QUININE & QUINIDINE
Quinine and quinidine
remain important therapies for falciparum malaria—especially severe
disease—although toxicity may complicate therapy. Resistance to quinine is
uncommon but may be increasing.
Quinine is derived
from the bark of the cinchona tree, a tradi-tional remedy for intermittent
fevers from South America. Thealkaloid quinine was purified from the bark in
1820, and it has been used in the treatment and prevention of malaria since
that time. Quinidine, the dextrorotatory stereoisomer of quinine, is at least
as effective as parenteral quinine in the treatment of severe falciparum
malaria. After oral administration, quinine is rapidly absorbed, reaches peak
plasma levels in 1–3 hours, and is widely distributed in body tissues. The use
of a loading dose in severe malaria allows the achievement of peak levels
within a few hours. The pharmacokinetics of quinine varies among populations.
Individuals with malaria develop higher plasma levels of the drug than healthy
controls, but toxicity is not increased, apparently because of increased
protein binding. The half-life of quinine also is longer in those with severe
malaria (18 hours) than in healthy controls (11 hours). Quinidine has a shorter
half-life than qui-nine, mostly as a result of decreased protein binding.
Quinine is primarily metabolized in the liver and excreted in the urine.
Quinine is a
rapid-acting, highly effective blood schizonticide against the four species of
human malaria parasites. The drug is gametocidal against P vivax and P ovale but
not P falciparum. It is not active
against liver stage parasites. The mechanism of action of quinine is unknown.
Increasing in vitro
resistance of parasites from a number of areas suggests that quinine resistance
will be an increasing prob-lem. Resistance to quinine is already common in some
areas of Southeast Asia, especially border areas of Thailand, where the drug
may fail if used alone to treat falciparum malaria. However, qui-nine still
provides at least a partial therapeutic effect in most patients.
Clinical Uses
For many years,
quinine dihydrochloride or quinidine gluconate have been the treatments of
choice for severe falciparum malaria, although intravenous artesunate now
provides an alternative for this indication. Quinine can be administered slowly
intravenously or, in a dilute solution, intramuscularly, but parenteral
prepara-tions of this drug are not available in the USA. Quinidine has been the
standard therapy in the USA for the parenteral treatment of severe falciparum
malaria. The drug can be administered in divided doses or by continuous
intravenous infusion; treatment should begin with a loading dose to rapidly
achieve effective plasma concentrations. Because of its cardiac toxicity and
the rela-tive unpredictability of its pharmacokinetics, intravenous quini-dine
should be administered slowly with cardiac monitoring. Therapy should be
changed to an effective oral agent as soon as the patient has improved and can
tolerate oral medications.
Quinine sulfate is
appropriate therapy for uncomplicated falci-parum malaria except when the
infection was transmitted in an area without documented chloroquine-resistant
malaria. Quinine is commonly used with a second drug (most often doxycycline or
in children, clindamycin) to shorten quinine’s duration of use (usually to 3
days) and limit toxicity. Quinine is less effective than chloroquine against
other human malarias and is more toxic. Therefore, it is not used to treat
infections with these parasites.
Quinine is not
generally used in chemoprophylaxis owing to its toxicity, although a daily dose
of 325 mg is effective.
Quinine is first-line
therapy, in combination with clindamycin, in the treatment of infection with Babesia microti or other human babesial
infections.
Therapeutic dosages of
quinine and quinidine commonly cause tinnitus, headache, nausea, dizziness,
flushing, and visual distur-bances, a constellation of symptoms termed cinchonism. Mild symptoms of cinchonism
do not warrant the discontinuation of therapy. More severe findings, often
after prolonged therapy, include more marked visual and auditory abnormalities,
vomiting, diarrhea, and abdominal pain. Hypersensitivity reactions include skin
rashes, urticaria, angioedema, and bronchospasm. Hematologic abnormalities
include hemolysis (especially with G6PD defi-ciency), leukopenia,
agranulocytosis, and thrombocytopenia. Therapeutic doses may cause hypoglycemia
through stimulation of insulin release; this is a particular problem in severe
infections and in pregnant patients, who have increased sensitivity to insulin.
Quinine can stimulate uterine contractions, especially in the third trimester.
However, this effect is mild, and quinine and quinidine remain drugs of choice
for severe falciparum malaria even during pregnancy. Intravenous infusions of
the drugs may cause throm-bophlebitis.
Severe hypotension can
follow too-rapid intravenous infusions of quinine or quinidine. Electrocardiographic
abnormalities (QT interval prolongation) are fairly common with intravenous
quini-dine, but dangerous arrhythmias are uncommon when the drug is
administered appropriately in a monitored setting.
Blackwater fever is
a rare severe illness that includes markedhemolysis and hemoglobinuria in the
setting of quinine therapy for malaria. It appears to be due to a
hypersensitivity reaction to the drug, although its pathogenesis is uncertain.
Quinine (or quinidine)
should be discontinued if signs of severe cinchonism, hemolysis, or
hypersensitivity occur. It should be avoided if possible in patients with
underlying visual or auditory problems. It must be used with great caution in
those with under-lying cardiac abnormalities. Quinine should not be given
concur-rently with mefloquine and should be used with caution in a patient with
malaria who has previously received mefloquine chemoprophylaxis. Absorption may
be blocked by aluminum-containing antacids. Quinine can raise plasma levels of
warfarin and digoxin. Dosage must be reduced in renal insufficiency.
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