A Textbook of Clinical Pharmacology and Therapeutics

BREAST-FEEDING 53

METABOLISM

At birth, the hepatic microsomal enzyme system (see Chapter
5) is relatively immature (particularly in the preterm infant),
but after the first four weeks it matures rapidly.
Chloramphenicol can produce ‘grey baby syndrome’ in
neonates due to high plasma levels secondary to inefficient
elimination. Conversely, hepatic drug metabolism can be
increased once enzyme activity has matured in older infants
and children, because the ratio of the weight of the liver to
body weight is up to 50% higher than in adults. Drugs admin-
istered to the mother can induce neonatal enzyme activity
(e.g. barbiturates). Phenobarbitonemetabolism is faster in
children than in adults because of greater induction of hepatic
enzyme activity.

PHARMACODYNAMICS

Documented evidence of differences in receptor sensitivity in

children is lacking, and the apparently paradoxical effects

of some drugs (e.g. hyperkinesia with phenobarbitone, sedation

of hyperactive children with amphetamine) are as yet

unexplained. Augmented responses to warfarinin prepubertal

patients occur at similar plasma concentrations as in adults,

implying a pharmacodynamic mechanism. Ciclosporinadded

in vitro to cultured monocytes (hence there is no opportunity for

a pharmacokinetic effect) has greater effects in cells isolated from

infants, providing another example of an age-related pharmaco-

dynamic difference.

BREAST-FEEDING

Breast-feeding can lead to toxicity in the infant if the drug

enters the milk in pharmacological quantities. The milk con-

centration of some drugs (e.g. iodides) may exceed the mater-

nal plasma concentration, but the total dose delivered to the

baby is usually very small. However, drugs in breast milk may

cause hypersensitivity reactions even in very low doses.

Virtually all drugs that reach the maternal systemic circulation

will enter breast milk, especially lipid-soluble unionized low-

molecular-weight drugs. Milk is weakly acidic, so drugs that

are weak bases are concentrated in breast milk by trapping of

the charged form of the drug (compare with renal elimination;

see Chapter 6). However, the resulting dose administered to

the fetus in breast milk is seldom clinically appreciable,

although some drugs are contraindicated (Table 10.2), and

breast-feeding should cease during treatment if there is no

safer alternative. Appendix 5 of the British National

Formulary provides very helpful practical advice.

Key points

Prevalence of chronic illness in children requiring drug

therapy:

• one in eight children have asthma;


• one in 250 children have epilepsy;


• one in 750 children have diabetes mellitus.

Key points

At birth, renal and hepatic function are less efficient than

in adulthood. Drug effects may be prolonged and

accumulation may occur. These factors are exaggerated in

the premature infant.

EXCRETION

All renal mechanisms (filtration, secretion and reabsorption)
are reduced in neonates, and renal excretion of drugs is rela-
tively reduced in the newborn. Glomerular filtration rate
(GFR) increases rapidly during the first four weeks of life, with
consequent changes in the rate of drug elimination (Table 10.1).

Table 10.1:Changes in rate of drug elimination with development

Stage of development Plasma half-life of gentamicin

Premature infant

48 hours old 18 hours

5–22 days old 6 hours

Normal infant

1–4 weeks old 3 hours

Adult 2 hours

Table 10.2:Some drugs to be avoided during breast-feeding

Amiodarone

Aspirin

Benzodiazepines

Chloramphenicol

Ciclosporin

Ciprofloxacin

Cocaine

Combined oral contraceptives

Cytotoxics

Ergotamine

Octreotide

Stimulant laxatives

Sulphonylureas

Thiazide diuretics

Vitamin A/retinoid analogues (e.g. etretinate)