Week 2 Review - pharm.pdf

Week 2: Digestive System Blood supply – 2 sources (ensure liver is receiving continuous supply of blood) Hepatic artery o 500 ml/min of oxygenated blood o 30% of liver’s blood supply Hepatic portal vein o 1000 ml/min of partly oxygenated blood...

Week 2: Digestive System Blood supply – 2 sources (ensure liver is receiving continuous supply of blood) Hepatic artery o 500 ml/min of oxygenated blood o 30% of liver’s blood supply Hepatic portal vein o 1000 ml/min of partly oxygenated blood o 70% of liver’s blood supply, plus rich supply of nutrients, toxins, drugs from stomach, small and large intestines, pancreas and spleen Portal venous system The portal venous system refers to a system of veins that come from the stomach, bowel, spleen and pancreas to the portal vein The portal vein then breaks off into smaller blood vessels and travels through the liver Main functions of the liver Blood filtration and detoxification Metabolism (carbohydrate, lipid and protein) Bile production Storage (vitamin, minerals, glycogen) Synthesis (hormones, proteins) Immune function Hepatitis Viral hepatitis Acute/Chronic Type of virus A Acute RNA B DNA C Acute or chronic D RNA E Acute Widespread inflammation of liver tissue Hepatitis virus destroys hepatocytes (liver cells) Large numbers destroyed in acute infection, causing necrosis Impairment of normal liver functions, including o Protein metabolism o Blood coagulation (synthesis of coagulation factors) o Synthesis of albumin o Production of bile Antigen-antibody immune complex Antigen – hepatitis virus Antibodies – protective proteins created by the immune system (important for detection and screening of hepatitis) Antigen-antibody complex initiates the immune response & activates the complement system Acute phase Can be asymptomatic Manifestations: anorexia, n&v, malaise, fatigue, h/a, low-grade fever, arthralgias, skin rash, RUQ discomfort Sense of taste can change Possible physical exam findings: o Hepatomegaly (RUQ), lymphadenopathy Jaundice o Icteric (jaundice is present), anicteric or non-icteric (no jaundice) Acute vs Chronic Hepatitis Clinical Manifestations Acute Chronic Altered taste and smell Fatigue Anorexia Hepatomegaly Arthralgias Malaise Dark urine Myalgia and arthralgia Fatigue Easy bruising Low-grade fever Palmar erythema  Headache Spider angiomas Hepatomegaly Splenomegaly Jaundice Clay-coloured stools -Hepatitis can present with wide range of Malaise symptoms Chronic hepatitis can have similar symptoms to Nausea & vomiting acute (ex. fatigue, megaly, malaise, etc.) Pruritis -more distinct to chronic = spider angiomas etc. RUQ tenderness -be able to differentiate if it is acute vs chronic Splenomegaly symptoms Weight loss **palmar erythema is most common manifestation of chronic hepatitis Bilirubin Bilirubin is created when the spleen breaks down old & damaged RBCs (RBC → heme + globin → bilirubin) o Orange yellow pigment, produced from normal breakdown of RBCs (gives bile its colour) Unconj. bilirubin (bound to albumin), iron and proteins then travel from the spleen to the liver o Unconjugated = indirect o Unconjugated is converted to conjugated (aka direct) bilirubin in the liver → makes it water soluble and allow it to be excreted in bile Liver processes bilirubin (makes it conjugated/soluble), which allows it to be excreted in bile Bilirubin metabolism Bilirubin metabolism happens in the liver Normally the liver creates bile from bilirubin and other waste products Bile normally moves through the bile ducts, into the gallbladder and the small intestine to help digestion o If liver doesn’t synthesize enough albumin, bile can’t get where it needs to go → buildup of bilirubin in liver → jaundice Clinical manifestations of increased levels of bilirubin Jaundice: bilirubin gets deposited in the skin and sclera Pruritis (itchiness): bile salts accumulate beneath the skin Dak amber urine: bilirubin is being excreted by the kidneys Clay-coloured or white stool that is floating: lack of bilirubin in stool, high fat content of stool Diagnostic tests o Serological – identifies specific antibodies and antigens (ex. Hepatitis B surface antigen = HBsAg o Liver enzymes ▪ ALT – elevated levels indicate liver cell injury or inflammation More specific marker bc found more primarily in liver ▪ AST – found in other tissues ▪ ALP – found in liver and other areas o GGT – also in bile ducts and other organs – marker for damage to bile duct Important function of livers – synthesizing albumin, clotting factors and bilirubin  In hepatitis – decreased albumin bc not able to synthesize albumin effectively o Bilirubin – inc bc can’t conjugate or clear it out o INR/prothrombin time – inc bc blood will take longer to clot if we don’t have enough clotting factors Usually only concerned when 2-3x above the normal liver Hepatitis A Cause: hepatitis A virus (HAV) Typically acute, self-limiting (resolves on its own) Route of transmission: oral-fecal route (contaminated food/water) Most infectious during 2 weeks before symptoms develop Viral serological tests: o Anti-HAV IgM means acute hepatitis – antibody to HAV immunoglobulin M ▪ IgM is first responder → short lived → recent new infection o Anti-HAV IgG means past infection, or vaccination – antibody to HAV immunoglobulin G ▪ IgG, produced later in infection process - provides long term immunity o Elevation in IgM → recently infected o Elevation in IgM and IgG → may be infected few weeks ago o Elevation in IgG → infected a long time ago Acute symptoms in adults, but typically not in children No specific treatment Management is focused on relief of symptoms → hydration, resting, avoid alcohol Recovery gives lifelong immunity Vaccine available (e.g. Havrix) Hepatitis B Cause: Hepatitis B Virus (HBV) Route of transmission: exposure to blood or blood products (parenteral or mucosal), sexual contact, perinatal transmission Infectious before symptoms appear, may be asymptomatic Infant born to an HBV-infected person needs to receive first dose of vaccination and immunoglobulins within 12 hours of birth o If not, infant will have acute infection (which typically is asymptomatic) and 90% will develop chronic infection Management focuses on symptom relief and education to prevent transmission Antiviral therapy may be needed Hepatitis B: selected viral serologic tests HBsAg: Hepatitis B surface antigen – indicates infection, and if present after 6 months indicates chronic infection Anti-HBs: antibody to hepatitis B surface antigen – indicates immunity, either from past infection or vaccination HBV DNA – indicates viral load (measures how much is in you) o this is a DNA type of virus so it is a good marker for active Hep B virus replication o not important for diagnosis, but important for ongoing management and treatment o if treatment is effective viral load will dec Hepatitis B pharmacotherapy to reduce viral load, slow the rate of disease progression, prevent long-term complications (such as cirrhosis, liver cancer) Indicated for patients who are having a severe acute course, persistent symptoms Pegylated-interferon alfa (old treatment) rarely used since advent of oral antiviral therapy Nucleoside analogues are oral antiviral agents (newer form of treatment that is more common now) o Work by inhibiting viral DNA replication o Agents include entecavir & tenofovir o Nucleoside analogues have very rare but possible AE of severe hepatomegaly & lactic acidosis o Tenofovir: possible AE of nephrotoxicity o Entecavir: contraindicated in pregnancy Hepatitis B Vaccine Hep B only – Energix-B, Recombivax Hep A & B – Twinrix Vaccines contain hep B surface antigen (HBsAg) Usually given 3 doses: at 0, 1, and 6 months Hepatitis C Cause: hepatitis C virus (HCV) Route of transmission: exposure to blood or blood products (parenteral or mucosal), sexual contact, perinatal transmission (like Hep B) Infectious 1-2 weeks before symptoms appear and can be asymptomatic Anti-HCV: antibody to hepatitis C virus – indicates past or current infection HCV RNA – viral load, confirms whether disease is active There are 6 diff genotypes of HCV – the different genotypes are important in determining treatment plans and predicting how diseases will progress Hepatitis C pharmacotherapy Evidence that more than 50% of people with acute hepatitis C will clear infection spontaneously, however early treatment is recommended to prevent complications Indicated for people with acute and chronic HCV infection Goal: cure HCV infection Direct-acting antiviral agents (DAAs) Direct-acting antiviral agents (DAAs) were introduced in 2011 o DAAs are medications that work by interfering with RNA replication of the HCV These drugs target specific steps in HCV replication (4 categories of drugs) o Protease inhibitors work by inhibiting viral protease, which is needed for RNA replication of HCV ▪ AE can include hepatic injury, severe rashes, photosensitivity o NS5A inhibitors inhibit the protein NS5A that is needed for RNA replication and assembly of HCV o NS5B nucleoside polymerase inhibitors (NPIs) o NS5B non-nucleoside polymerase inhibitors (NNPIs) ▪ NS5B inhibitors (NPIs and NNPIs) inhibit the protein NS5B that is needed for RNA replication of HCV o Common AE of all are headache & fatigue Used in children older than 3 years Not recommended during pregnancy These agents are used in combo to dec developing viral resistance 12 week course of therapy is typical Need to check response to agents by checking HCV RNA (viral load) at 12 weeks after the end of therapy Interferon alpha and ribavirin in combination are rarely (if ever) used since advent of DAAs Ribavirin may be used with DAAs o Common side effects include: anemia, fatigue, H/A, nausea, insomnia o AE include hemolytic anemia, teratogenic effects Hepatitis D Cause: Hepatitis D virus (HDV) Hep D can only cause infection if Hep B is present Route of transmission is same as hep B Treatment of acute HDV is mostly supportive Chronic cases may require treatment with pegylated interferon alpha o Flu-like symptoms occur in up to 90% of patients, other side effects include fatigue, anorexia, nausea, diarrhea, weight loss, hair loss, bone marrow suppression Hepatitis E Cause: hepatitis E virus (HEV) Route of transmission is oral-fecal Zoonotic: may be transmitted from animals to humans Outbreaks typically associated w contaminated water supply Treatment is mostly supportive; disease is usually mild and self-limiting Chronic disease usually occurs in immunocompromised patients; treatments may include ribavirin Cirrhosis Chronic progressive disease characterized by fibrosis (development of scar tissue) and inflammation Fibrosis occurs when the cells try to regenerate, but the regeneration is disorganized Results in an overgrowth of new, fibrous connective tissue which distorts the normal structure of the liver’s lobules o Effects liver structure and function o Gold standard: biopsy to look at cells, but often can diagnose with basic U/S bc of how different the appearance is o Final stage of liver disease  o Can be prevented! Causes of cirrhosis Cirrhosis is the final state of chronic liver disease o Chronic viral hepatitis – hep B and C can become chronic (not all) o Alcohol (excessive use) – alcohol has a direct, hepatoxic effect that causes cell necrosis & fatty infiltration in the liver o Non-alcoholic fatty liver disease – characterized by too much fat being stored in liver cells (i.e. obesity, type 2 diabetes, high cholesterol) o Genetic diseases o liver congestion associated with heart failure Pathophysiology of cirrhosis key changes that happen during cirrhosis o tissue that isn’t well perfumed and damaged can lead to reduced blood flow to the liver —> ischemia and necrosis o body will try to replace those cells but will replace with scar tissue o when it is replaced, liver loses functionality o fibrous tissue can form nodules —> hallmark for cirrhosis o nodules can further disrupt normal architecture of the liver o damage —> impaired blood flow —> decreased function d/t irregular cell growth, lack of nutrition, and hypoxia Clinical manifestations of cirrhosis compensated o liver is still able to function normally o often is undetected o may have abdo pain, non-specific signs & symptoms o want to do routine tests like LFTs decompensated o liver is not functioning normally o illustrated by tests of liver function: low albumin, high bilirubin, inc INR o clinical signs & symptoms of liver disease – i.e. jaundice (common), as cites, hepatic encephalopathy o our focus will be on decompensated cirrhosis Clinical manifestations of cirrhosis: Endocrine disturbances one of the functions of the liver is to metabolize estrogen & testosterone (maintains hormonal balance) o if the liver function is impaired, then the body will accumulate estrogen o increase in estrogen can cause gynecomastia (in males), palmar erythema, spider angiomas, amenorrhea in younger women and vaginal bleeding in older women ▪ gynecomastia: an increase in the amount of breast gland tissue in males ▪ palmar erythema: rare condition that makes your palms red; they may also feel warm ▪ spider angioma: collection of blood vessels under the surface of your skin (red to purple) ▪ amenorrhea: absence of menstruation o in addition, a decrease in testosterone (not enough protein to bind to) can cause impotence and testicular atrophy Portal hypertension fibrosis and changes to the blood vessels in the liver due to cirrhosis leads to resistance to blood flow within the portal venous system this causes portal HTN, which is abnormally high BP in the portal venous system most complications of cirrhosis are related to portal HTN o esophageal & gastric varices – swollen blood vessels in the upper gastrointestinal tract that can cause bleeding – caused by blockage in blood flow to liver o ascites – condition that occurs when fluid collects in spaces in your belly (can be painful)  o hepatic encephalopathy – potentially reversible; characterized by a range of neuropsychiatric and neuromuscular abnormalities resulting from the buildup of toxic substances in the bloodstream —> impacting brain function o hepatorenal syndrome - multi organ condition of acute kidney injury – pts with this condition prevent with s&s of liver failure and oliguria Decrease of pressure in portal venous system will prevent complications When you have a lot of pressure developing the body will try to bypass the high pressure areas New vessels can reform to get blood around the liver This circulation can lead to development of esophageal varices (most common type), gastric varices, and hemorrhoids Prominent veins in abdo can be a sign of this Esophageal & gastric varices Varices are enlarged, tortuous veins (large and winding d/t inc pressure in the venous system) Esophageal & gastric varices can rupture & bleed May see hematemesis (vomiting blood) or melena (more common for gastric) Bleeding esophageal varies are an emergency Management of varices Avoidance of irritants: ASA, NSAIDs o NSAIDs can irritate stomach lining Non-selective beta-blocker agents may be used to prevent bleeding, such as propranolol o Reduces portal venous pressure by decreasing the C/O Bleeding varices need treatment with medication and endoscopic therapy o Initial management: hemodynamics stabilization o Medications: octreotide or vasopressin, used to reduce blood flow o Octreotide used more often, fewer adverse effects Endoscopy o Sclerotherapy (done with endoscopy) – injecting solution in varices that causes clotting o Variceal ligation (this is use of elastic bands to tie off the vessels that are bleeding) o Compression of the varices with an inflatable tube or balloon (balloon tamponade) – temporary control but applies direct pressure until we can do more definitive treatment such as sclerotherapy or ligation Shunting procedure o Interventional radiology to create a shunt from the portal vein to the inferior vena cava (done as last step) —> transjugular intrahepatic portosystemic shunt (TIPS) ▪ Radiologist inserts stent in jugular to liver ▪ Imaging used to visualize it and guide it down to where it has to go ▪ Stent created a channel between portal vein and hepatic vein, and allows blood flow to bypass liver and go into systemic circulation ▪ Minimally invasive  ▪ But detoxification issue – one of key functions of liver is to filter out ammonia and other toxins from blood —> can lead to complications (last resort) Peripheral edema Swelling of the tissues (lower extremities) because of fluid accumulation Decreased oncotic pressure o Oncotic pressure is pressure exerted by proteins o Largest protein exerting this pressure is albumin o In cirrhosis we have reduced oncotic pressure which can allow fluid to leak from vasculature into tissues Portal hypertension – increased pressure in portal vein pushing fluid out of vasculature into other areas Ascites The accumulation of serous fluid in the peritoneal cavity Serous fluid fills the body’s cavities, it is typically a thin, watery, pale yellow, transparent fluid There are several factors that lead to ascites, and 3 important factors are o Portal hypertension o Hypoalbuminemia o Hyperaldosteronism Pathophysiology of ascites  Portal hypertension: increased pressure in the portal venous system pushes proteins from the blood vessels into the lymphatic space, but lymphatic drainage is impaired, and protein & water leak into the peritoneal cavity Hypoalbuminemia: the decreased synthesis of albumin means that there is decreased colloidal oncotic pressure o fluid accumulates in the interstitial spaces and leaks into the peritoneal cavity Hyperaldosteronism o Damaged hepatocytes stop metabolizing aldosterone o Aldosterone accumulates, and aldosterone stimulates the kidneys to increase water & sodium reabsorption ▪ If the CO is decreased, there is activation of the renin-angiotensin-aldosterone-system which leads to an inc in anti-diuretic hormone, which leads to additional water retention Clinical manifestations of Ascites Abdo distension with weight gain Umbilicus can be everted Abdominal striae with distended abdominal wall veins Signs of dehydration – all the fluid is going into the peritoneal space, not where it needs to be in vasculature space Management of Ascites Assessment & monitoring o Vitals, abdominal girth, fluid balance, electrolytes, albumin o Be aware of respiratory distress – peritoneal cavity may be pushing up on the lungs —> poor lung expansion ▪ Have these pts sit upright to help with lung expansion and breathing o Measure abdominal girth – daily weights to see if retaining fluid Sodium restriction o Limit sodium to 2 grams/day can help reduce fluid retention Diuretic therapy o Increase sodium excretion o Combination of drugs is typically used that work at different. Sites of the nephron (i.e. spironolactone and furosemide) Paracentesis o Catheter is used to remove fluid from the abdominal cavity o Generally only done to relieve symptoms – relief is temporary o Remove 1-2 L of fluid at a time and see how patients are coping. While they are doing this, pts can lose 10-30 g of protein o Risk of infection is there o In addition to removing fluid, they will send it to be analyzed to determine cause of ascites Number of hematological conditions can stem Cirrhosis leads to scaring of liver which increases pressure which causes blood to backup to spleen and other organs Backup of blood leads to engorged organs (splenomegaly – engorged spleen) o Large spleen can trap and destroy more blood cells than normal at a faster rate —> anemia (RBC, leukopenia (WBC), thrombocytopenia (Plts) o With thrombocytopenia – liver function is impaired which can exacerbate thrombocytopenia Hematological conditions Decreased clotting factors In advanced cirrhosis, the liver is unable to produce prothrombin and other factors needed for blood clotting Signs & symptoms include increased bleeding o Epistaxis: nosebleed o Purpura and petechiae ▪ Petechiae: tiny red dots caused by broken blood vessels (type of purpura) ▪ Purpura: larger spots that are between 4-10 mm in diameter, they are caused by small blood vessels leaking blood under the skin o Easy bruising o Gingival bleeding Hepatic encephalopathy This is a serious complication of cirrhosis o protein digestion in small intestines – once absorbed, amino acids transported to liver production of ammonia from intestine —> converts to urea by normal healthy liver o clinical signs of hepatic encephalopathy: liver is not able to detoxify NH3 —> accumulation —> crosses BBB Clinical manifestations of Hepatic Encephalopathy Early signs o Emotionally labeled (highs and lows) o Apathy o Irritability, agitation o Memory loss o Drowsiness, insomnia o Slows slurred speech o Impaired judgment Late signs o Confusion o Asterixis (flapping tremors) – caused by nerve damage; brief, irregular, involuntary jerking movements in the muscles (usually fingers and wrists o Fetor hepaticus – “breath of the dead” – sweet, musty or like a combination of rotten eggs and garlic Management of hepatic encephalopathy Goal is to reduce ammonia formation by decreasing the amount of ammonia formed in the intestines Lactulose (osmotic laxative) is used to prevent ammonia absorption (lactulose can be administered PO, NG, or via retention enema) Lactulose traps the ammonia in the intestine and the laxative action expels it o If patient does not respond to lactulose, rifaximin (antibiotic) can be added to reduce production of ammonia by targeting gut bacteria that produces it Hepatorenal syndrome This is renal failure with advancing azotemia, oliguria and intractable ascites o Azotemia: nitrogenous waste (urea/creatinine) accumulation Results bc of dec blood volume to kidneys secondary to portal HTN In patients with cirrhosis, it is typically seen following diuretic therapy, gastrointestinal hemorrhage, or paracentesis Creatinine will be elevated Liver transplantation will reverse the kidney failure – dialysis may be helpful Often times pts are resistant to treatment —> overworking the kidney following ascites treatment Certain meds may be helpful to shunt off blood: vasodilators Cirrhosis: diagnostic tests LFTs (AST, ALT, GGT) are increased Decreased albumin PT and INR prolonged Increased bilirubin (hyperbilirubinemia) CBC: thrombocytopenia, leukopenia, anemia Liver biopsy: to identify liver cell changes (not necessary with clinical manifestations of cirrhosis) (gold standard) Ultrasound o Can identify changes in liver size, shape, texture; assess degree of fibrosis (scarring) o Identify complications (i.e. ascites, splenomegaly) o Evaluate presence/severity of portal hypertension Cirrhosis: management Medications: no specific med therapy for cirrhosis, but used to treat underlying cause (e.g. antivirals for hepatitis), or symptoms (e.g. antacids for gastric discomfort) and complications (i.e. diuretics for ascites) Lifestyle changes (i.e. avoid alcohol, healthy diet, exercise) Vitamins & nutritional supplements may be needed Diet: high in calories, high in carbohydrates, moderate to low levels of fat Sodium restriction with ascites & peripheral edema Procedures (i.e. paracentesis, TIPS) Regular monitoring (e.g. blood tests, imaging, endoscopies) Liver transplant Review Questions 1. Which of the following proteins is primarily synthesized by the liver? a. Insulin b. Hemoglobin c. Albumin d. Immunoglobulins 2. Which of the following statements correctly describes the blood supply to the liver? a. the hepatic artery provides most of the liver’s blood supply b. the hepatic portal vein provides most of the liver’s blood supply c. all of the blood supply to the liver comes from the hepatic artery d. the hepatic artery and the hepatic portal vein each provide 50% of the liver’s blood supply 3. which of the following substances is primarily detoxified by the liver? a. Bilirubin b. Creatinine c. Ammonia (forms urea) d. Lactate 4. Which of the following clinical manifestations is most characteristic of chronic hepatitis? a. Dark urine  b. Jaundice c. Palmar erythema d. Nausea and vomiting 5. Which of the following classes of medications is commonly used in treatment of chronic hepatitis B? a. Nucleotide analogs b. Protease inhibitors c. NS5A inhibitors d. Nucleoside analogs 6. Which of the following hepatitis viruses are preventable through vaccination in Canada? a. Hep A & B b. Hep A, B and D c. Hep A, B, C, and D d. Hep A & D 7. Hepatic fat accumulation is seen in which form of cirrhosis? a. Biliary cirrhosis b. Hepatitis-C related cirrhosis c. Postnecrotic cirrhosis d. Alcoholic cirrhosis 8. The most common clinical manifestation of portal HTN is ________ bleeding a. Rectal b. Duodenal c. Esophageal d. Intestinal 9. Which of the following is a key management strategy for managing cirrhosis? a. High-fat diet to improve energy levels b. Regular use of broad-spectrum antibiotics to prevent infections c. Diuretics and sodium restriction to manage ascites d. Routine administration of corticosteroids to reduce liver