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

Therapeutic window Toxic level Narrow Minimum Cp therapeutic level time

Therapeutic window Toxic level Wide Minimum therapeutic level Cp time

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

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

Oral bioavailability can be altered by formulation 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 Slower the rate of absorption time to peak longer amplitude of peak is less drug in body for longer Cp sc oral time

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

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

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)

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)

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 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

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

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

Plasma clearance (ClP) Litres hr-1 70kg-1 Vd (litres) Cl (L hr-1 70kg-1) frusemide 7 8 aspirin 14 39 propranolol 273 50 digitoxin 38 0.25 digoxin 640 8

Plasma half life (t1/2) = 0.693 Vd Cl

Plasma half life (t1/2) = 0.693 Vd Cl Vd (litres) Cl (L hr-1 70kg-1) t1/2 (h) frusemide 7 8 1.5 aspirin 14 39 0.25 propranolol 273 50 3.9 digitoxin 38 0.25 161 digoxin 640 8 39

More complex pharmacokinetic models: The two compartment model plasma tissues elimination Redistribution + elimination Cp 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 t1/2 time

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

Drug t1/2 (h) Time to >96% of steady state Lignocaine 2 10 hours Valproate 6 30 hours Digoxin 39 8.1 days Digitoxin 161 33.5 days

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

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

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

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

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

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

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

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

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).

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)

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