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

1410 Therapeutic or higher doses of primaquine may cause acute
hemolysis and hemolytic anemia in humans with G6PD deficiency
(Vale et al., 2009). This X-linked condition, primarily owing to
amino acid substitutions in the G6PD enzyme, affects >200 million
people worldwide. More than 400 genetic variants of G6PD produce
variable responses to oxidative stress. About 11% of African
Americans have the A variant of G6PD, and are therefore vulnerable
to hemolysis caused by pro-oxidant drugs such as primaquine.
G6PD deficiency is uncommon in Latin America but may be present
in those residents of African descent. Primaquine-induced hemolysis
can be even more severe in white ethnic groups, including
Sardinians, Sephardic Jews, Greeks, and Iranians; these populations
have a G6PD variant in which two amino acid substitutions impair
both enzyme stability and activity. Because primaquine sensitivity is
inherited through an X-linked gene, hemolysis is often of intermediate
severity in heterozygous females who have two populations of
red blood cells, one normal and the other deficient in G6PD. Owing
to “variable penetrance,” these females may be affected less frequently
than predicted. Primaquine is the prototype of >50 drugs,
including antimalarial sulfonamides, that cause hemolysis in G6PDdeficient
individuals.
Precautions and Contraindications. G6PD deficiency
should be ruled out prior to administration of primaquine.
Primaquine has been used cautiously in subjects
with the A form of G6PD deficiency, although
benefits of treatment may not necessarily outweigh the
risks. The drug should not be used in patients with
more severe deficiency. If a daily dose of >30 mg primaquine
base (>15 mg in potentially sensitive patients)
is given, then blood counts should be followed carefully.
Patients should be counseled to look for dark or
blood-colored urine, which would indicate hemolysis.
Primaquine should not be given to pregnant women,
and, in treating lactating mothers, it should be prescribed
only after ascertaining that the breast-feeding
infant has a normal G6PD level (which can be difficult
to assess soon after birth).
Primaquine is contraindicated for acutely ill
patients suffering from systemic disease characterized
by a tendency to granulocytopenia (e.g., active forms
of rheumatoid arthritis and lupus erythematosus).
Primaquine should not be given to patients receiving
other drugs capable of causing hemolysis or depressing
the myeloid elements of the bone marrow.
SECTION VII
CHEMOTHERAPY OF MICROBIAL DISEASES
SULFONAMIDES AND SULFONES
History. Shortly after their introduction into clinical practice, the
sulfonamides were found to have antimalarial activity, a property investigated
extensively during World War II. The efficacy of sulfones
was demonstrated in the first trial of dapsone against P. falciparum
in 1943. The sulfonamides combined with pyrimethamine have
been used to treat chloroquine-resistant P. falciparum malaria, particularly
in parts of Africa. The sulfonamides and sulfones are
slow-acting blood schizonticides and more active against P. falciparum
than P. vivax.
Mechanism of Action. Sulfonamides are p-aminobenzoic acid
analogs that competitively inhibit Plasmodium dihydropteroate
synthase. These agents are combined with an inhibitor of parasite
dihydrofolate reductase to enhance their antimalarial action. The
synergistic “antifolate” combination of sulfadoxine, a long-acting
sulfonamide, with pyrimethamine has been extensively used to
treat malaria. As observed for pyrimethamine, sulfadoxine resistance
appeared quickly in vivo after the introduction of this treatment
as monotherapy.
Drug Resistance. Sulfadoxine resistance is conferred by several point
mutations in the dihydropteroate synthase gene; the more widespread
is the substitution Ala437Gly. These sulfadoxine-resistance mutations,
when combined with mutations of dihydrofolate reductase and
conferring pyrimethamine resistance, greatly increase the likelihood
of sulfadoxine-pyrimethamine treatment failure. Sulfadoxinepyrimethamine,
given intermittently during the second and third
trimesters of pregnancy, is a routine component of antenatal care
throughout Africa. Intermittent preventive treatment strategies might
also benefit infants (Aponte et al., 2009). However, there are substantial
concerns about these strategies in the face of the expanding profile
of resistance to pyrimethamine-sulfadoxine. A recent report found
that intermittent preventive treatment in pregnancy exacerbated placental
inflammation and caused increased levels of parasitemia and
increased selective pressure for drug-resistant infections (Harrington
et al., 2009). Thus, there is a clear need to identify alternative intermittent
preventive treatment regimens. Generally, one can anticipate
that, in the absence of novel antifolates effective against existing drugresistant
strains, the use of these antimalarials for either prevention or
treatment will continue to decline.
TETRACYCLINES AND OTHER
ANTIBIOTIC AGENTS
Tetracyclines are a group of antibiotic agents initially derived from
Streptomyces. The pharmacological properties of tetracyclines are
presented in Chapter 55. Two members of this group, tetracycline
and doxycycline, are useful in malaria treatment. In addition, clindamycin,
a lincosamide antibiotic (Chapter 55), is also recommended.
These agents are slow-acting blood schizonticides that can be
used alone for short-term chemoprophylaxis in areas with chloroquineand
mefloquine-resistant malaria (only doxycycline is recommended
for malaria chemoprophylaxis). All of these antibiotics act via a
delayed death mechanism resulting from their inhibition of protein
translation in the parasite plastid. This effect on malarial parasites
manifests as death of the progeny of drug-treated parasites, resulting
in slow onset of antimalarial activity (Dahl and Rosenthal, 2008).
Their relatively slow mode of action makes these drugs ineffective
as single agents for malaria treatment. However, their efficacy as
treatment is increased when they are used as an adjunct to quinine,
quinidine, or artesunate, and in this context, they can be used to treat
uncomplicated or severe P. falciparum malaria. These antibiotics are
not clinically used to eliminate liver stage infection.
Dosage regimens for tetracyclines and clindamycin are listed
in Tables 49–2 and 49–3. Because of their adverse effects on bones