Page 93 - 80 guidelines for the treatment of malaria_opt

N
N
CI
2
HN CH 3 CI HN O S O N N CH 3 H N N N CH 3
N CH 3 N O
H
O NH 2
OH CH 3 H N CH 3 CI
2
ANNEX 3. Pharmacology of antimalarial medicines
N CH 3
H
a3.5 mefloquine 3 C
Molecular weight: 378.3
F
Mefloquine is a 4-methanolquinoline and is H 3 C H 3 C
H 3 C
F F
F related to quinine. It is soluble in alcohol but only
F
N very slightly soluble in water. It should be protected O O C O O C
O
O
C
F from light. The drug is effective against all forms O O
O
of malaria. O CH 3 O CH 3 O O CH 3
H ÿ H H A3 H 3 C H H HO H H
HO O O O
H H H
HN CH 3 CH 3 O CH 3
Formulations
Mefloquine is administered by mouth as the hydrochloride salt (250 mg base equivalent CI
H 3 C
to 274 mg hydrochloride salt). H 3 C
• Tablets containing either 250 mg salt (United States of America) O or 250 mg base CH 3 NH
O
(elsewhere). O O C O O C HN 2
CH 3 CH 3 CI CI N
O
Pharmacokinetics H O H H
H
H 3 C H 3 C
Mefloquine is reasonably well absorbed from the gastrointestinal tract but there is marked O
O
HO
H 3 C
H
H
interindividual variation in the time required to achieve peak plasma concentrations. H 3 C N
CH 3
CH 3
Splitting the 25 mg/kg dose into two parts given at an interval of 6–24 h augments OH
absorption and improves tolerability (15). Mefloquine undergoes enterohepatic recycling.
It is approximately 98% bound to plasma proteins and is widely distributed throughout
the body. The pharmacokinetics of mefloquine may be altered by malaria infection with
reduced absorption and accelerated clearance (16,17). When administered with artesunate, CI
CI
H
H
H
blood concentrations are increased, probably as an indirect effect of increased absorption CH 3 CI O
N
N
N
H
resulting from more rapid resolution of symptoms (15). Mefloquine is excreted in small NH NH CH 3 H N S NH 2
2
NH
amounts in breast milk. It has a long elimination half-life of around 21 days, which is H H H O
NH
CH 3
CI
O
shortened in malaria to about 14 days, possibly because of interrupted enterohepatic cycling N N N CH 3
(18–20). Mefloquine is metabolized in the liver and excreted mainly in the bile and faeces.
H
Its pharmacokinetics show enantioselectivity after administration of the racemic mixture,
with higher peak plasma concentrations and area under the curve values, and lower volume
OH
O
of distribution and total clearance of the enantiomer than its antipode (21–23).
Toxicity
Minor adverse effects are common following mefloquine treatment, most frequently
H 2 C
CH 3, loss of
nausea, vomiting, abdominal pain, anorexia, diarrhoea, headache, dizziness OH CH 3 CI
H
H 3 C
N
HO
balance, dysphoria, somnolence and sleep disorders, notably insomnia and abnormal OH O OH O O O CH 3
H
CH 3
OH
dreams. Neuropsychiatric disturbances (seizures, encephalopathy, psychosis) occur N N
N NH 2 H 3 C H H O
HO H NH 2 79 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