revision of pharmacokinetic terms therapeutic window bioavailability plasma half life first, zero,...
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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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Toxic level
Minimumtherapeutic levelCp
time
Therapeutic window
Narrow
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Toxic level
Minimumtherapeutic levelCp
time
Therapeutic window
Wide
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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
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Oral bioavailability
frusemide 0.61aspirin 0.68propranolol 0.26digitoxin 0.90digoxin 0.70diazepam 1lithium 1morphine 0.24
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Same drug, same dose, different formulation• different amounts absorbed• different peak concentration• different AUCs
Cp
time
Oral bioavailability can be altered by formulation
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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
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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
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Half life (t1/2)
time for plasma concentration to fall by 50%
Cp
time
time
Plasma half life
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Cp
time
time
Plasma half life
Half life (t1/2)
time for plasma concentration to fall by 50%
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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
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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
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Cp
time
Zero order elimination
rate of elimination is constant and independent of plasma concentration – elimination mechanism is saturated
Drug elimination kinetics
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Cp
time
Zero order elimination
Half life varies with concentration
Drug elimination kinetics
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Cp
time
Pseudo-zero order eliminationethanol, phenytoin
Drug elimination kinetics
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Cp
time
Pseudo-zero order eliminationethanol, phenytoin
Drug elimination kinetics
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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
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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)
Cp
time
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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)
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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
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Plasma half life (t1/2) = 0.693 VdCl
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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
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More complex pharmacokinetic models:The two compartment model
plasma tissues
elimination
Cp
time
Redistribution + elimination
elimination
e.g. thiopentone
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At steady staterate of infusion = rate of elimination
= Css x Clearance
Css (plateau)
Intravenous infusion
Cp
time
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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
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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
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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
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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
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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
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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
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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
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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
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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
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time
Cp
Loading doses
e.g. Tetracycline t1/2 = 8 hours
500mg loading dose followed by 250mg every 8 hours
Maintenance doses
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Cssav = F . Dose Clearance. T
Cssav
F = oral bioavailabilityT = dosing interval
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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
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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
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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).
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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)
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Altered pharmacokinetic profile
• liver metabolismDiseasePharmacogenetics (cytochrome P450 polymorphisms)
• renal impairment (e.g. digoxin)DiseaseElderly