PHRM-511-L.S.No-7v-1

PHARMACOTHERAPY OF HEPATIC DISORDERS

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• The liver is the largest organ in the body and performs many important functions, so it is not surprising that diseases of the liver are a major cause of morbidity and mortality throughout the world.

• • • Cirrhosis, e.g., was responsible for more than 25,000 deaths in the USA in 2003.

In the developed world, the most common cause liver disease is alcohol abuse.

Although in keeping with the rise in obesity rates, the incidence of non alcoholic fatty liver disease ( NAFLD) is rapidly increasing.

• In contrast, in the developing world, infections caused by hepatitis virus and parasites are responsible for most chronic liver disease and hepatobiliary cancer.

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Major Hepatic Functions

• The liver performs a wide variety of functions: • More than half the glucose is absorbed is taken up by the liver and stored as glycogen or converted to glycerol and fatty acids ( to avoid hyperglycemia).

• • Amino acids are used for hepatic and plasma protein synthesis and excess amino acids are catabolised to urea.

(During fasting the liver release glucose, derived either from the breakdown of glycogen or from gluconeogenesis using amino acids released from extra hepatic tissues/ muscle).

• In both fed and fasting condition the liver plays a central role in lipid metabolism, producing very low density lipoprotein and further metabolizing low and high density lipoproteins. 3

Additional Hepatic functions:

• *The liver plays a central role in the metabolism of billirubin, bile salts, drugs and alcohol.

• Some vitamins, such as A, D and B12 are stored by the liver in large amounts. While other, Vitamin K and folate are stored in smaller conc.

• The liver can store minerals such as iron & copper.

• • • • *The liver cells are (1) Hepatocyte (2) Kupffer Cell (3) Stellate Cell (4) Endothelial cells.

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Jaundice

• Jaundice is a yellow discoloration of the skin, mucous membranes, and the whites of the eyes caused by increased amounts of bilirubin in the blood. Jaundice is a sign of an underlying disease process. • • Bilirubin is a by-product of the daily natural breakdown and destruction of RBC in the body. The hemoglobin molecule that is released into the blood by this process is split, with the heme portion undergoing a chemical conversion to bilirubin.

• Normally, the liver metabolizes and excretes the bilirubin in the form of bile. However, if there is a disruption in this normal metabolism and /or production of bilirubin, jaundice may result. 5

Bilirubin Metabolism

• Unconjugated bilirubin is conjugated by the endoplasmic reticulum enzyme (Glucoronyl Transferase).

• • They form mono- and diglucoronide.

This bilirubin conjugate are water soluble are exported into bile via specific carriers on the hepatocyte membrane • Conjugated bilirubin is metabolised by colonic bacteria to form stercobilinogen, which may be further oxidized to stercobilin.

• • • Both stercobilinogen and stercobilin are then excreted in the stool.

A small amount of stercobilinogen is absorbed from the bowel , passes through the liver and is excreted in the urine, where it is known as urobilinogen, following further oxidization, Urobilin.

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• • Hemolytic Jaundice Increased destruction of red blood cells or their precursors in the bone marrow, causing increased production of bilirubin. Jaundice due to hemolysis is usually mild because a healthy liver can excrete a bilirubin load six times greater than normal before unconjugated bilirubin accumulates in the plasma.

• • Non-hemolytic Hyperbilirubinemia Decreased conjugation of bilirubin, which accumulates as unconjugated bilirubin in the blood. The unconjugated bilirubin increases during fasting and fall during treatment with phenobarbital.

• • Hepatocellular Jaundice: An inability of the liver to transport bilirubin into the bile -- bilirubin in the blood increase.

 causes parenchymal liver diseases. Bilirubin transport across the hepatocyte may be impaired at any point. As a result, the conc. of conjugated & unconjugated • • Cholestatic Jaundice: More & more severe, because conjugated bilirubin is unable to enter the bile canaliculi and passes back into the blood, and there is a failure of clearance of unconjugated bilirubin arriving at the liver cells.

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Cirrhosis

• Cirrhosis is a complication of many liver diseases that is characterized by abnormal structure and function of the liver. • The diseases that lead to cirrhosis do so because they injure and kill liver cells, and the inflammation and repair that is associated with the dying liver cells causes scar tissue to form. • There are many causes of cirrhosis; they include chemicals (such as alcohol, fat, and certain medications), viruses, toxic metals (such as iron and copper that accumulate in the liver as a result of genetic diseases), and autoimmune liver disease in which the body's immune system attacks the liver. 9

Hepatic Encephalopathy

• Patients with an abnormal sleep cycle, impaired thinking, odd behavior, or other signs of hepatic encephalopathy usually should be treated with a low protein diet and oral lactulose. Dietary protein is restricted because it is a source of the toxic compounds that cause hepatic encephalopathy. • • Lactulose, which is a liquid, traps the toxic compounds in the colon. Consequently, they cannot be absorbed into the blood stream and cause encephalopathy. • • If symptoms of encephalopathy persist, oral antibiotics such as neomycin or metronidazole (Flagyl), can be added to the treatment regimen. Antibiotics work by blocking the production of the toxic compounds by the bacteria in the colon. 10

Liver cancer

• Several types of liver disease that cause cirrhosis are associated with a particularly high incidence of liver cancer, for example, hepatitis B and C, and it would be useful to screen for liver cancer since early surgical treatment or transplantation of the liver can cure the patient of cancer. • The difficulty is that the methods available for screening are only partially effective, identifying at best only 50% of patients at a curable stage of their cancer. • Despite the partial effectiveness of screening, most patients with cirrhosis, particularly hepatitis B and C, are screened yearly or every six months with ultrasound examination of the liver and measurements of cancer-produced proteins in the blood, e.g. alpha fetoprotein.

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Liver transplantation

• • • Cirrhosis is irreversible. Many patients' liver function will gradually worsen despite treatment and complications of cirrhosis will increase and become difficult to treat.

Therefore, when cirrhosis is far advanced, liver transplantation often is the only option for treatment. Recent advances in surgical transplantation and medications to prevent infection and rejection of the transplanted liver have greatly improved survival after transplantation. • On average, more than 80% of patients who receive transplants are alive after five years. Not everyone with cirrhosis is a candidate for transplantation.

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Viral Hepatitis

• Hepatitis means inflammation of the liver. Many illnesses and conditions can cause inflammation of the liver, for example, drugs, alcohol, chemicals, and autoimmune diseases. • Many viruses, for example, the virus of mononucleosis and the cytomegalovirus can inflame the liver. Most viruses, however, do not primarily attack the liver; the liver is just one of several organs that the viruses affect. • There are several hepatitis viruses; they have been named types A, B, C, D, E, F (not confirmed), and G. • As our knowledge of hepatitis viruses grows, it is likely that this alphabetical list will become longer. The most common hepatitis viruses are types A, B, and C. 13

Hepatitis A

• The hepatitis A virus belongs to the picornavirus group of enteroviruses.

• The hepatitis caused by HAV is an acute illness (acute viral hepatitis) that never becomes chronic. At one time, hepatitis A was referred to as "infectious hepatitis" because it could be spread from person to person like other viral infections. • Infection with hepatitis A virus can be spread through the ingestion of food or water, especially where unsanitary conditions allow water or food to become contaminated by human waste containing hepatitis A (the fecal-oral mode of transmission). • It also is common to have infection spread to customers in restaurants and among children and workers in day care centers if hand washing and sanitary precautions are not observed. 14

Hepatitis B

• The hepatitis B virus consists of a core containing DNA and DNA polymerase enzyme needed for virus replication. The core of the virus is surrounded by surface protein, and excess of its surface protein circulate in the blood.

• It is now known that hepatitis B can spread by sexual contact, the transfer of blood or serum through shared needles in drug abusers, accidental needle sticks with needles contaminated with infected blood, blood transfusions, hemodialysis, and by infected mothers to their newborns. • Patients with chronic hepatitis B infection also are at risk of developing cirrhosis, liver failure and liver cancer. 15

Hepatitis C

• This is caused by RNA flavivirus. Most individuals will be unaware of when they become infected and are only identified when they develop chronic liver diseases.

• There are about 150,000 new cases of hepatitis C each year. Type C hepatitis was previously referred to as "non-A, non-B hepatitis," because the causative virus had not been identified, but it was known to be neither hepatitis A nor hepatitis B. • The hepatitis C virus (HCV) usually is spread by shared needles among drug abusers, blood transfusion, hemodialysis, and needle sticks.

• Approximately 90% of transfusion-associated hepatitis is caused by hepatitis C. An estimated 50-70% of patients with acute hepatitis C infection develop chronic HCV infection. 16

Classification of Antiviral drugs:

• • • • • • • • • • • (1) Inhibition of penetration of host cell by virus: Drug of Choice: i. Amantadine (Amantadine acts by interfering with the uncoating and thus transfer of free viral nucleic acid into the host cell).

ii. Gamma Globulin (Acts by neutralize the viruses and prevent their attachment to host cells).

(2) Inhibition of viral replication: Drug of Choice: Vidarabine, Acyclovir, Ganciclovir etc.

(This drugs inhibit the synthesis of viral nucleic acid by inhibit viral DNA polymerase; Ganciclover is used against cytomegalovirus).

(3) Immunomodulators: Drug of Choice: Interferons (Interferons induce the host cells ribosomes, enzymes which inhibit viral m RNA. It can stimulate host immune response; Alpha-interferon is used for Hepatitis B & C.) 17

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Interferons (IFN)

• • Interferon is a protective glycoprotein or immunomodulator. A virus infected cell will release interferons causing nearby cells to ramp up their anti-viral defenses. Its plasma half-life is 2-4 hrs. • Types: (1) Alpha-Interferon (Induced by virus from WBC & fibroblast; produced by leukocyte).

• (2) Beta-Interferon (Induced by virus from WBC & fibroblast; produced by fibroblast).

(3) Gamma-Interferon (Produced by T-lymphocytes).

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• IFNs belong to the large class of proteins known as cytokines. Interferons are named for their ability to "interfere" with viral replication by protecting cells from virus infection. • IFNs also have other functions: they activate immune cells, such as natural killer cells and macrophages; they increase host defenses by up-regulating antigen presentation by virtue of increasing the expression of major histocompatibility complex (MHC) antigens. • Certain symptoms of infections, such as fever, muscle pain and "flu like symptoms", are also caused by the production of IFNs and other cytokines.

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M/A of Interferon: Interferon Synthesis of Translation Inhibitory Protein (TIP) in viral infected cell.

TIP inhibit translation of viral mRNA.

Viral protein synthesis is inhibited.

(They act in the early phase of viral diseases to limit the spread of virus as they are produced within 4-48 hours of infection).

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• Mechanism of Interferons (1): • A virus-infected cell releases viral particles that can infect nearby cells. • However, the infected cell can prime neighboring cells for a potential infection by the virus by releasing interferon. • In response to interferon, cells produce large amounts of an enzyme known as protein kinase R (PKR). • • This enzyme phosphorylates a protein known as eIF-2 in response to new viral infections; the phosphorylated eIF-2 forms an inactive complex with another protein, called eIF2B, to reduce protein synthesis within the cell. 22

• Another cellular enzyme, RNAse L—also induced by interferon action—destroys RNA within the cells to further reduce protein synthesis of both viral and host genes. • Inhibited protein synthesis destroys both the virus and infected host. • In addition, interferons induce production of hundreds of other proteins—known collectively as interferon-stimulated genes (ISGs)— that have roles in combating viruses and other actions produced by interferon. • They also limit viral spread by increasing activity, which kills virus infected cells by promoting apoptosis.

• The effect of IFN is also linked to its protective role against certain cancers cells.

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• Mechanism of Interferon (2) • Interferons is to upregulate major histocompatibility complex molecules, MHC I (Major histocompatibility Complex) and MHC II, and increase immunoproteasome activity. • Higher MHC I expression increases presentation of viral peptides to cytotoxic T cells (Killer cell), while the immunoproteasome processes viral peptides for loading onto the MHC I molecule, thereby increasing the recognition and killing of infected cells. • Higher MHC II expression increases presentation of viral peptides to helper T cells; these cells release cytokines (such as more interferons and interleukins, among others) that signal to and co-ordinate the activity of other immune cells.

• Interferons, such as interferon gamma, directly activate other immune cells, such as macrophages and natural killer cells.

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Limitations of Antiviral drugs:

• • (1) Obtaining of selective toxicity against virus is difficult. Because their replication is intimately involved with the normal synthetic process of the host cells.

• (2) The drugs are relatively ineffective. Because viral replication occurs during the incubation period. When the patient has a recognized systemic disease, the virus has spread throughout the body.

• (3) Some viruses become latent within cells. No antiviral drug can eradicate them.

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