Page 87 - 80 guidelines for the treatment of malaria_opt

ANNEX 3. Pharmacology of antimalarial medicines

ANNEX 3
pHarmacoloGy of antimalarial medicines

a3.1 chloroquine

Molecular weight: 436.0 A3
Chloroquine is a 4-aminoquinoline which
CI N CI N
has been used extensively for the treatment
and prevention of malaria. Widespread H N N
resistance has now rendered it virtually O O N N 2 CH 3
HN CH 3 useless against P. falciparum infections N S O CH 3 N
HN
in most parts of the world, although it CH 3 N
H
still maintains considerable efficacy for OH CH 3 H N O CH 3 NH 2 CI
the treatment of P. vivax, P. ovale and 2
N CH 3 P. malariae infections. As with other
4-aminoquinolines, it does not produce
H 3 C radical cure.
Chloroquine interferes with parasite haem detoxification (1, 2). Resistance is related to
genetic changes in transporters (PfCRT, PfMDR), which reduce the concentrations of
F
chloroquine at its site of action, the parasite food vacuole. H 3 C H 3 C H 3 C
F F
F
F
N O O O
Formulations F O O C O O C O O C
• Tablets containing 100 mg or 150 mg of chloroquine base as phosphate or sulfate. CH 3 O CH 3 O O CH 3
O
H ÿ H H H 3 C H H HO H H
Pharmacokinetics O O O
HO
H H H
CH 3 gastrointestinal
Chloroquine is rapidly and almost completely absorbed from the CH 3 O CH 3
HN
tract when taken orally, although peak plasma concentrations can vary considerably.
Absorption is also very rapid following intramuscular and subcutaneous administration
(3–5). Chloroquine is extensively distributed into body tissues, including the placenta CI
H 3 C
H 3 C
and breast milk, and has an enormous total apparent volume of distribution. The
relatively small volume of distribution of the central compartment means that transiently CH 3
O
O
C
O
O
C
cardiotoxic levels may occur following intravenous administration unless the rate of HN NH 2
O
O
parenteral delivery is strictly controlled. Some 60% of chloroquine is bound to plasma CI CI N
CH 3
CH 3
O
O
Hdrug
proteins, and the H is eliminated slowly from the body via the kidneys,
Hwith an
H
estimated terminal elimination half-life of 1–2 months. Chloroquine is metabolized H 3 C H 3 C O
O
HO
H 3 C
H H
73 OH
CH 3 CH 3 H 3 C N
CI CI
H H H
N N N CH 3 CI O
H NH NH CH 3
H N S NH 2
2
NH NH CH 3
CI H H H O
O N N N CH 3
H
OH
O
H 2 C H H 3 C CH 3 OH CI
HO CH 3 H N OH O O O CH 3 O CH 3
OH OH N
NH N
N 2 H H
H 3 C O
HO H NH 2 CH 3
OH H HO S
OH H H
O OH O OH O O
H 3 C H 3 C OH N HO OH
H 3 C CH 3
N