Anti-Herpes Agents: Thymidine Kinase Agents – Antiviral Drugs

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.