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PDA > 5 Quantitive Pharmacokinetics > Flashcards

5 Quantitive Pharmacokinetics Flashcards

1
Q

concentration =

A

mass/ volume

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2
Q

Volume of Distribution, VD

A

Used to estimate dose required to result in a certain [drug] in plasma

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3
Q

Volume of Distribution, VD

A

VD is the (apparent) volume of distribution.
The volume of plasma that would be required to contain the drug dose at the concentration measured in plasma.
Can be greater than total volume of a human due to tissue binding ! eg VD for amiodarone = 7000 L
Units: either L or can be expressed as L/Kg (to correct for different size patients)

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4
Q

Dose =

A

C VD

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5
Q

K is..

A

the elimination rate constant

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6
Q

Cl

A

clearance - the volume of plasma cleared of drug per unit time

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7
Q

Ca > Cv or Ca < Cv

A

The concentration of the drug in the blood leaving the liver will be lower

Ca > Cv

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8
Q

Amount of drug entering/minute =

A

QCa

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9
Q

Amount of drug leaving/minute =

A

QCv

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10
Q

Extraction ratio =

A

E = Ca-Cv/ Ca

E = 1 all eliminated 
E= 0 none eliminated
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11
Q

What is the extraction ratio

A

The extraction ratio is the fraction of drug entering a tissue that is eliminated

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12
Q

Rate of elimination =

A

blood flow rate x fraction of blood cleared of drug blood x Conc of drug in blood
Cl x C

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13
Q

Volume of distribution is..

A

volume that it appears the drug is dissolved in

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14
Q

Clearance varies with..

A

age and disease

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15
Q

Dose =

A

Cl x AUC∞

By measuring AUC∞ we can calculate Cl

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16
Q

Half life, t1⁄2

A

The time required for elimination of half of the absorbed drug

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17
Q

First order

A

– The Rate is proportional to “one variable” (hence “first”) – Here Rate depends on [Drug]
Rate α [Drug]
Rate = k [Drug]

(if [Drug] doubles, so does the rate)

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18
Q

Zero order

A

– The rate is constant
– It depends on “zero variables” (hence “Zero order”)

Rate is constant and doesn’t change with [Drug]

Rate = k
(if [Drug] doubles, rate stays the same)

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19
Q

First order drug elimination following intravenous bolus administration

A

C=C0e-kt

C0 = concentration of drug in plasma at t=0 (immediately after administration) 
k = elimination rate constant, fraction of drug eliminated per minute
k = 0.1 min-1  10% of drug is eliminated per minute
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20
Q

k =

A
  • slope x 2.303
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21
Q

kt1⁄2 =

A

ln2

22
Q

VD =

A

Dose/ C0

23
Q

ASSUMING: first order conditions, no non-linear PK, fast absorption and distribution
• Doubling the dose..

A

extends exposure above a certain concentration by t1⁄2

24
Q

Relationship of Clearance and elimination rate constant

A
  • k = elimination rate constant,
  • k = fraction of drug eliminated per minute

k = Cl/ VD

K is the fraction of the drug thats eliminated per min

25
Q

larger volume of distribution results in..

A

slower elimination

26
Q

Half life depends on..

A

clearance and volume distribution

27
Q

t1/2 =

A

0.693 x VD / Clearance

28
Q

Effects on Volume of Distribution

  • Ageing
  • Obesity
  • Pathologic fluid

How do these effect half-life

A

Aging (decreased muscle mass → decreased distribution)
Decreased

Obesity (increased adipose mass → increased distribution)
Increased

Pathologic fluid (increased distribution)
increased
29
Q

Effects on Clearance

  • Cytochrome P450 induction
  • Cytochrome P450 inhibition
  • Cardiac failure
  • Hepatic failure
  • Renal failure

How do these effect half-life

A

Cytochrome P450 induction (increased metabolism)
Decreased

Cytochrome P450 inhibition (decreased metabolism)
Increased

Cardiac failure (decreased clearance)
Increased
Hepatic failure (decreased clearance)
Increased
Renal failure (decreased clearance)
Increased
30
Q

Intravenous Infusion

A 
• Drug delivered over minutes-hours
– allows precise and controlled exposure
– adjust concentration
– stop if required
– short infusion sometimes used to reduce Cmax and adverse events following rapid bolus injection
31
Q

Intravenous Infusion

• Drug concentration increases..

A

• Drug concentration increases to a plateau value Css
– rate of elimination = rate of infusion

C = Css(1-e-kt)

32
Q

Intravenous Infusion

Calculation of infusion rate

A

•At plateau (“steady state concentration): Rate of elimination = Rate of infusion
•Rate elimination = Cl x Css
k = Cl VD
•so if we know Cl and the Css we wish to achieve we can calculate the required infusion rate
•Required rate of infusion Rinf = Cl x Css

33
Q

Intravenous Infusion

Loading Dose

A
  • Useful to quickly reach Css
  • bolus iv dose
  • Loading dose = CssVD
34
Q

Intravenous Infusion

the longer the half life..

A

the longer it will take to get to the steady state

35
Q

Intravenous Infusion

- Plateau concentration determined by..

A
  1. Plateau concentration determined by infusion rate and clearance
    Rinf = Cl x Css Css = Rinf/Cl
    Increasing the infusion rate will increase the final Css
36
Q

Intravenous Infusion

- Time to reach plateau depends on..

A
  1. Time to reach plateau depends on the elimination constant (or t1/2).
    Increasing the infusion rate will NOT REDUCE the time to reach Css because Css will be increased.
37
Q

• Linear pharmacokinetics

A

– pharmacokinetic parameters don’t change with dose

– increasing dose increases exposure (AUC Css etc) proportionately

38
Q

• Non-linear pharmacokinetics

A

– Pharmacokinetic parameters change with dose of drug
– increasing dose has a disproportionate effect on exposure
» eg exposure may be higher than expected because a metabolising enzyme is saturated
» eg exposure may be lower than expected because VD increases (eg drug accumulates in a different compartment at higher dose)

39
Q

Rate of increase of drug in body =

A

Rate of absorption - Rate of elimination

40
Q

Effect of dose & absorption rate on concentration profile

Increased dose results in

A

– increased Cmax and AUC

– no effect on Tmax

41
Q

Effect of dose & absorption rate on concentration profile

Changing absorption kinetics results in

A

– eg different formulation, p.o. admin with food

– Cmax and Tmax altered

42
Q

Effect of dose & absorption rate on concentration profile

Absorption can become..

A

rate-limiting

– usually elimination (disposition) is rate limiting
– but in some cases absorption is so slow that this becomes limiting:
» declining phase represents decrease absorption and elimination
» elimination rate = absorption rate

43
Q

kel =

A

Clearance / VD

independent of dose

44
Q

Bioavailability , F

A

• i.v. administration – all of the dose is bioavailable – F=1 (sometimes expressed as F=100% )
• Non i.v. – some drug may not reach systemic circulation
– incomplete absorption
» insufficient time, poor dissolution, poor permeability
– metabolism before absorption
» eg p.o. : gut flora, enzymes in gut wall, first pass metabolism
– F<1
• amount reaching systemic circulation = F x Dose

45
Q

How can we measure bioavailability, F ?

A

Fpo =

Doseiv AUCpo/ Dosepo AUCiv

46
Q

Repeated doses

A

2nd dose of drug is given before the 1st one has been eliminated. Thats why 2nd dose is higher

47
Q

Repeated dose equation

dose =

A

Dose = t Cl Css,av/ F

48
Q

Css,av depends on..

A

dose & frequency

49
Q

Loading Dose

A

– an initial “high” dose of drug to quickly plasma drug concentration to the desired level
– particularly important for drugs with large VD

Doseloading = VD Css/ F

50
Q

Maintenance dose

A

– once desired plasma drug concentration is achieved, them maintenance dose compensates for drug elimination

Dosemaintenance = t Cl Css, av/ F

PDA (18 decks)

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