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

for 3 months after mefloquine use because of the prolonged t 1/2
of
this agent.
This drug is contraindicated for patients with a history of
seizures, depression, bipolar disorder and other severe neuropsychiatric
conditions, or adverse reactions to quinoline antimalarials such
as quinine, quinidine, halofantrine, mefloquine, and chloroquine.
Mefloquine may counteract seizures in epileptic patients. Although
this drug can be taken safely 12 hours after a last dose of quinine,
taking quinine shortly after mefloquine can be very hazardous
because the latter is eliminated so slowly. Treatment with or after
halofantrine or within 2 months of prior mefloquine administration
is contraindicated.
Recent studies do not indicate that mefloquine compromises
the performance of tasks that require good motor coordination, e.g.,
driving or operating machinery. Although some advise against the
use of mefloquine for patients in occupations that require focused
concentration, dexterity and cognitive function in safety-sensitive
settings, such as pilots, controlled studies suggest that mefloquine
does not impair performance in persons who tolerate the drug.
Primaquine
History. The weak anti-Plasmodium activity of methylene blue,
first discovered by Ehrlich in 1891, led to the development of the
8-aminoquinoline antimalarials, of which pamaquine was the first
introduced into medicine. During World War II the search for more
potent and less toxic 8-aminoquinoline antimalarials resulted in the
discovery of primaquine (Figure 49–2).
Primaquine, in contrast to other antimalarials, acts on exoerythrocytic
tissue stages of plasmodia in the liver to prevent and
cure relapsing malaria. The striking hemolysis that may follow primaquine
therapy led directly to the landmark discovery of G6PD
deficiency, the first genetic disorder associated with an enzyme.
Hemolysis remains notoriously identified with primaquine. Patients
should be screened for G6PD deficiency prior to therapy with this
drug. The pressing need for alternatives to this important drug has
resulted in the evaluation of multiple 8-aminoquinoline analogs (Vale
et al., 2009). These include tafenoquine, a compound under clinical
evaluation that is active against relapsing liver stage forms of P.
vivax, and multidrug resistant asexual blood stage forms of P. falciparum
(Wells et al., 2009).
Mechanisms of Action and Parasite Resistance.
Primaquine acts against primary and latent hepatic
stages of Plasmodium spp. and prevents relapses in
P. vivax and P. ovale infections. This drug and other
8-aminoquinolines also display gametocytocidal activity
against P. falciparum and other Plasmodium species.
However, primaquine is inactive against asexual blood
stage parasites.
The mechanism of action of the 8-aminoquinolines has not
been elucidated. Primaquine may be converted to electrophilic intermediates
that act as oxidation-reduction mediators. Such activity
could contribute to antimalarial effects by generating reactive oxygen
species or by interfering with mitochondrial electron transport
in the parasite (Vale et al., 2009). Some strains of P. vivax can exhibit
partial resistance to primaquine (Baird, 2009).
Absorption, Fate, and Excretion. Absorption of primaquine
from the GI tract approaches 100%. After a
single dose, the plasma concentration reaches a maximum
within 3 hours and then falls with a variable elimination
t 1/2
averaging 7 hours.
The apparent volume of distribution is several times that of
total-body water, due to extensive tissue distribution. Primaquine binds
preferentially to the acute-phase reactant protein α1-glycoprotein,
which may alter the distribution of free drug depending on its concentration
in the blood. Primaquine is metabolized rapidly, and only a
small fraction of an administered dose is excreted as the parent drug.
Importantly, primaquine induces CYP1A2. Thus, caution should be
taken in administering primaquine with drugs metabolized by
CYP1A2 (including warfarin) (Hill et al., 2006). The major metabolite,
carboxyprimaquine, is inactive.
Therapeutic Uses. Primaquine is used primarily for terminal
chemoprophylaxis and radical cure of P. vivax
and P. ovale (relapsing) infections because of its high
activity against the latent tissue forms (hypnozoites) of
these Plasmodium species. The compound is given
together with a blood schizonticide, usually chloroquine,
to eradicate erythrocytic stages of these plasmodia
and reduce the possibility of emerging drug
resistance.
For terminal chemoprophylaxis, primaquine regimens should
be initiated shortly before or immediately after a subject leaves an
endemic area (Table 49–2). Radical cure of P. vivax or P. ovale
malaria can be achieved if the drug is given either during an asymptomatic
latent period of presumed infection (based on travel to or residence
within an endemic region) or during an acute attack.
Simultaneous administration of a schizonticidal drug plus primaquine
is more effective in radical cure than sequential treatment. Limited
studies have shown efficacy in prevention of P. falciparum and P.
vivax malaria when primaquine is taken as chemoprophylaxis (Taylor
and White, 2004). Gametocytocidal activity of primaquine should
also reduce the transmission potential during drug treatment of P. falciparum.
However, this approach to prophylaxis is not routine clinical
practice. Primaquine is generally well tolerated when taken for
up to 1 year.
Toxicity and Side Effects. Primaquine has few side effects when given
to most whites in the usual therapeutic doses. Primaquine can cause
mild to moderate abdominal distress in some individuals. Taking the
drug at mealtime often alleviates these symptoms. Mild anemia,
cyanosis (methemoglobinemia), and leukocytosis are less common.
High doses (60-240 mg daily) worsen the abdominal symptoms and
cause some degree of methemoglobinemia in most subjects.
Methemoglobinemia can occur even with usual doses of primaquine
and can be severe in individuals with congenital deficiency of NADH
methemoglobin reductase (Coleman and Coleman, 1996). Chloroquine
and dapsone may synergize with primaquine to produce methemoglobinemia
in these patients. Granulocytopenia and agranulocytosis are
rare complications of therapy and usually are associated with overdosage.
Other rare adverse reactions are hypertension, arrhythmias, and
symptoms referable to the CNS.
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CHAPTER 49
CHEMOTHERAPY OF MALARIA