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Revision of pharmacokinetic terms Therapeutic window Bioavailability Plasma half life First, zero, pseudo-zero order elimination Clearance Volume of Distribution Intravenous infusion Oral dosing Plasma monitoring of drugs. time. Therapeutic window. Toxic level. Narrow.

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  • Revision of pharmacokinetic terms

    • Therapeutic window

    • Bioavailability

    • Plasma half life

    • First, zero, pseudo-zero order elimination

    • Clearance

    • Volume of Distribution

    • Intravenous infusion

    • Oral dosing

    • Plasma monitoring of drugs

time


Therapeutic window

Toxic level

Narrow

Minimum

therapeutic level

Cp

time


Therapeutic window

Toxic level

Wide

Minimum

therapeutic level

Cp

time


Bioavailability (F)

Measure of the amount of drug absorbed into the systemic circulation

Area under the curve (AUC)

obtained from the Cp versus time plot

gives a measure of the amount of drug absorbed

Foral = AUCoral

AUCiv

Clearance = F. dose

AUC

iv bolus

NB: same dose given iv and orally

Cp

oral dose

time


Oral bioavailability

frusemide 0.61

aspirin 0.68

propranolol 0.26

digitoxin 0.90

digoxin 0.70

diazepam 1

lithium 1

morphine 0.24


Oral bioavailability can be altered by formulation

  • Same drug, same dose, different formulation

  • different amounts absorbed

  • different peak concentration

  • different AUCs

Cp

time


Different routes of administration give different Cp versus time profiles(rates of absorption different)

Assume the bioavailability is the same (i.e. 1 for all routes)

iv

Cp

sc

oral

time


Different routes of administration give different Cp versus time profiles(rates of absorption different)

Assume the bioavailability is the same (i.e. 1 for all routes)

iv

  • Slower the rate of absorption

  • time to peak longer

  • amplitude of peak is less

  • drug in body for longer

Cp

sc

oral

time


Plasma half life time profiles

Half life (t1/2)

time for plasma concentration to fall by 50%

Cp

time

time


Plasma half life time profiles

Half life (t1/2)

time for plasma concentration to fall by 50%

Cp

time

time


Drug elimination kinetics time profiles

First order elimination – majority of drugs

Cp

time

Rate of elimination depends on plasma concentration

C = C0e-kt (k= rate constant of elimination)


Drug elimination kinetics time profiles

First order elimination – majority of drugs

Half life independent of concentration

Cp

time

Rate of elimination depends on plasma concentration

C = C0e-kt (k= rate constant of elimination)


Drug elimination kinetics time profiles

Zero order elimination

Cp

time

rate of elimination is constant and independent of plasma concentration –

elimination mechanism is saturated


Drug elimination kinetics time profiles

Zero order elimination

Half life varies with concentration

Cp

time


Drug elimination kinetics time profiles

Pseudo-zero order elimination

ethanol, phenytoin

Cp

time


Drug elimination kinetics time profiles

Pseudo-zero order elimination

ethanol, phenytoin

Cp

time


Volume of time profilesdistribution (Vd)

Vd = dose

C0

Volume of water in which a drug would have to be distributed to give its plasma concentration at time zero.

Litres 70kg-1

Can be larger than total body volume (e.g. peripheral tissue accumulation)

frusemide 7

aspirin 14

propranolol 273

digitoxin 38

digoxin 640


Plasma clearance (Cl) time profiles

Volume of blood cleared of its drug content in unit time (not same as Rate of Elimination – for drugs eliminated by 1st order kinetics rate of eliminatiuon changes with Cp, value of clearance does not change)

Cp

time


Plasma clearance (Cl) time profiles

Volume of blood cleared of its drug content in unit time (not same as Rate of Elimination – for drugs eliminated by 1st order kinetics rate of eliminatiuon changes with Cp, value of clearance does not change)

Rate of elimination different,

Clearance the same

Cp

time


Plasma clearance (Cl time profilesP)

Litres hr-1 70kg-1

Vd (litres)Cl (L hr-1 70kg-1)

frusemide 7 8

aspirin 14 39

propranolol 273 50

digitoxin 38 0.25

digoxin 640 8


Plasma half life (t time profiles1/2) = 0.693 Vd

Cl


Plasma half life (t time profiles1/2) = 0.693 Vd

Cl

Vd (litres)Cl (L hr-1 70kg-1)t1/2 (h)

frusemide 7 8 1.5

aspirin 14 39 0.25

propranolol 273 50 3.9

digitoxin 38 0.25 161

digoxin 640 8 39


More complex pharmacokinetic models: time profiles

The two compartment model

tissues

plasma

elimination

Redistribution + elimination

Cp

e.g. thiopentone

elimination

time


Intravenous infusion time profiles

At steady state

rate of infusion = rate of elimination

= Css x Clearance

Css (plateau)

Cp

time


Intravenous infusion time profiles

At steady state

rate of infusion = rate of elimination

= Css x Clearance

Css (plateau)

Cp

Time to >96 % of Css = 5 x t1/2

time


At steady state time profiles

rate of infusion = rate of elimination

= Css x Clearance

Height of plateau is

governed by the rate of infusion

Rate of infusion2x mg min-1

Cp

Rate of infusion x mg min-1

time


Drug t time profiles1/2 (h)Time to >96% of steady state

Lignocaine 2 10 hours

Valproate 6 30 hours

Digoxin 39 8.1 days

Digitoxin 161 33.5 days


Use of loading infusion time profiles

Height of plateau is

governed by the rate of infusion

Cp

rate of infusion x mg min-1

Desired Css

time


Use of loading infusion time profiles

Height of plateau is

governed by the rate of infusion

rate of infusion2x mg min-1

Cp

rate of infusion x mg min-1

Desired Css

time


Use of loading infusion time profiles

Height of plateau is

governed by the rate of infusion

Switch

here

Initial loading infusion2x mg min-1

Cp

Followed by maintenance infusion x mg min-1

Desired Css

time


Use of loading infusion time profiles

Height of plateau is

governed by the rate of infusion

Switch

here

Initial loading infusion2x mg min-1

Cp

Followed by maintenance infusion x mg min-1

Desired Css

time

saved

time


Multiple oral dosing time profiles

Cssav = F . Dose

Clearance. T

At Steady State

amount administered = amount eliminated between doses

F = oral bioavailability

T = dosing interval

Cp

time


Multiple oral dosing time profiles

Cssav = F . Dose

Clearance. T

At Steady State

amount administered = amount eliminated between doses

F = oral bioavailability

T = dosing interval

Cssav

Cp

time


Loading doses time profiles

Cp

Maintenance doses

time

e.g. Tetracycline t1/2 = 8 hours

500mg loading dose followed by 250mg every 8 hours


C time profilesssav = F . Dose

Clearance. T

F = oral bioavailability

T = dosing interval

Cssav


C time profilesssav = F . Dose

Clearance. T

F = oral bioavailability

T = dosing interval

Cssav

Reducing the dose AND reducing the interval

Cssav remains the same but fluctuation in Cp is less


  • Drug plasma concentration monitoring is helpful for drugs time profiles

    • that have a low therapeutic index

    • that are not metabolised to active metabolites

    • whose concentration is not predictable from the dose

    • whose concentration relates well to either the therapeutic effect

    • or the toxic effect, and preferably both

    • that are often taken in overdose


  • For which specific drugs is drug concentration monitoring helpful?

  • The important drugs are:

    • aminoglycoside antibiotics (e.g. gentamicin)

    • ciclosporin

    • digoxin and digitoxin

    • lithium

    • phenytoin

    • theophylline

    • paracetamol and aspirin/salicylate (overdose)

  • Other drugs are sometimes measured:

    • anticonvulsants other than phenytoin (eg carbamazepine, valproate)

    • tricyclic antidepressants (especially nortriptyline)

    • anti-arrhythmic drugs (eg amiodarone).


  • The uses of monitoring are helpful?

    • to assess adherence to therapy

    • to individualize therapy

    • to diagnose toxicity

    • to guide withdrawal of therapy

    • to determine whether a patient is already taking a drug before starting therapy (e.g. theophylline in an unconscious patient with asthma)

    • in research (e.g. to monitor for drug interactions)


  • Altered pharmacokinetic profile helpful?

  • liver metabolism

  • Disease

  • Pharmacogenetics (cytochrome P450 polymorphisms)

  • renal impairment (e.g. digoxin)

    • Disease

    • Elderly


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