Hepatitis medications

Definitions & Key takeaways

The medications for hepatitis can be divided into two broad categories: those that clear the virus from the body (i.e. antivirals) and those that work to protect the liver from further damage (i.e. hepatoprotectives).

Antiviral medications for hepatitis include pegylated interferon, ribavirin, and telbivudine. These medications are typically used in combination with each other and are very effective at clearing the virus from the body.

Hepatoprotective medications for hepatitis include milk thistle, ursodeoxycholic acid, and vitamin E. These medications protect the liver from further damage and can be quite effective at preventing or slowing the progression of liver disease.

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Introduction0:00–0:43

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.

Pathology0:43–2:14

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.

Nucleoside and nucleotide analogues2:14–4:55

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.

Side effects4:55–6:00

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.
It can also interfere with the activity of other medications like HIV nucleoside reverse transcriptase inhibitors like zidovudine.
Lamivudine can cause anorexia. Keep in mind that HBV strains often develop resistance to lamivudine due to mutation in DNA polymerase enzyme.
This can cause the infection to return once the medication is stopped. Next, at higher doses, adefovir can damage the kidneys, which causes proteinuria, or increased protein in the urine; glycosuria, or increased glucose in urine; and azotemia, or increased nitrogen-containing compounds like urea and creatinine in the blood.

Interferons6:00–8:32

The next group of anti-hepatitis medication are the interferons. Interferons are cytokines, or signalling proteins, produced by virus infected cells and cancer cells in the body, as a warning sign for the other healthy cells.
As their name implies, they interfere with processes like viral replication. There are two types of Interferons: Type I and Type II.
Type I interferons include Interferon alpha and Interferon beta. When surrounding hepatocytes detect these type I interferons, an alarm is raised and they try to protect themselves by synthesizing proteins that degrade mRNA.
This blocks viruses from rapidly making copies of themselves, inhibit protein synthesis which blocks viral proteins from being produced, and they increase expression of MHC molecules, which makes it easier for cytotoxic CD8+ T cells and NK cells to do surveillance and kill them if they’re infected.
Now, the only Type II Interferon is interferon gamma. Like the type I interferons, interferon gamma also promotes an anti-viral state, but it also helps activate macrophages and CD4+ helper T cells which then secrete their own interferon gamma and IL-2.
In order to be used as a medication interferons are artificially synthesized using recombinant DNA technology. Interferons are either given as intramuscular or subcutaneous injection, which is typically given thrice a week.
Sometimes interferons can be given in the form of pegylated interferon, which is interferon plus polyethylene glycol, for example, pegylated interferon alfa, or pegINF-α.
Pegylated interferons are absorbed more slowly than plain interferons, so they require less frequent dosing of about once per week, and also cause fewer side effects.
Currently only two types of interferons, IFNα2A and IFNα2B, are available for clinical use. IFNα2A has a longer half-life than IFNα2B, meaning it stays in the blood longer.
Interferons are used in the treatment of both chronic HBV and chronic HCV infections. IFNα2A, or IFNα2B, or their pegylated forms are used to treat chronic HCV infections either alone or in combination with other antiviral medication like ribavirin.
They are also used in the treatment of chronic HBV infection. In addition interferons are also used in the treatment of herpes virus infection, papillomavirus infection, and Kaposi’s sarcoma occurring in HIV infections.

Side effects8:32–8:55

Side effects of IFN-α includes flu-like symptoms such as fever, malaise, nausea, and vomiting; bone marrow suppression leading to neutropenia and thrombocytopenia; neurotoxicity leading to sleepiness, depression, and behavioral disturbance; liver dysfunction leading to elevated liver enzymes.
It can also cause alopecia, which is more common in children. Now, we want to make a simple and fun mnemonic that’ll help you efficiently memorize and retain all these pharmacology facts!

Memory palace8:55–10:49

Since we’re talking about liver damage, let’s go to a bar during the prohibition era. Understandably, this bar is not busy and we have the Bartender, representing hepatitis B, standing at one end, and his only Customer, representing hepatitis C, at the other end.
Now this bar is disguised as a pet shop to fool the cops so let’s put some animals in here to represent the nucleotide and nucleoside analogues.
By the bartender, we have entecavir, an anteater, lamivudine, a lamb, adefovir, an aardvark, and tenofovir, a tentacled octopus.
These medications treat HBV infection. By the customer representing HCV infection we have ribavirin, an angry rhino, and sofosbuvir, a leather sofa that used to be a cow.
For side effects Ribavirin can cause hemolytic anemia, so let’s impale a large red blood cell on the horn of the rhino. It’s also contraindicated during pregnancy so let’s have an angry pregnant lady riding on its back.
Adefovir causes renal damage so let’s have the aardvark eating a tasty kidney that someone left on the ground. Now two police officers busted into this bar to interfere with the good times, and they have the letters A and B on their uniform for interferon alpha 2a and 2b.
They are standing directly between the bartender/petshop owner and the customer, since they can treat both types of viral hepatitis.
For their side effects, one of them is holding a bone like a club for bone marrow suppression, while the other is holding a damaged liver he found while looking for evidence.
If we look at the heads of the two officers, one is bald for alopecia, while the other has his brains showing to help you remember interferons can cause neurotoxicity.
The most common side effect is flu like symptoms so let’s give them both runny noses and thermometers in their mouths. All right, as a quick recap… Anti-hepatitis medications refers to a group of antivirals used in the treatment of viral hepatitis.

Review10:49–11:38

They can be divided into two groups. The first is nucleoside or nucleotide analogues.
Ribavirin and sofosbuvir inhibits HCV RNA-dependent RNA polymerase. Ribavirin also inhibits inosine-5′-phosphate dehydrogenase, which decreases synthesis of guanine nucleotides.
Entecavir, lamivudine, adefovir, and tenofovir inhibits HBV DNA polymerase and are used to treat chronic HBV infection. Next we have the interferons like IFNα2A and IFNα2B, which stimulate the body’s cells to synthesize proteins that degrades viral RNA and also surface proteins that alerts immune cells like natural killer cells.
But wait, there’s more: Here’s a mind map with all of the mnemonics. Go ahead and pause the video so you can test yourself to see what you remember.

Mind map11:38–11:46

Stay tuned for the answers after the credits.