McKenna's Pharmacology for Nursing, 2e

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C H A P T E R 1 4  Antineoplastic agents

Pharmacokinetics Methotrexate is absorbed well from the GI tract and is excreted unchanged in the urine. People with renal impairment may require reduced dose and increased monitoring when taking methotrexate. Methotrexate readily crosses the blood–brain barrier. Cytarabine, clofarabine, colaspase, fluorouracil, gemcitabine and pemetrexed are not absorbed well from the GI tract and need to be administered parenterally. They are metabo­ lised in the liver and excreted in the urine, necessitating close monitoring of individuals with hepatic or renal impairment who are receiving these drugs. Mercapto­ purine and thioguanine are absorbed slowly from the GI tract and are metabolised in the liver and excreted in the urine. Contraindications and cautions Antimetabolites are contraindicated for use during pregnancy and breastfeeding because of the potential for severe effects on the fetus and neonate . Caution is necessary when administering antimetabolites to any individual with a known allergy to any of them; with bone marrow suppression, which is often the index for redosing and dosing levels ; with renal or hepatic dys­ function, which might interfere with the metabolism or excretion of these drugs and often indicates a need to change the dose ; and with known GI ulcerations or ulcerative diseases that might be exacerbated by the effects of these drugs. Adverse effects Adverse effects frequently encountered with the use of the antimetabolites are listed here. To counteract the effects of treatment with one antimetabolite—metho­ trexate—the drug Leucovorin is sometimes given (see Box 14.6). Leucovorin (calcium folinate) is an active form of folic acid that is used to “rescue” normal cells from the adverse effects of methotrexate therapy in the treatment of osteosarcoma. This drug is also used to treat folic acid deficiency conditions such as sprue, nutritional deficiency, pregnancy and breastfeeding. Leucovorin is given orally or intravenously at the time of methotrexate therapy and for the next 72 hours at a dose of 12 to 15 g/m 2 PO or IV followed by 10 mg/m 2 PO q 6 hours for 72 hours. Use of this drug has been associated with pain at the injection site. ■■ BOX 14.6  A drug that protects against an antimetabolite

Haematological effects include bone marrow sup­ pression, with leucopenia, thrombocytopenia, anaemia and pancytopenia, secondary to the effects of the drugs on the rapidly multiplying cells of the bone marrow. Toxic GI effects include nausea, vomiting, anorexia, diarrhoea and mucous membrane deterioration, all of which are related to drug effects on the rapidly multiply­ ing cells of the GI tract. CNS effects include headache, drowsiness, aphasia, fatigue, malaise and dizziness. People should be advised to take precautions if these conditions occur. There is a risk of pulmonary toxicity, including interstitial pneumonitis with these drugs. As with alkylating agents, effects of the antimetabolites may include possible hepatic or renal toxicity, depending on the exact mechanism of action. Alopecia may also occur. Clinically important drug–drug interactions Antimetabolites that are known to cause hepatic or renal toxicity should be used with care with any other drugs known to have the same effect. In addition, drugs that are toxic to the liver may adversely affect drugs that are metabolised in the liver or that act in the liver (e.g. oral anticoagulants). Check for specific drug–drug interactions for each agent in a drug guide. Prototype summary: Methotrexate Indications: Treatment of gestational choriocarcinoma, chorioadenoma destruens, hydatidiform, meningeal leukaemia; symptomatic control of severe psoriasis; rheumatoid arthritis; juvenile rheumatoid arthritis. Actions: Inhibits folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication; affects the most rapidly dividing cells. Pharmacokinetics: Route Onset Peak Oral Varies 1–4 hours Intravenous Rapid 0.5–2 hours T 1/2 : 2–4 hours, excreted unchanged in the urine. Adverse effects: Fatigue, malaise, rashes, alopecia, ulcerative stomatitis, hepatic toxicity, severe bone marrow suppression, interstitial pneumonitis, chills, fever, anaphylaxis.