Cirrhosis and PHN final Pharmacotherapy PDF

Gastrointestinal Disorders Pharmacotherapy Cirrhosis and Portal Hypertension  Brief description Cirrhosis represents a late stage of progressive hepatic fibrosis with distortion of the architecture of the liver with formation of regenerative nodules. It can result from any...

Gastrointestinal Disorders Pharmacotherapy Cirrhosis and Portal Hypertension  Brief description Cirrhosis represents a late stage of progressive hepatic fibrosis with distortion of the architecture of the liver with formation of regenerative nodules. It can result from any cause of chronic liver disease e.g, chronic viral hepatitis, alcoholic liver disease.  Patients with cirrhosis develop a variety of complications which cause marked morbidity and mortality. The common complications include ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, hepatorenal syndrome and hepatocellular carcinoma.  Outline Complication of Cirrhosis Portal Hypertension & its complication Ascites & Spontaneous Bacterial Peritonitis Esophageal Varices Hepatic Encephalopathy Hepatorenal Syndrome  Introduction Cirrhosis, or end-stage liver disease Is fibrosis of the hepatic parenchyma resulting in nodule formation and altered hepatic function which results from a sustained wound healing response to chronic or acute liver injury from a variety of causes Most cases of cirrhosis: world wide chronic viral hepatitis liver injury associated with chronic alcohol consumption  Portal Hypertension and Cirrhosis: Introduction Definition : Cirrhosis, or end-stage liver disease, defined as  a diffuse process characterized by fibrosis and a conversion of the normal hepatic architecture into structurally abnormal nodules  Results increased resistance to blood flow in portal hypertension and the development of varices and ascites  Hepatocyte loss and intrahepatic shunting of blood results in diminished metabolic and synthetic function, which leads to hepatic encephalopathy (HE) and coagulopathy 5 Portal Hypertension and Cirrhosis: Introduction  Clinical consequences of cirrhosis include  impaired hepatocyte function, increased intrahepatic resistance of portal hypertension, and hepatocellular carcinoma  Circulatory irregularities such as splanchnic vasodilation, vasoconstriction and hypoperfusion of the kidneys, water and salt retention, and increased cardiac output 6  Pathophysiology and Etiology  Cirrhosis results in  Elevation of portal blood pressure because of fibrotic changes within the hepatic sinusoids  Changes in the levels of vasodilatory and Vasoconstrictor mediators, and  An increase in blood flow to the splanchnic vasculature Cont’d… patho  Fatty liver or steatosis from ethanol:  the first stage of liver injury - is characterized by lipid deposition in the hepatocytes  Steatosis is followed by liver inflammation (steatohepatitis), hepatocyte death, and collagen deposition leading to fibrosis  The specific mechanisms: not clear but suggestions ethanol-induced oxidative stress on the liver Consequences:  Cirrhosis and the pathophysiologic abnormalities that cause it result in  Ascites  Portal Hypertension  Esophageal varices  Hepatic encephalopathy, and  Coagulation disorders  Clinical Presentation: Sn and Sx  Anorexia, nausea, abdominal discomfort, weight loss, and malaise  Ascites, peripheral edema, jaundice, palmar erythema  Gynecomastia, testicle atrophy, amenorrhea, pubical hair lost  Hepatomegaly, spleenomegaly, encephalopathy, and bleeding Laboratory Findings  Initially elevated ALT and AST level but at the end stage they can be normal or below normal  Elevated bilrubin most of the time  Low albumin level  Prolong prothrombin time (PT) and APTT  Elevated serum creatinine and blood urea nitrogen (BUN)  An elevation of prothrombin time was the single most reliable manifestation of cirrhosis.  The combination of thrombocytopenia, encephalopathy, and ascites had the highest predictive value. Treatment: Cirrhosis  The major goals of treating patients with cirrhosis include:  Slowing or reversing the progression of liver disease  Preventing superimposed insults to the liver  Preventing and treating the complications  Determining the appropriateness and optimal timing for liver transplantation Portal Hypertension  Portal pressure is a function of flow and resistance to that flow across the hepatic vasculature  Normal portal pressure is below 6mmHg, and in cirrhotic patients may increase to 7 to 9mmHg  Portal hypertension:  results from both an increase in resistance to portal flow increased intrahepatic resistance due on intrahepatic vasoconstriction, sinusoidal compression, and fibrosis  and also an increase in portal venous inflow Caused by splanchnic vasodilation Portal Hypertension and Varices  Portal pressure increases to 5 mmHg more than the pressure in the inferior vena cava  Development of varices and alternative routes of blood flow  Risk of varices when portal pressure exceed the vena cava pressure by > 12 mmHg  Hemorrhage from varices occurs in 25-40% of cirrhotic patients  Each episode of bleeding carries a 30% risk of death  How Varices form  Portal hypertension causes blood flow to be forced backward, causing veins to enlarge and varices to develop across the esophagus and stomach from the pressure in the portal vein  The backup of pressure also causes the spleen to become enlarged  Management of varices  Involves three strategies:  Primary prophylaxis (prevention of the first bleeding episode);  Treatment of acute variceal hemorrhage; and  Secondary prophylaxis (prevention of rebleeding in patients who have previously bled) Primary Prophylaxis  Nonselective Beta -Adrenergic Blockade(Propranolol or nadolol)  The mainstay of primary prophylaxis  reduce portal pressure by reducing portal venous inflow via two mechanisms: a decrease in cardiac output through beta1-adrenergic blockade and a decrease in splanchnic blood flow through beta2-adrenergic blockade.  HR not less than 55 beats/min & SBP not less than 90 mm Hg  Adverse effects in 27% of patients  should be continued for life unless it is not tolerated BB in Varices…cont’d  Only nonselective β-blockers :  have an adrenergic dilatory effect in mesenteric arterioles ---- decrease in portal blood circulation and pressure  Propanolol & Nadolol :  start: Propranolol 20 mg BID or 10 mg three times a day or nadolol 20 mg once daily  dose titration to a reduction in resting heart rate of 20% to 25%, an absolute heart rate of 55 to 60 beats/min, or the development of adverse effects.  Selective β-blockers (e.g., atenolol and metoprolol) have little effect on mesenteric arterioles  have not been shown to be effective in primary prophylaxis  Isosorbide-5-mononitrate: mentioned; alone vs with BB???? Cont’d primary Px  Treatment Recommendations: Variceal Bleeding—Primary Prophylaxis  Prophylaxis therapy with a nonselective beta -adrenergic blocker pts with small varices (< 5 mm) who have not bled & have no criteria for increased risk of bleeding ……controversy, most agree Pts with small varices plus risk factors medium to large varices (varices > 5 mm} & have not bled plus high risk factor endoscopic variceal ligation can be used instead of BB But not for low risk factor, unless intolerant or CI to BB Acute Variceal Hemorrhage  An emergency and feared cxn of cirrhosis  Treatment goals include:  Volume resuscitation, acute treatment of bleeding, and prevention of recurrence of variceal bleeding Replenishment of blood volume and correction of coagulopathy must be done with packed erythrocytes (to increase Hb concentration to 10 g/dL) and fresh frozen plasma and platelets Protection of airway from aspiration of blood Antibiotics to prevent SBP and G-ve systemic infection Control of bleeding Prevention of rebleeding, and preservation of liver function Drug therapy: Acute variceal Bleeding  Drug Therapy  Drugs employed to manage acute variceal bleeding include: The somatostatin analogue octreotide or vapreotide and Vasopressin, terlipressin,  Work as splanchnic vasoconstrictors, thus decreasing portal blood flow and pressure  Endoscopic Therapy may be indicated Endoscopic variceal band ligation (EVL) Drug therapy: Acute variceal Bleeding  Infection Prophylaxis—Short-Term Antibiotics  Norfloxacin 400 mg BID for 7 days Vs no treatment controls: Norfloxacin group had a significantly lower incidence of SBP No significant difference was seen in mortality  Guidelines recommend: 7 days of antibiotic prophylaxis for prevention of SBP in patients with variceal hemorrhage with oral norfloxacin (400 mg BID) or ciprofloxacin IV (400 mg BID) if P.O. no possible  Ceftriaxone IV (1 g/day) for 7 days : FQ resistance high Secondary Prophylaxis/Prevention of Rebleeding  Secondary Prophylaxis: Prevention of Rebleeding  Prevent a recurrence of bleeding if survived first episode of bleeding  Combination therapy with beta-adrenergic blockers and chronic EVL : best option  Combo : BB + ISDN : unable to undergo EVL  initiation of β-blockers be delayed until after recovery of the initial variceal hemorrhage Block the patient’s acute tachycardia if pt hypotension Initiate: pt has had no bleeding for at least 24 hours and before the patient is discharged from the hospital  Ascites and Spontaneous Bacterial Peritonitis  Ascites is the accumulation of fluid within the peritoneal cavity  Most common complication of cirrhosis  Spontaneous bacterial peritonitis (SBP)  is an infection of preexisting ascitic fluid without evidence for an intra-abdominal secondary source such as a perforated viscus  SBP is almost always seen in the setting of end-stage liver disease Ascites mgt  Goals of therapy  To mobilize ascitic fluid  To diminish abdominal discomfort, back pain, and difficulty in ambulation  To prevent major complications  Non pharmacological management  Na+ and water restriction, therapuetic paracentesis  Pharmacological management  Diuretics Combination of spironolactone and furosemide  Treatment Objectives of treatment  Reduce complication rates  Treating the complications  Decrease hospitalization 28  Non pharmacologic  Salt restriction (< 2 g/day)-for ascites  Monitor weight regularly  Bed rest  Low protein diet-for encephalopathy  Endoscopic sclerotherapy and/or banding-for variceal bleeding 29  Pharmacologic treatment I. For ascites/edema First line o Spironolactone - Starting dose 100 mg/day in single or two divided doses - If there is response, increase doses every 3-7days (in 100 steps) - Maximum dose 400mg/day - Serum potassium should be checked regularly: at start, a dose increments and on each follow up visit 30  Add-on or alternative  Furosemide - Ass add-on: in patients who do not respond to spironolactone (body weight reduction less than 2 kg in one week) - As an alternative: in patients who have hyperkalemia or impaired kidney function at baseline or develop later - Starting dose from: 20mg, BID - Increments by 40mg/day - Maximum dose for this indication: 160 mg/day (80mg BID) 31  II. Encephalopathy  Encephalopathy is a group of conditions that cause brain dysfunction. Brain dysfunction can appear as confusion, memory loss, personality changes and/or coma in the most severe form.  Lactulose, 10–30mL PO (Via NG tube) 8 hourly. Aim for 2 soft stools /day and no diarrhea PLUS  Lactulose is a synthetic sugar used to treat constipation. It is broken down in the colon into products that pull water out from the body and into the colon  Metronidazole, 250mg, PO every 8 hour 32 III. Esophageal varices-prevention of variceal bleeding (Both primary and secondary)  Propranolol, 20mg – 40mg, PO, two to three times daily start low dose and escalate gradually. 33  IV. Spontaneous bacterial peritonitis  Treatment of Spontaneous bacterial peritonitis o First line: Ceftriaxone, 1000mg, IV, BID for 7-10 days  Alternative: Ciprofloxacin, 200mg, IV, BID for 7- 10 days 34  Prophylaxis for spontaneous bacterial peritonitis (SBP)  Indications to start prophylaxis - Patients who recover from an episode of SBP - Advanced cirrhosis and ascitic fluid protein lower than 1.5 g/dl without prior SBP - In patients with gastrointestinal bleeding and severe liver disease o First line: Norfloxacin, 400mg, P.O. daily  Duration of prophylaxis: Generally indefinite but if there is long-lasting improvement with disappearance of ascites, prophylaxis can be discontinued. 35 Approach to the patient with Ascites and SBP 36 Diuretics Therapy: Ascites Diuretics Therapy: Choice of agent  High level of circulating aldosterone  Decrease execration and increase production  Activation of RAS  hepatic impairment prolongs the half life of aldosterone  Low concentration of albumin  Spironolactone is rational choice  Dose 100 mg to 200 mg up to 400 mg  Combination with other diuretics, Furosemide  Spironolactone to furosemide ratio (100 : 40 mg)  Can be increased every 3 to 5 days simultaneously keeping ratio Ascite Rx cont’d…  Monitoring: diuretic therapy  Triamterene and amiloride : alternative to spironolactone if intolerable side effects  goal is a weight loss of 0.5 to 1 kg/day net fluid volume loss of about 0.5 to 1 L/day If presented with both edema and ascites : initial fluid loss of up to 1 L/day would be reasonable  Diuresis > 0.5 to 1 kg/day (0.5–1 L) : associated with volume depletion, hypotension, and compromised renal function  Monitoring fluid intake and urine output urine output should exceed fluid intake by about 300 to 1,000 mL/day Diuretic Complications and Management  Initiate: with single morning doses of spironolactone 100 mg and furosemide 40 mg administered orally  Titrate diuretic therapy every 3 to 5 days using the 100 mg:40 mg ratio to attain adequate natriuresis and weight loss  reasonable daily weight loss goal is 0.5 kg  Maximum daily doses are 400 mg spironolactone and 160 mg furosemide….. maintains normokalemia  D/C diuretic: experience uncontrolled or recurrent encephalopathy, severe hyponatremia, renal insufficiency Cxn…cont’d..  Electrolyte And Acid-base Disturbances  Hyponatremia, hyperkalemia, metabolic alkalosis Hyponatremia : temporary withdrawal of diuretics and free water restriction Hyperkalemia [in refractory ascites and impaired renal function requiring high doses of spironolactone] Decreasing or holding spironolactone depending on renal function and serum potassium Metabolic alkalosis [hypokalemia] : Furosemide can be temporarily withheld Prerenal azotemia [over diuresis]: Gradual diuresis Drug therapy: SBP  SBP  >92% of all cases of SBP are monomicrobial, with Escheria coli (the most common isolate),Klebsiella species, Other G-ve bacteria  G+ve organisms, Streptococcal (25%)  Anaerobic infection (rare