plasma cleared of drug per time (L/h)

Front 60

units of vd

Back 60

L

Front 61

decline rate is defined as

Back 61

CL/V
volume of plasma per time divided by total volume to be cleared