This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.AScites is one of the major complications of cirrhosis and its usual treatment consists of sodium restricted diet and diuretics. The usual diuretic regimen consists of a combination of spironolactone and furosemide. This is effective in majority of the patients; however, some become resistant to such therapy and pose a therapeutic challenge. There have been several efforts to develop methods to alleviate resistance to loop diuretics in various fluid retentive states (e.g. intravenous albumin administration in cirrhosis or sulfisoxazole in nephrotic syndrome). Previous studies have demonstrated that diminished glomerular filtration rate (GFR) is one of the mechanisms for diuretic resistance to loop diuretics in patients with cirrhotic ascites. It recently has been demonstrated that midodrine, and alpha-1 agonist, can improve the GFR in non-azotemic cirrhotics with ascites. Based on this background, we hypothesize that midodrine co-administration enhances the efficacy of furosemide in patients with cirrhotic ascites through its effects on pharmacokinetics and pharmacodynamics of the furosemide and/or the renal hemodynamics. We propose a randomized, two phased, crossover study of cirrhotics with ascites to assess whether midodrine co-administration enhances the response to furosemide. Two phases are (a) furosemide 40 mg intravenously + midodrine 15 mg orally (b) furosemide 40 mg + oral placebo. We will measure the effect of midodrine co-administration on the response to furosemide (urinary volume and sodium excretion), the pharmacokinetics (elimination of half-life, V d, serum clearance) and pharmacodynamics (by relating the excretion rate of furosemide to the excretion rate by biothalamate clearance). This study will examine the effects of midodrine co-administration on the pharmacokinetics of furosemide, and the renal hemodynamics in patients with cirrhotic ascites.
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