DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

therapeutic doses, and thick smears of peripheral blood generally
are negative by 48-72 hours. If patients fail to respond during the
second day of chloroquine therapy, resistant strains should be suspected
and therapy instituted with quinine plus tetracycline or doxycycline,
or atovaquone-proguanil, or artemether-lumefantrine, or
mefloquine if the others are not available. Although chloroquine can
be given safely by parenteral routes to comatose or vomiting
patients, quinidine gluconate usually is given in the U.S. In comatose
children, chloroquine is well absorbed and effective when given
through a nasogastric tube. Tables 49–2 and 49–3 provide information
about recommended chemoprophylactic and therapeutic dosage
regimens involving the use of chloroquine. These regimens are subject
to modification according to clinical judgment, geographic patterns
of chloroquine resistance, and regional usage.
Chloroquine and its analogs are also used to treat certain nonmalarial
conditions, including hepatic amebiasis. Chloroquine and
hydroxychloroquine have also been used as secondary drugs to treat
a variety of chronic diseases because both alkaloids concentrate in
lysosomes and have anti-inflammatory properties. Thus, these compounds,
often together with other agents, have clinical efficacy in
rheumatoid arthritis, systemic lupus erythematosus, discoid lupus,
sarcoidosis, and photosensitivity diseases such as porphyria cutanea
tarda and severe polymorphous light eruption.
Toxicity and Side Effects. Taken in proper doses and for
recommended total durations, chloroquine is very safe.
However, its safety margin is narrow, and a single dose
of 30 mg/kg may be fatal (Taylor and White, 2004).
Acute chloroquine toxicity is encountered most frequently
when therapeutic or high doses are administered too rapidly by parenteral
routes. Toxic manifestations relate primarily to the cardiovascular
system and the CNS. Cardiovascular effects include
hypotension, vasodilation, suppressed myocardial function, cardiac
arrhythmias, and eventual cardiac arrest. Confusion, convulsions, and
coma may also result from overdose. Chloroquine doses of >5 g given
parenterally usually are fatal. Prompt treatment with mechanical ventilation,
epinephrine, and diazepam may be lifesaving.
Doses of chloroquine used for oral therapy of the acute malarial
attack may cause GI upset, headache, visual disturbances, and
urticaria. Pruritus also occurs, most commonly among dark-skinned
persons. Prolonged treatment with suppressive doses occasionally
causes side effects such as headache, blurring of vision, diplopia,
confusion, convulsions, lichenoid skin eruptions, bleaching of hair,
widening of the QRS interval, and T-wave abnormalities. These complications
usually disappear soon after the drug is withheld. Rare
instances of hemolysis and blood dyscrasias have been reported.
Chloroquine may cause discoloration of nail beds and mucous membranes.
This drug has also been reported to interfere with the
immunogenicity of certain vaccines (Pappaioanou et al, 1986).
High daily doses of chloroquine or hydroxychloroquine
(>250 mg) leading to cumulative total doses of >1 g/kg, such as those
used for treatment of diseases other than malaria, can result in
irreversible retinopathy and ototoxicity. Retinopathy presumably is
related to drug accumulation in melanin containing tissues and can
be avoided if the daily dose is ≤250 mg (Rennie, 1993). Prolonged
therapy with high doses of chloroquine or hydroxychloroquine also
can cause toxic myopathy, cardiopathy, and peripheral neuropathy.
These reactions improve if the drug is withdrawn promptly (Estes
et al., 1987). Rarely, neuropsychiatric disturbances, including suicide,
may be related to overdose.
Precautions and Contraindications. Chloroquine is not recommended
for treating individuals who have epilepsy or myasthenia gravis. This
drug should be used cautiously if at all in the presence of advanced
liver disease or severe GI, neurological, or blood disorders. In individuals
with decreased renal function, dosage should be adjusted to
avoid elevated plasma concentrations. In rare cases, chloroquine can
cause hemolysis in patients with G6PD deficiency (see later section
on primaquine). Concomitant use of gold or phenylbutazone (no
longer available in the U.S.) with chloroquine, in the treatment of
rheumatoid arthritis, should be avoided because of the tendency of
all three agents to produce dermatitis. Chloroquine should not be
prescribed for patients with psoriasis or other exfoliative skin conditions
because it can cause severe reactions. Because of the danger
of cutaneous reactions, it should also not be used to treat malaria in
patients with porphyria cutanea tarda; however it can be used in
lower doses for treatment of manifestations of this form of porphyria.
Chloroquine inhibits CYP2D6 and interacts with a variety of different
drugs. It attenuates the efficacy of the yellow fever vaccine when
administered at the same time. It should not be given with mefloquine
because of increased risk of seizures and lack of added benefit.
Most important, chloroquine opposes the action of
anticonvulsants and increases the risk of ventricular arrhythmias
when co-administered with amiodarone or halofantrine. By increasing
plasma levels of digoxin and cyclosporine, chloroquine also can
increase the risk of toxicity from these agents. Patients receiving
long-term, high-dose therapy should undergo ophthalmological and
neurological evaluations every 3-6 months.
Quinine and Quinidine
History. The medicinal use of quinine dates back >350 years (Rocco,
2003). Quinine is the chief alkaloid of cinchona, the powdered bark
of the South American cinchona tree, otherwise known as Peruvian,
Jesuit’s, or Cardinal’s bark. It had been used by indigenous Peruvians
to treat shivering. In 1633, an Augustinian monk named Calancha,
of Lima, Peru, first wrote that a powder of cinchona “given as a beverage,
cures the fevers and tertians.” By 1640, cinchona was used to
treat fevers in Europe. The Jesuit fathers were the main importers
and distributors of cinchona in Europe.
For almost two centuries the bark was employed for medicine
as a powder, extract, or infusion. In 1820, Pelletier and
Caventou isolated quinine from cinchona. Quinine still is a mainstay
for treating attacks of chloroquine- and multidrug-resistant
P. falciparum malaria (Table 49–3). However, combination therapy
(now standard artemisinin-derivative combinations) with other antimalarials
is supplanting quinine regimens because of increasing
resistance of P. falciparum to quinine in Southeast Asia and parts of
the Amazon basin. Quinine toxicity, usually seen in overdose, can
include pulmonary edema, immune thrombocytopenic purpura, irreversible
deafness, or arrhythmias.
Oral quinine is FDA approved for the treatment of uncomplicated
P. falciparum malaria and is currently available from one
manufacturer in the U.S. Intravenous quinine is not available in the
U.S. The more potent enantiomer, quinidine, is the preferred intravenous
form.
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CHAPTER 49
CHEMOTHERAPY OF MALARIA