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Revision of pharmacokinetic terms Therapeutic window Bioavailability Plasma half life First, zero, pseudo-zero order elimination Clearance

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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

aspirin0.68

propranolol0.26

digitoxin0.90

digoxin0.70

diazepam1

lithium1

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

Half life (t1/2)

time for plasma concentration to fall by 50%

Cp

time

time

Plasma half life

Half life (t1/2)

time for plasma concentration to fall by 50%

Cp

time

time

Drug elimination kinetics

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

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

Zero order elimination

Cp

time

rate of elimination is constant and independent of plasma concentration –

elimination mechanism is saturated

Drug elimination kinetics

Zero order elimination

Half life varies with concentration

Cp

time

Drug elimination kinetics

Pseudo-zero order elimination

ethanol, phenytoin

Cp

time

Drug elimination kinetics

Pseudo-zero order elimination

ethanol, phenytoin

Cp

time

Volume ofdistribution (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

aspirin14

propranolol273

digitoxin38

digoxin640

Plasma clearance (Cl)

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)

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 (ClP)

Litres hr-1 70kg-1

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

frusemide 7 8

aspirin14 39

propranolol273 50

digitoxin38 0.25

digoxin640 8

Plasma half life (t1/2) = 0.693 Vd

Cl

Plasma half life (t1/2) = 0.693 Vd

Cl

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

frusemide 7 81.5

aspirin14 390.25

propranolol273 503.9

digitoxin38 0.25161

digoxin640 839

More complex pharmacokinetic models:

The two compartment model

tissues

plasma

elimination

Redistribution + elimination

Cp

e.g. thiopentone

elimination

time

Intravenous infusion

At steady state

rate of infusion = rate of elimination

= Css x Clearance

Css (plateau)

Cp

time

Intravenous infusion

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

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 t1/2 (h)Time to >96% of steady state

Lignocaine210 hours

Valproate630 hours

Digoxin398.1 days

Digitoxin16133.5 days

Use of loading infusion

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

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

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

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

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

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

Cp

Maintenance doses

time

e.g. Tetracycline t1/2 = 8 hours

500mg loading dose followed by 250mg every 8 hours

Cssav = F . Dose

Clearance. T

F = oral bioavailability

T = dosing interval

Cssav

Cssav = 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
- 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
- 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
- liver metabolism
- Disease
- Pharmacogenetics (cytochrome P450 polymorphisms)
- renal impairment (e.g. digoxin)
- Disease
- Elderly