A Textbook of Clinical Pharmacology and Therapeutics

CONSTANT-RATE INFUSION

If a drug is administered intravenously via a constant-rate

pump, and blood sampled from a distant vein for measure-

ment of drug concentration, a plot of plasma concentration

versus time can be constructed (Figure 3.1). The concentration

rises from zero, rapidly at first and then more slowly until a

plateau (representing steady state) is approached. At steady

state, the rate of input of drug to the body equals the rate of

elimination. The concentration at plateau is the steady-state

concentration (CSS). This depends on the rate of drug infusion

and on its ‘clearance’. The clearance is defined as the volume

of fluid (usually plasma) from which the drug is totally elimi-

nated (i.e. ‘cleared’) per unit time. At steady state,

administration rateelimination rate

elimination rateCSSclearance

so

clearanceadministration rate/CSS

●Introduction 11

●Constant-rate infusion 11

●Single-bolus dose 12

●Repeated (multiple) dosing 13

●Deviations from the one-compartment model

with first-order elimination 14

●Non-linear (‘dose-dependent’) pharmacokinetics 15

CHAPTER 3

PHARMACOKINETICS

INTRODUCTION

Pharmacokinetics is the study of drug absorption, distribu-
tion, metabolism and excretion (ADME) – ‘what the body does
to the drug’. Understanding pharmacokinetic principles, com-
bined with specific information regarding an individual drug
and patient, underlies the individualized optimal use of the
drug (e.g. choice of drug, route of administration, dose and
dosing interval).
Pharmacokinetic modelling is based on drastically simplif-
ying assumptions; but even so, it can be mathematically cum-
bersome, sadly rendering this important area unintelligible to
many clinicians. In this chapter, we introduce the basic con-
cepts by considering three clinical dosing situations:

• constant-rate intravenous infusion;


• bolus-dose injection;


• repeated dosing.

Bulk flow in the bloodstream is rapid, as is diffusion over
short distances after drugs have penetrated phospholipid mem-
branes, so the rate-limiting step in drug distribution is usually
penetration of these membrane barriers. Permeability is deter-
mined mainly by the lipid solubility of the drug, polar water-
soluble drugs being transferred slowly, whereas lipid-soluble,
non-polar drugs diffuse rapidly across lipid-rich membranes.
In addition, some drugs are actively transported by specific
carriers.
The simplest pharmacokinetic model treats the body as a
well-stirred single compartment in which an administered
drug distributes instantaneously, and from which it is elimi-
nated. Many drugs are eliminated at a rate proportional to
their concentration – ‘first-order’ elimination. A single (one)-
compartment model with first-order elimination often approx-
imates the clinical situation surprisingly well once absorption
and distribution have occurred. We start by considering this,
and then describe some important deviations from it.

[Drug] in plasma

Constant infusion of drug

Time →

Figure 3.1:Plasma concentration of a drug during and after a

constant intravenous infusion as indicated by the bar.