2.

Clinical Pharmacokinetics: Clinical relevance of the pharmacokinetic

parameters (steady- state plasma concentration, volume of distribution,
elimination half-life, min and max therapeutic concentration). Dosage
regimens.
Pharmacokinectics-
the study of the movement of drugs in the body, ADME- absorbtion,
distribution, metabolism, excretion.
` Steady state plasma concentration-
A State of Equilibrium between the Absorption and the Elimination of
the drug following multiple application.

It is important to know when a drug administered at a constant rate achieves

a steady-state plasma concentration.
When a drug is given at a constant rate (continuous or repeated
administration), the time to reach steady state depends only on the t½ and,
for all practical purposes, after 5 _ t½ periods the amount of drug in the body
is constant and the plasma concentration is at a plateau.

Similarly, starting at any steady-state plasma concentration (100%),

discontinuing the dose will cause the plasma concentration to fall to virtually
zero in 5 _ t½ periods, Note that the difference between the rate of drug
administration (input) and the rate of elimination (output) determines the
actual level of any steady-state plasma concentration (as opposed to the
time taken to reach it). If drug elimination remains constant and
administration increases by 50%, in time the plasma concentration will reach
a new steady-state concentration, which will be 50% greater than the
original.
The relation between t½ and time to reach steady-state plasma
concentration applies to all drugs that obey first-order kinetics. This holds as
much to dobutamine (t½ 2 min), when it is useful to know that an alteration
of infusion rate will reach a plateau within 10 min, as to digoxin (t½ 36 h).

Volume of Distribution-
VOLUME OF DISTRIBUTION (Vd )
Vd represents the theoretical volume into which a given drug dose must be
distributed in the body to achieve a concentration equal to that of plasma.
Drugs that are highly lipid soluble, such as digoxin, have a high Vd. Drugs
that are lipid insoluble, such as neuromuscular blockers, remain
predominantly in the plasma and will have a low Vd.
Clinically, the larger the volume of distribution the longer it will take to reach
a therapeutic level and, therefore, a loading dose may be necessary. The
volume of distribution can be calculated as:
The pattern of distribution from plasma to other body fluids and tissues is a
characteristic of each drug that enters the circulation, and it varies between
drugs.
• If a drug remains mostly in the plasma, its distribution volume will be small.
• If a drug is present mainly in other tissues, the distribution volume will be
large.
Some highly polar drugs, such as penicillins, distribute mainly into “central”
compartments and have a small Vd, while highly lipid soluble drugs, such as
tricyclic antidepressants, distribute far more widely and have a large Vd.
Such information can be useful. In drug overdose, if a major proportion of the
total body load is known to be in the plasma, i.e. the distribution volume is
small, then haemodialysis/filtration is likely to be a useful option (as is the
case with severe salicylate poisoning), but it is an inappropriate treatment for
overdose with dosulepin.
Selective distribution within the body occurs because of special affinity
between particular drugs and particular body constituents. Many drugs bind
to proteins in the plasma; phenothiazines and chloroquine bind to melanin-
containing tissues, including the retina, which may explain the occurrence of
retinopathy. Drugs may also concentrate selectively in a particular tissue
because of specialised transport mechanisms, e.g. iodine in the thyroid.

LOADING DOSE
Defined as the initial dose of a drug required to rapidly achieve a desired
plasma concentration. The time required to achieve a steady state plasma
concentration will be long if a drug has a long t½ (time taken to reach steady
state is approximately 4½ half-lives). Therefore it is desirable to administer a
loading dose to attain a therapeutic plasma concentration immediately.
Examples of drugs requiring a loading dose regime include amiodarone,
digoxin and warfarin.
The main factor determining a loading dose is the volume of distribution
(Vd). In order for a drug to reach a steady state plasma concentration (Cp),
the tissues into which the drug distributes must be saturated first. The
relationship between loading dose and volume of distribution is defined
below:

Loading dose =Vd * Cp

Elimination half life-

min and max therapeutic concentration-

Dosage regimen-
Types of Dosing Regimes:
• Cumulative: equal doses with equal dosing interval: (Drugs
with short t½);
• Non- Cumulative: starting with higher doses with shorter
dosing interval for short period, followed by lower doses with equal
dosing interval: (Drugs with prolonged t½);