Transcript Document

Revision of pharmacokinetic terms
• Therapeutic window
• Bioavailability
• Plasma half life
• First, zero, pseudo-zero order elimination
time
• Clearance
• Volume of Distribution
• Intravenous infusion
• Oral dosing
• Plasma monitoring of drugs
Therapeutic window
Toxic level
Narrow
Cp
Minimum
therapeutic level
time
Therapeutic window
Toxic level
Wide
Cp
Minimum
therapeutic level
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
iv bolus
Cp
Clearance = F. dose
NB: same dose given iv and orally AUC
oral dose
time
Oral bioavailability
frusemide
aspirin
propranolol
digitoxin
digoxin
diazepam
lithium
morphine
0.61
0.68
0.26
0.90
0.70
1
1
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
Cp
sc
Slower the rate of absorption
• time to peak longer
• amplitude of peak is less
• drug in body for longer
oral
time
Plasma half life
Cp
time
time
Half life (t1/2)
time for plasma concentration to fall by 50%
Plasma half life
Cp
time
time
Half life (t1/2)
time for plasma concentration to fall by 50%
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 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
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)
Cp
Rate of elimination different,
Clearance the same
time
Plasma clearance (ClP)
Litres hr-1 70kg-1
frusemide
aspirin
propranolol
digitoxin
digoxin
Vd (litres)
Cl (L hr-1 70kg-1)
7
14
273
38
640
8
39
50
0.25
8
Plasma half life (t1/2) = 0.693 Vd
Cl
Plasma half life (t1/2) = 0.693 Vd
Cl
frusemide
aspirin
propranolol
digitoxin
digoxin
Vd (litres)
Cl (L hr-1 70kg-1)
t1/2 (h)
7
14
273
38
640
8
39
50
0.25
8
1.5
0.25
3.9
161
39
More complex pharmacokinetic models:
The two compartment model
plasma
tissues
elimination
Cp
Redistribution + elimination
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
Height
of plateau
is
rate of infusion
= rate
of elimination
governed
by xthe
rate of infusion
= Css
Clearance
Rate of infusion 2x 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
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 infusion 2x 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
Cp
Initial loading infusion 2x mg min-1
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
Cp
Initial loading infusion 2x mg min-1
Followed by maintenance infusion x mg min-1
Desired Css
time
saved
time
Multiple oral dosing
Cssav =
F . Dose
Clearance.
T
At Steady
State
F = oral bioavailability
T = eliminated
dosing interval
amount administered = amount
between doses
Cp
time
Multiple oral dosing
Cssav =
F . Dose
Clearance.
T
At Steady
State
F = oral bioavailability
T = eliminated
dosing interval
amount administered = amount
between doses
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