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.
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:
Which anti-herpes drug is a prodrug of acyclovir?
Which anti-herpes drug is NOT an obligate chain terminator?
What is NOT associated with acyclovir and ganciclovir toxicity?
What is the advantage of using valacyclovir over acyclovir?
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