what medication is used to lower ammonia levels

Therap Adv Gastroenterol. 2011 May; 4(3): 199–206.

Rifaximin treatment for reduction of risk of overt hepatic encephalopathy recurrence

Abstract

Hepatic encephalopathy (HE) is a common problem in patients with chronic liver affliction and is characterized past diminished mentation and neuromuscular abnormalities. Symptoms range from subtle cognitive changes to blackout and death. Gut-derived toxins such as ammonia are thought to play a central part in the pathogenesis of HE. Handling strategies are directed at increased emptying or reduction of gut-derived ammonia in add-on to correction of dynamic atmospheric condition that provoke bouts of HE. The standard of intendance for treatment of acute HE is lactulose, a nonabsorbable disaccharide that is thought to increase elimination and reduce absorption of ammonia. Although lactulose seems to work in the astute setting, the charge per unit of recurrent HE on maintenance lactulose is high. Medications have been sought that reduce the rate of recurrent HE in patients at high risk for HE but none have been identified. Rifaximin is a poorly absorbed antibiotic that is idea to reduce ammonia product by eliminating ammonia-producing colonic leaner. Many small studies have suggested that rifaximin is constructive in treating astute HE and is extremely well tolerated. This led to a randomized, placebo-controlled, multicenter, multinational trial investigating the efficacy of rifaximin over a 6-month period in reducing the risk of recurrent HE in patients at baseline, but with a history of at least two bouts of acute HE in the previous 6 months prior to enrollment. Lactulose could be administered at the discretion of the investigator. A total of 299 patients were randomized to receive rifaximin or placebo; 91% of patients in each grouping received lactulose. Compared with placebo, patients at high take a chance for recurrent HE in the rifaximin group had highly statistically significant reductions in bouts of astute HE (58%) and reductions in hospitalizations related to HE (50%) over a 6-calendar month period. The medication was well tolerated with a side-event profile comparable to placebo. This led to the approval of rifaximin for reduction of take a chance of recurrent HE by the US Food and Drug Administration in March 2010. It is recommended that patients with a history of recurrent acute HE should be maintained on rifaximin with or without lactulose to reduce the risk of recurrent HE and related hospitalization.

Keywords: ammonia, cirrhosis, hepatic encephalopathy, lactulose, rifaximin

Introduction

Overt hepatic encephalopathy (HE) is a common complication of chronic liver affliction, occurring in 30–45% of patients with cirrhosis [Poordad, 2007]. It is characterized by a spectrum of clinical manifestations that are potentially reversible, including changes in mentation and neuromuscular abnormalities. Symptoms range from balmy cerebral abnormalities to blackout and decease [Ferenci et al. 1998]. The pathogenesis remains incompletely understood, although gut-derived toxins such as ammonia are thought to play a cardinal part. Not merely is HE difficult to manage and treat, information technology is besides associated with increased mortality. Management strategies consist of identifying and treating precipitating factors and reducing the effects of gut-derived toxins. Many therapeutic alternatives are available for handling of acute HE, although the failure rate of therapy is high.

Rifaximin is a poorly absorbed antibody that has been used to treat astute HE. A recent randomized, placebo-controlled, multicenter, multinational trial supports the administration of rifaximin to prevent recurrent bouts of HE in patients at high gamble for HE.

Pathogenesis

The pathophysiology of HE remains incompletely understood despite decades of study. Ammonia, a gut-derived nitrogenous toxin, is thought to play a central role [Keiding et al. 2006]. Gut-derived nitrogenous toxins reach the systemic circulation from the portal venous apportionment as a issue of impaired liver function and portal-systemic shunting that is present in the setting of portal hypertension. Ammonia is taken up past astrocytes in the encephalon and combined with glutamate. Glutamine is produced causing astrocyte swelling that, in turn, is thought to atomic number 82 to the symptomatic presentation of HE. Ammonia lonely, however, does not account for the evolution of HE. Inflammatory mediators are as well thought to play a role [Shawcross et al. 2004]. Oxidative stress, endogenous opioids and/or benzodiazepine-like ligands, gamma-aminobutyric acid-like molecules, abnormal histamine and serotonin neurotransmission, and manganese toxicity have besides been implicated [Cordoba and Blei, 2007].

Classification and grading

HE is characterized by a spectrum of both neurocognitive and neuromuscular abnormalities. Three categories of HE have been proposed (Tabular array one) [Ferenci et al. 1998]. Type C is the category associated with cirrhosis and portal hypertension and is the patient group discussed in this manuscript.

Table one.

Type A: HE associated with acute liver failure

Type B: HE associated with portosystemic bypass and no intrinsic liver disease

Type C: HE associated with cirrhosis and portal hypertension

Neurocognitive abnormalities are graded on a clinical ground past the Due west Haven criteria (also known as the Conn score) (Table 2) [Conn, 1994]. Clinical manifestations range from impaired retentiveness, poor concentration, and subtle changes in personality to languor, confusion, gross disorientation and coma. Neuromuscular manifestations include asterixis, slow monotonous speech, loss of fine motor skills and hyperreflexia in milder cases to decorticate and decerebrate posturing in severe cases [Mullen, 2007].

Table 2.

Class 0

Lack of detectable changes in personality or behavior

No asterixis

Form 1

Trivial lack of sensation, shortened attention span, sleep disturbance, and contradistinct mood

Asterixis may exist present

Grade two

Sluggishness, disorientation to time, amnesia of contempo events, impaired simple computations, inappropriate beliefs, slurred spoken language

Asterixis is present

Grade 3

Somnolence, confusion, disorientation to identify, bizarre behavior, clonus, nystagmus, positive Babinski sign

Asterixis usually absent-minded

Grade 4

Coma and lack of verbal, eye, and oral response

Clinical presentation

HE is generally an acute procedure that is reversible. The spectrum of clinical symptoms is broad [Conn and Lieberthal, 1979]. Symptoms may be subtle and include poor short-term memory and concentration or mild confusion. Manifestations may be more than severe and include slurred speech, personality changes, or gross disorientation, and, in life-threatening situations, coma. Asterixis, a flapping tremor, may be observed on physical examination.

Although chronic liver disease and portal hypertension that develop over many years underlie the predisposition to HE, patients may progress from baseline mentation to coma in a matter of minutes. Patients can likewise ameliorate remarkably quickly. This is not considering liver function changes on a moment-to-moment ground. Rather, HE occurs ordinarily because one or more than dynamic precipitating factors increase both the amount and effect of gut-derived nitrogenous toxins such as ammonia. Mutual precipitating factors include aridity and electrolyte abnormalities (perchance exacerbated by diuretic therapy), infection (including spontaneous bacterial peritonitis), upper gastrointestinal bleeding, and psychoactive medications (including narcotics, benzodiazepines, antihistamines and sleeping medications). Identification and correction of possible precipitating factors are critical to the management of acute HE. In addition, attempts to reduce product and assimilation of gut-derived ammonia and facilitate its emptying are central to the treatment of astute HE.

Pharmacological treatment of astute hepatic encephalopathy

There are many pharmacological handling options for astute HE. Strategies include attempts to reduce nitrogen production or absorption from the colon, increase ammonia metabolism, alter neurotransmission, and liver transplantation. Pharmacological therapy that is most commonly administered includes the nonabsorbable dissacharide lactulose and antibiotics.

Lactulose, a nonabsorbable disaccharide, is considered first-line therapy for pharmacological therapy of acute HE. Information technology has been approved for treatment of HE for more than 30 years despite a paucity of stiff data supporting its efficacy [Als-Nielsen et al. 2004]. The machinery of activity of lactulose remains poorly understood. Lactulose is not captivated in the minor bowel because people do not have the disaccharidase that metabolizes the carbohydrate. Lactulose then is bachelor for colonic bacteria that can intermission it down. Postulated mechanisms of activity of lactulose include metabolism by colonic bacteria to fat acids, with consequent decreased pH in the colon. This results in formation of poorly absorbed ammonium ion from ammonia, and therefore decreases overall absorption of ammonia [Mortensen, 1992]. In add-on, lactulose causes changes in the colonic bacterial milieu via its cathartic upshot that favorably impact toxin elimination. Lactulose is poorly tolerated because it has an unpleasant sweet taste, causes flatus, abdominal cramps and is dosed to two to 3 loose bowel movements daily [Fritz et al. 2005]. Not but are many patients noncompliant with the medication, diarrhea is mutual and really may lead to dehydration and cause worsened encephalopathy [Bajaj et al. 2010]. Although many patients seem to benefit from lactulose therapy in the astute setting, it has also been observed on an anecdotal basis that patients maintained on lactulose with a history of HE and who thus are at loftier risk for recurrent HE ofttimes pause through and endure from recurrent bouts.

Antibiotics have been administered in the treatment of HE, ordinarily employed equally second-line therapy. The machinery is thought to relate to decreased colonic deaminating bacteria that produce nitrogenous compounds (i.due east. ammonia) by metabolism of urea. The well-nigh common antibiotics used on a historic ground for HE include neomycin and metronidazole. Neomycin is approved as adjuvant therapy in hepatic coma. Metronidazole is not approved for HE. Neomycin is improve studied than metronidazole [Strauss et al. 1992; Conn et al. 1977]. There are several controlled trials involving neomycin. Almost studies, including those with metronidazole, are modest and uncontrolled. Few support the utilise of either antibiotic for handling of HE. Furthermore, long-term employ of neomycin is express past ototoxicity and nephrotoxicity. Long-term employ of metronidazole is limited by gastrointestinal upset and neurotoxicity.

Rifaximin

Rifaximin is a poorly absorbed, oral antibiotic [Williams and Bass, 2005]. It is derived from rifamycin and has a wide spectrum of activity confronting Gram-positive and Gram-negative, aerobic and anaerobic, enteric bacteria. It is idea to diminish deaminating enteric bacteria to decrease production of nitrogenous compounds that are later on absorbed and cause HE.

Data are available to support the usage of rifaximin in the treatment of acute HE [Sama et al. 2004; Loguercio et al. 2003; Mas et al. 2003; Williams et al. 2000; Bucci and Palmieri, 1993; Massa et al. 1993; Pedretti et al. 1991]. Farther, rifaximin is well tolerated. In fact, rifaximin has been approved for treatment of HE in many countries and was granted orphan drug condition for the treatment of HE in the Us in 1998.

Reduction in risk of recurrent hepatic encephalopathy

Despite the availability of many therapeutic alternatives for the handling of acute HE, the aforementioned therapies are limited past poor efficacy and poor patient compliance due to intolerable side effects. Recurrent bouts of HE that crave evaluation and hospitalization cause a pregnant burden to patients, their families and caregivers besides equally to the healthcare organization. Constructive therapy is sought to decrease the incidence of recurrent HE in a high-adventure population, that is, patients that have had previous bouts of HE.

The number and length of hospitalizations for astute HE were significantly reduced in patients treated with rifaximin in comparison to lactulose [Leevy and Phillips, 2007; Neff et al. 2006]. Since rifaximin has efficacy in the treatment of acute HE and has a favorable side-result profile that lends itself to long-term therapy, a trial was undertaken to examine the result of rifaximin on the reduction of risk of recurrence of HE in a group of patients at high risk.

The efficacy and safe of rifaximin in maintaining remission of HE over 6 months in patients at high gamble were assessed inside the context of a phase 3, randomized, double-bullheaded, placebo-controlled, multicenter, multinational trial [Bass et al. 2010].

Eligible patients

Patients were eligible for enrollment if they were at least eighteen years old and had had at least two episodes of overt HE (Conn score of 2 or more) in the setting of chronic liver disease (cirrhosis or portal hypertension) within six months of screening. Patients must have had a Model for Cease-Stage Liver Disease (MELD) score of 25 or lower. Exclusion criteria included weather known to provoke HE such every bit gastrointestinal haemorrhage, anemia (hemoglobin <viii g/dl), electrolyte abnormalities (sodium, Na < 125 mmol/l), renal insufficiency (creatinine, Cr > 2.0 mg/dl), infection or respiratory insufficiency. A Transjugular Intrahepatic Portosystemic Shunt (TIPS) could exist present, only it could not take been placed or revised within the past 3 months. Patients could not be on daily condom antibiotic therapy at the first. At the time of screening, the patient must accept been in remission as defined by a Conn score of 0 or one.

Objectives

The chief objective was to assess the fourth dimension to the first breakthrough to overt HE as defined by an increase in the Conn score from 0 or i to ii or more, or an increase in the Conn score from 0 to 1 and an increase in the asterixis score of i form.

The key secondary objective was to assess the fourth dimension to the first HE-related hospitalization. Other secondary objectives included time to whatsoever increase from baseline in Conn score, time to any increment from baseline in asterixis course, hateful modify in baseline in fatigue domain scores on the Chronic Liver Disease Questionnaire (CLDQ) at the cease of handling and mean change from baseline in venous ammonia concentration at the finish of treatment.

Methods

Patients were administered rifaximin at a dosage of 550 mg or placebo twice daily for a period of 24 weeks. Patients were withdrawn if a bout of HE occurred. Lactulose usage was non prohibited in the study; rather, information technology was administered at the discretion of the investigator. Lactulose use was strictly monitored throughout. A full of 299 patients were enrolled; 140 received rifaximin and 159 received placebo. The results were analyzed on an intention to treat basis.

Results

Baseline characteristics were similar in the ii groups. Rifaximin treatment yielded a 58% reduction compared with placebo in the risk of breakthrough HE [hazard ratio (Hr) 0.421] (run into Figure 1) [Bass et al. 2010]. A total of 22% of patients in the handling group compared with 46% in the placebo group suffered from recurrent HE over the 24-week treatment course. In fact, benefit was derived in all subgroups assessed, including gender, age, race, region, MELD score, initial Conn score, presence or absence of diabetes, duration of current remission at the first and number of HE episodes prior to enrollment (see Figure 2) [Bass et al. 2010].

An external file that holds a picture, illustration, etc. Object name is 10.1177_1756283X11401774-fig1.jpg

(a) Time to showtime quantum hepatic encephalopathy episode (main endpoint). (b) Fourth dimension to outset hepatic encephalopathy related hospitalization (key secondary endpoint).

An external file that holds a picture, illustration, etc. Object name is 10.1177_1756283X11401774-fig2.jpg

Subgroup cess of response (recurrent encephalopathy) comparing rifaximin and placebo groups.

HE-related hospitalizations were reduced by 50% with rifaximin therapy in comparison to placebo (HR 0.500) (Figure ane) [Bass et al. 2010]. A total of 14% of patients in the rifaximin group in comparison to 24% of patients in the placebo grouping had HE-related hospitalizations. Statistically significant improvements were also observed in Conn score increase from baseline, asterixis course increment from baseline, fatigue domains as measured past the CLDQ and serum venous ammonia levels in favor of rifaximin.

It is of import to annotation that lactulose was given to 91% of patients in both groups. Furthermore, the amount of lactulose used was statistically equivalent in both groups. Therefore, any differences between the groups could not be attributed to differences in the administration of lactulose.

Tolerability

Adverse events were frequently reported in the trial. This is not surprising because it involved patients with advanced liver disease, many of whom were maintained on lactulose. Even so, in that location were no differences in adverse-event profiles in the rifaximin grouping compared with the placebo group. In addition, there was no indication that Clostridium difficile infection was related to the usage of rifaximin in the study (ii cases were reported in the treatment group and cypher in the placebo grouping). In fact, the two patients with C. difficile in the rifaximin group had other risk factors and remained on rifaximin with successful treatment of C. difficile.

There were 20 deaths in the written report (9 in the rifaximin group and eleven in the placebo grouping). None of the deaths were attributed to rifaximin.

Conclusions

Rifaximin at a dosage of 550 mg twice daily was highly effective in diminishing the recurrence of HE and decreasing the rate of HE-related hospitalizations over a 24-week menstruation in a group of patients at loftier run a risk for HE.

Discussion

In a randomized, placebo-controlled, multicenter, multinational trial, the vast bulk of patients in both the rifaximin and placebo groups were maintained on lactulose and usage was monitored closely. In patients at loftier risk of HE recurrence, nearly 50% who were maintained on lactulose and placebo had recurrent HE and nearly 25% had HE-related hospitalization, showing the substantial failure rate of lactulose in preventing recurrent HE in this population. Withal, rifaximin not but significantly reduced recurrent HE and hospitalizations secondary to HE, it was likewise effective when administered with lactulose and was well tolerated. This led to rifaximin existence approved for prevention of recurrent HE past the United states Food and Drug Assistants in March 2010.

This trial confirms that rifaximin is indicated in all patients who accept suffered from recurrent astute HE to decrease the risk of recurrence. Rifaximin was not studied in patients who had just had a single tour of astute HE. However, given the high failure rate of lactulose and the significant success rate of rifaximin in preventing recurrent HE in patients who had had multiple bouts of HE, information technology is reasonable to consider rifaximin for patients later on a unmarried bout of acute HE.

The efficacy of rifaximin in patients with highly advanced liver illness (MELD score >25) was not established in this trial. Hereafter studies in this population are awaited. In addition, the results of long-term studies to verify the long-term efficacy and condom of rifaximin beyond 24 weeks are too awaited.

Summary

Overt HE is a mutual, reversible process observed in patients with cirrhosis and characterized past neurocognitive and neuromuscular symptoms. Information technology is a distressing problem with poor treatment options. The standard of care has been lactulose, which is poorly tolerated and oft ineffective in the safety setting. Rifaximin, a minimally absorbed oral antibiotic, was shown within the context of a randomized, placebo-controlled trial to significantly reduce the gamble of breakthrough HE and hospitalization related to HE over a 6-month period in patients with a history of recurrent HE. It works in conjunction with lactulose and is well tolerated. Therefore, rifaximin should be administered in patients with a history of recurrent HE to subtract the gamble of recurrence.

Funding

This research received no specific grant from whatever funding agency in the public, commercial, or non-for-profit sectors.

Conflicts of involvement statement

Speakers bureau and consultant for Salix Pharmaceuticals, Inc.

References

Als-Nielsen B., Gluud 50.L., Gluud C. (2004) Non-absorbable disaccharides for hepatic encephalopathy: systematic review of randomized trials. BMJ 328: 1046–1046 [PMC gratis article] [PubMed] [Google Scholar]
Bajaj J.Due south., Sanyal A.J., Bell D., Gilles H., Heuman D.M. (2010) Predictors of the recurrence of hepatic encephalopathy in lactulose-treated patients. Ailment Pharmacol Ther 31: 1012–1017 [PubMed] [Google Scholar]
Bass North.1000., Mullen K.D., Sanyal A., Poordad F., Neff Thousand., Leevy C.B., et al. (2010) Rifaximin treatment in hepatic encephalopathy. N Engl J Med 362: 1071–1081 [PubMed] [Google Scholar]
Bucci L., Palmieri Grand.C. (1993) Double-blind, double-dummy comparing betwixt treatment with rifaximin and lactulose in patients with medium to severe degree hepatic encephalopathy. Curr Med Res Opin 13: 109–118 [PubMed] [Google Scholar]
Conn H.O. (1994) Hepatic encephalopathy: Syndromes and therapies. In: Conn H.O., Bircher J. (eds). Quantifying the severity of hepatic encephalopathy, Medi-ed Printing: Bloomington, IL, 373–383 [Google Scholar]
Conn H.O., Leevy C.K., Vlahcevic Z.R., Rodgers J.B., Maddrey Due west.C., Seef 50., et al. (1977) Comparing of lactulose and neomycin in the treatment of chronic portal systemic encephalopathy. A double bullheaded controlled trial. Gastroenterology 72: 573–583 [PubMed] [Google Scholar]
Conn H.O., Lieberthal Yard.G. (1979) The Hepatic Blackout Syndromes and Lactulose, Williams & Wilkins: Baltimore, MD [Google Scholar]
Cordoba J., Blei A. (2007) Diseases of liver. In: Schiff Due east.R., Sorell M.F., Maddrey Due west.C. (eds). Hepatic Encephalopathy, Lippincott Williams and Wilkins: Philadelphia, PA, 569–599 [Google Scholar]
Ferenci P., Lockwood A., Mullen Grand., Tarter R., Weissenborn K., Blei A.T. (1998) Hepatic encephalopathy—definition, nomenclature, diagnosis, and quanitification: final report of the working political party at the 11th World Congress of Gastroenterology, Vienna, 1998. Hepatology 35: 716–721 [PubMed] [Google Scholar]
Fritz Eastward., Hammer H.F., Lipp R.W., Hogenauer C., Stauber R., Hammer J. (2005) Effects of lactulose and polyethylene glycol on colonic transit. Ailment Pharmacol Ther 21: 259–268 [PubMed] [Google Scholar]
Keiding S., Sorenson M., Bender D., Munk O.L., Ott P., Vilstrup H. (2006) Encephalon metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by position emission tomography. Hepatology 43: 42–50 [PubMed] [Google Scholar]
Leevy C.B., Phillips J.A. (2007) Hospitalizations during the use of rifaximin versus lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci 52: 737–741 [PubMed] [Google Scholar]
Loguercio C., Federico A., De Girolamo V., Ferrieri A., Del Vecchio Blanco C. (2003) Cyclic treatment of chronic hepatic encephalopathy with rifaximin. Results of a double-blind clinical study. Minerva Gastroenterol Dietol 49: 53–62 [PubMed] [Google Scholar]
Mas A., Rodes J., Sunyer 50., Rodrigo L., Planas R., Vargas V., et al. (2003) Comparison of rifaximin and lactitol in the treatment of acute hepatic encephalopathy: Results of a randomized, double-blind, double-dummy, controlled clinical trial. J Hepatol 38: 51–58 [PubMed] [Google Scholar]
Massa P., Vallerino East., Dodero M. (1993) Treatment of hepatic encephalopathy with rifaximin: double-blind, double dummy study versus lactulose. Eur J Clin Res 4: vii–18 [Google Scholar]
Mortensen P.B. (1992) The issue of oral-administered lactulose on colonic nitrogen metabolism and excretion. Hepatology sixteen: 1350–1356 [PubMed] [Google Scholar]
Mullen K.D. (2007) Pathogenesis, clinical manifestation, and diagnosis of hepatic encephalopathy. Semin Liver Dis 27(Suppl. 2): ten–17 [Google Scholar]
Neff G.West., Kemmer North., Zacharias V.C., Kaiser T., Duncan C., McHenry R., et al. (2006) Analysis of hospitalizations comparing rifaximin versus lactulose in the management of hepatic encephalopathy. Transplant Proc 38: 3552–3555 [PubMed] [Google Scholar]
Pedretti G., Calzetti C., Missale Yard., Fiaccadori F. (1991) Rifaximin versus neomycin on hyperammoniemia in chronic portal systemic encephalopathy of cirrhotics. A double-blind, randomized trial. Ital J Gastroenterol 23: 175–178 [PubMed] [Google Scholar]
Poordad F.F. (2007) Review article: The brunt of hepatic encephalopathy. Ailment Pharmacol Ther 25: 3–9 [PubMed] [Google Scholar]
Sama C., Morselli-Labate A.1000., Pianta P., Lambertini 50., Berardi South., Martini G. (2004) Clinical furnishings of rifaximin in patients with hepatic encephalopathy intolerant or nonresponsive to previous lactulose handling: An open labeled report. Curr Ther Res 65: 413–422 [PMC gratuitous commodity] [PubMed] [Google Scholar]
Shawcross D.Fifty., Davies Due north.A., Williams R., Jalan R. (2004) Systemic inflammatory response exacerbates the neuropsychological effects of induced hyperammonemia in cirrhosis. J Hepatol twoscore: 247–254 [PubMed] [Google Scholar]
Strauss E., Tramote R., Silva Due east.P., Caly W.R., Honain Northward.Z., Maffei R.A., et al. (1992) Double-bullheaded randomized clinical trial comparing neomycin and placebo in the treatment of exogenous hepatic encephalopathy. Hepatogastroenterology 39: 542–545 [PubMed] [Google Scholar]
Williams R., Bass N. (2005) Rifaximin, a nonabsorbed oral antibody, in the treatment of hepatic encephalopathy: Antimicrobial activity, efficacy, and safety. Rev Gastroenterol Disord 5(Suppl): ten–18 [PubMed] [Google Scholar]
Williams R., James O.F., Warnes T.West., Morgan One thousand.Y. (2000) Evaluation of the efficacy and safety of rifaximin in the treatment of hepatic encephalopathy: A double-blind, randomized, dose-finding multi-eye report. Eur J Gastroenterol Hepatol 12: 203–208 [PubMed] [Google Scholar]

Articles from Therapeutic Advances in Gastroenterology are provided here courtesy of SAGE Publications

villarrealshink1946.blogspot.com

Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3105611/