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

lungs depends on both the size of particles generated by the nebulizer
and the patient’s ventilatory patterns.
Therapeutic Uses. Pentamidine isethionate is used for the treatment
of early-stage T. brucei gambiense and is given by intramuscular
injection in single doses of 4 mg/kg per day for 7 days. Pentamidine
has been used successfully in courses of 15-20 intramuscular doses
of 4 mg/kg every other day to treat visceral leishmaniasis (Alvar
et al., 2006). This compound provides an alternative to antimonials,
lipid formulations of amphotericin B, or miltefosine but it is overall
the least well tolerated of the available therapies and is not used routinely
for this disease. Pentamidine isethionate given as 4-7 intramuscular
doses of 4 mg/kg every other day has enjoyed some
success in the treatment of cutaneous leishmaniasis (Oriental sore
caused by L. tropica) but is not used routinely to treat this infection
(Alvar et al., 2006).
Pentamidine is one of several drugs or drug combinations
used to treat or prevent Pneumocystis infection. Pneumocystis pneumonia
(PCP) is a major cause of mortality in individuals with HIV
infection and AIDS and can occur in patients who are immunosuppressed
by other mechanisms (e.g., high-dose corticosteroids or
underlying malignancy). The availability of highly active antiretroviral
therapy (HAART) has reduced the number of cases of PCP
significantly within the U.S. and E.U. and greatly reduced the number
of individuals requiring prophylaxis for PCP. Trimethoprimsulfamethoxazole
is the drug of choice for the treatment and
prevention of PCP (Chapter 52). Pentamidine is reserved for two
indications. Pentamidine given intravenously as a 4 mg/kg single
daily dose for 21 days is used to treat severe PCP in individuals who
cannot tolerate trimethoprim-sulfamethoxazole and are not candidates
for alternative agents such as atovaquone or the combination
of clindamycin and primaquine. Pentamidine has been recommended
as a “salvage” agent for individuals with PCP who failed to
respond to initial therapy (usually trimethoprim-sulfamethoxazole),
but a meta-analysis suggested that pentamidine is less effective than
other therapies (specifically the combination of clindamycin and
primaquine or atovaquone) for this indication (Smego et al., 2001).
Pentamidine administered as an aerosol preparation is used for the
prevention of PCP in at-risk individuals who cannot tolerate
trimethoprim-sulfamethoxazole and are not deemed candidates for
either dapsone (alone or in combination with pyrimethamine) or
atovaquone. Candidates for PCP prophylaxis are individuals with
HIV infection and a CD4 count of <200/mm 3 and individuals with
HIV infection and persistent unexplained fever or oropharyngeal
candidiasis. Secondary prophylaxis is recommended for everyone
with a documented PCP episode. For prophylaxis, pentamidine
isethionate is given monthly as a 300-mg dose in a 5-10% nebulized
solution over 30-45 minutes. Although the monthly dosage
regimen is convenient, aerosolized pentamidine has several disadvantages,
including its failure to treat any extrapulmonary sites of
Pneumocystis, the lack of efficacy against any other potential opportunistic
pathogens (compared with trimethoprim-sulfamethoxazole),
and a slightly increased risk for pneumothorax. Long-term
aerosolized pentamidine prophylaxis (≥5 years) has not been associated
with the development of any pulmonary disease (Obaji et al.,
2003). For individuals who receive HAART and develop CD4
counts persistently above 200/mm 3 for 3 months, primary or secondary
PCP prophylaxis can be stopped.
Toxicity and Side Effects. Pentamidine is a toxic agent, and ~50% of
individuals receiving the drug at recommended doses (4 mg/kg per
day) show some adverse effect. Intravenous administration of pentamidine
may be associated with hypotension, tachycardia, and
headache. These effects are probably secondary to the ability of
pentamidine to bind imidazoline receptors (Chapter 14) and can be
ameliorated by slowing the rate of the intravenous infusion (Wood
et al., 1998). As noted earlier, the diamidines were designed originally
for use as hypoglycemics, and pentamidine retains that property.
Hypoglycemia, which can be life threatening, may occur at
any time during pentamidine treatment, even weeks into therapy.
Careful monitoring of blood sugar is key. Paradoxically, pancreatitis,
hyperglycemia, and the development of insulin-dependent diabetes
have been seen in some patients. Pentamidine is nephrotoxic
(~25% of treated patients show signs of renal dysfunction), and if
the serum creatinine concentration rises >1.0-2.0 mg/dL, it may be
necessary to withhold the drug temporarily or change to an alternative
agent. Individuals developing pentamidine-induced renal dysfunction
are at higher risk for hypoglycemia. Other adverse effects
include skin rashes, thrombophlebitis, anemia, neutropenia, and elevation
of hepatic enzymes. Intramuscular administration of pentamidine,
while effective, is associated with the development of
sterile abscesses at the injection site, which can become infected
secondarily. For this reason, most authorities recommend intravenous
administration. Aerosolized pentamidine is associated with
few adverse events.
Quinacrine
Quinacrine is an acridine derivative used widely during World War II
as an antimalarial agent. Quinacrine hydrochloride is very effective
against G. lamblia, producing cure rates of at least 90%. However,
quinacrine is no longer available in the U.S. For a description of the
pharmacology and toxicology of quinacrine, consult the fifth and
earlier editions of this book.
Sodium Stibogluconate
Antimonials were introduced in 1945 and have been
used for therapy of leishmaniasis and other protozoal
infections (Alvar et al., 2006; Croft, 2008; Olliaro et al.,
2005). The first trivalent antimonial compound used to
treat cutaneous leishmaniasis and kala azar was antimony
potassium tartrate (tartar emetic), which was both
toxic and difficult to administer. Tartar emetic and other
trivalent arsenicals eventually were replaced by pentavalent
antimonial derivatives of phenylstibonic acid.
An early member of this family of compounds was
sodium stibogluconate (sodium antimony gluconate,
PENTOSTAM). This drug is used widely today and,
together with meglumine antimonate (GLUCANTIME), a
pentavalent antimonial compound preferred in Frenchspeaking
countries, has been the mainstay of the treatment
of leishmaniasis. However, increasing resistance
to antimonials has reduced their efficacy and they are
no longer useful in India (Croft, 2008; Croft et al.,
1435
CHAPTER 50
CHEMOTHERAPY OF PROTOZOAL INFECTIONS