PHARMACOTHERAPY OF CIRRHOSIS

ANTON RAKHMAN
SCHOOL OF PHARMACY

EPIDEMIOLOGY

Based on the trial at UMMC (Qua and Goh, 2011)

From a total of 460 Pxs, the major causes of cirrhosis were:
chronic hepatitis B, n=212, (46.1) ; chronic hepatitis C,
(18.5%); cryptogenic, n=71, (15.4%); alcohol (12.6%) and
autoimmune (2.0%).
Alcohol was the main etiology in Indians (51.1%) compared
to Malay (0%) and Chinese (4.4%) (both P<0.001).
Hepatitis B was the predominant etiology in Malay (47.9%)
and Chinese (58.8%) compared to Indians (5.6%).
Hepatitis C cirrhosis was highest in Malays (25.0%). 136
patients (29.6%) had concurrent HCC.

1. DEFINITION
Chronic, irreversible, severe disease
Fibrosis of the hepatic parenchyma resulting in
altered hepatic function, activation of the
RAAS, restricted venous outflow, and
development of the complications: ascites,
portal hypertension, spontaneous bacterial
peritonitis, others.

LIVER CIRRHOSIS

2. CLASSIFICATION
Cirrhosis classify into 2 main categories:
i. Compensated
- Cirrhotic patient with a portal pressure < 10
mmHg.
- Absence of complications (ex. Ascites, variceral
hemorrhage, or encephalopathy).
ii. Decompensated
- Presence of the complications.

2. CLASSIFICATION: CHILD-TURCOTTE-PUGH

Parameter
Bilirubin
(mg/dL)

1 POINT
<2

2 POINTS 3 POINTS
2-3
>3

Albumin
(mg/dL)

> 3.5

2.8 -3.5

< 2.8

INR
Ascites

< 1.7
None

1.7-2.3
Mild to
moderate

> 2.3
Severe

Encephalopa- None
thy (grade 1
and 2)

Mild to
moderate
(1 and 2)

Severe (3
and 4)

2. ETIOLOGY
Cirrhosis results from a sustained woundhealing response to chronic or acute liver
injury:
- Viral Hepatitis especially B and C.
- Alcohol.
- Immunologic: Autoimmune hepatitis.
- Others: drugs, vascular disease (BuddChiari).

3. MAJOR COMPLICATIONS

1. Portal Hypertension
2. Ascites
3. Spontaneus Bacterial Peritonitis (SBP)

4. Splenomegaly
5. Hepatic Encephalophaty

3.1 PORTAL HYPERTENSION

Elevation of the hepatic venous pressure gradient
(HVPG) to > 5-6 mmHg.
- produce variceral bleeding when the portal
pressure increases to greater than 10-12 mmHg.
Etiology:
Is caused by combination of :
i. Increase in resistance to portal flow and
ii. Increase in portal venous inflow.

PORTA
L
VENO
US
SYSTE
M

3.1.1 PRIMARY COMPLICATIONS OF PORTAL

HYPERTENSION
Gastroesophageal varices with hemorrhage.
- Varices occur because of the bodys need to
find collateral outlets to relieve the increased
pressure of portal hypertension.
- Collateral outlets, include:
esophageal and gastric vessels, retroperitoneal
vessels, hemorrhoidal venous plexus, a
recanalized umbilical vein, and intrahepatic
shunts.

3.2 ASCITES
Accumulation of fluid within the peritoneal cavity.
Approximately half of all cirrhotic patients
develop ascites within 10 years of diagnosis.
Clinical manifestation:
increase in abdominal girth that is often
accompanied by the development of peripheral
edema; abdominal pain and distention; shortness
of breath; malnourished; fatique; weakness;
muscle wasting.

3.2.1 PATHOGENESIS OF ASCITES

3.2.2 DIAGNOSIS OF ASCITES

i. Physical examination.
ii. Abdominal imaging: by abdominal CT-scan or ultrasound.
iii. Performed diagnostic paracentesis to characterize the
fluid:
- Total protein (< 1 g/dL).
- Albumin
- Blood cell count & differential: if the PMN leukocytes
> 250/L is indicate ascitic fluid infection.
- The amount of fluid at least 1-2 L in the abdomen.
iv. Ascitic fluid culture.

3.3 SPONTANEOUS BACTERIAL PERITONITIS

(SBP)
Spontaneous infection of the ascitic fluid without an
intraabdominal source.
SBP can occur in up to 30% of individuals with cirrhosis
and ascites and can have a 25% in-hospital mortality rate.
3.3.1 Etiology
Escherichia coli; Klebsiella species
Gram-positive bacteria, including Streptococcus viridans,
Staphylococcus aureus, and Enterococcus sp.

3.3.2 PATHOPHYSIOLOGY
CIRRHOSIS

Intestinal bacterial overgrowth

Enhanced the intestinal permeability
Bacterial translocation from the gut into
mesenteric lymph nodes
- Bacteremia
- Seeding of the ascitic fluid

3.3.3 DIAGNOSIS
Positive bacterial culture of the ascitic fluid.
PMN of greater than or equal to 250 cells/mL.
With or without clinical symptoms of infection.

3.4 SPLEENOMEGALY

Enlarged spleen due to portal hypertension

with pooling platelets in the spleen.
Clinical features:
- Enlarged spleen.
- Thrombocytopenia.
- Leukopenia.
- Pain on left-sided and left upper quadrant
abdominal pain.

3.5 HEPATIC COMA/ENCEPHALOPATHY

Metabolic disorder of the CNS that is defined as an
alteration in mental status and cognitive function.
Result from gut-derived neurotoxin that are not
removed by the liver because vascular shunting (portal
systemic shunting) and decreased hepatic mass get to
the brain.
ammonia, glutamate, GABA-benzodiazepine
receptor agonists, manganese.
Occurs in patients with either advanced cirrhosis or
fulminate hepatic failure.

3.5.1 CLINICAL FINDINGS FOR HE

GRADE LEVEL OF
PERSONALITY NEUROLOGIC
CONSCIOUSNE /INTELLECT
ABNORMALIT
SS
IES
0

Normal

Normal

None

Inverted sleep
patterns/restless

Mild confusion,
Slight tremor,
Euphoria,
apraxia,
Depression,
incoordination
Decreased
attention,
irritable, inability
to perform mental
tasks.

3.5.1 CLINICAL FINDINGS FOR HE

GRADE LEVEL OF
PERSONALITY NEUROLOGIC
CONSCIOUSNE /INTELLECT
ABNORMALIT
SS
IES
2

Lethargic, drowsy,
intermittent
disorientation
(usually for time)

Obvious
Asterixis,
personality
abnormal
changes,
reflexes.
inappropriate
behavior, inability
to perform mental
tasks.

3.5.1 CLINICAL FINDINGS FOR HE

GRADE

LEVEL OF
PERSONALITY NEUROLOGIC
CONSCIOUSNE /INTELLECT
ABNORMALIT
SS
IES

Somnolent but
aroushable,
markedly
confused,
disorientation to
time and/or place,
amnesia

Coma/unaroushab None
le

Unable to perform Abnormal

mental tasks,
reflexes.
occasional fits of
rage, speech
present but
incomprehensible
Decerebrate,
Babinski sign.

4. TREATMENT

GENERAL APPROACHES TO TREATMENT

1. Identify and eliminate the causes of cirrhosis.
2. Assess the risk for variceral bleeding and begin
pharmacologic prophylaxis when indicated.
3. Evaluate clinical signs of ascites and manage with
pharmacologic therapy (ex. diuretics) and
paracentesis.
4. HEs patient needs clinical vigilance and proper
treatment.

4.1 MANAGEMENT of
VARICEAL BLEEDING

PORTAL

HYPERTENSION

i. Primary Prophylaxis (prevention of the first bleeding

episode):
-blocker: propranolol 20 mg twice daily or nadolol
40 mg once daily.
Endoscopic variceal ligation (EVL).
ii. Management acute variceal hemorrhage.

iii. Secondary prophylaxis (prevention of rebleeding in

patients who have previously)

and

4.1.1 MANAGEMENT of ACUTE VARICEAL HEMORRHAGE

4.1.1 MANAGEMENT of ACUTE VARICEAL HEMORRHAGE

a. Drug Therapy
Mechanism of action: reduction in portal pressure &
port-collateral
blood
flow
through
splanchnic
vasoconstriction.
Ex. octreotide (somatostatin analogue); vasopressin.
Dose of octreotide:
iv bolus 50 g followed by a continuous iv infusion of 50
g per hour for 5 days.
Dose of vasopressin:
continuous iv infusion of 0.2 to 0.4 U/minute, which can
be increased to a maximal dose of 0.8 U/minute.

4.1.1 MANAGEMENT of ACUTE VARICEAL HEMORRHAGE

b. Endoscopic intervention
i. Endoscopic variceal ligation (EVL).
Placement of rubber bands around the varix.
ii. Sclerotherapy
Injection of 1 to 4 mL of sclerosing agent into lumen of the
varices to tamponade blood flow.
c. Interventional and Surgical Treatment Approaches.
.For patient with refractory to pharmacologic or endoscopic
therapy.
.Such as balloon tamponade and transjugular intrahepatic
portossystemic shunt (TIPS).

4.1.2 SECONDARY
REBLEEDING

PROPHYLAXIS:

PREVENTION

OF

Rebleeding after initial control of variceal

hemorrhage occurs in 60% of patients within 1 to
2 years without treatment and carries mortality
need secondary prophylaxis.
Therapy:
1st line: combination -adrenergic blockers and
EVL.
start as soon as possible, once the patient has
had no bleeding for at least 24 hours.

4.1 MANAGEMENT of ASCITES

Abstinence from alcohol.
Abdominal paracentesis.
Diuretic therapy.
- Spironolactone alone: patient with minimal fluid
overload.
- Combination of spironolactone and furosemide: patient
with refractory ascites.
starting spironolactone 100 mg and furosemide 40
mg simultaneously--> increased every 3 to 5 days
(maintaining the ratio).

4.2 MANAGEMENT of SBP

Empirical antibiotics followed by definitive
antibiotics.
Agent:
- Cefotaxime 2 g every 8 hours or others thirdgeneration of cephalosporin for 5 days.
- Ofloxacin 400 mg every 12 hours po for 8 days.
- Quinolones.
- TMP-SMZ (trimethoprim-sulfamethoxazole).

4.2 MANAGEMENT of HE
Treatment approaches:
i. Avoidance and prevention of precipitating
factor, such as: GI bleeding, infection,
electrolyte abnormalities.
ii. Reducing ammonia blood concentration by:
- dietary restriction.
- drug therapy.
iii. Inhibition of the -aminobutyric acid (GABA)benzodiazepine receptors.

4.2.1 HYPERAMMONEMIA TREATMENT

Restriction of vegetable-sorce, dairy-source, meat-source

protein.
Branched-chain amino acid (BCCA): balance the ratio of the
branched chain to aromatic amino acid.
Lactulose.
- standard therapy for both acute and chronic HE.
Lactulose is broken down by GI bacteria to form lactic,
acetic, and formic acids--> acidification of colonic contents,
converts ammonia into ammonium ion--> lower plasma
ammonia concentration.
Cathartic effect (osmotic diarrhea).

4.2.1 HYPERAMMONEMIA TREATMENT

- Dose of lactulose:
acute HE: (10 g/15 mL syrup), 30 to 45
mL administered every hour until evacuation
occurs. Chronic HE: oral lactulose
administered daily to 4x daily.
Benzodiazepine Antagonist
- Flumazenil 1 mg iv bolus for short-term
therapy.

THANK YOU