Page 91 - 80 guidelines for the treatment of malaria_opt

ANNEX 3. Pharmacology of antimalarial medicines

Blood disorders that have been reported include agranulocytosis, aplastic anaemia,
thrombocytopenia, leukopenia and hypoprothrombinaemia. Acute haemolytic anaemia
is a rare complication, which may be antibody mediated or associated with glucose-
6-phosphate dehydrogenase (G6PD) deficiency. Other adverse effects, which may be
manifestations of a generalized hypersensitivity reaction include fever, interstitial
nephritis, a syndrome resembling serum sickness, hepatitis , myocarditis, pulmonary
eosinophilia, fibrosing alveolitis, peripheral neuropathy and systemic vasculitis, including
polyarteritis nodosa. Anaphylaxis has been reported only rarely. Other adverse reactions
that have been reported include hypoglycaemia, jaundice in neonates, aseptic meningitis,
drowsiness, fatigue, headache, ataxia, dizziness, drowsiness, convulsions, neuropathies, A3
psychosis and pseudomembranous colitis.

a3.4 pyrimethamine

CI N CI N
Molecular weight: 248.7
Pyrimethamine is a diaminopyrimidine used in
H N N
N N 2
O O CH 3 combination with a sulfonamide, usually sulfadoxine
HN CH 3 HN S CH 3 N or dapsone. It exerts its antimalarial activity by
N CH 3 N O
H inhibiting plasmodial dihydrofolate reductase thus
O NH 2 indirectly blocking the synthesis of nucleic acids
OH H N CI
CH 3
2 CH 3
in the malaria parasite. It is a slow-acting blood
schizontocide and is also possibly active against
N CH 3
pre-erythrocytic forms of the malaria parasite and
H 3 C inhibits sporozoite development in the mosquito
vector. It is effective against all four human malarials,
although resistance has emerged rapidly.
F
H 3 C H 3 C Pyrimethamine is H 3 C also used in the treatment of toxoplasmosis, and isosporiasis and
F F
F as prophylaxis against Pneumocystis carinii pneumonia. Pyrimethamine is no longer
F
N O O used alone as an antimalarial, only in synergistic combination with slowly eliminated
O
O C O C O C
F O O sulfonamides for treatment (sulfadoxine, sulfalene) or with dapsone for prophylaxis.
O
ÿ O CH 3 O CH 3 O O CH 3
H H H H 3 C H H HO Formulations H H
HO O O Pyrimethamine is currently used mainly in a fixed-dose combination with slowly
O
H H H
HN CH 3 CH 3 O eliminated sulfonamides, either of 20 parts sulfadoxine with 1 part pyrimethamine
CH 3
(Fansidar®) for which there are oral and parenteral formulations.
77
H 3 C H 3 C CI

CH 3
O O NH
O C O C 2
O O HN
CH 3 CH 3 CI CI N
O O
H H H H
H 3 C H 3 C
HO H 3 C O O
H H
CH 3 CH 3 H 3 C N
OH

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 CH 3 O
O N N N
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