A Textbook of Clinical Pharmacology and Therapeutics

●Introduction 52

●Pharmacokinetics 52

●Pharmacodynamics 53

●Breast-feeding 53

●Practical aspects of prescribing 54

●Research 54

CHAPTER 10

DRUGS IN INFANTS AND

CHILDREN

INTRODUCTION

Children cannot be regarded as miniature adults in terms
of drug response, due to differences in body constitution,
drug absorption and elimination, and sensitivity to adverse
reactions. Informed consent is problematic and commercial
interest has been limited by the small size of the market,
so clinical trials in children have lagged behind those in
adults. Regulatory agencies in the USA and Europe now rec-
ognize this problem and are attempting to address it, for
example, by introducing exclusivity legislation designed to
attract commercial interest. Traditionally, paediatricians have
used drugs ‘off-label’ (i.e. for unlicensed indications), often
gaining experience in age groups close to those for which a
product is licensed and then extending this to younger chil-
dren. That this empirical approach has worked (at least to
some extent) is testament to the biological fact that while
not just ‘miniature adults’ children do share the same drug
targets (e.g. receptors, enzymes), cellular transduction mecha-
nisms and physiological processes with their parents. Drug
responses are thus usually qualitatively similar in children
and adults, although there are important exceptions, including
some central nervous system (CNS) responses and immuno-
logical responses to ciclosporin. Furthermore, some adverse
effects occur only during certain stages of development, for
example, retrolental fibroplasia induced by excess oxygen
in the premature neonate and staining of teeth by
tetracyclinewhich occurs only in developing enamel. The
processes of drug elimination are, however, immature at
birth so quantitative differences (e.g. in dose) are important.
Establishing optimal doses for drugs prescribed for children is
thus an extremely important clinical challenge. Current
regimes have been arrived at empirically, but guidelines are
evolving for paediatric dosing in clinical trials and in future
greater use may be made of pharmacokinetic/pharmacody-
namic modelling in children, so hopefully this Cinderella

of therapeutics will soon be making her (belated) entry to

the ball.

PHARMACOKINETICS

ABSORPTION

Gastro-intestinal absorption is slower in infancy, but absorption

from intramuscular injection is faster. The rate of gastric empty-

ing is very variable during the neonatal period and may be

delayed by disease, such as respiratory distress syndrome and

congenital heart disease. To ensure that adequate blood concen-

trations reach the systemic circulation in the sick neonate, it is

common practice to use intravenous preparations. In older and

less severely ill children, oral liquid preparations are commonly

used, resulting in less accurate dosing and a more rapid rate of

absorption. This is important for drugs with adverse effects that

occur predictably at high plasma concentration, and which show

lack of efficacy if trough concentration is low (e.g. carbamazepine

andtheophylline). Infant skin is thin and percutaneous absorp-

tion can cause systemic toxicity if topical preparations (e.g. of

potent corticosteroids) are applied too extensively.

DISTRIBUTION

Body fat content is relatively low in children, whereas water

content is greater, leading to a lower volume of distribution of

fat-soluble drugs (e.g. diazepam) in infants. Plasma protein

binding of drugs is reduced in neonates due to a lower plasma

albumin concentration and altered binding properties. The

risk of kernicterus caused by displacement of bilirubin from

albumin by sulphonamides (see Chapter 12) is well recog-

nized. The blood–brain barrier is more permeable in neonates

and young children, leading to an increased risk of CNS

adverse effects.