Page 105 - 80 guidelines for the treatment of malaria_opt

ANNEX 3. Pharmacology of antimalarial medicines

Formulations
• Tablets of quinine hydrochloride, quinine dihydrochloride, quinine sulfate and quinine
bisulfate containing 82%, 82%, 82.6% and 59.2% quinine base respectively.
• Injectable solutions of quinine hydrochloride, quinine dihydrochloride and quinine
sulfate containing 82%, 82% and 82.6% quinine base respectively.

Pharmacokinetics
The pharmacokinetic properties of quinine are altered significantly by malaria infection,
with reductions in apparent volume of distribution and clearance in proportion to disease A3
severity (16,62). In children under 2 years of age with severe malaria, concentrations
are slightly higher than in older children and adults (63). There is no evidence for
dose-dependent kinetics. Quinine is rapidly and almost completely absorbed from the
gastrointestinal tract and peak plasma concentrations occur 1–3 h after oral administration
of the sulfate or bisulfate (64). It is well absorbed after intramuscular injection in severe
malaria (65, 66). Plasma-protein binding, mainly to alpha 1-acid glycoprotein, is 70% in
healthy subjects but rises to around 90% in patients with malaria (67–69).
Quinine is widely distributed throughout the body including the cerebrospinal fluid (2–7%
of plasma values), breast milk (approximate 30% of maternal plasma concentrations) and
the placenta (70). Extensive metabolism via the cytochrome P450 enzyme CYP3A4 occurs
in the liver and elimination of more polar metabolites is mainly renal (71, 72). The initial
metabolite 3-hydroxyquinine contributes approximately 10% of the antimalarial activity
of the parent compound, but may accumulate in renal failure (73). Excretion is increased
in acid urine. The mean elimination half-life is around 11 h in healthy subjects, 16 h in
uncomplicated malaria and 18 h in severe malaria (62). Small amounts appear in the bile
and saliva.
Toxicity
Administration of quinine or its salts regularly causes a complex of symptoms known
as cinchonism, which is characterized in its mild form by tinnitus, impaired high tone
hearing, headache, nausea, dizziness and dysphoria, and sometimes disturbed vision
(7). More severe manifestations include vomiting, abdominal pain, diarrhoea and severe
vertigo. Hypersensitivity reactions to quinine range from urticaria, bronchospasm,
flushing of the skin and fever, through antibody-mediated thrombocytopenia and
haemolytic anaemia, to life-threatening haemolytic-uraemic syndrome. Massive
haemolysis with renal failure (“black water fever”) has been linked epidemiologically
and historically to quinine, but its etiology remains uncertain (74). The most important
adverse effect in the treatment of severe malaria is hyperinsulinaemic hypoglycaemia
(75). This is particularly common in pregnancy (50% of quinine-treated women with
severe malaria in late pregnancy). Intramuscular injections of quinine dihydrochloride
are acidic (pH 2) and cause pain, focal necrosis and in some cases abscess formation, and

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