Page 870 - Basic _ Clinical Pharmacology ( PDFDrive )

856 SECTION VIII Chemotherapeutic Drugs

A. Infusion-Related Toxicity compartments, including the cerebrospinal fluid. It is eliminated
Infusion-related reactions are nearly universal and consist of fever, by glomerular filtration with a half-life of 3–4 hours and is
chills, muscle spasms, vomiting, headache, and hypotension. They removed by hemodialysis. Levels rise rapidly with renal impair-
can be ameliorated by slowing the infusion rate or decreasing ment and can lead to toxicity. Toxicity is more likely to occur
the daily dose. Premedication with antipyretics, antihistamines, in AIDS patients and those with renal insufficiency. Peak serum
meperidine, or corticosteroids can be helpful. When starting ther- concentrations should be measured periodically in patients with
apy, many clinicians administer a test dose of 1 mg intravenously renal insufficiency and maintained between 50 and 100 mcg/mL.
to gauge the severity of the reaction. This can serve as a guide to
an initial dosing regimen and premedication strategy. Mechanisms of Action & Resistance
Flucytosine is taken up by fungal cells via the enzyme cytosine
B. Cumulative Toxicity permease. It is converted intracellularly first to 5-FU and then to
Renal damage is the most significant toxic reaction. Renal impair- 5-fluorodeoxyuridine monophosphate (FdUMP) and fluorouridine
ment occurs in nearly all patients treated with clinically significant triphosphate (FUTP), which inhibit DNA and RNA synthesis,
doses of amphotericin. The degree of azotemia is variable and respectively (Figure 48–1). Human cells are unable to convert the
often stabilizes during therapy, but it can be serious enough to parent drug to its active metabolites, resulting in selective toxicity.
necessitate dialysis. A reversible component is associated with Synergy with amphotericin B has been demonstrated in vitro
decreased renal perfusion and represents a form of prerenal renal and in vivo. It may be related to enhanced penetration of the flu-
failure. An irreversible component results from renal tubular cytosine through amphotericin-damaged fungal cell membranes.
injury and subsequent dysfunction. The irreversible form of In vitro synergy with azole drugs also has been seen, although the
amphotericin nephrotoxicity usually occurs in the setting of mechanism is unclear.
prolonged administration (>4 g cumulative dose). Renal toxicity Resistance is thought to be mediated through altered metabo-
commonly manifests as renal tubular acidosis and severe potas- lism of flucytosine, and, although uncommon in primary isolates,
sium and magnesium wasting. There is some evidence that the it develops rapidly in the course of flucytosine monotherapy.
prerenal component can be attenuated with sodium loading, and
it is common practice to administer normal saline infusions with Clinical Uses & Adverse Effects
the daily doses of amphotericin B.
Abnormalities of liver function tests are occasionally seen, as is The spectrum of activity of flucytosine is restricted to C neofor-
a varying degree of anemia due to reduced erythropoietin produc- mans, some Candida sp, and the dematiaceous molds that cause
tion by damaged renal tubular cells. After intrathecal therapy with chromoblastomycosis. Flucytosine is rarely used as a single agent
amphotericin, seizures and a chemical arachnoiditis may develop, because of its demonstrated synergy with other agents and to
often with serious neurologic sequelae. avoid the development of secondary resistance. At present clinical
use is confined to combination therapy with amphotericin B for
FLUCYTOSINE cryptococcal meningitis, or with itraconazole for chromoblasto-
mycosis. Flucytosine also has limited utility as monotherapy for
Chemistry & Pharmacokinetics fluconazole-resistant candidal urinary tract infections.
The adverse effects of flucytosine result from metabolism (pos-
Flucytosine (5-FC) was discovered in 1957 during a search for sibly by intestinal flora) to the toxic antineoplastic compound
novel antineoplastic agents. Though devoid of anti-cancer prop- fluorouracil. Bone marrow toxicity with anemia, leukopenia,
erties, it became apparent that it is a potent antifungal agent. and thrombocytopenia are the most common adverse effects,
Flucytosine is a water-soluble pyrimidine analog related to the with derangement of liver enzymes occurring less frequently. A
chemotherapeutic agent 5-fluorouracil (5-FU). Its spectrum of form of toxic enterocolitis can occur. There seems to be a narrow
action is much narrower than that of amphotericin B. therapeutic window, with an increased risk of toxicity at higher
drug levels and resistance developing rapidly at subtherapeutic
H
concentrations. The use of drug concentration measurements may
N
O be helpful in reducing the incidence of toxic reactions, especially
when flucytosine is combined with nephrotoxic agents such as
N amphotericin B.
F
NH 2
Flucytosine AZOLES
Chemistry & Pharmacokinetics
Flucytosine is currently available in North America only in an
oral formulation. The dosage is 100 mg/kg/d in divided doses in Azoles are synthetic compounds that can be classified as either
patients with normal renal function. It is well absorbed (>90%), imidazoles or triazoles according to the number of nitrogen
with serum concentrations peaking 1–2 hours after an oral dose. atoms in the five-membered azole ring, as indicated below. The
It is poorly protein-bound and penetrates well into all body fluid imidazoles consist of ketoconazole, miconazole, and clotrimazole