5-fluorouracil adverse effects

Fluorouracil is a pyrimidine analogue (see Chapter 27, Section II.b.3). Topical application may be used for malignant and premalignant skin conditions, including actinic keratosis. Adverse effects include local inflammatory and allergic reactions. Photosensitivity reactions during and for up to 2 months after treatment may become manifest. 

Flucytosine is converted into the anti metabolite 5-fluorouracil that inhibits thymidilate synthetase, thereby disrupting DNA synthesis. It also interferes with protein synthesis by incorporation of fluorouracil into RNA in place of uracil. Although active against most Candida species, its spectrum of antifungal activity, overall, is narrow. Since resistance can develop rapidly it is usually coadministered with another agent and its main value is that it facilitates a reduction in the dose (and, presumably, the toxic effect) of amphotericin when co-prescribed in this way. The main adverse effects are marrow aplasia and hepatotoxicity. 

There have been attempts to unravel the mechanism of fluorouracil-induced hyperammonemia, lactic acidosis, and encephalopathy, a rare adverse effect associated with high-dose therapy. The cause is not known, although Krebs cycle metabolism is almost certainly involved (415,416). 

Fentanyl Care should be taken to avoid skin contact and inhalation of fentanyl citrate to prevent adverse effects. Incompatibility has been reported with other drugs such as thiopentone sodium, methohexitone sodium, and fluorouracil.54 This drug should not be administered along with alkaline drugs. 

Flucytosine (5-fluorocytosine) is metabolised in the fungal cell to 5-fluorouracil which inhibits nucleic acid synthesis. It is weU absorbed from the gut, penetrates effectively into tissues and almost all is excreted unchanged in the urine (t) 4 h). The dose should be reduced for patients with impaired renal function, and the plasma concentration should be monitored. The drug is well tolerated when renal function is normal. Candida albicans rapidly becomes resistant to flucytosine which ought not to be used alone it may be combined with amphotericin (see Table 14.2) but this increases the risk of adverse effects (leucopenia, thrombocytopenia, enterocolitis) and it is reserved for serious infections where the risk-benefit balance is favourable (e.g. Cryptococcus neoformans meningitis). 

Fluorouracil-containing regimens have been linked with several ocular adverse effects, including marked lacri-mation, ocular pruritus, and a burning sensation in the eyes (60). 

Striate melanokeratosis of the retina has been associated with 5-fluorouracil in reports from a number of centers there has been no consistent explanation of the pathogenesis of this adverse effect (61-63). 

Cases of deliberate overdosage are unknown, but excessive duration or dosage of therapy will produce life-threatening toxicity because of the hematological effects and other symptoms and signs that are qualitatively similar to the adverse effects. There is no specific antidote to fluorouracil toxicity treatment consists of supportive care, including G-CSF and antidiarrheal agents. 

Reduced folates are co-factors for the 5-fluorodeoxy-uridine monophosphate-thymidilate synthetase reaction. Leucovorin (calcium fohnate) therefore potentiates the toxicity of 5-fluorouracil, and fatal adverse effects have been reported in patients over 65 years of age receiving high-dose treatment with leucovorin simultaneously with fluorouracil. This has led some groups to recommend that initial dose levels of fluorouracil should be lowered by 20% and that therapy be stopped temporarily at the first sign of distal gastrointestinal adverse effects (SEDA-15, 414). 

The efficacy of levamisole has been studied in several studies of patients with colorectal carcinoma (13-15). In a phase III trial 5-fluorouracil alone, 5-fluorouracil with levamisole, and 5-fluorouracil with hepatic irradiation have been compared in patients with residual, non-measurable, intra-abdominal metastases after resection of colorectal carcinoma (13). The adverse effects were as expected, and there were no differences between any of the treatments. The main adverse effects were hematological and gastrointestinal. However, analysis of life-threatening adverse effects showed some slight differences there were fewer than expected in the 5-fluorouracil alone group, and more than expected in the 5-fluorouracil plus hepatic irradiation group. There was no treatment advantage for any of the combinations over 5-fluorouracil alone. 

QUASAR was a study of the effects of a higher dose of leucovorin or the addition of levamisole to 5-fluorouracil and leucovorin on survival in 4927 patients with colorectal cancer with no evidence of residual disease after resection (14). High-dose leucovorin was not associated with a survival or recurrence benefit compared with low-dose leucovorin. The addition of levamisole had no apparent survival benefit compared with placebo, with slightly more deaths in patients assigned to levamisole than placebo. Tumor recurrences were also higher in those who took levamisole. Dermatological adverse effects were significantly more frequent in those who took levamisole compared with placebo. 

Adverse effects of fluorouracil are less likely, but similar to methotrexate. 

Irinotecan is a prodrug that is converted mainly in the liver by the carboxylesterase enzyme to the SN-38 metabolite, which is 1000-fold more potent as an inhibitor of topoisomerase I than the parent compound. In contrast to topotecan, irinotecan and SN-38 are mainly eliminated in bile and feces, and dose reduction is required in the setting of liver dysfunction. Irinotecan was originally approved as second-line monotherapy in patients with metastatic colorectal cancer who had failed fluorouracil-based therapy. It is now approved as first-line therapy when used in combination with 5-FU and leucovorin. Myelosuppression and diarrhea are the two most common adverse events. There are two forms of diarrhea an early form that occurs within 24 hours after administration and is thought to be a cholinergic event effectively treated with atropine, and a late form that usually occurs 2-10 days after treatment. The late diarrhea can be severe, leading to significant electrolyte imbalance and dehydration in some cases. 

Approximately 6% of a topically applied dose is absorbed—an amount insufficient to produce adverse systemic effects. Most of the absorbed drug is metabolized and excreted as carbon dioxide, urea, and ct-fluoro-B-alanine. A small percentage is eliminated unchanged in the urine. Fluorouracil inhibits thymidylate synthetase activity, interfering with the synthesis of DNA and, to a lesser extent, RNA. These effects are most marked in atypical, rapidly proliferating cells. 

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