Hepatitis medications

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Hepatitis medications

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What is the mechanism of resistance to Ribavirin?

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Content Reviewers:

Yifan Xiao, MD

Anti-hepatitis medications are a group of antiviral agents used to treat viral hepatitis, which is the inflammation of the liver caused by some sort of virus that targets and damages liver cells.

Now, viral hepatitis can be acute or chronic.

Acute hepatitis lasts for six months or less, and usually resolves on its own without any antiviral treatment.

Chronic hepatitis lasts for more than six months, sometimes even for decades.

Anti-hepatitis medications are mainly used to treat chronic hepatitis and the two main viruses are hepatitis B virus, or HBV, and hepatitis C virus, or HCV.

Alright, so, HCV is a single stranded RNA virus.

What this means is that HCV inject its RNA into the host’s cell and it can immediately use its host’s ribosomes and translate the proteins needed to make more viruses, like capsomere proteins and enzymes like RNA-dependent RNA polymerase.

This RNA-dependent RNA polymerase uses the viral RNA as a template, and uses the hepatocyte’s nucleotides to transcribe a complementary strand of RNA, which is then used to form new baby viruses!

HBV on the other hand is a double stranded DNA virus.

Once the DNA gets injected into a new cell, it enters the cell’s nucleus and is replicated by the host cell’s machinery.

It’s also transcribed into several messenger RNAs and a pregenomic RNA, and then the messenger RNAs are used to make capsomere proteins and enzymes like DNA polymerase.

DNA polymerase uses the pregenomic RNA to synthesize new copies of the viral DNA, which is combined with the capsomere proteins to assemble new viruses.

With each type of virus, whether it’s RNA or DNA, it’s turning your own cells into virus making factories and pumping out new viruses.

This process strains, damages and potentially kills the infected hepatocytes.

When these liver cells die, the liver gets inflamed and that’s called hepatitis.

The anti-hepatitis medications can be divided into two groups based on their mechanism of action; nucleoside or nucleotide analogues and interferons.

Let’s start with the nucleoside and nucleotide analogues. This group includes nucleoside analogues like ribavirin, entecavir and lamivudine; nucleotide analogues like adefovir, tenofovir, and sofosbuvir.

However, entecavir, lamivudine, adefovir, and tenofovir are used to treat HBV infections and ribavirin and sofosbuvir are used to treat HCV infections.

In both types of infected cells, the analogues are first phosphorylated by cellular enzymes into either a diphosphate, or triphosphate form.

The phosphorylated forms are similar in structure to natural nucleotides present in the cells, so we can think of them as fake nucleotide molecules.

Viral enzymes will try to use these fake nucleotide molecules when trying to synthesize new nucleic acid.

In the HBV infected cell, this enzyme is HBV DNA polymerase, while in the HCV infected cell, the target enzyme is RNA-dependent RNA polymerase.

Once these fake nucleotides are incorporated into the growing DNA or RNA, no additional nucleotides can be added, and viral nucleic acid synthesis stops.

In addition to this, ribavirin also has another mechanism.

Ribavirin is initially phosphorylated to a monophosphate form, which inhibits the enzyme inosine-5′-phosphate dehydrogenase.

Inosine-5′-phosphate dehydrogenase is an enzyme in the host cell, which converts inosine monophosphate into xanthosine monophosphate, which then goes on to make guanine nucleotides.

Ribavirin monophosphate resembles inosine monophosphate, and binds to its site on the enzyme.

This inhibits the inosine-5′-phosphate dehydrogenase, reducing the synthesis of guanine nucleotides, which in turn reduces the synthesis of viral mRNA.

These nucleoside and nucleotide analogues are given per oral.

Adefovir and tenofovir are poorly absorbed when given orally, so adefovir is given in the form of the prodrug, adefovir dipivoxil, and tenofovir is given in the form of tenofovir disoproxil.

These prodrugs are rapidly absorbed and converted into adefovir and tenofovir, respectively, in the intestinal cells by an esterase enzyme.

Eventually nucleotide and nucleoside analogues are transported out into the blood, and carried to the kidneys, where they are excreted via urine.

Ribavirin undergoes another extra step where it is first dephosphorylated by a phosphatase present in the host cell’s nucleus.

This causes ribavirin to start accumulating within cells which lack a nucleus like the red blood cells.

Now, nucleoside and nucleotide analogues commonly cause side effects like headache, nausea, fatigue, and abdominal pain.

In addition, ribavirin can cause hemolytic anemia and hyperuricemia, or increase in uric acid levels due to its accumulation within the red blood cells.

Ribavirin can also cause rash, itching, insomnia, cough, and also birth defects, when used in pregnant women.

Ribavirin increases the efficacy of interferons when used together.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Is Tenofovir Alafenamide Safer than Tenofovir Disoproxil Fumarate for the Kidneys?" AIDS Rev (2016)
  5. "Sofosbuvir and Ribavirin Liver Pharmacokinetics in Patients Infected with Hepatitis C Virus" Antimicrobial Agents and Chemotherapy (2018)
  6. "Review article: long-term safety of oral anti-viral treatment for chronic hepatitis B" Alimentary Pharmacology & Therapeutics (2018)
  7. "Oral Direct-Acting Agent Therapy for Hepatitis C Virus Infection" Annals of Internal Medicine (2017)