Clinical Pharmacology and Therapeutics

MALARIA 363
Pharmacokinetics
Chloroquine is rapidly and well absorbed from the intestine.
It is approximately 50% bound to plasma proteins. About 70%
of a dose is excreted unchanged in the urine, and the main
metabolite is desethylchloroquine. The mean t 1/2 is 120 hours.
High tissue concentrations (relative to plasma) are found,
especially in melanin containing tissues, e.g. the retina.
Drug interactions
Chloroquine and quinine are antagonistic and should not
used in combination.
ARYLAMINOALCOHOLS (4-AMINOQUINOLINE
DERIVATIVES)
This group consists of quinoline methanols (quinine, quinidine
and mefloquine) and the phenanthrene methanol halofantrine.
QUININE
Uses
Quinine is the main alkaloid of cinchona bark. The mechanism
of its antimalarial activity remains unclear, but may be
similar to that of chloroquine.
1. Quinine sulphate (quinidine gluconate in the USA) is the
drug of choice in the treatment of an acute attack of
falciparum malaria where the parasite is known to be
resistant to chloroquine. Initially, these drugs may be
given intravenously and then orally when the patient
improves. The mean t 1/2 is quite long and in patients with
renal or hepatic dysfunction dosing should be reduced to
once or twice daily. Doxycycline or clindamycin may be
used as an adjunct to quinine.
2. Quinine should not be used for nocturnal cramps as its
adverse effects outweigh any benefit in this benign
condition.
Adverse effects
These include the following:
• large therapeutic doses of quinine cause cinchonism
(tinnitus, deafness, headaches, nausea and visual
disturbances);
• abdominal pain and diarrhoea;
• rashes, fever, delirium, stimulation followed by
depression of respiration, renal failure, haemolytic
anaemia, thrombocytopenic purpura and
hypoprothrombinaemia;
• intravenous quinine can produce neurotoxicity such as
tremor of the lips and limbs, delirium, fits and coma.
Pharmacokinetics
Quinine is almost completely absorbed in the upper part of
the small intestine and peak concentrations occurring 1–3
hours after ingestion are similar following oral or intravenous
administration. The mean t 1/2 is ten hours, but is longer in
severe falciparum malaria. Approximately 95% or more of a
single dose is metabolized in the liver, principally to inactive
hydroxy derivatives, with less than 5% being excreted
unaltered in the urine. The uses and properties of other arylaminoalcohols
are listed in Table 47.1.
Table 47.1: Uses and properties of other arylaminoalcohols
Drug Use and Pharmacokinetics Side effects Precautions/
pharmacodynamics
comments
Mefloquine Used for prophylaxis and Acute treatment: oral Gastro-intestinal Not used in pregnancy or
acute treatment of drug- dosing disturbances are in patients with
resistant malaria (especially Hepatic metabolism with common (up to neuropsychiatric disorders
P. falciparum) enterohepatic circulation 50% of cases) Do not use in patients
Schizonticidal in the blood t 1/2 is 14–22 days CNS – hallucinations, with renal or hepatic
psychosis, fits
dysfunction
Potentiates bradycardia of
beta-blockers and
quinine potentiates its
toxicity
Halofantrine Used for only uncomplicated Acute treatment: oral Gastro-intestinal Embryotoxic in animals –
chloroquine-resistant dosing disturbances; less not used in pregnancy
P. falciparum Food improves absorption. common than with Cross-resistance with
Schizonticidal in the blood t 1/2 is 1–2 days. Hepatic mefloquine mefloquine may occur
metabolism to an active Pruritus
metabolite
Prolongs the QTc
Hepatitis. CNS –
neuromuscular
spasm