Quang Bui, Pharm D.

Candidate 2010
Rotation: Acute Care 1 at CCRMC
Preceptors: Karen Finck, Pharm D. (CCRMC)
& Adrienne Nazareno, Pharm. D (QVH)
 Hepatic Encephalopathy (HE):
Goal & Objectives
• Goal
• Understand the use of rifaximin in HE

• Objectives
• Understand the pathogenesis of HE
• Understand the guideline of HE
• Know the drug of choice for HE
• Know the parameters for using rifaximin
 CNS = center nervous system
Pathophysiology 1 BBB = blood brain barrier

• Metabolic disorder of CNS

– Advanced cirrhosis or fulminate hepatic failure
– Fully reversible
– Sometimes indistinguishable with other syndrome
(eg, brain atrophy or edema)2
• Ammonia = neurotoxin
– Byproduct of glutamine from enterocytes2
– Byproduct of microbial protein metabolism
– Digestion of proteins from protein-rich food
and blood into GI tract
– RNA oxidative stress in astrocytes modulate
NMDA receptor activation2 & disrupt BBB3
– Changes excitatory and inhibitory
postsynaptic potentials2
 NT = neurotransmitter
Pathophysiology 1

• Amino acid imbalance

– Normal ratio of branched chain to methionine
and aromatic amino acids is 4.6:1
– Branched chain amino acids (eg Val, Leu, Ile)
are used in skeletal muscle in liver failure
– Aromatics cross BBB & alter NT balance

• γ-Aminobutyric acid
• Gut derived GABA escapes hepatic
metabolism & crosses BBB
• Endogenous benzodiazepine-like
substances agonizes symptoms
 Signs & Symptoms1
• 3 main clinical features
– Altered Mental Status
– Asterixis
• Flapping tremor every 1-2 seconds
– Fector hepaticus
• Sweetish, musty, pungent breath odor
• Result of unmetabolized mercaptans

Graph of evolution of hepatic encephalopathy4

 Diagnosis 4
• Rule out other causes for change in mental status CMDHE
– Differential diagnosis of hyperammonemia (eg Urea Cycle
Enzyme Deficiency)4
• World Organization of Gastroenterology (OMGE)’s
Working Party consensus statement5
– Nomenclature of hepatic encephalopathy
 The Portal-Systemic Encephalopathy Score6
The West Haven Criteria
and the Glagow Coma
Scale are recommended by
the American College of
Gastroenterology in
classification of HE severity.

Example of the Glagow Coma Scale

Can be found at the CDC website:
http://www.bt.cdc.gov/masscasualties/gscale.asp
 Precipitating Factors1

• Excess sodium load

– Bleed from GI/esophageal varix,
hemorrhoid, and PUD
– Excess protein intake
– Azotemia, diuretic-induced hypovolemia,
uremia or renal failure, excessive
enterohepatic circulation of BUN
– Infection: tissue catabolism
– Constipation
 Precipitating Factors1

• Metabolic & electrolyte abnormalities

– Hypokalema, diuretic-induced, dietary deficiency,
excessive diarrhea, hyperaldosteronism
– Alkalosis, hypokalemia-induced, excessive n/v

• Drug-induced CNS depression

– Sedatives, tranquilizers, phenothizines
– Hepatotoxics, narcotic analgesics
 Case Study
• TB came to the ED complaining of feeling
lightheaded and off balance for the last several
days.
• This would be his 7th visit within 3 months.
• TB ran out of lactulose at home several days ago
and began to stagger more, noticed that he lose
balance often and almost fell to the side.
• TB has a problem with urination. When he
actually does urinate, he notices that there’s
blood in the urine.
• TB’s PMH includes hepatitis C alcoholic cirrhosis
(last drink 1990), HTN, chronic pain, and prostate
problems. He was a substance abuser as well as
a tobacco user.
 Case Study
• Admission vital signs:
– T 97.5 oral, BP 107/74, HR 66, RR 17, SO2 99%
• Abnormal lab values:
Lab Result Interpretation CCRMC Reference Range
Serum Ammonia 134 HIGH 10-35
Total bilirubin 3.9 HIGH 0.2-1.2
AST 464 HIGH 10-38
ALT 44 HIGH 0-36
Chloride 108 HIGH 98-107
Albumin 2.6 LOW 3.5-4.8
RBC 4.1 LOW 4.7-6.1
Hgb 14.4 LOW 14-18
Hct 39.6 LOW 42-54

• A urine sample has been collected

Treatment Choices : Lactulose1
• Goal = decrease ammonia conc.
– Clinical benefits within 12-48 hours
– Most patients weaned off after few
days or weeks but some may
require long-term administration
– Chronic administration helps with
dietary protein tolerance

• Highly efficacious
– May need NG if patient is comatose
or rectal retention enema (300 mL/ 1
L water) retained for 1 hour
– ~70-80% of patients clinically
improve7
Treatment Choices : Lactulose1

• MOA
– Disaccharide form broken down
by GI bacteria into lactic, acetic &
formic acid
– Acidification of the colon converts
ammonia into less readily
absorbed ammonium ion
– Lactulose-induced osmotic
diarrhea decreases intestinal
transit time
Treatment Choices : Lactulose1

• Side effects:
– Dehydration & hypokalemia
• Exacerbate hepatic
encephalopathy
– Syrup is excessive sweat
• May dilute with fruit juice,
carbonated drinks or water
– Well tolerated but 20%
patients have gaseous
distension, flatulence, or
belching
Treatment Choices : Neomycin1
• Goal: Decreases ammonia levels by increasing
protein-metabolizing bacteria in GI tract
• MOA: (non)absorable antimicrobial

• Side effects
– 1-3% of neomycin is absorbed but rarely causes
ototoxicity or nephrotoxicity
• Monitor SCr, urine protein & CrCl for patients
receiving high doses or long duration
– Reversible malabsorption syndrome
• Suppressed absorption of fat, N, carotene, Fe,
Vitamin B12, xylose, and glucose
– Decreased absorption of Digoxin, PCN, and vitaminK
• Hence lactulose is preferred in long term use
Treatment Choices : Rifaximin
• Goal
– Decreases bacterial byproducts

• MOA
– Nonabsorbable rifampin derivative
– Antimicrobial (broad spectrum)

• Side effects
– Has comparable SE to placebo
– May not improve severe
encephalopathy symptoms as rapidly
as lactulose8
 Rifaximin vs. Lactitol – Efficacy/Safety9
• Comparison of rifaximin and lactitol in the treatment of
acute hepatic encephalopathy: results of a randomized,
double-blind, double-dummy, controlled clinical trial
– Mas A, Rodes J, Sunyer L, et al
– Journal of Hepatology. 2003;38:51-58

• Objective
– Efficacy & safety of rifaximin vs. lactitol

• Methods
– Randomize 103 patients grade 1-3 acute HE
• 50 patients taking rifaximin 1200 mg/day for 5-10 days
• 53 patients taking lactitol 60g/day for 5-10 days
– Evaluate the changes of the portal-systemic encephalopathy
(PSE) index (2 tail p-value test)
 Rifaximin vs. Lactitol – Efficacy/Safety9
• Sample size:
– N = 120 for 80% power. Study has 103
– Exclusion criteria:
• Major pyschiatric illness, chronic renal/respiratory
insufficiency, intercurrent infections, hypersensitivity,
treatment with sedatives or antibiotics within 7 days,
pregnant/lactating, did not fulfill protocol requirements

• Assessments:
– PSE
• Mental status, asterixis, number connection test,
electroencephalogram, blood ammonia levels
– Adverse events
• Time onset, duration, severity, and relationship
• CBC & plasma biochemistry at start & end of study to
evaluate tolerability
 Rifaximin vs. Lactitol – Efficacy/Safety9
• Conclusion
– 11 withdrawals due to inefficacy (6 in rifaximin, 5 in lactitol)
– 4 withdrawals due to intolerability (2 & 2)
– Both treatments were well tolerated
– No differences in end treatment
– “In acute HE of moderate to severe grade, rifaximin may be
good alternatives”

• Critiques
– Underpowered
– Good baseline demographic & clinical data homogeneity
– Use of PSE scores
– Rifaximin tablets and lactitol sachets are from same
manufacturer (Alfa Wasserman Pharmaceutical Company in
Italy)
Rifaximin vs. Lactulose – Hospitalization10
• Hospitalizations during the use of rifaximin versus
lactulose for the treatment of hepatic encephalopathy
– Carroll B Leevy and James A Phillips
– Dig Dis Sci. 2007;52:737-741

• Methods
– Retrospective chart review
• Frequencey, duration, and hospitalization charges
• HE discharge diagnosis, clinical status, and adverse events
– Patients with lactulose 30 cc twice daily for ≥ 6 months then
rifaximin 400 mg 3 times daily for ≥ 6 months (start 2004)
– Exclusions: liver transplant during therapy
– Primary end point: mean hospitalization during each treatment
– Secondary end points: average length of hospitalization, mean
total time hospitalized, and hospitalization charges per patient
(2005 dollars)
– Clinical end points: West Haven grades, asterixis, adverse events
Rifaximin vs. Lactulose – Hospitalization10
• Conclusions:
– Reduced need for hospital care and its associated charges in
patients using rifaximin compared to lactulose
• 3 times lower in frequency & duration of hospitalizations over 6
months
• 4 times lower in hospitalization charges over 6 months (>
$42,000)
– Better compliance in rifaximin group (92% rifaximin, 31%
lactulose)
• Poor tolerability in lactulose group due to diarrhea & nausea
• Comparable tolerability between rifaximin & placebo

• Critique
– Patients with rifaximin has less severe illness
– Retrospective & observation study
– Single center with 145 patients
– Tolerability results comparable to published literature
Treatment Choices : Flumazenil1

• MOA
– Antagonizes the GABA-ergic neurotransmitters
– Responses may be due to the reversal of
benzodiazepines

• Recommend detection of exogenous

benzodiazepines and their metabolites
before starting Flumazenil (Romazicon)

• Not a true improvement in encephalopathy

 Treatment Choices : Review
Drug & DosingKK Price ($) Cost per day ($)

Lactulose 40 x 30 mL
Initial dose 30-45 mL PO TID QVH = 23.26; AWP = 119.20 8.94
Then titrate to symptomatic resolution
or until 3 soft stools per day 480 mL
QVH = 3.09; AWP = 34.70 6.51
Neomycin 100 x 500 mg tabs
1-2 grams PO QID or 1% solution QVH = 14.79; AWP = 57.05 4.56 – 9.13
retention enema x20-60 min QID
Rifaximin 100 x 200 mg
400 mg PO TID QVH = 360.04; AWP = 31.28
521.35

30 x 200 mg 31.28
QVH = 124.21; AWP =
Flumazenil 0.1 mg/mL [10 x 5 mL]
156.39
0.5 mg IV x1min QVH = 49.56; AWP = 886.85 88.69
Or 25 mg PO BID
0.1 mg/mL [10 x 10 mL]
QVH = 19.18; AWP = 78.00 3.90
 Case Study Revisit
• TB current medications include:
– Lactulose 30 mL daily, Inderal 20 mg BID
– Spironolactone 100 mg daily, Atarax 25 mg Q4-6h prn
– Omeprazole 20 mg daily, Neomycin 2 tablets Q6h
– Questran powder daily

• TB’s medication course:

– 4 am : Neomycin tablets
– 10 am: Neomycin, Lasix, Inderal, Spironolactone
– 12 pm: Lactulose solution

• TB is monitored for LFT, chem 7 and nutrition,

BM, mental status and fall risk.
 Case Study Revisit
• One day after admission, TB’s ammonia level is
significantly reduced to 58 and his symptoms
improved dramatically.

• TB is discharged from the hospital with education

on low dietary protein intake and fluid restriction
of < 2L per day and is scheduled for a follow up 1
week later.

• Medications upon discharge includes:

– Lactulose and Neomycin,
– Furosemide, Sprionolactone and Propranolol
 References
• 1. Olyaei AJ. In: Koda-Kimble MA, Young LY, Kradjan WA, et al. Applied therapeutic: the
clinical use of drugs. Chapter 29. 8th ed. Baltimore MA: Lippincott Williams & Wilkins;
2005.
• 2. Ferenci P. Pathogenesis of hepatic encephalopathy. UpToDate. Accessed 3/9/09.
• 3. Lawrence KR and Klee JA. Rifaximin for the treatment of hepatic encephalopathy.
Pharmacotherapy. 2008;28(8):1019-1032.
• 4. Ferenci P. Clinical manifestations and diagnosis of hepatic encephalopathy.
UpToDate. Accessed 3/9/09.
• 5. Ferenci P, Lockwood A, Mullen K, et al. Hepatic encephalopathy – definition,
nomenclature, diagnosis, and quantification: final report of the Working Party at the 11th
World Congresses of Gasteroenterology, Vienna, 1998. Hepatology. 2002; 35:716-721.
• 6. Lawrence KR and Klee JA. Rifaximin for the treatment of hepatic encephalopathy.
Pharmacotherapy. 2008;28(8):1019-1032.
• 7. Ferenci P. Treatment of hepatic encephalopathy. UpToDate. Accessed 3/9/09.
• 8. Wolf DC. Hepatic encephalopathy. www.emedicine.com/med/topic3185. Accessed on
10/20/08.
• 9. Mas A, Rodes J, Sunyer L, et al. Comparison of rifaximin and lactitol in the treatment
of acute hepatic encephalopathy: results of a randomized, double-blind, double-dummy,
controlled clinical trial. J Hepatology. 2003;38:51-58.
• 10. Leevy CB and Phillips JA. Hospitalizations during the use of rifaximin versus
lactulose for the treatment of hepatic encephalopathy. Dig Dis Sci. 2007;52:737-741.
Questions?
Question 1
• Altered mental status is most prominent in
patients with hepatic encephalopathy.
Which of the following is the main culprit
for the change?
– Hyperammonemia
– Hypoammonemia
– Hypotension
– Hypertension
– Hyperlipidemia
Question 2
• What are the three main clinical features of
hepatic encephalopathy?
– Unexplained bruising, fish belching, and flu-like
symptoms
– Altered mental status, asterixis, and fector
hepaticus
– Absent seizures, jaundice, and acanthosis
nigricans
– Hypertension, insulin resistance, and sweat
breath odor
– Depression, oral thrush, and flu-like symptoms
Question 3
• Why is rifaximin a treatment choice for
hepatic encephalopathy?
– Rifaximin is a non-absorbable active derivative
of rifampin with broad-spectrum antibiotic
action.
– Rifaximin is an absorbable antigen that
neutralizes the ammonia in the blood, hence
preventing altered mental status.
– Rifaximin improves severe hepatic
encephalopathy as rapid as lactulose.
– Rifaximin paralyses the hands so it will stop the
patient’s flapping tremor action.
– Rifaximin closes the blood brain barrier so that
ammonia may not enter the brain.
Question 4
• What is the drug of choice for patients with
hepatic encephalopathy.
– Rifaximin
– Lactulose
– Neomycin
– Flumanezil
– Metronidazole
Question 5
• The pathophysiology of a patient with
hepatic encephalopathy may include:
– Ammonia acts as a neurotoxin
– Higher ratio of aromatic amino acids compared
to skeletal amino acids
– Escaped GABA from the gut
– A&B
– All of the above