Page 113 - 80 guidelines for the treatment of malaria_opt

ANNEX 3. Pharmacology of antimalarial medicines

requiring concomitant administration of fatty foods, and oral bioavailability will be reduced
in vomiting patients or those with a rapid transit time. Atrophy of the bowel mucosa, which
occurs in severe protein-energy malnutrition, will also hinder absorption.
Children with oedematous lower limbs may be expected to have altered absorption from
intramuscular injections. Patients with protein-energy malnutrition frequently have poor
peripheral perfusion due to circulatory insufficiency associated with bradycardia, hypotension
and a reduced cardiac output. Thus absorption of intramuscular and possibly intrarectal
drugs may be expected to be slower than in patients without protein-energy malnutrition.
Diminished muscle mass may make repeated intramuscular injections difficult. A3

• Distribution
Total body water increases in proportion to the degree of malnutrition, mainly owing
to an expansion of the extracellular fluid (most obvious in oedematous patients). Thus
the volume of distribution of some drugs can be expected to be larger and plasma
concentrations lower. Albumin is the most important plasma protein for binding of many
drugs, but in protein-energy malnutrition hypoalbuminaemia results from decreased
synthesis as dietary deficiency occurs. With highly bound drugs this could in theory lead
to an increase in the amount of unbound drug, which may increase both the elimination,
since more drug is available for metabolism, and potential toxicity. There are other plasma
proteins less severely affected by decreased synthesis, and if these are able to bind some
free drug then the increase in free fraction might not be as great as anticipated.

• Metabolism

Fatty infiltration occurs but jaundice is uncommon unless septicaemia is present. Liver
function tests may be abnormal and urea cycle enzymes are decreased. Children with
kwashiorkor excreted a higher proportion of unchanged chloroquine before therapy than
in the recovery phase (85). This suggests that hepatic function was inadequate during
the acute phase of kwashiorkor. Animal studies have demonstrated that some enzyme
systems, such as cytochrome P450, have decreased activity in the presence of significant
malnutrition.

• Elimination
Owing to the reduction in cardiac output, the kidneys receive less than the usual 25% of
renal blood flow. Glomerular filtration rate, renal blood flow and tubular function have
all been shown to be inadequate, and compounded by concomitant dehydration. Drugs
dependent on renal excretion might be expected to have elevated plasma concentrations
under such circumstances. Abnormal excretion of drugs into bile has also been described
in severe protein-energy malnutrition.

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