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Anti-Herpes Agents: Thymidine Kinase Agents – Antiviral Drugs

by Pravin Shukle, MD

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    00:01 Let's move on in our discussion of antiviral agents.

    00:04 Let's focus now on those agents that are active against herpes.

    00:08 Now, these agents are important in the nucleic acid synthesis portion of antiviral therapy.

    00:17 These thymidine kinase dependent agents include acyclovir and ganciclovir.

    00:22 They're active against HSV-1 and HSV-2, as well as varicella-zoster.

    00:29 They have a very short half life and they're often administered three to five times a day.

    00:34 Now, their renal, they excreted as well.

    00:36 So we do adjust the dose in renal failure.

    00:39 Let's have a look at where they work on our slide here.

    00:43 Now as we're going through the production of DNA, we have several steps.

    00:49 Now the host kinase is are acted upon by acyclovir and ganciclovir to prevent the diphosphate form of these agents from being produced.

    00:59 They're a competitive substrate for DNA polymerase, and they lead to chain termination after incorporation into the DNA.

    01:07 Because they are defective agents, because they cause a defect in the actual DNA, you're unable to continue production of the DNA chain itself.

    01:18 That's why we call it chain termination.

    01:22 Now, valacyclovir or Valtrex is a prodrug of acyclovir.

    01:26 So you can see here that I've placed it in a little pink box above acyclovir and ganciclovir.

    01:32 Now, valacyclovir is able to achieve three to five times greater concentration levels.

    01:38 And it also lasts a lot longer.

    01:40 So, for the most part, it's replaced acyclovir as a means of therapy for certain types of disease.

    01:49 Penciclovir actually works at the level of the DNA polymerase.

    01:53 So it doesn't cause chain termination.

    01:56 But what it does is it inhibits the production of DNA.

    02:00 Now, famciclovir is converted to penciclovir by the liver.

    02:05 So once again, I've put this prodrug form in a little pink box just under the penciclovir.

    02:12 Ganciclovir is a guanine derivative.

    02:16 Acyclovir is a guanosine derivative.

    02:19 So you can see how they're acting at slightly different agents within the DNA molecule.

    02:25 Now, when we're looking at these agents, we know that they're inhibiting DNA polymerase and cytomegalovirus, and HSV alike.

    02:32 They're used in CMV retinitis and other CMV infections in patients who are immunocompromised as well.

    02:40 The toxicity of these agents include leukopenia, thrombocytosis, and mucositis.

    02:48 Now, there is another agent that's a prodrug that I just want to mention quickly.

    02:52 Valganciclovir is a prodrug of ganciclovir.

    02:55 It has a very high bioavailability and a longer half life.

    02:59 So, I anticipate that this is going to be something that will come onto the market quite strongly and start to replace the ganciclovir.

    03:09 Now, when you take a look at all of these drugs, and just sort of throw them into a class as a whole, the toxicities that we are concerned about is GI distress and nephrotoxicity.

    03:18 So these are present in significant numbers, enough that we have to keep a very close eye on them.

    03:24 With most antiviral agents, you're going to have some kind of neurological side effects.

    03:29 So we talk about headache, tremor, seizure, sometimes delirium as well.

    03:36 In terms of bone, there was a concern that there would be an effect on bone marrow, but we're actually not seeing that play out in real life.

    03:45 How do agents develop resistance to drugs like acyclovir? It will occur in two different ways.

    03:51 The first way is a change in the viral DNA polymerase.

    03:55 So obviously, if there's a change in the target molecule, the drug won't work as well on that target molecule.

    04:01 The other way that it'll work is that some strains of virus actually lack the thymidine kinase that it's active upon.

    04:09 So, this can be a viral specific phosphorylation of acyclovir and these agents will be crossed resistant to each other.

    04:16 So, you have to be aware that there's multiple ways of resistance and these are the two.

    04:23 Let's move on to Host kinase agents.

    04:25 Now, host kinase agents are going to work on several areas of function, but mostly we're going to be focusing on the late protein synthesis, and processing of the virus.

    04:37 So cidofovir is activated by host cell kinases.

    04:42 It's active in herpes simplex virus infections, cytomegalovirus, adenovirus, and others.

    04:49 Now, it does not require viral kinase.

    04:52 It's active against many resistant viruses.

    04:58 The activity we use it against CMV retinitis and mucocutaneous herpes simplex virus, and sometimes we'll use it against genital warts as well.

    05:09 The toxicity that we're most concerned about is really nephrotoxicity.

    05:13 So this is important to monitor renal function in patients on these agents.


    About the Lecture

    The lecture Anti-Herpes Agents: Thymidine Kinase Agents – Antiviral Drugs by Pravin Shukle, MD is from the course Antimicrobial Pharmacology. It contains the following chapters:

    • Anti-Herpes Agents: Thymidine Kinase Agents
    • Host Kinase Agents

    Included Quiz Questions

    1. Valacyclovir
    2. Foscarnet
    3. Cidofovir
    4. Penciclovir
    5. Ganciclovir
    1. Penciclovir
    2. Valacyclovir
    3. Valganciclovir
    4. Ganciclovir
    5. Acyclovir
    1. Leukemia
    2. GI distress
    3. Seizures
    4. Delirium
    5. Nephrotoxicity
    1. Longer half-life
    2. Less resistance potential
    3. Crosses blood-brain barrier
    4. Less GI side effects
    5. Does not require phosphorylation

    Author of lecture Anti-Herpes Agents: Thymidine Kinase Agents – Antiviral Drugs

     Pravin Shukle, MD

    Pravin Shukle, MD


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