Transcript Document
Revision of pharmacokinetic terms
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Therapeutic window Bioavailability Plasma half life First, zero, pseudo-zero order elimination Clearance Volume of Distribution Intravenous infusion Oral dosing time
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Plasma monitoring of drugs
Therapeutic window Cp
Narrow
Toxic level Minimum therapeutic level time
Therapeutic window Cp
Wide
Toxic level 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 F oral = AUC oral AUC iv Cp iv bolus 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
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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
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Slower the rate of absorption time to peak longer amplitude of peak is less drug in body for longer oral time
Cp
Plasma half life
time time Half life (t 1/2 ) time for plasma concentration to fall by 50%
Plasma half life
Cp time time Half life (t 1/2 ) 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 = C 0 e -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 = C 0 e -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 C 0 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 aspirin 7 14 propranolol digitoxin 273 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 1 st 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 1 st 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 (Cl P ) Litres hr -1 70kg -1 frusemide aspirin propranolol digitoxin digoxin Vd (litres) 7 14 273 38 640 Cl (L hr -1 70kg -1 ) 8 39 50 0.25
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Plasma half life (t 1/2 ) = 0.693 Vd Cl
Plasma half life (t 1/2 ) = 0.693 Vd Cl frusemide aspirin propranolol digitoxin digoxin Vd (litres) 7 14 273 38 640 Cl (L hr -1 70kg -1 ) 8 39 50 0.25
8 t 1/2 (h) 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 t 1/2 time
Cp At steady state Rate of infusion 2x mg min -1 Rate of infusion x mg min -1 time
Drug Lignocaine Valproate Digoxin Digitoxin t 1/2 (h) Time to >96% of steady state 2 6 39 161 10 hours 30 hours 8.1 days 33.5 days
Cp
Use of loading infusion
Height of plateau is governed by the rate of infusion rate of infusion x mg min -1
Desired Css
time
Cp
Use of loading infusion
Height of plateau is governed by the rate of infusion rate of infusion 2x mg min -1 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
Initial loading infusion 2x mg min -1 Cp 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
Initial loading infusion 2x mg min -1 Cp Followed by maintenance infusion x mg min -1
Desired Css
time saved time
Multiple oral dosing C ss av = F . Dose At Steady State F = oral bioavailability Cp time
Multiple oral dosing C ss av = F . Dose At Steady State F = oral bioavailability C ss av Cp time
Loading doses Cp Maintenance doses time e.g. Tetracycline t 1/2 = 8 hours 500mg loading dose followed by 250mg every 8 hours
C ss av = F . Dose Clearance. T F = oral bioavailability T = dosing interval C ss av
C ss av = F . Dose Clearance. T F = oral bioavailability T = dosing interval C ss av Reducing the dose AND reducing the interval C ss av remains the same but fluctuation in Cp is less
Drug plasma concentration monitoring is helpful for drugs
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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)
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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
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to assess adherence to therapy
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to individualize therapy
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to diagnose toxicity
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to guide withdrawal of therapy
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to determine whether a patient is already taking a drug before starting therapy (e.g. theophylline in an unconscious patient with asthma)
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in research (e.g. to monitor for drug interactions)
Altered pharmacokinetic profile
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liver metabolism Disease Pharmacogenetics (cytochrome P450 polymorphisms)
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renal impairment (e.g. digoxin) Disease Elderly