introduction

The rational use of drugs dates from the latter part of the nineteenth century and may be attributed to
three distinct developments. First was the birth of synthetic organic chemistry and the question whether
some new compounds might have medicinal value, Among the earliest chemicals recognized to be of
therapeutic importance were the general anaesthetics and chemotherapeutic agents such as salvarsan.
The second pillar of modern therapeutics was the elucidation of the mode of action of these chemicals
by means of experiments in animals and in man. Third has been the development in the understanding
of the basis of human disease expressed in terms of perturbation of underlying physiological control
mechanisms and morbid anatomical changes.

From these disparate origins, clinical pharmacology has emerged as a discipline whose aim is, broadly
speaking, the scientific study of drugs in man. There are many aspects of clinical pharmacology.
Pharmacokinetic, the mathematical description of the fate of drugs in the body, including the processes
of drug absorption, distribution, metabolism and excretion, has probably attracted attention
disproportionate to its importance because of the ability to make precise measurements of drug
concentrations in biological fluids using refined analytical technology. Pharmacodynamics encompasses
studies of the effects of drugs on the body and of the underlying modes of drug action; this stiil remains
the niain challenge in clinical pharmacology since available techniques are either invasive and thus
generally inapplicable or are non invasive and tend to be crude and imprecise. Toxicology is that aspect
of pharmacology dealing with the adverse effects of drugs used in therapy and of chemical substances
used in the household, in industry, or found in the environment. For political reasons this is the face of
clinical pharmacology most frequently shown to the public and is one reason for current trends away
from allopathic medicine. A separate facet of clinical pharmacology is the testing of new drugs in man by
means of the clinical trial. Such studies are only as good as the methods used to assess drug effects, and
the statistical methods to evaluate the results.

the rational use of drugs in clinical medicine obviously presents a challenge to the clinical
pharmacologist. New fiscal measures to restrain the choice of drugs available to the practising physician
both in the United Kingdom and elsewhere make the assessment of the value of individual therapeutic
agents even more relevant than hitherto. Lists of drugs available for limited prescribing must be based
on the sound clinical pharmacological principles which are outlined in the following paragraphs.

The principles underlying drug therapy are fundamentally similar for any condition in which drugs are
used. Obvious variables include the nature and stage of the disease, the chemical nature and dose of the
drug used. The aim of all therapy is to administer the appropriate drug in the correct dose to produce
the desired therapeutic effect with the minimum of adverse side-effects. This chapter outlines the
principles on which the achievement of this aim rests.
Basic concept of drug action

Physicochemical characteristics of drug

The three most important physicochemical properties of a drug are lipid solubility, degree of ionization,
and molecular size.

Lipid solubility is the principal determinant of the ability of a drug to cross the membranes of cell walls
be the of the gastrointestinal tract, renal tubule, or blood-brain barrier. The relevance of lipid solubility
can best be appreciated by considering the fate of drugs in the nephron. Filtered at the glomerulus, a
lipid soluble drug is completely reabsorbed in the renal tubular system to remain in the body for an
indefinite time. Drug metabolism can thus be viewed as a mechanism to change lipid soluble compounds
into those with a higher degree of water solubility, i.e. greater polarity. The behaviour of water soluble
metabolites in the renal tubules is quite different from the parent compound. By virtue of their new
found polarity, metabolites tend not to be reabsorbed in the renal tubules and will be eliminated in the
urine. Lipid solubility can be measured by in vitro methods using partition of a drug between an organic
and an aqueous solvent. Table 1 shows the partition coefficients of a series of beta adrenoceptor
blocking agents between octanol and water. This has clinical relevance since those beta blockers with a
high degree of lipid solubility,e.g. propranolol and oxprenolol, tend to be well absorbed from the gut, to
show a high first pass effect in the gut and the liver, and to have a relatively short half-life. They also gain
easy access to the cerebral cortex and thus have the propensity to produce central side-effects. On the
ether hand less lipid soluble beta adrenoceptor blocking drugs such as atenolol and sotolol are not so
readily absorbed, are not extensively metabolized in the liver, and tend to be eliminated unchanged via
the kidney. Further, they do not gain such easy access to the brain as more lipid soluble counterparts.

The extent to which a drug is ionized depends on the pKa of the drug and the pH of the medium in
which the drug is dissolved. pKa is defined as the pH at which 50 per cent of the drug is ionized. If a
weakly acidic drug is represented as HA, then :

From this, it can be seen that changes in pH near the pKa of a drug such as phenobarbitone (pKa 7.4) will
give rise to considerable changes in extent of its ionization. This is put to clinical use in patients
overdosed with phenobarbitone in whom the urine can be made alkaline by sodium bicarbonate
administration to facilitate its excretion. At urine pH of 8.0, over 95 per cent of phenobarbitone will be
ionized and thus will not be reabsorbed in the kidney. For a basic drug, e.g. amphetamine or quinidine,
(represented as BH), equation (3) is rearranged so that :

By the same arguments as above, acidification of the urine will promote the elimination of basic drugs
and this may also be made use of in treating an overdose.

the degree of drug ionization has implications for drug absorption from the gastrointestinal tract. Under
the acid conditions in the stomach, it can be appreciated from equation (3) that acidic drugs such as
salicylate or warfarin will exist preferentially in the non-ionized lipid seluble form. Basic drugs sach as
chlorpromazine and tricyclic antiiepressants will tend to be ionized and be relatively lipid insoluble in the
stomach on this pH partition hypothesis. However, the larger surface area of the small intestine dictates
that both types of drug. pH and pKa notwithstanding. will tend to be maximally absorbed lower in the
gastrointestinal tract than the stomach. The basis that only non-ionized drugs will prefetentially cross
the gastrointestinal tract is illustrated in Fig. 1.

Molecular size is probably the least important of the three physical properties of a drug. Biliary excretion
is largely determined by molecular size; in man, compounds of molecular weight of greater than 400 are
excreted in the bile. This molecular weight shows considerable species variation and applies to drug
conjugates too. This property can also be used therapeutically. Ampicillin is excreted in the bile and use
is made of this in the treatment of biliary tract infections. Once drug conjugates have reached the gut via
the bile, they may be broken down by the enzymes of gut bacteria, liberating free drug for reabsorption.
This process of enterohepatic recirculation is described below.