Page 90 - 80 guidelines for the treatment of malaria_opt

nd
Guidelines for the treatment of malaria – 2 edition

a3.3 sulfadoxine

CI N CI N
Molecular weight: 310.3
Ninated
Sulfadoxine is a slowly elim
2
N N H N
O O sulfonamide. It is very slightly soluble
CH 3
N
HN CH 3 HN S CH 3 in water. Sulfonamides are structural
N CH 3 N O
H analogues and competitive antagonists
O NH 2
OH H N of p-aminobenzoic acid. They are CI
CH 3
2 CH 3
competitive inhibitors of dihydropteroate
N CH 3 synthase, the bacterial enzyme responsible
for the incorporation of p-aminobenzoic
H 3 C acid in the synthesis of folic acid.
Formulations
F Sulfadoxine is used in a fixed-dose combination of 20 parts sulfadoxine with 1 part
H 3 C H 3 C H 3 C
F F pyrimethamine and may be administered orally or by the intramuscular route.
F
F
N O • Tablets containing 500 mg of sulfadoxine and 25 mg of pyrimethamine. O
O
O C O C O C
F O • Ampoules containing 500 mg of sulfadoxine and 25 mg of pyrimethamine in 2.5 ml
O
O
ÿ O CH 3 of injectable solution for intramuscular use. O O CH 3
CH 3
O
H H H H 3 C H H HO H H
O
HO O Pharmacokinetics O
H H H
HN CH 3 Sulfadoxine is readily absorbed from the gastrointestinal tract. Peak blood concentrations
O
CH 3
CH 3
occur about 4 h after an oral dose. The terminal elimination half-life is 4–9 days. Around
90–95% is bound to plasma proteins. It is widely distributed to body tissues and fluids,
passes into the fetal circulation and is detectable in breast milk. The drug is excreted very
H 3 C H 3 C CI
slowly in urine, primarily unchanged.
CH 3
O O C O O C Toxicity HN NH 2
O O
CI
CI
N
CH 3 CH 3 Sulfadoxine shares the adverse effect profile of other sulfonamides, although allergic
O O
H H H H reactions can be severe because of its slow elimination. Nausea, vomiting, anorexia and
H 3 C H 3 C
HO H 3 C O diarrhoea may occur. Crystalluria causing lumbar pain, haematuria and oliguria is rare
O
H H compared with more rapidly eliminated sulphonamides. Hypersensitivity reactions
H 3 C N
CH 3 CH 3
may effect different organ system. Cutaneous manifestations can be severe and include
OH
pruritus, photosensitivity reactions, exfoliative dermatitis, erythema nodosum, toxic
epidermal necrolysis and Stevens-Johnson syndrome (12). Treatment with sulfadoxine
should be stopped in any patient developing a rash because of the risk of severe allergic
reactions (13). Hypersensitivity to sulfadoxine may also cause interstitial nephritis,
CI CI
H H H lumbar pain, haematuria and oliguria. This is due to crystal formation in the urine
N N N CH 3 CI O
H (crystalluria) and may be avoided by keeping the patient well hydrated to maintain a
NH
NH
CH 3
H N
NH
S
2
2
NH NH CH 3 high urine output. Alkalinization of the urine will also make the crystals more soluble.
CI H H H CH 3 O
O N N N
76
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 3 C H 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