Page 938 - Basic _ Clinical Pharmacology ( PDFDrive )

924 SECTION VIII Chemotherapeutic Drugs

when the infection was transmitted in an area without docu- MEFLOQUINE
mented chloroquine resistance. Quinine is commonly used with a
second drug (most often doxycycline or, in children, clindamycin) Mefloquine is effective therapy for many chloroquine-resistant
to shorten the duration of use (usually to 3 days) and limit toxic- strains of P falciparum and against other species. Although toxic-
ity. Quinine is not generally used to treat nonfalciparum malaria. ity is a concern, mefloquine is one of the recommended chemo-
prophylactic drugs for use in most malaria-endemic regions with
3. Malarial chemoprophylaxis—Quinine is not generally used chloroquine-resistant strains.
in chemoprophylaxis owing to its toxicity, although a daily dose
of 325 mg is effective.
Chemistry & Pharmacokinetics
4. Babesiosis—Quinine is first-line therapy, in combination Mefloquine hydrochloride is a synthetic 4-quinoline methanol
with clindamycin, in the treatment of infection with Babesia that is chemically related to quinine. It can only be given orally
microti or other human babesial infections. because severe local irritation occurs with parenteral use. It is
well absorbed, and peak plasma concentrations are reached in
Adverse Effects about 18 hours. Mefloquine is highly protein-bound, extensively
distributed in tissues, and eliminated slowly, allowing a single-dose
Therapeutic dosages of quinine and quinidine commonly cause treatment regimen. The terminal elimination half-life is about
tinnitus, headache, nausea, dizziness, flushing, and visual distur- 20 days, allowing weekly dosing for chemoprophylaxis. With
bances, a constellation of symptoms termed cinchonism. Mild weekly dosing, steady-state drug levels are reached over a number
symptoms of cinchonism do not warrant the discontinuation of weeks. Mefloquine and its metabolites are slowly excreted,
of therapy. More severe findings, often after prolonged therapy, mainly in the feces.
include more marked visual and auditory abnormalities, vomiting,
diarrhea, and abdominal pain. Hypersensitivity reactions include
skin rashes, urticaria, angioedema, and bronchospasm. Hema- Antimalarial Action & Resistance
tologic abnormalities include hemolysis (especially with G6PD Mefloquine has strong blood schizonticidal activity against
deficiency), leukopenia, agranulocytosis, and thrombocytopenia. P falciparum and P vivax, but it is not active against hepatic stages
Therapeutic doses may cause hypoglycemia through stimulation or gametocytes. The mechanism of action is unknown. Sporadic
of insulin release; this is a particular problem in severe infections resistance to mefloquine has been reported from many areas, but
and in pregnant patients, who may have increased sensitivity to resistance appears to be uncommon except in regions of Southeast
insulin. Quinine can stimulate uterine contractions, especially in Asia with high rates of multidrug resistance (especially border
the third trimester. However, this effect is mild, and quinine and areas of Thailand). Mefloquine resistance does not appear to be
quinidine remain appropriate for treatment of severe falciparum associated with resistance to chloroquine.
malaria during pregnancy. Intravenous infusions of the drugs may
cause thrombophlebitis. Clinical Uses
Severe hypotension can follow too-rapid intravenous infu-
sions of quinine or quinidine. Electrocardiographic abnor- 1. Chemoprophylaxis—Mefloquine is effective in prophy-
malities (QT interval prolongation) are fairly common with laxis against most strains of P falciparum and probably all other
intravenous quinidine, but dangerous arrhythmias are uncom- human malarial species. Mefloquine is therefore among the
mon when the drug is administered appropriately in a moni- drugs recommended by the CDC for chemoprophylaxis in all
tored setting. malarious areas except those with no chloroquine resistance
Blackwater fever is a rare severe illness that includes marked (where chloroquine is preferred) and some rural areas of South-
hemolysis and hemoglobinuria in the setting of quinine therapy east Asia with a high prevalence of mefloquine resistance. As
for malaria. It appears to be due to a hypersensitivity reaction to with chloroquine, eradication of P vivax and P ovale requires a
the drug, although its pathogenesis is uncertain. course of primaquine.

Contraindications & Cautions 2. Treatment—Mefloquine is effective in treating uncompli-
cated falciparum malaria. The drug is not appropriate for treating
Quinine (or quinidine) should be discontinued if signs of severe individuals with severe or complicated malaria, since quinine,
cinchonism, hemolysis, or hypersensitivity occur. It should be quinidine, and artemisinins are more rapidly active, and since
avoided if possible in patients with underlying visual or audi- drug resistance is less likely with those agents. The combination of
tory problems. It must be used with great caution in those with artesunate plus mefloquine showed excellent antimalarial efficacy
underlying cardiac abnormalities. Quinine should not be given in regions of Southeast Asia with some resistance to mefloquine,
concurrently with mefloquine and should be used with caution and this regimen is now one of the combination therapies rec-
in a patient with malaria who has recently received mefloquine. ommended by the WHO for the treatment of uncomplicated
Absorption may be blocked by aluminum-containing antacids. falciparum malaria (Table 52–4). Artesunate-mefloquine is the
Quinine can raise plasma levels of warfarin and digoxin. Dosage first-line therapy for uncomplicated falciparum malaria in a num-
must be reduced in renal insufficiency. ber of countries in Asia and South America.