Revision of pharmacokinetic terms

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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
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Therapeutic window
Toxic level
Narrow
Minimum therapeutic level
Cp
time
3
Therapeutic window
Toxic level
Wide
Minimum therapeutic level
Cp
time
4
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
5
Oral bioavailability frusemide
0.61 aspirin 0.68 propranolol 0.26 digitoxin
0.90 digoxin 0.70 diazepam 1 lithium 1 morp
hine 0.24
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Oral bioavailability can be altered by formulation

• Same drug, same dose, different formulation
• different amounts absorbed
• different peak concentration
• different AUCs

Cp
time
7
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
8
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
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Plasma half life
Half
life (t1/2)
time for plasma concentration to fall by
50
Cp
time
time
10
Plasma half life
Half
life (t1/2)
time for plasma concentration to fall by
50
Cp
time
time
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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)
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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)
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Drug elimination kinetics
Zero order elimination
Cp
time
rate of elimination is constant and independent
of plasma concentration elimination mechanism
is saturated
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Drug elimination kinetics
Zero order elimination Half life varies with
concentration
Cp
time
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Drug elimination kinetics
Pseudo-zero order elimination ethanol, phenytoin
Cp
time
16
Drug elimination kinetics
Pseudo-zero order elimination ethanol, phenytoin
Cp
time
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Volume of distribution (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
18
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
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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
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Plasma clearance (ClP) 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
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Plasma half life (t1/2) 0.693 Vd Cl
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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 3
8 0.25 161 digoxin 640 8 39
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More complex pharmacokinetic models The two
compartment model
tissues
plasma
elimination
Redistribution elimination
Cp
e.g. thiopentone
elimination
time
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Intravenous infusion
At steady state rate of infusion rate of
elimination Css x Clearance
Css (plateau)
Cp
time
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Intravenous infusion
At steady state rate of infusion rate of
elimination Css x Clearance
Css (plateau)
Cp
Time to gt96 of Css 5 x t1/2
time
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At steady state rate of infusion rate of
elimination Css x Clearance
Height of plateau is governed by the rate of
infusion
Rate of infusion 2x mg min-1
Cp
Rate of infusion x mg min-1
time
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Drug t1/2 (h) Time to gt96 of steady
state
Lignocaine 2 10 hours Valproate 6 30
hours Digoxin 39 8.1 days Digitoxin 161 33.5
days
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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
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Use of loading infusion
Height of plateau is governed by the rate of
infusion
rate of infusion 2x mg min-1
Cp
rate of infusion x mg min-1
Desired Css
time
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Use of loading infusion
Height of plateau is governed by the rate of
infusion
Switch here
Initial loading infusion 2x mg min-1
Cp
Followed by maintenance infusion x mg min-1
Desired Css
time
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Use of loading infusion
Height of plateau is governed by the rate of
infusion
Switch here
Initial loading infusion 2x mg min-1
Cp
Followed by maintenance infusion x mg min-1
Desired Css
time saved
time
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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
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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
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Loading doses
Cp
Maintenance doses
time
e.g. Tetracycline t1/2 8 hours 500mg loading
dose followed by 250mg every 8 hours
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Cssav F . Dose Clearance.
T
F oral bioavailability T dosing interval
Cssav
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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
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• Altered pharmacokinetic profile
• liver metabolism
• Disease
• Pharmacogenetics (cytochrome P450 polymorphisms)
• renal impairment (e.g. digoxin)
• Disease
• Elderly