PATHOPHYSIOLOGY OF CIRRHOSIS, MANAGEMENT OF DISEASE THAT OCCUR DUE TO CIRRHOSIS AND CLINICAL CONTROVERSY OF DRUGS .

2. Cirrhosis
Presented by:
Sharique Raza
M.Pharm 1st sem
Clinical pharmacy
Jamia Hamdard

3. Content
• Definition
• Etiology
• Pathophysiology
• Diagnosis
• Pharmacotherapy
• Clinical controversy

4. Definition
The word cirrhosis is
derived from the Greek
kirrhos , meaning
orange-yellow.
Cirrhosis is an advanced
stage of liver fibrosis.
Fibrosis, defined as the
encapsulation or
replacement of injured
tissue by collagenous
scar, results from an
abnormal perpetuation
of the normal wound
healing process

6. Etiology
Chronic alcohol consumption
Chronic viral hepatitis (types B, C, and D)
Metabolic liver disease:
 Hemochromatosis
 Wilson’s disease
 Alpha 1-antitrypsin deficiency
 Nonalcoholic steatohepatitis (“fatty liver”)
 Cystic fibrosis

7.  Immunologic disease
 Autoimmune hepatitis
 Primary biliary cirrhosis
 Primary sclerosing cholangitis (90% associated with
ulcerative colitis)
 Vascular disease
 Budd-Chiari
 Cardiac failure
 Drugs
Isoniazid, methyldopa, amiodarone, methotrexate,
tamoxifen, retinol (vitamin A), propylthiouracil, didanosine

8. PATHOPHYSIOLOGY
 Hepatic stellate cells function:
 to store vitamin A and
 help to maintain the normal matrix in the sinusoidal space.
 During chronic liver disease, hepatic stellate cells undergo an
“activation” process, which is the central event in the
development of hepatic fibrosis.
 Activation causes stellate cells:
 to lose vitamin A,
 become highly proliferative,
 and synthesize fibrotic scar tissue, which accumulates in the
sinusoidal space.

9.  This leads to loss of:
 hepatocyte microvilli,
 loss of sinusoidal endothelial fenestrae,
 deterioration of hepatocyte function, and,
 if fibrosis progresses, eventual cirrhosis

11. Signs and Symptoms
• Asymptomatic
• Hepatomegaly, splenomegaly
• Pruritis, jaundice, palmar erythema, spider
angiomata, hyperpigmentation
• Gynecomastia, reduced libido
• Ascites, edema, pleural effusion, and respiratory
difficulties
• Malaise, anorexia, and weight loss
• Encephalopathy

12. DIAGNOSIS
Laboratory Tests
• Hypoalbuminemia
• Elevated prothrombin time
• Thrombocytopenia
• Elevated alkaline phosphatase
• Elevated aspartate transaminase (AST), alanine
transaminase (ALT), and γ -glutamyl transpeptidase
(GGT)

13. PHYSIOLOGY EFFECT OF CIRRHOSIS
• Portal hypertension and varices bleeding
• Hepatic encephalopathy
• Ascites

14. General approaches to treatment
• Identify and eliminate, where possible, the
causes of cirrhosis (e.g., alcohol abuse).
• Assess the risk for variceal bleeding and begin
pharmacologic prophylaxis when indicated.
• Evaluate the patient for clinical signs of ascites
and manage with pharmacologic therapy (e.g.,
diuretics) and paracentesis.
• Careful monitoring for spontaneous bacterial
peritonitis (SBP) should be used in patients with
ascites who undergo acute deterioration

15. • Hepatic encephalopathy is a common
complication of cirrhosis and requires clinical
vigilance and treatment with dietary restriction,
elimination of central nervous system
depressants, and therapy to lower ammonia
levels.
• Frequent monitoring for signs of hepatorenal
syndrome, pulmonary insufficiency, and
endocrine dysfunction is necessary.

16. Portal hypertension and varices
bleeding
The management of varices involves three
strategies:
• (a) primary prophylaxis (prevention of the first
bleeding episode);
• (b) treatment of acute variceal hemorrhage;
and
• (c) secondary prophylaxis (prevention of
rebleeding in patients who have previously
bled)

17. Primary Prophylaxis
• β-Adrenergic Blockade:
• The mainstay of primary prophylaxis is the use of
nonselective β -adrenergic blocking agents such as
propranolol or nadolol.
• propranolol :20 mg twice daily, or nadolol: 20 to 40 mg once
daily,
• These agents reduce portal pressure by reducing portal
venous inflow via two mechanisms:
 a decrease in cardiac output through β 1 -adrenergic blockade
and
 a decrease in splanchnic blood flow through β 2 -adrenergic
blockade

18. • Patients with contraindications to therapy with
nonselective β -adrenergic blockers (i.e., those with
asthma, insulin-dependent diabetes with episodes of
hypoglycemia, and peripheral vascular disease)
• or intolerance to β -adrenergic blockers should be
• considered for alternative prophylactic therapy with
EVL.
• EVL has been compared to nonselective β -adrenergic
blocker therapy in patients with large varices and found
to be associated with a significantly lower incidence of
first variceal bleed

19. Management of visceral hemorrhage
Treatment goals include:
 (a) adequate blood volume resuscitation,
 (b) protection of airway from aspiration of blood,
 (c) correction of significant coagulopathy and/or
thrombocytopenia with fresh frozen plasma and
platelets,
 (d) prophylaxis against SBP and other infections,
 (e) control of bleeding,
 (f) prevention of rebleeding, and
 (g) preservation of liver function

20.  Somatostatin and octreotide cause :
 a reduction in portal pressure and
 port-collateral blood flow through inducing splanchnic
vasoconstriction without causing the systemic effects
associated with vasopressin.
 Therapy is initiated with an intravenous bolus of 50 mcg and is
followed by a continuous infusion of 50 mcg per hour for 3 to
5 days.

21. Secondary Prophylaxis: Prevention of
Rebleeding
The combination of EVL and a nonselective β -
adrenergic blocking agent provides the most
rational approach for secondary prophylaxis
because :
 nonselective β -adrenergic blocking agents can
protect against variceal rebleeding and
 β –adrenergic blocking agents will also delay variceal
recurrence.

22. Pharmacologic therapy should be initiated with a
• nonselective β -blocker such as propranolol 20 mg
twice daily or
• nadolol at a dose of 20 mg once daily
EVL should be conducted every 1 to 2 weeks until
variceal obliteration,
Patients should be monitored for evidence of heart
failure, bronchospasm,or glucose intolerance

23. Combination therapy with nonselective β –blocker
plus isosorbide mononitrate can be considered in
patients who are unable to undergo EVL.

24. HEPATIC ENCEPHALOPATHY
 Treatment approaches include:
 (1) reduction in blood ammonia concentrations by dietary
restrictions,
• with drug therapy aimed at inhibiting ammonia production
• or enhancing its removal (lactulose and antibiotics); and
 (2) inhibition of γ-aminobutyric acid-benzodiazepine
receptors by flumazenil.
 To reduce blood ammonia concentrations in patients with
episodic HE,
 protein intake is limited or withheld (while maintaining
caloric intake) until the clinical situation improves.

25.  To reduce blood ammonia concentrations in episodic HE,
lactulose is initiated at 45 mL orally every hour (or 300 mL
lactulose syrup with 700 mL water given as a retention enema
held for 60 minutes) until catharsis begins.
 Antibiotic therapy with metronidazole or neomycin is
reserved for patients who have not responded to diet and
lactulose.
 Rifaximin 550 mg twice daily plus lactulose can be used for
patients with inadequate response to lactulose alone.
 Zinc acetate supplementation (220 mg twice daily) is
recommended for long-term management in patients with
cirrhosis who are zinc deficient

26. DRUGS ADVERSE EEFFECT
Lactulose: Electrolyte disturbances ,Serum electrolytes
Neomycin: Ototoxicity, nephrotoxicity
Metronidazole :Neurotoxicity neuropathy
Rifaximin: Nausea, diarrhea

27. ASCITES
The therapeutic goals for patients with ascites
are :
to control the ascites,
prevent or relieve ascites-related symptoms
(dyspnea and abdominal pain and distention),
and
prevent SBP and hepatorenal syndrome

28. The treatment of ascites secondary to portal
hypertension includes: abstinence from
alcohol, sodium restriction (to 2 g/day),
• and diuretics
• Spironolactone:100 mg, and
• furosemide: 40 mg,

29. CLINICAL CONTROVERSY
Rifaximin:
Though studies to date have enrolled relatively small
numbers of patients and even though it does not carry
the indication for HE in the United States,rifaximin is
largely considered second-line therapy for patients
with HE who fail therapy or have inadequate results
with lactulose.
Whether or not rifaximin should be considered as
• first-line therapy over lactulose or
• whether rifaximin should be considered first-line
therapy in addition to lactulose remains controversial.

30. • The combination of nonselective β -adrenergic blocker and
isosorbide mononitrate could be more effective than nonselective β
-adrenergic blocker therapy alone for lowering HVPG.
• Only one trial has evaluated nonselective β –adrenergic blocker
plus isosorbide mononitrate verus nonselective β -adrenergic
blocker alone. Rebleeding rates were lower with combination
therapy, but no statistically significant differencein rebleeding rates
were attained.
• A randomized, controlled trial comparing variceal rebleeding in
patients treated with combination therapy plus EVL versus patients
treated with combination therapy alone found rebleeding rates that
were significantly lower with combination therapy plus EVL versus
combination therapy alone

31. • However, patients treated with combination therapy plus EVL
had similar rebleeding rates compared with those treated
with nonselective β –adrenergic blocker plus EVL.
• Patients treated with combination therapy are more likely to
discontinue therapy than patients treated with nonselective β
-adrenergic blocker therapy alone.
• Whether nitrate therapy should be added to nonselective β -
adrenergic blocker therapy in patients with prior history of
variceal bleeding remains controversial, especially in
patients who are able to undergo EVL.
• The unresolved questions surrounding HVPG measurement
further compound this quandary.

32. Thank you