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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

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

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

First order elimination – majority of drugs

Cp

time

Rate of elimination depends on plasma concentration

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

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)

Zero order elimination

Cp

time

rate of elimination is constant and independent of plasma concentration –

elimination mechanism is saturated

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

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

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

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 (t1/2) = 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:

The two compartment model

tissues

plasma

elimination

Redistribution + elimination

Cp

e.g. thiopentone

elimination

time

At steady state

rate of infusion = rate of elimination

= Css x Clearance

Css (plateau)

Cp

time

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

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

Lignocaine 2 10 hours

Valproate 6 30 hours

Digoxin 39 8.1 days

Digitoxin 161 33.5 days

Height of plateau is

governed by the rate of infusion

Cp

rate of infusion x mg min-1

Desired Css

time

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

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

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

Cssav = F . Dose

Clearance. T

At Steady State

amount administered = amount eliminated between doses

F = oral bioavailability

T = dosing interval

Cp

time

Cssav = F . Dose

Clearance. T

At Steady State

amount administered = amount eliminated between doses

F = oral bioavailability

T = dosing interval

Cssav

Cp

time

Cp

Maintenance doses

time

e.g. Tetracycline t1/2 = 8 hours

500mg loading dose followed by 250mg every 8 hours

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).

- 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

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