Liver disease therapy

1. 21 September University
Faculty of Clinical Pharmacy
Complications of ESLD 2
Abdullah Saadallah
B.pharm, M.pharm (Clinical pharmacy)
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5. HEPATIC ENCEPHALOPATHY:
• Hepatic encephalopathy (HE) is a spectrum of central nervous system
(CNS) abnormalities ranging from subclinical alterations to coma and
caused by advanced liver disease and/or portosystemic shunting of
blood.
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6. HE is classified according to four criteria:
(1) Underlying disease:
a) Acute Liver Failure [Type A]
b) Resulting from portosystemic bypass or shunting [Type B]
c) From cirrhosis [Type C]
(2) Severity of manifestations
(3) According to time course (episodic, recurrent, or persistent HE)
(4) According to precipitating factors (nonprecipitated or precipitated)
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7. • During the early phase of HE, the altered mental state may present as
a slight derangement of judgment, and change in personality, sleep
pattern, or mood. Drowsiness and confusion become more prominent
as the HE progresses. Finally, unresponsiveness to arousal and deep
coma ensue.
• Asterixis, or flapping tremor, is often present in the early to middle
stages of HE that precede stupor or coma.
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8. • Asterixis can be demonstrated by having the patient hyperextend his
or her wrist with the forearms outstretched and fingers separated.
• It is characterized by bilateral, synchronous, repetitive arrhythmic
motions occurring in bursts of one flap (twitch) every 1 to 2 seconds.
• Asterixis is not specific for HE and may also be present in uremia,
hypokalemia, heart failure, ketoacidosis, respiratory failure, and
sedative overdose.
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9. Prognosis
• HE is fully reversible; therefore, it is likely a metabolic or
neurophysiologic rather than an organic disorder.
• Severe, progressive HE can lead to irreversible brain damage
(caused by increased intracranial pressure), brain herniation, and
death.
• Treatments depend on:
• pathogenesis
• Severity
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10. Pathogenesis
• Several theories exist about the pathogenesis of HE. The most widely
referenced theories involve:
A. Abnormal ammonia metabolism
B. Altered ratio of branched chain to aromatic amino acids
C. Imbalance in brain neurotransmitters, such as γ-aminobutyric
acid (GABA) and serotonin
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11. Pathogenesis
AMMONIA:
• Ammonia is a byproduct of dietary protein metabolism or digestion of
protein-rich blood in the GI tract (e.g., from bleeding esophageal
varices).
• Bacteria present in the GI tract digest protein into polypeptides,
amino acids, and ammonia. These substances are then absorbed
across the intestinal mucosa.
• Ammonia is readily metabolized in the liver to urea, which is then
renally eliminated. However, when blood flow and hepatic
metabolism are impaired by cirrhosis, serum and CNS concentrations
of ammonia are increased.
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12. Pathogenesis
• The ammonia that enters the CNS combines with α-ketoglutarate to
form glutamine, an aromatic amino acid.
• Ammonia has been considered central to the pathogenesis of HE. An
increased ammonia level raises the amount of glutamine within
astrocytes, causing an osmotic imbalance, cell swelling, and
ultimately brain edema.
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13. Pathogenesis
• AMINO ACID BALANCE:
In both acute and chronic liver failure, the ratio of the branched chain
to aromatic amino acids is altered.
Because of the higher permeability of aromatic amino acid across the
blood–brain barrier and into the cerebrospinal fluid, some aromatic
compounds can lead to production of “false neurotransmitters” that
can lead to hepatic encephalopathy with altered mental status.
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14. Pathogenesis
γ-AMINOBUTYRIC ACID:
in liver disease, gut-derived GABA escapes hepatic metabolism, crosses
the blood–brain barrier, binds to its postsynaptic receptor sites, and
causes the neurologic abnormalities associated with HE.
Others hypothesize that endogenous benzodiazepine-like substances,
via their agonist properties, contribute to the pathogenesis of hepatic
encephalopathy by enhancing GABA-ergic neurotransmission.
The role of GABA and endogenous benzodiazepines in HE is still not
clearly defined.
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15. Pathogenesis
Other precipitating factors include:
• Infections!
• electrolyte disorders!
• GI bleeding!
• Constipation!
• over diuresis!
• Drugs !!
• These factors may increase the serum ammonia and precipitate an
exacerbation of HE.
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16. Treatment and General Management
• Correcting the cause
• Suitable treatment
An energy intake of 35 to 40 kcal/kg of body weight/day and a protein
intake of 1.2 to 1.5 g/kg of ideal body weight/day for cirrhotic patients.
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17. Treatment of HE
A. LACTULOSE
B. RIFAXIMIN
C. Neomycin
D. FLUMAZENIL
E. COMBINATION THERAPY WITH LACTULOSE
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18. • LACTULOSE:
• Lactulose-induced osmotic diarrhea decreases intestinal transit time
available for ammonia production and absorption, and it may help
clear the GI tract of blood.
• Lactulose is broken down by GI bacteria to form lactic, acetic, and
formic acids, which acidify colonic contents converting ammonia into
the less readily absorbed ammonium ion. Back diffusion of ammonia
from the plasma into the GI tract can also occur.
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19. • Lactulose Dose: 45 mL orally every 1–2 hours until the patient has a loose
bowel movement and then titrate to two or three loose bowel movements
per day and clear mentation in order to avoid complications of overuse of
lactulose (aspiration, dehydration, severe perianal skin irritation, and
precipitation of HE). (typically, 15 to 45 mL two or three times daily); may
also administer as an enema (300 mL plus 700 mL of water retained for 1
hour). The beneficial clinical effect of lactulose occurs within 12 to 48
hours.
• Patients may need long-term administration of lactulose as maintenance
therapy, especially in patients with recurring HE. For prevention of
recurrence of OHE, oral daily prophylactic dosing of lactulose should be
maintained.
• If precipitating factors have been removed or liver function improved,
prophylactic therapy may be tapered and potentially discontinued.
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20. RIFAXIMIN:
Rifaximin is a synthetic antibiotic structurally related to rifamycin. It has
a wide spectrum of antibacterial activity against gram-negative and
gram-positive bacteria, both aerobic and anaerobic.
Of note, 96.6% of the drug is recovered in the feces as unchanged drug,
and what is absorbed undergoes metabolism with minimal renal
excretion of unchanged drug.
FDA-approved dose for HE is 550 mg twice daily. Rifaximin is well
tolerated, but can cause flatulence, nausea, and vomiting. Some
urticarial skin reactions have been reported with prolonged use.
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21. NEOMYCIN:
• Neomycin is also an antibiotic effective in reducing plasma-ammonia
concentrations (presumably by decreasing protein-metabolizing
bacteria in the GI tract). Approximately 1% to 3% of the neomycin
dose is absorbed.
• Typical HE dosage for neomycin ranges from 500 to 1,000 mg 4 times
daily, or as a 1% solution (125 mL) given as a retention enema
(retained for 30–60 minutes) 4 times daily.
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22. • FLUMAZENIL:
flumazenil, a benzodiazepine antagonist, has been evaluated for its role
in the treatment of HE.
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23. Hepatorenal syndrome (HRS)
• Hepatorenal syndrome (HRS) is a complication of advanced cirrhosis
characterized by an intense renal vasoconstriction, which leads to a
very low renal perfusion and glomerular filtration rate, as well as a
severe reduction in the ability to excrete sodium and free water.
• HRS is diagnosed by exclusion of other known causes of kidney
disease in the absence of parenchymal disease.
• Hepatorenal syndrome can be classified into two categories:
Type 1 HRS
Type 2 HRS
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24. • Type 1 HRS is characterized by an acute and progressive kidney failure
defined by doubling of the initial serum creatinine concentrations to a
level greater than 2.5 mg/dL in less than 2 weeks.
• Type 1 HRS is precipitated by factors such as SBP or large-volume
paracentesis, but can occur without a precipitating event.
• This usually occurs within the setting of an acute deterioration of
circulatory function characterized by hypotension and activation of
endogenous vasoconstrictor systems. It may be associated with
impaired cardiac and liver functions as well as HE. The prognosis of
patients exhibiting type 1 HRS is very poor.
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25. • In contrast, type 2 HRS is a progressive deterioration of kidney
function with a serum creatinine from 1.5 to 2.5 mg/dL.
• It is often associated with refractory ascites, and has a better survival
rate than that of patients with type 1 HRS.
• Again:
Type 1: Doubling of SCr to greater than 2.5 mg/dL or a 50% reduction
in creatinine clearance (CrCl) to less than 20 mL/minute/1.73 m2 in less
than 2 weeks
Type 2: Non-rapid progression of worsening of renal function.
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26. • Criteria in patients with cirrhosis and ascites:
• SCr > 1.5 mg/dL, no improvement in SCr to less than 1.5 mg/dL after
withdrawal of diuretics and administration of albumin,
• absence of shock,
• no current nephrotoxins,
• absence of parenchymal kidney disease and microhematuria,
• a normal renal ultrasound
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27. Treatment
• HRS is associated with a high mortality rate (within 2 weeks for type 1
HRS and 6 months for type 2 HRS).
• The definitive treatment for type 1 and type 2 HRS is liver
transplantation, which is the only treatment that assures long-term
survival.
• The main goal of pharmacologic therapy is to manage HRS sufficiently
so that the patient can survive long enough to obtain a suitable donor
liver. Diuretic therapy worsens HRS and should be discontinued.
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28. • Targeted treatment increases central venous system volume.
Peripheral vasoconstriction redistributes fluid from the periphery to
the venous system;
• fluid is retained in the vascular space by administering albumin (to
increase oncotic pressure).
• The ultimate goal is to increase renal perfusion.
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29. • A common regimen involves giving albumin 1 g/kg on day of diagnosis
(day 1), followed by 20 to 40 g on subsequent treatment days.
• This regimen is used in combination with midodrine (an α-agonist)
and octreotide.
• The initial midodrine dose is 7.5 mg orally three times daily; (12.5 mg
three times daily maximum) octreotide is administere subcutaneously
(as opposed to IV during variceal bleeding) 100-200 mcg three times
daily.
• Both drugs can be titrated as tolerated to achieve increases in mean
arterial pressure of at least 15 mm Hg.
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30. Spontaneous bacterial peritonitis (SBP)
Background
Definition: SBP is the infection of previously sterile ascitic fluid without
an apparent intraabdominal source; it is considered primary, as
opposed to secondary, peritonitis.
May be present in 10%–30% of hospitalized patients with cirrhosis
and ascites
Associated with 20%–40% of in-hospital mortality; poor prognosis
after recovery, with 2-year survival after initial episode reported at
about 30%
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31. Pathophysiology of SBP
 Principal theory is seeding of the ascitic fluid from an episode of
bacteremia.
The bacteria present are usually enteric pathogens; thus, they may enter
the blood because of increases in gut permeability secondary to portal
hypertension, suppression of hepatic reticuloendothelial cells, or
translocation of the gut wall and dissemination through the mesenteric
lymph system.
Reduced opsonic activity of the ascitic fluid and alterations in neutrophil
function may also be contributing factors.
Enteric gram-negative pathogens are most commonly involved, and more
than 90% of cases involve a single bacterial species.
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32. Most Commonly Isolated Bacteria Responsible for
Spontaneous Bacterial Peritonitis
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33. • Clinical and laboratory features
a. Clinical presentation can vary. Common symptoms include fever,
abdominal pain, nausea, vomiting, diarrhea, rebound tenderness, and
exacerbation of encephalopathy. About 33% of patients
present with renal failure, which is associated with significant
increases in mortality. GI bleeding
and septic shock or hypotension rarely occur.
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34. b. Laboratory
i. May see systemic leucocytosis or increases in SCr
ii. Abdominal paracentesis must be performed
The presence of more than 250 polymorphonuclear cells/mm3 is
diagnostic for SBP.
Lactate dehydrogenase, glucose, and protein values may help to
distinguish it from secondary peritonitis.
iii. Blood culture results are positive in 50%–70% of cases; ascitic fluid
culture results positive in 67% of cases.
iv. Gram stain of ascitic fluid is typically low yield.
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35. Treatment of acute SBP:
Because of the high associated mortality, treatment should be initiated
promptly in patients with clinical and laboratory features consistent
with SBP. If there are fewer than 250 cells/mm3 ascetic fluid
polymorphonuclear cells, empiric antibiotic therapy can be initiated if
other signs of infection are present.
Up to 86% of ascitic fluid culture results may be negative if one dose of
an antibiotic is given before cultures are obtained.
Predictors of poor outcomes include bilirubin greater than 8 mg/dL,
albumin less than 2.5 g/dL, creatinine greater than 2.1 mg/dL, hepatic
encephalopathy, hepatorenal syndrome, and upper GI bleeding.
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36. • The initial antibiotic should be an IV third-generation cephalosporin
(eg, cefotaxime 2 g every 8 hours, ceftriaxone 1 g every 24 hours).
• These agents cover the most common gram-negative and gram
positive organisms implicated in SBP, but local resistance patterns
must be taken into account when choosing empiric antibiotic
therapy.
• SBP is the primary cause of HRS. The risk of renal failure can
be reduced with albumin therapy, 1.5 g/kg initially, followed by
1 g/kg on day 3 of SBP therapy.
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37. Prevention
Prophylactic oral antibiotics are used to reduce the number of enteric
organisms in the GI tract (GI decontamination), with the hope of
reducing the chance of bacterial translocation to prevent SBP in high-
risk patients.
Antibiotic regimens are similar for both primary and secondary
prevention:
i. Fluoroquinolones: ciprofloxacin or norfloxacin
ii. Trimethoprim/sulfamethoxazole 1 double-strength tablet
for 5 consecutive days per week
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38. Primary prevention
i. During acute upper GI bleeding, give 7-day course of ceftriaxone
during hospitalization.
ii. Can also consider indefinite antibiotic prophylaxis in patients without
GI bleeding if:
ascetic fluid protein concentration is less than 1.5 g/dL and at least
one of the following is present:
SCr > 1.2 mg/dL, BUN > 25 mg/dL, sodium < 130 mg/dL, or Child-
Turcotte-Pugh score > 9 with bilirubin > 3 mg/dL
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39. iii. Use norfloxacin 400 mg once daily or
trimethoprim/sulfamethoxazole or ciprofloxacin 750 mg daily.
Secondary prevention:
i. All patients recovering from an initial episode of SBP should be
treated with oral prophylactic antibiotics indefinitely.
ii. Consider patient for liver transplantation because 2-year survival is
25%–30% after recovery.
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40. Case no 1
• A 47-year-old woman with a history of alcoholic cirrhosis (Child-Turcotte-Pugh
class C) is admitted to the hospital with nausea, abdominal pain, and fever.
Physical examination reveals a distended abdomen with shifting dullness, a
positive fluid wave, and the presence of diffuse rebound tenderness. She also has
1+ lower extremity edema. Current medications include furosemide 80 mg twice
daily and spironolactone 200 mg once daily. A diagnostic paracentesis reveals
turbid ascitic fluid, which was sent for culture. Laboratory analysis of the fluid
revealed an albumin concentration of 0.9 g/dL and the presence of 1 × 10^3
white blood cells (45% polymorphonuclear neutrophils). Serum laboratory
studies reveal SCr 1.2 mg/dL, BUN 37 mg/dL, AST 60 IU/ mL, ALT 20 IU/mL, serum
albumin 2.5 g/dL, and total bilirubin 3.2 mg/dL.
What is the best course of action?
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41. A. Initiate intravenous albumin and await culture results.
B. Initiate intravenous vancomycin plus tobramycin.
C. Initiate intravenous cefotaxime plus albumin therapy.
D. Initiate oral trimethoprim/sulfamethoxazole double strength.
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42. Case 2
A 56-year-old man with a history of Child-Turcotte-Pugh class B cirrhosis
secondary to alcohol abuse is admitted with a 2-day history of confusion,
disorientation, somnolence, and reduced oral intake. On examination, he is
afebrile, with abdominal tenderness, reduced reflexes, dry mucous
membranes, and asterixis. Paracentesis is negative for infection. He takes
propranolol 40 mg three times daily. Which recommendation is best for
treating this patient’s hepatic encephalopathy?
A. Initiate rifaximin 550 mg orally twice daily.
B. Initiate lactulose 30 mL orally every 2 hours.
C. Initiate polyethylene glycol 3350 17 g orally twice daily.
D. Initiate ceftriaxone 1 g intravenously daily.
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43. Case 3
• A 68-year-old woman referred to a gastroenterologist has intermittent
upper abdominal pain with anemia and heme-positive stools. She has a
history of hypertension and type 2 diabetes with peripheral neuropathy.
She reports no known drug allergies and takes metformin 1000 mg twice
daily, aspirin 325 mg daily, lisinopril 20 mg daily, and gabapentin 1000 mg
three times daily. In addition, she reports using OTC ketoprofen daily for
the past 2 months secondary to uncontrolled pain. The results of a
colonoscopy are negative, but endoscopy reveals a 1-cm gastric ulcer with
an intact clot. A rapid urease test for CLO is negative. Which treatment is
best for this patient’s ulcer?
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44. A. Ranitidine 150 mg twice daily for 4 weeks.
B. Lansoprazole 30 mg twice daily plus amoxicillin 1000 mg twice daily
plus clarithromycin 500 mg twice daily for 10 days.
C. Lansoprazole 30 mg/day for 8 weeks.
D. Misoprostol 200 mcg twice daily for 8 weeks.
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45. Case 4
• A 42-year-old man is in the clinic with the chief concern of sharp
epigastric pain for the past 6 weeks. He states that the pain is often
worse with eating and that it is present at least 5 days/week. He
states that although he initially tried OTC antacids with some relief,
the pain returns about 3 hours after each dose. He currently takes no
other medications. He reports an allergy to sulfa-containing
medications (rash). His practitioner is concerned about a potential
peptic ulcer and tests him for H. pylori using a UBT, the result of which
is positive. Which treatment for H. pylori is best?
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46. A. Amoxicillin 1 g twice daily plus clarithromycin 500 mg twice daily plus
omeprazole 20 mg twice daily for 5 days.
B. Cephalexin 1 g twice daily plus clarithromycin 500 mg twice daily plus
omeprazole 20 mg twice daily for 10 days.
C. Bismuth subsalicylate 525 mg four times daily plus tetracycline 500 mg
four times daily plus metronidazole 500 mg three times daily plus
omeprazole 20 mg twice daily for 14 days.
D. Levofloxacin 500 mg once daily plus metronidazole 500 mg twice daily
plus omeprazole 20 mg twice daily for 21 days.
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47. Case 5
• A 68-year-old Hispanic man is assessed in the emergency department for a
36-hour history of black, tarry stools; dizziness; confusion; and vomiting a
substance resembling coffee grounds. He has a medical history of
osteoarthritis, hypertension, myocardial infarction (MI) in 1996 and 1998,
and seasonal allergies. He has taken naproxen 500 mg twice daily for 4
years, metoprolol 100 mg twice daily, aspirin 325 mg/day, and loratadine
10 mg/day. Nasogastric (NG) aspiration is positive for blood, and
subsequent endoscopy reveals a 3-cm antral ulcer with a visible vessel. The
vessel is obliterated using an epinephrine solution, and a rapid urease test
is negative for Helicobacter pylori.
• Which recommendation is best for this patient?
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48. A. Intravenous ranitidine 50 mg/hour for 5 days.
B. Sucralfate 1 g four times daily by NG tube.
C. Oral lansoprazole 15 mg/day by NG tube.
D. Pantoprazole 80 mg intravenous bolus, followed by an 8-mg/hour
infusion.
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49. Case 6
• A 45-year-old African American man with a history of alcoholic cirrhosis
(Child-Pugh class B) was seen in the clinic for a follow-up. He was recently
referred for a screening endoscopy, which revealed several large
esophageal varices. He has no history of bleeding; 1 month ago,
propranolol 10 mg orally three times daily was initiated. At that time, his
vital signs included body temperature 98.7°F (37°C), heart rate 85
beats/minute, respiratory rate 15 breaths/minute, and blood pressure
130/80 mm Hg. At his evaluation today, he seems to be tolerating the
propranolol dose and has no new concerns. His vital signs now include
body temperature 98.6°F, heart rate 79 beats/minute, respiratory rate
14 breaths/minute, and blood pressure 128/78 mm Hg. What is the best
course of action?
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50. A. Continue current therapy, with a close follow-up in 4 weeks.
B. Increase propranolol to 20 mg orally three times daily.
C. Add isosorbide dinitrate 10 mg orally three times daily.
D. Change propranolol to atenolol 25 mg orally once daily.
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51. Case 7
• A 50-year-old woman is seen in the clinic for severe pain related to the
swelling of three of her metacarpophalangeal joints on each hand and
swelling of her right wrist. She cannot write or perform her usual
household activities. Radiograms of these joints reveal bony
decalcifications and erosions. A serum rheumatoid factor is obtained,
which is elevated. Her medical history includes type 2 diabetes,
hypertension, and dyslipidemia. Her medications include metformin 1000
mg twice daily, glyburide 10 mg/day, metoprolol 100 mg twice daily, aspirin
81 mg/day, and rosuvastatin 5 mg/ day. The primary care provider would
like to initiate systemic anti-inflammatory therapy for this patient’s
rheumatoid arthritis with high-dose nonsteroidal anti-inflammatory drug
(NSAID) therapy; however, the primary care provider is worried about
potential gastrointestinal (GI) toxicity. What is the best regimen for
treating this patient’s pain while minimizing the risk of GI toxicity?
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52. A. Celecoxib 400 mg twice daily.
B. Indomethacin 75 mg/day plus ranitidine 150 mg/day.
C. Naproxen 500 mg twice daily plus omeprazole 20 mg/day.
D. Piroxicam 20 mg/day plus misoprostol 600 mcg three times daily.
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53. Case 8
• A 58-year-old African American man presents with a 2-month history of
burning epigastric pain and intermittent difficulty swallowing. The pain is
not relieved by positional changes or eating, and he has tried calcium
carbonate (500 mg) chewable tablets when symptoms occur, resulting in
minimal relief. He takes amlodipine 5 mg/day for hypertension and
ibuprofen for occasional back pain. Which action is best for this patient?
A. Initiate famotidine 20 mg/day.
B. Refer for possible endoscopic evaluation.
C. Initiate omeprazole 20 mg twice daily.
D. Change amlodipine to hydrochlorothiazide.
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