Anti-Herpes Agents: Thymidine Kinase Agents – Antiviral Drugs

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

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

00:08 Specially let's focus on what we call "Thymidine Kinase Agents." Now these agents are important in the nucleic acid synthesis, portion of antiviral therapy.

00:20 These thymidine kinase dependent agents include a acyclcovir and ganciclovir.

00:26 They are active against HSV-1 and HSV-2 as well as varicella zoster.

00:33 They have a very short half life and they are often administered three to five times a day.

00:38 Now they are renally excreted as well.

00:40 So we do adjust the dose in renal failure.

00:43 Let's have a look where they work on our slide here.

00:47 Now as we're going through the production of DNA, we have several steps.

00:53 Now the host kinases are acted upon acyclcovir, and ganciclovir to prevent the diphosphate form of these agents from being produced.

01:03 There are competitive substrates for DNA polymerase.

01:06 And they lead to chain termination after incorporation into the DNA.

01:12 Because they are defective agents, because they cause a defect in the actual DNA, you are unable to continue production of the DNA chain itself.

01:23 That's why we call it chain termination.

01:25 Now valacyclovir or Valtrex is a prodrug of acyclovir.

01:31 So you can see here that I've pasted it in a little pink box above acyclcovir and ganciclovir.

01:37 Now valacyclovir is able to achieve three to five times greater concentration levels and it also lasts lot longer.

01:45 So for the most part it's replaced acyclovir as a means of therapy for certain types of disease.

01:54 Pencyclovir actually works at the level of the DNA polymerase.

01:57 So it doesn't cause chain termination.

02:00 But what it does is it inhibits the production of DNA.

02:04 Now famciclovir is converted to pencicyclovir by the liver.

02:09 So once again I've put this prodrug form in a little pink box just under the pencyclovir.

02:16 Ganicyclovir is a guanine derivative.

02:20 Acyclovir is a guanosine derivative.

02:23 So you can see, how they are acting at slightly different agents within the DNA molecule.

02:29 Now when we're looking at these agents we know that they are inhibiting DNA polymerase inside cytomegalovirus and HSV alike.

02:37 They are used in CMV retinitis and other CMV infections in patients who are immunocompromised as well.

02:44 The toxicity of these agents include leukopenia, thrombocytosis and mucositis.

02:52 Now there is another agent that is a prodrug that I just want to mention quickly.

02:56 Valgancyclovir is a prodrug of ganciclovir.

03:00 It has a very high bioavailability and a longer half life.

03:04 So I anticipate that this is going to be something that will come on to the market quite strongly and start to replace the ganciclovir.

03:11 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.

03:22 So these are present insignificant numbers enough that we have to keep a very close eye on them.

03:28 With most antiviral agents, you are going to have some kind of neurological side effects.

03:33 So we talk about headache, tremor, seizure, sometimes delirium as well.

03:39 In terms of bone there was a concern that there would be an effect on bone marrow.

03:45 But we are actually not seeing that play out in real life.

03:48 How do agents develop resistance to drugs like acyclovir? It'll occur in two different ways.

03:55 The first way is a change in the viral DNA polymerase.

04:00 So obviously if there is a change in the target molecule, the drug won't work as well on that target molecule.

04:05 The other way that it will work, is that some strains of virus actually lack the thymidine kinase that it's active upon.

04:13 So this can be a viral specific phophorylation of acyclovir.

04:18 And these agents will be cross resistant to each other.

04:20 So you have to be aware that there is multiple ways of resistance and these are the two.

04:26 Let's move on to Host Kinase Agents.

04:30 Now host kinase agents are going to work on several areas of function.

04:35 But mostly we're going to be focusing on the late protein synthesis processing of the virus.

04:41 So cidofovir is activated by host cell kinsases.

04:46 It's active in herpes simplex virus infection, cytomegalovirus, adenovirus and others.

04:52 Now, it does not require viral kinase.

04:57 It's active against many resistant viruses.

05:00 The activity we use it against CMV retinitis and mucocutaneous herpes simplex virus.

05:08 And sometimes we'll use it against genital warts as well.

05:12 The toxicity that we're most concerned about is really nephrotoxicity.

05:17 So this important to monitor renal function in patients on these agents.