Page 102 - 80 guidelines for the treatment of malaria_opt

N
CI
N
2
CH 3
HN
CH 3
H
NH
2
CI
2
F
H 3 C
F
F
N
O
O
H
H
H
HO
CH 3
CI
H 3 C
H 3 C
O
O HN H F H 3 C C F F N CH 3 CI ÿ O O HN CH 3 O O H O O C H C OH CH 3 N CH 3 CH 3 H N H 3 C O O H 3 C O O O S H O O N C H N O CH 3 N CH 3 O CH 3 HO O H N N N O HN O CH 3 O H 3 C CH 3 O H O NH H C 2 CH 3
O O
CH 3 CH 3 CI CI N
O O
H H H H
nd
Guidelines for the treatment of malaria – 2 edition H 3 C H 3 C
HO H 3 C O O
H H
CH 3 CH 3 H 3 C N
OH
a3.9 atovaquone
Molecular weight: 366.8
CI Atovaquone is a hydroxynaphthoquinone CI
antiparasitic drug active against all Plasmodium CI O
H
H
H
N
N
N
H species. It also inhibits pre-erythrocytic CH 3 NH NH CH 3 NH
development in the liver, and oocyst development H N S 2
2
NH
NH
CH 3
CI
O in the mosquito. It is combined with proguanil H H H CH 3 O
N
N
N
for the treatment of malaria – with which
H
it is synergistic. Atovaquone interferes with
OH cytochrome electron transport.
O
Formulations
Atovaquone is available for the treatment of malaria in a coformulation with proguanil.
H 2 C containing 250 mg of atovaquone and 100 mg of proguanil
• Film-coated tablets H H 3 C OH CI
hydrochloride for adults. HO CH 3 H N CH 3 OH O O O CH 3 O CH 3
• Tablets containing 62.5 mg of atovaquone and 25 mg of proguanil hydrochloride for OH N N
OH
paediatric use. N NH 2 H H
H 3 C O
HO H NH 2 H CH 3
Pharmacokinetics OH OH HO S
O OH O OH O O H H
Atovaquone is poorly absorbed from the gastrointestinal tract but bioavailability following H 3 C OH N HO OH
H 3 C
oral administration can be improved by taking the drug with fatty foods. Bioavailabillity H 3 C CH 3
N
is reduced in patients with AIDS. Atovaquone is 99% bound to plasma proteins and has
a plasma half-life of around 66–70 h due to enterohepatic recycling. It is excreted almost
exclusively in the faeces as unchanged drug. Plasma concentrations are significantly
reduced in late pregnancy (53).
Toxicity
Atovaquone is generally very well tolerated (54). Skin rashes, headache, fever, insomnia,
nausea, diarrhoea, vomiting, raised liver enzymes, hyponatraemia and, very rarely,
haematological disturbances, such as anaemia and neutropenia, have all been reported.
Drug interactions
Reduced plasma concentrations may occur with concomitant administration
of metoclopramide, tetracycline and possibly also acyclovir, antidiarrhoeal drugs,
benzodiazepines, cephalosporins, laxatives, opioids and paracetamol. Atovaquone
decreases the metabolism of zidovudine and cotrimoxazole. Theoretically, it may displace
other highly protein-bound drugs from plasma-protein binding sites.
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