Liver continuous intravenous infusion

Argatroban is a small molecule thrombin inhibitor that is FDA-approved for use in patients with HIT with or without thrombosis and coronary angioplasty in patients with HIT. It, too, has a short half-life, is given by continuous intravenous infusion, and is monitored by aPTT. Its clearance is not affected by renal disease but is dependent on liver function dose reduction is required in patients with liver disease. Patients on argatroban will demonstrate elevated INRs, rendering the transition to warfarin difficult (ie, the INR will reflect contributions from both warfarin and argatroban). (INR is discussed in detail in the discussion of warfarin administration.) A nomogram is supplied by the manufacturer to assist in this transition. 

A 70-year-old patient with a metastatic carcinoid tumor of the liver presented with a hypertensive crisis after being given pethidine 10 mg/hour by continuous intravenous infusion (4). The patient remained hypertensive with a systolic blood pressure of 210 mmHg, even after chemoembolization of the tumor. The blood pressure... 

The drug is metabolized rapidly in the liver, kidney, intestinal mucosa, and even red blood cells. Therefore it has a plasma half-life of only 10 min after bolus intravenous application. The major metabolite, uracil arabinoside (ara-U), can be detected in the blood shortly after cytarabine administration. About 80% of the dose is excreted in the urine within 24 h, with less than 10% appearing as cytarabine the remainder is ara-U. After continuous infusion, cytarabine levels in the liquor (cerebro-spinal fluid) approach 40% of that in plasma. Continuous infusion schedules allow maximal efficiency, with uptake peaks of 5-7 pM. It can be administered intrathecally as an alternative to methotrexate. 

In addition to the usual intravenous or oral routes, some anticancer agents have been administered by regional intraarterial perfusion to increase drug delivery to the tumor itself and at the same time diminish systemic toxicity. Thus, patients with metastatic carcinomas of the liver and little or no disease elsewhere (a common occurrence in colorectal cancer) can be treated with a continuous infusion of fluorouracil or floxuridine through a catheter implanted in the hepatic artery. 

In the clinical setting, anthracyclines are administered via the intravenous route (Table 55 1). The anthracyclines are metabolized extensively in the liver, with reduction and hydrolysis of the ring substituents. The hydroxylated metabolite is an active species, whereas the aglycone is inactive. Up to 50% of drug is eliminated in the feces via biliary excretion, and for this reason dose reduction is required in the setting of liver dysfunction. Although anthracyclines are usually administered on an every-3-week schedule, alternative schedules of administration such as low-dose weekly or 72-96 hour continuous infusions have been shown to yield equivalent clinical efficacy with reduced overall toxicity. 

Further studies have validated this hypothesis, in part,4 and ultimately this inventive premise was borne out in clinical practice. As a result, 5-FU (5) was eventually approved for treatment of solid tumors, such as breast, colorectal, and gastric cancers. Marketed as Adrucil when administered intravenously, 5-FU can be used either as monotherapy or combination therapy with various cytotoxic drugs and biochemical modulators, such as leucovorin and methotrexate.5 Because 5-fluorouracil is not orally bioavailable, it must be administered by continuous infusion to optimize its efficacy due to its short half-life in plasma. In addition, 5-FU has poor selectivity toward tumors in vivo, and its distribution into tissues such as bone marrow, the gastrointestinal tract, the liver and skin causes high incidences of toxicity. In addition, in spite of its limited lipid solubility, 5-fluorouracil diffuses readily across the blood-brain barrier into cerebrospinal fluid and brain tissue.1,5... 

An example of this approach can be obtained by continuing the theophylline patient case from the section on drug dosing in liver disease. In this example, a 55-year-old, 70-kg man with liver cirrhosis was prescribed a loading dose of theophylline 350 mg intravenously over 20 to 30 minutes, followed by a maintenance dose of 15 mg/h of theophylline as a continuous infusion. The infusion began at 9 A.M., blood samples were obtained at 10 A.M. and 4 P.M., and the clinical laboratory reported the theophylline serum concentrations as 10.9 and 12.3 mg/L, respectively. The patient s theophylline clearance and revised continuous infusion to maintain a Css of 15 mg/L can be computed as follows (patient s Vo estimated at 0.5 L/kg) ... 

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