Post on 28-Mar-2015
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
Toxic level
Minimumtherapeutic levelCp
time
Therapeutic window
Narrow
Toxic level
Minimumtherapeutic levelCp
time
Therapeutic window
Wide
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. doseAUC
iv bolus
oral dose
Cp
time
NB: same dose given iv and orally
Oral bioavailability
frusemide 0.61aspirin 0.68propranolol 0.26digitoxin 0.90digoxin 0.70diazepam 1lithium 1morphine 0.24
Same drug, same dose, different formulation• different amounts absorbed• different peak concentration• different AUCs
Cp
time
Oral bioavailability can be altered by formulation
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
sc
oral
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)
Slower the rate of absorption• time to peak longer• amplitude of peak is less• drug in body for longer
iv
sc
oral
Cp
time
Half life (t1/2)
time for plasma concentration to fall by 50%
Cp
time
time
Plasma half life
Cp
time
time
Plasma half life
Half life (t1/2)
time for plasma concentration to fall by 50%
Cp
time
First order elimination – majority of drugs
Rate of elimination depends on plasma concentration
C = C0e-kt (k= rate constant of elimination)
Drug elimination kinetics
Cp
time
First order elimination – majority of drugs
Half life independent of concentration
Rate of elimination depends on plasma concentration
C = C0e-kt (k= rate constant of elimination)
Drug elimination kinetics
Cp
time
Zero order elimination
rate of elimination is constant and independent of plasma concentration – elimination mechanism is saturated
Drug elimination kinetics
Cp
time
Zero order elimination
Half life varies with concentration
Drug elimination kinetics
Cp
time
Pseudo-zero order eliminationethanol, phenytoin
Drug elimination kinetics
Cp
time
Pseudo-zero order eliminationethanol, phenytoin
Drug elimination kinetics
Volume of distribution (Vd)
Vd = doseC0
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
Cp
time
Rate of elimination different, Clearance the same
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)
Plasma clearance (ClP)
Litres hr-1 70kg-1
Vd (litres) Cl (L hr-1 70kg-1)
frusemide 7 8aspirin 14 39propranolol 273 50digitoxin 38 0.25digoxin 640 8
Plasma half life (t1/2) = 0.693 VdCl
Vd (litres) Cl (L hr-1 70kg-1) t1/2 (h)
frusemide 7 8 1.5aspirin 14 39 0.25propranolol 273 50 3.9digitoxin 38 0.25 161digoxin 640 8 39
Plasma half life (t1/2) = 0.693 VdCl
More complex pharmacokinetic models:The two compartment model
plasma tissues
elimination
Cp
time
Redistribution + elimination
elimination
e.g. thiopentone
At steady staterate of infusion = rate of elimination
= Css x Clearance
Css (plateau)
Intravenous infusion
Cp
time
At steady staterate of infusion = rate of elimination
= Css x Clearance
Css (plateau)
Time to >96 % of Css = 5 x t1/2
Intravenous infusion
Cp
time
Rate of infusion x mg min-1
Rate of infusion 2x mg min-1
Height of plateau is governed by the rate of infusion
Cp
time
At steady state rate of infusion = rate of elimination
= Css x Clearance
Lignocaine 2 10 hours
Valproate 6 30 hours
Digoxin 39 8.1 days
Digitoxin 161 33.5 days
Drug t1/2 (h) Time to >96% of steady state
rate of infusion x mg min-1
Height of plateau is governed by the rate of infusion
Cp
time
Use of loading infusion
Desired Css
rate of infusion x mg min-1
rate of infusion 2x mg min-1
Height of plateau is governed by the rate of infusion
Cp
time
Use of loading infusion
Desired Css
Followed by maintenance infusion x mg min-1
Initial loading infusion 2x mg min-1
Height of plateau is governed by the rate of infusion
Cp
time
Use of loading infusion
Switch here
Desired Css
Followed by maintenance infusion x mg min-1
Initial loading infusion 2x mg min-1
Height of plateau is governed by the rate of infusion
Cp
time
Use of loading infusion
timesaved
Switch here
Desired Css
At Steady State amount administered = amount eliminated between doses
Multiple oral dosing
time
Cp
Cssav = F . Dose Clearance. T F = oral bioavailability
T = dosing interval
Cssav
At Steady State amount administered = amount eliminated between doses
Multiple oral dosing
time
Cp
Cssav = F . Dose Clearance. T F = oral bioavailability
T = dosing interval
time
Cp
Loading doses
e.g. Tetracycline t1/2 = 8 hours
500mg loading dose followed by 250mg every 8 hours
Maintenance doses
Cssav = F . Dose Clearance. T
Cssav
F = oral bioavailabilityT = dosing interval
Cssav = F . Dose Clearance. T
Cssav
Reducing the dose AND reducing the intervalCssav remains the same but fluctuation in Cp is less
F = oral bioavailabilityT = dosing interval
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 metabolismDiseasePharmacogenetics (cytochrome P450 polymorphisms)
• renal impairment (e.g. digoxin)DiseaseElderly