Useful revision guide

Instant Clinical PharmacologyE.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

Toxic level

Minimumtherapeutic levelCp

time

Therapeutic window

Revision of pharmacokinetic terms

1st order eliminationrate 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

PlasmaConcn(Cp)

time

1st

zero

PlasmaConcn(Cp)

time

Zero order elimination

Half life varies with concentration

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.Can be larger than total body volume

frusemide 7 litresaspirin 14 litrespropranolol 273 litresdigitoxin 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. doseAUC

iv

oral

Cp

time

Same drug, same dose different formulation• different amounts absorbed• different peak concentration• different AUCs

Cp

time

Toxic level

Minimumtherapeutic level

Same drug, same route, different doses

Cp

time

Therapeutic window

Different rates of absorption (different routes of administration)

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• longer drug in body

iv

sc

oral

Cp

time

Two compartment model

plasma tissues

elimination

PlasmaConcn(Cp)

time

Redistribution + elimination

elimination

e.g. thiopentone

At steady staterate of infusion = rate of elimination

= Css.Clearance

Css (plateau)

Time to 90 % of Css = 4 t1/2

Intravenous infusion

Cp

time

C = Css(1- e-kt)

Lignocaine 2 8 hours

Valproate 6 24 hours

Digoxin 32 6 days

Digitoxin 161 28 days

Half life hours steady state

X mg min-1

2X mg min-1

Rising phase of the infusion curve is governed by the rate of elimination

Height of plateau is governed by the rate of infusion

Cp

time

Dosing interval

MTLCp

time

Cavss

At Steady State amount administered = amount eliminated between doses

Multiple dosing

time

CpRising phase of the curve is stillgoverned by the rate of elimination

Loading dose(s)

time

Cp

Loading dose = Cpeak . Volume of distribution

Tetracycline t1/2 = 8 hours

500mg loading dose followed by 250mg every 8 hours

Cavss = F . Dose Clearance. T

Cavss

Reducing the dose AND reducing the intervalCavss remains the same but fluctuation in Cp is less

T = dosing interval

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 metabolismDiseasePharmacogenetics (cytochrome P450 polymorphisms)

• renal impairmentDiseaseElderly