Download pmcjcr/ pharmacokinetics

Useful revision guide
Instant Clinical Pharmacology
E.J. Begg
Useful information on individual drugs
(although a bit old now)
Basic Clinical Pharmacokinetics (2nd Edition)
M.E. Winter
Drug dosing
Important factors
• concentration of drug in plasma
• rate of drug elimination
• rate of drug absorption
Therapeutic window
Toxic level
Cp
Minimum
therapeutic level
time
Revision of pharmacokinetic terms
Plasma
Concn
(Cp)
zero
1st
time
1st order elimination
rate of elimination depends on plasma concentration
C = C0e-kt
(k= rate constant of elimination)
Half life (t1/2)
time for plasma concentration to fall by 50%
Zero order elimination (pseudo zero order)
rate of elimination is constant and independent of plasma concentration
Zero order elimination
Half life varies with concentration
Plasma
Concn
(Cp)
time
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.
Can be larger than total body volume
frusemide
7 litres
aspirin
14 litres
propranolol
273 litres
digitoxin
38 liters
4 ml min-1
digoxin
640 litres
130ml min -1
Plasma clearance (ClP)
volume of blood cleared of its drug content in unit time
CP= ClM + ClR + ClB + …….
Bioavailability (F)
measure of the amount of drug absorbed into the general circulation
Area under the curve (AUC)
obtained from the plasma concentration v time plot
gives a measure of the amount of drug absorbed
Foral = AUCoral
AUCiv
Clearance = F. dose
AUC
iv
Cp
oral
time
Same drug, same dose different formulation
• different amounts absorbed
• different peak concentration
• different AUCs
Cp
time
Therapeutic window
Same drug, same route, different doses
Toxic level
Cp
Minimum
therapeutic level
time
Different rates of absorption
(different routes of administration)
Assume the bioavailability is the same (i.e. 1 for all routes)
iv
Cp
sc
Slower the rate of absorption
• time to peak longer
• amplitude of peak is less
• longer drug in body
oral
time
Two compartment model
plasma
tissues
elimination
Plasma
Concn
(Cp)
Redistribution + elimination
e.g. thiopentone
elimination
time
Intravenous infusion
At steady state
rate of infusion = rate of elimination
= Css.Clearance
Css (plateau)
Cp
C = Css(1- e-kt)
Time to 90 % of Css = 4 t1/2
time
Half life
hours
steady state
Lignocaine
2
8 hours
Valproate
6
24 hours
Digoxin
32
6 days
Digitoxin
161
28 days
Rising phase of the infusion
curve is governed by the
rate of elimination
Height of plateau is
governed by the rate of infusion
2X mg min-1
Cp
X mg min-1
time
Dosing interval
MTL
Cp
time
Multiple dosing
At Steady State
amount administered = amount eliminated between doses
Cavss
Cp
Rising phase of the curve is still
governed by the rate of elimination
time
Loading dose(s)
Loading dose = Cpeak . Volume of distribution
Cp
time
Tetracycline t1/2 = 8 hours
500mg loading dose followed by 250mg every 8 hours
Cavss =
F . Dose
Clearance. T
T = dosing interval
Cavss
Reducing the dose AND reducing the interval
Cavss remains the same but fluctuation in Cp is less
Drug plasma concentration monitoring is helpful for drugs
•that have a low therapeutic index
•that are not metabolized 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 (plasma or serum)
• ciclosporin (whole blood)
• digoxin and digitoxin (plasma or serum)
• lithium (serum)
• phenytoin (plasma or serum)
• theophylline (plasma or serum)
• paracetamol and salicylate (overdose) (plasma or serum).
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
(eg theophylline in an unconscious patient with asthma)
• in research (eg to monitor for drug interactions in post-marketing surveillance
using population pharmacokinetics).
Altered pharmacokinetic profile
• liver metabolism
Disease
Pharmacogenetics (cytochrome P450 polymorphisms)
• renal impairment
Disease
Elderly