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

Pathophysiology1

• 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

CNS = center nervous systemBBB = blood brain barrier

Pathophysiology1

• γ-Aminobutyric acid• Gut derived GABA escapes hepatic

metabolism & crosses BBB• Endogenous benzodiazepine-like

substances agonizes symptoms

• 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

NT = neurotransmitter

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 ScaleCan 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:

• A urine sample has been collected

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

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)

• 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. Lactitol – Efficacy/Safety9

• 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

Rifaximin vs. Lactulose – Hospitalization10

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 : ReviewDrug & DosingKK Price ($) Cost per day ($)

LactuloseInitial dose 30-45 mL PO TIDThen titrate to symptomatic resolution or until 3 soft stools per day

40 x 30 mL QVH = 23.26; AWP = 119.20

480 mLQVH = 3.09; AWP = 34.70

8.94

6.51

Neomycin1-2 grams PO QID or 1% solution retention enema x20-60 min QID

100 x 500 mg tabsQVH = 14.79; AWP = 57.05 4.56 – 9.13

Rifaximin400 mg PO TID

100 x 200 mgQVH = 360.04; AWP = 521.35

30 x 200 mgQVH = 124.21; AWP = 156.39

31.28

31.28

Flumazenil0.5 mg IV x1min Or 25 mg PO BID

0.1 mg/mL [10 x 5 mL]QVH = 49.56; AWP = 886.85

0.1 mg/mL [10 x 10 mL]QVH = 19.18; AWP = 78.00

88.69

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 11 th 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