Effects of clonidine on diuretic response in ascitic patients with cirrhosis and activation of sympathetic nervous system†‡

Abstract

The effects of the addition of clonidine to diuretics on the mobilization of ascites in the short term (diuretic response and requirement of diuretics) and the long term (readmissions for tense ascites and requirement of diuretics) were examined in patients with cirrhosis and with increased sympathetic nervous system (SNS) activity. We also studied neurohormonal, hemodynamic effects and side effects of clonidine and diuretics. Patients were randomized to receive placebo (group1, n ‫؍‬ 32) or clonidine (0.075 mg) twice daily (group 2, n ‫؍‬ 32) for 3 months. After 8 days and for 10 days duration, spironolactone (200 mg/day) was added in both groups. After this period, the dosages of diuretics were individually increased until diuretic response. Responding patients were discharged and followed at the outpatient clinic. During the first hospitalization, the time needed for diuretic response was shorter in group 2 than in group 1. The mean requirement for diuretics was significantly higher in group 1 than in group 2, and the diuretic complications (hyperkalemia and renal impairment) were significantly lower in group 2. Clonidine induced a permanent decrease in SNS activity and delayed decrease in renin/aldosterone levels. During the follow-up, the time to the first readmission for tense ascites was shorter in group 1 than in group 2. Readmissions related to tense ascites or diuretic complications were significantly lower in group 2. The mean requirement for diuretics was significantly higher in group 1 than in group 2. In conclusion, the additional administration of clonidine to diuretics induced an earlier diuretic response associated with fewer diuretic requirements and complications. T he mechanisms leading to renal sodium retention in cirrhosis are not fully understood. Splanchnic arterial vasodilatation associated with portal hypertension induces a reduction in effective blood volume and permanent activation of antinatriuretic and vasoconstrictive mechanisms (stimulation of renin/aldosterone and sympathetic systems, vasopressin secretion). 1 The sympathetic nervous system (SNS) contributes to renal hypoperfusion and sodium retention. The activated SNS stimulates renal ␣ 1 -adrenoreceptors and causes decreases in renal blood flow and glomerular filtration rate. Additionally, norepinephrine increases proximal tubular reabsorption of sodium and enhances renin, aldosterone, and vasopressin secretions. 2, 3 We recently showed that in patients with cirrhosis and ascites, the marked activation of SNS and renin/aldosterone axis reduced diuretic response. 4 Consequently, inhibitions of SNS activity and renin/aldosterone system would improve diuretic response.Clonidine, a centrally acting ␣ 2 -agonist, has been shown to offer sympatholytic activity in patients with arterial hypertension or cirrhosis. [5][6][7][8] Co-administration of clonidine and spironolactone has been shown to increase natriuresis and body weight loss more efficiently than spironolactone alone in patients with cirrhosis and ascites and activated SNS i...

What’s new in the treatment of ascites and spontaneous bacterial peritonitis

“…First is the combination of diuretics with drugs that improve the circulatory function or suppress the increased activity of antinatriuretic systems. In this regard, a recent study showed that the combination of diuretics with oral clonidine (0.75 mg twice daily), a drug that suppresses the activity of the sympathetic nervous system (which is markedly increased in patients with refractory ascites), led to a more rapid mobilization of ascites with fewer complications than placebo in patients with cirrhosis, ascites, and a plasma norepinephrine level greater than 300 pg/mL [17]. In another study, the administration of oral midodrine (an alpha-1 adrenergic agonist), 10 mg three times daily for 7 days, to patients with cirrhosis and ascites was associated with increased natriuresis and glomerular filtration rate and improvement in circulatory function with suppression of antinatriuretic systems (ie, renin-angiotensin-aldosterone system) [18].…”

Ascites

“…Clonidine, a centrally acting α 2 -agonist and sympatholitic agent, was evaluated as an adjunct treatment in patients with cirrhosis and ascites. In a randomized study, oral clonidine (0.075 mg, two times daily) led to a more rapid mobilization of ascites with fewer complications than placebo in patients with cirrhosis, ascites, and a plasma norepinephrine level of >300 pg/ mL [75]. This medication was also evaluated in a randomized study of clonidine plus diuretics versus diuretics alone which showed that the highest efficacy was obtained in patients who had high serum levels of norepinephine and the presence of two specificgenetic polymorphisms that predicted clonidine response in cirrhotic patients [76].…”

Drug therapies in liver disease

“…In a randomised controlled trial, clonidine combined with spironolactone was more effective than spironolactone alone, with a more rapid clinical response and reduced diuretic requirement. 13 Adverse effects include postural hypotension, dry mouth, fatigue, drowsiness and erectile dysfunction.…”