P1: PCX Printer: Yet To Come
9780521704632c06 CUFX213A/Peck 9780521618168 December 27, 2007 14:11
Section IBasic principlesThreshold for toxicitytimeAConcentrationFigure 6.13.Accumulation of a drug with intermittent boluses.The dosing interval is
equal to the half-life and after five doses this approaches a steady-state. This can be compared
with an infusion designed to give the same steady-state concentration. This steady-state
concentration is reached after approximately five half-lives. If the peak effect with bolus
dosing exceeds the toxic threshold (dotted line) then doses should be reduced and dosing
interval increased, as at point A.Giving drug by repeated dose delivers a ‘saw-tooth’ pattern of plasma concentra-
tion. If we need to keep plasma concentration constant or within very narrow limits
then an infusion may be appropriate. To do this we need to establish a steady-state
where the rate of drug input (Ratein)must equal the rate of drug output (i.e. rate of
elimination):Ratein=Rateel.The rate of drug elimination is the product of clearance and plasma concentration,
so to keep plasma concentration constant we must ensure that:Ratein=Cl·Cp.This last equation tells us how fast to run the drug infusion assuming we know its
clearance. If no loading dose is given, and the infusion is started at a constant rate,
steady-state will be reached after five half-lives or three time constants. The time
to reach equilibrium is determined by the rate constant for elimination and the
plasma level achieved at equilibrium is determined by the ratio of the infusion rate
to the clearance. The delay in reaching equilibrium can be reduced either by giving a
loading dose or by starting with a higher initial infusion rate that is reduced back to
maintenance levels when the desired plasma concentration has been reached. The
latter produces a smoother concentration profile than the former and is used in TCI
(target-controlled infusion) pumps.