1. First, zero, pseudo-zero order elimination Clearance
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. Therapeutic window Toxic level Narrow Minimum Cp therapeutic level
time

3. Therapeutic window
Toxic level
Wide
Minimum
therapeutic level Cp
time

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

5. Oral bioavailability frusemide 0.61 aspirin 0.68 propranolol 0.26
digitoxin 0.90
digoxin 0.70
diazepam 1
lithium 1
morphine 0.24

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

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

9. Plasma half life Cp time time Half life (t1/2)
time for plasma concentration to fall by 50% Cp
time
time

10. Plasma half life Cp time time Half life (t1/2)
time for plasma concentration to fall by 50% Cp
time
time

11. 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)

12. 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)

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

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

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

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

17. 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

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

19. 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)
Rate of elimination different,
Clearance the same Cp
time

20. Plasma clearance (ClP)
Litres hr-1 70kg-1
Vd (litres) Cl (L hr-1 70kg-1)
frusemide
aspirin
propranolol
digitoxin
digoxin

21. Plasma half life (t1/2) = 0.693 VdCl

22. Plasma half life (t1/2) = 0.693 Vd Cl
Vd (litres) Cl (L hr-1 70kg-1) t1/2 (h)
frusemide
aspirin
propranolol
digitoxin
digoxin

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

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

25. 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

26. At steady state
rate of infusion = rate of elimination
= Css x Clearance
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
time

27. Drug t1/2 (h) Time to >96% of steady state
Lignocaine hours
Valproate hours
Digoxin days
Digitoxin days

28. 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

29. 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

30. 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

31. 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

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

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

34. Loading doses Cp
Maintenance doses
time
e.g. Tetracycline t1/2 = 8 hours
500mg loading dose followed by 250mg every 8 hours

35. Cssav = F . Dose Clearance. T Cssav F = oral bioavailability
T = dosing interval
Cssav

36. Reducing the dose AND reducing the interval
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

37. that have a low therapeutic index
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)
Elderly