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Revision of pharmacokinetic terms Therapeutic window Bioavailability Plasma half life First, zero, pseudo-zero order elimination Clearance Volume of Distribution.

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Presentation on theme: "Revision of pharmacokinetic terms Therapeutic window Bioavailability Plasma half life First, zero, pseudo-zero order elimination Clearance Volume of Distribution."— Presentation transcript:

1 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

2 Toxic level Minimum therapeutic level Cp time Therapeutic window Narrow

3 Toxic level Minimum therapeutic level Cp time Therapeutic window Wide

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 F oral = AUC oral AUC iv Clearance = F. dose AUC iv bolus oral dose Cp time NB: same dose given iv and orally

5 Oral bioavailability frusemide 0.61 aspirin0.68 propranolol0.26 digitoxin0.90 digoxin0.70 diazepam1 lithium1 morphine 0.24

6 Same drug, same dose, different formulation different amounts absorbed different peak concentration different AUCs Cp time Oral bioavailability can be altered by formulation

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 sc oral Cp 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) Slower the rate of absorption time to peak longer amplitude of peak is less drug in body for longer iv sc oral Cp time

9 Half life (t 1/2 ) time for plasma concentration to fall by 50% Cp time Plasma half life

10 Cp time Plasma half life Half life (t 1/2 ) time for plasma concentration to fall by 50%

11 Cp time First order elimination – majority of drugs Rate of elimination depends on plasma concentration C = C 0 e -kt (k= rate constant of elimination) Drug elimination kinetics

12 Cp time First order elimination – majority of drugs Half life independent of concentration Rate of elimination depends on plasma concentration C = C 0 e -kt (k= rate constant of elimination) Drug elimination kinetics

13 Cp time Zero order elimination rate of elimination is constant and independent of plasma concentration – elimination mechanism is saturated Drug elimination kinetics

14 Cp time Zero order elimination Half life varies with concentration Drug elimination kinetics

15 Cp time Pseudo-zero order elimination ethanol, phenytoin Drug elimination kinetics

16 Cp time Pseudo-zero order elimination ethanol, phenytoin Drug elimination kinetics

17 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 7 aspirin14 propranolol273 digitoxin38 digoxin640

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 1 st order kinetics rate of eliminatiuon changes with Cp, value of clearance does not change) Cp time

19 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 1 st order kinetics rate of eliminatiuon changes with Cp, value of clearance does not change)

20 Plasma clearance (Cl P ) Litres hr -1 70kg -1 Vd (litres)Cl (L hr -1 70kg -1 ) frusemide 7 8 aspirin14 39 propranolol digitoxin digoxin640 8

21 Plasma half life (t 1/2 ) = Vd Cl

22 Vd (litres)Cl (L hr -1 70kg -1 )t 1/2 (h) frusemide aspirin propranolol digitoxin digoxin Plasma half life (t 1/2 ) = Vd Cl

23 More complex pharmacokinetic models: The two compartment model plasma tissues elimination Cp time Redistribution + elimination elimination e.g. thiopentone

24 At steady state rate of infusion = rate of elimination = Css x Clearance Css (plateau) Intravenous infusion Cp time

25 At steady state rate of infusion = rate of elimination = Css x Clearance Css (plateau) Time to >96 % of Css = 5 x t 1/2 Intravenous infusion Cp time

26 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

27 Lignocaine210 hours Valproate630 hours Digoxin398.1 days Digitoxin days Drug t 1/2 (h) Time to >96% of steady state

28 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

29 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

30 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

31 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 time saved Switch here Desired Css

32 At Steady State amount administered = amount eliminated between doses Multiple oral dosing time Cp C ss av = F. Dose Clearance. T F = oral bioavailability T = dosing interval

33 C ss av At Steady State amount administered = amount eliminated between doses Multiple oral dosing time Cp C ss av = F. Dose Clearance. T F = oral bioavailability T = dosing interval

34 time Cp Loading doses e.g. Tetracycline t 1/2 = 8 hours 500mg loading dose followed by 250mg every 8 hours Maintenance doses

35 C ss av = F. Dose Clearance. T C ss av F = oral bioavailability T = dosing interval

36 C ss av = F. Dose Clearance. T C ss av Reducing the dose AND reducing the interval C ss av remains the same but fluctuation in Cp is less F = oral bioavailability T = dosing interval

37 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

38 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).

39 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)

40 Altered pharmacokinetic profile liver metabolism Disease Pharmacogenetics (cytochrome P450 polymorphisms) renal impairment (e.g. digoxin) Disease Elderly


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