A-Textbook-of-Clinical-Pharmacology-and-Therapeutics-5th-edition

CHAPTER 10
DRUGS IN INFANTS AND
CHILDREN
● Introduction 52
● Pharmacokinetics 52
● Pharmacodynamics 53
● Breast-feeding 53
● Practical aspects of prescribing 54
● Research 54
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 recognize
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 children.
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 mechanisms
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 immunological
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
tetracycline which 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/pharmacodynamic
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 emptying
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 concentrations
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
and theophylline). Infant skin is thin and percutaneous absorption
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 recognized.
The blood–brain barrier is more permeable in neonates
and young children, leading to an increased risk of CNS
adverse effects.