Hepatitis Treatment – Antiviral Drugs

by Pravin Shukle, MD

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    00:00 Let's move on to anti-hepatitis drugs.

    00:03 Now the anti-hepatitis drugs really the main say of therapy has been the interferon alpha agents.

    00:12 Now interferon alpha seems to work in viral penetration.

    00:16 And by inhibiting viral penetration, you are inhibiting probably the first or second step in viral replication.

    00:23 Anti-hepatitis B drugs are suppressive not curative.

    00:28 So we are not necessary curing the patient with hepatitis B.

    00:32 Anti-hepatitis C drugs are targeted for viral eradication.

    00:38 And in fact we have seen eradication in many patients.

    00:40 Let's talk about interferon alpha.

    00:45 Now interferon alpha is a cytokine.

    00:48 And it acts through the Janus kinases.

    00:51 So Janus was mythical Greek god, actually he was an Olympian, who had ten heads.

    01:00 And so we talk about Janus kinases as being those agents that seem to have a whole bunch of faces to them.

    01:08 Now the Janus kinase is phosphorylate STAT that stands for Signal Transducers and Activators of Transcription.

    01:16 So we call these JAK STAT receptors.

    01:20 And you can see the JAK portion down at the bottom.

    01:24 Now this causes an increase production of antiviral proteins.

    01:29 There is a specific activation of ribonuclease that degrades the viral messengerRNA when you activate these agents.

    01:37 This promotes the formation of natural killer cells that destroy infected liver cells.

    01:42 So that's why interferon alpha is such an important component of our immune system.

    01:48 Now, intramuscular injections, interferon alpha are usually how we administer this medication.

    01:55 The formulations vary from time and place.

    01:59 Now the absorption is relatively slow.

    02:02 It's given about two or three times per week.

    02:04 We do have something called pegylated forms that can be given once a week.

    02:09 Pegylated forms are first to encasing the inferon in certain types of almost mycells or liposomes.

    02:16 The elimination is through hydrolysis and proteolysis in the kidney.

    02:21 In terms of where we use these medications, they are most commonly used in chronic hepatitis B.

    02:27 But we have actually used in hepatitis C as well, usually acute hepatitis C.

    02:32 And we often combine it with ribavirin.

    02:35 In less common uses, we've used it in Kaposi's sarcoma in HIV patients.

    02:42 We've also used in papillomatosis and genital warts as well.

    02:46 Although that's actually much less commonly used.

    02:50 Now I have another category here called "Others" under anti-hepatitis drugs.

    02:55 It's actually quite a large category.

    02:57 Now we already spoke about interferon alpha.

    03:00 So I'm not going to go through it again.

    03:02 Now the other drugs that we use with hepatitis includes the DNA polymerase agents, the nucleoside inhibitors, the broad spectrum replication inhibitors and another set of drugs that I just call miscellaneous.

    03:18 Let's take a look at the DNA polymerase inhibitors.

    03:21 The prototypical drug of the DNA polymerase inhibitors is adefovir.

    03:28 It inhibits DNA polymerase of hepatitis B virus which results in chain termination of -- results in chain termination after incorporation of the virus into the cell.

    03:40 It has good oral bioavailability and it's unaffected by foods.

    03:45 You can do dose reduction in renal dysfunction because it is excreted by the kidney.

    03:50 It works quite well against viruses that are resistant to lamivudine which is another antiviral agent that I'll talk about.

    04:01 In fact let's talk about lamivudine now.

    04:03 It's a nucleoside inhibitor.

    04:06 And if you recall nucleoside inhibitors are working on that very important step of nucleic acid synthesis.

    04:12 It inhibits HIV reverse transcriptase.

    04:15 It's a very long acting agent in hepatitis B infected cells.

    04:20 Compared to say it's limited activity in HIV infected cells.

    04:25 It's often used as monotherapy in hepatitis B.

    04:30 It's relatively non-toxic and it causes a rapid suppression of hepatitis B viruses.

    04:38 Other agents that are active against hepatitis include the broad spectrum replication inhibitors.

    04:46 We also know this is ribavirin and it's actually quite a well known drug.

    04:51 It inhibits replication of a wide range of DNA and RNA.

    04:56 It effects influenza A and B.

    04:59 It effects parainfluenza and respiratory syncytial virus.

    05:04 It also is active against paramyxoviruses and hepatitis C as well as HIV.

    05:10 In terms of the mechanisms of action, we're not entirely sure how this particular drug works.

    05:17 We'll believe that it acts directly with guanine triphosphate to somehow cause an inhibition and capping of the viral messengerRNA.

    05:24 It also blocks RNA dependent polymerases which is why we use it so often.

    05:31 Now in terms of using this medication, remember that in order to improve it's absorption we actually want more acidity in the stomach.

    05:43 So we tend to tell patients to avoid antacids when you're taking ribavirin.

    05:48 It's eliminated by the kidney so we have to act dose reductions if there is renal failure.

    05:54 We often use it with interferon alpha in chronic hepatitis C.

    06:00 Remember that monotherapy with this particular agent is not very effective.

    06:05 In terms of toxicity, there's a dose dependent hemolytic anemia that's associated with this drug.

    06:11 And it is contraindicated in pregnancy.

    06:16 Miscellaneous drugs use to treat hepatitis patients include the following.

    06:23 Now we have nucleoside analogs that work against DNA polymerase.

    06:31 We have agents that are approved for lamivudine resistance.

    06:36 We have agents that inhibit RNA polymerase.

    06:40 This particular agent is quite active in hepatitis C virus.

    06:45 And we actually can achieve 95% curates when used in association with ribavirin.

    06:51 Boceprefir is also a protease inhibitor and it's used with ribavirin as well.

    About the Lecture

    The lecture Hepatitis Treatment – Antiviral Drugs by Pravin Shukle, MD is from the course Antimicrobial Pharmacology. It contains the following chapters:

    • INF-alpha
    • Nucleoside Inhibitors
    • Broad sprectrum Replication Inhibitors
    • Miscellaneous

    Author of lecture Hepatitis Treatment – Antiviral Drugs

     Pravin Shukle, MD

    Pravin Shukle, MD

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