A Textbook of Clinical Pharmacology and Therapeutics

MALARIA 363

Pharmacokinetics

Chloroquineis 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 t1/2is 120 hours.
High tissue concentrations (relative to plasma) are found,
especially in melanin containing tissues, e.g. the retina.

Drug interactions

Chloroquineandquinineare antagonistic and should not
used in combination.

ARYLAMINOALCOHOLS (4-AMINOQUINOLINE
DERIVATIVES)

This group consists of quinoline methanols (quinine,quinidine
andmefloquine) and the phenanthrene methanol halofantrine.

QUININE

Uses

Quinineis the main alkaloid of cinchona bark. The mechan-
ism of its antimalarial activity remains unclear, but may be
similar to that of chloroquine.

1. Quinine sulphate(quinidine gluconatein 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 t1/2is quite long and in patients with
   renal or hepatic dysfunction dosing should be reduced to

once or twice daily. Doxycyclineorclindamycinmay be

used as an adjunct to quinine.

2.Quinineshould 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 quininecause 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;


• intravenousquininecan produce neurotoxicity such as
  tremor of the lips and limbs, delirium, fits and coma.

Pharmacokinetics

Quinineis 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 t1/2is 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 aryl-

aminoalcohols 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 t1/2is 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 t1/2is 1–2 days. Hepatic mefloquine mefloquine may occur

metabolism to an active Pruritus

metabolite Prolongs the QTc

Hepatitis. CNS –

neuromuscular

spasm