Slide 1

PHARMACOTHERAPY OF CIRRHOSIS

ANTON RAKHMANSCHOOL OF PHARMACY 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 3Albumin (mg/dL)> 3.52.8 -3.5< 2.8INR< 1.71.7-2.3> 2.3AscitesNoneMild to moderateSevereEncephalopa-thy (grade 1 and 2)NoneMild to moderate(1 and 2)Severe (3 and 4)2. CLASSIFICATION: CHILD-TURCOTTE-PUGHCirrhosis results from a sustained wound-healing response to chronic or acute liver injury:- Viral Hepatitis especially B and C.- Alcohol.- Immunologic: Autoimmune hepatitis.-Others: drugs, vascular disease (Budd-Chiari).2. ETIOLOGY3. MAJOR COMPLICATIONS3.1 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 andii. Increase in portal venous inflow.PORTAL VENOUS SYSTEM

3.1.1 PRIMARY COMPLICATIONS OF PORTAL HYPERTENSIONGastroesophageal 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.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 ASCITES3.2.1 PATHOGENESIS OF ASCITES

Physical examination.Abdominal imaging: by abdominal CT-scan or ultrasound.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.

3.2.2 DIAGNOSIS OF ASCITESSpontaneous 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 EtiologyEscherichia coli; Klebsiella speciesGram-positive bacteria, including Streptococcus viridans, Staphylococcus aureus, and Enterococcus sp.

3.3 SPONTANEOUS BACTERIAL PERITONITIS(SBP)Bacterial translocation from the gut into mesenteric lymph nodes3.3.2 PATHOPHYSIOLOGYCIRRHOSISIntestinal bacterial overgrowthEnhanced the intestinal permeabilityBacteremiaSeeding of the ascitic fluid

Positive bacterial culture of the ascitic fluid.PMN of greater than or equal to 250 cells/mL.With or without clinical symptoms of infection. 3.3.3 DIAGNOSISEnlarged 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.3.4 SPLEENOMEGALYMetabolic 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 HEPATIC COMA/ENCEPHALOPATHYGRADELEVEL OF CONSCIOUSNESSPERSONALITY/INTELLECTNEUROLOGIC ABNORMALITIES0NormalNormalNone1Inverted sleep patterns/restlessMild confusion,Euphoria, Depression, Decreased attention, irritable, inability to perform mental tasks.Slight tremor, apraxia, incoordination3.5.1 CLINICAL FINDINGS FOR HE3.5.1 CLINICAL FINDINGS FOR HEGRADELEVEL OF CONSCIOUSNESSPERSONALITY/INTELLECTNEUROLOGIC ABNORMALITIES2Lethargic, drowsy, intermittent disorientation (usually for time)Obvious personality changes, inappropriate behavior, inability to perform mental tasks.Asterixis, abnormal reflexes.3.5.1 CLINICAL FINDINGS FOR HEGRADELEVEL OF CONSCIOUSNESSPERSONALITY/INTELLECTNEUROLOGIC ABNORMALITIES3Somnolent but aroushable, markedly confused, disorientation to time and/or place, amnesiaUnable to perform mental tasks, occasional fits of rage, speech present but incomprehensibleAbnormal reflexes.4Coma/unaroushableNoneDecerebrate, Babinski sign.GENERAL APPROACHES TO TREATMENTIdentify and eliminate the causes of cirrhosis.Assess the risk for variceral bleeding and begin pharmacologic prophylaxis when indicated.Evaluate clinical signs of ascites and manage with pharmacologic therapy (ex. diuretics) and paracentesis.HEs patient needs clinical vigilance and proper treatment.4. TREATMENT4.1 MANAGEMENT of PORTAL HYPERTENSION and VARICEAL BLEEDING4.1.1MANAGEMENT of ACUTE VARICEAL HEMORRHAGE

Drug TherapyMechanism 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.4.1.1MANAGEMENT of ACUTE VARICEAL HEMORRHAGEb. Endoscopic interventioni. Endoscopic variceal ligation (EVL).Placement of rubber bands around the varix.ii. SclerotherapyInjection of 1 to 4 mL of sclerosing agent into lumen of the varices to tamponade blood flow.Interventional and Surgical Treatment Approaches.For patient with refractory to pharmacologic or endoscopic therapy.Such as balloon tamponade and transjugular intrahepatic portossystemic shunt (TIPS).4.1.1MANAGEMENT of ACUTE VARICEAL HEMORRHAGERebleeding 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.4.1.2SECONDARY PROPHYLAXIS: PREVENTION OF REBLEEDINGAbstinence 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).

4.1 MANAGEMENT of ASCITESEmpirical antibiotics followed by definitive antibiotics.Agent:- Cefotaxime 2 g every 8 hours or others third-generation of cephalosporin for 5 days.- Ofloxacin 400 mg every 12 hours po for 8 days.- Quinolones.- TMP-SMZ (trimethoprim-sulfamethoxazole).4.2 MANAGEMENT of SBPTreatment approaches:Avoidance and prevention of precipitating factor, such as: GI bleeding, infection, electrolyte abnormalities.Reducing ammonia blood concentration by:- dietary restriction.- drug therapy.iii.Inhibition of the -aminobutyric acid (GABA)-benzodiazepine receptors.4.2 MANAGEMENT of HERestriction 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. 4.2.1 HYPERAMMONEMIA TREATMENTTHANK YOU