acyclovir and ganciclovir

[Enzymes]

I have a couple of questions about these drugs:

1. Does anyone know how acyclovir resistance occurs? First AID says mutated viral thymidine kinase, but apparently there are qbank questions that want you to know that resistance is due to lack of thymidine kinase enzyme (not alteration). Anyone know which?

2. For ganciclovir: is it doing two different things? It works as a chain terminator, but also directly inhibits CMV DNA polymerase? Or are these two mechanisms interconnected?

Thanks!

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[Donald Juan]

I believe that "lack of thymidine kinase" and "mutated so as to be nonfunctional thymidine kinase" are essentially interchangeable in most contexts. Do the qbank questions specifically differentiate these two things? Like are both a choice and only one is considered correct?

I'm not sure about the ganciclovir mechanism. I always thought of it as two ways of saying the same things, but Katzung pharm book makes it sound like two different things with little explanation.

 

[dyspareunia]

I have a couple of questions about these drugs:

1. Does anyone know how acyclovir resistance occurs? First AID says mutated viral thymidine kinase, but apparently there are qbank questions that want you to know that resistance is due to lack of thymidine kinase enzyme (not alteration). Anyone know which?

2. For ganciclovir: is it doing two different things? It works as a chain terminator, but also directly inhibits CMV DNA polymerase? Or are these two mechanisms interconnected?

Thanks!

1. As the above posted said, I don't think you have to differentiate between the two (unless you've seen a question with both answers as answer choices).

2. It's a chain terminator, but only if CMV is there to activate it . Kind of the same idea as Acyclovir and HSV. The two mechanisms are interconnected in the sense that DNA polymerase is necessary for DNA elongation. They are separate mechanisms in the sense that ganciclovir inhibits viral DNA polymerase directly, but also inhibits chain elongation if it gets incorporated into DNA.

 

[Enzymes]

Thanks all. I haven't seen the question, but Pholston (from SDN) mentioned in one of his powerpoints that acyclovir resistance was due to lack of enzyme, not alteration (both were answer choices). I highly doubt they would make you distinguish this on the boards. Thanks guys.

 

[dyspareunia]

Thanks all. I haven't seen the question, but Pholston (from SDN) mentioned in one of his powerpoints that acyclovir resistance was due to lack of enzyme, not alteration (both were answer choices). I highly doubt they would make you distinguish this on the boards. Thanks guys.

You sure he wasn't talking about the mechanism of acyclovir resistance in CMV?

 

[Enzymes]

Here is a quote from Pholston: "HHV1-4 resistance is due to LACK (NOT ALTERED) OF VIRAL THYMIDINE KINASE. I’ve seen altered kinase and lack of kinase as answers to the same question; the latter is the real deal and also in FA."

I am shocked this actually came up, but if both answers are presented, I am going with lack of the enzyme I guess.

 

[dyspareunia]

Here is a quote from Pholston: "HHV1-4 resistance is due to LACK (NOT ALTERED) OF VIRAL THYMIDINE KINASE. I’ve seen altered kinase and lack of kinase as answers to the same question; the latter is the real deal and also in FA."

I am shocked this actually came up, but if both answers are presented, I am going with lack of the enzyme I guess.

Interestingly, FA 2011 says "Lack of viral thymidine kinase" as the mechanism of resistance for acyclovir. FA 2013 and 2014 say "Mutated viral thymidine kinase".

I'm going to go with mutation if it shows up.

 

[CherryRedDracul]

Doing a quick literature search, both a lack of thymidine kinase and a mutation (e.g. frameshift) in it are common forms of resistance. When did Phloston say that resistance is due to a lack? Since he's an author of First Aid and I think he did the microbio section, I'd go with the latest information from FA 2013 and 2014.

If Phloston said it recently, if I come upon a question on Step 1 where both a lack and a mutation are answer choices, I will opt for the proverbial coin toss.

 

[Phloston]

From UpToDate:

"MECHANISM OF RESISTANCE — The mechanisms of resistance to valacyclovir are identical to those described for acyclovir. Three mechanisms have been shown to endow herpes simplex viruses with resistance to acyclovir, a phenomenon rare in the immunocompetent host [5]:

●Reduced or absent thymidine kinase

●Altered thymidine kinase activity resulting in decreased acyclovir phosphorylation

●Altered viral DNA polymerase with decreased affinity for acyclovir triphosphate"

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I've just started as an editor for USMLE Rx QBank. Any preexisting question that specifies one mechanism over the other can't necessarily be justified because in reality there are multiple mechanisms, and it doesn't make a difference in terms of alternative therapy which one had occurred.

When I had said in my slides that I had seen both mechanisms as answers to the same question and "lack of" was correct over "altered," as I just said above now, this can no longer be justified. In terms of the real deal, they would not require you to make this distinction, however "lack of" is most certainly an answer they would assess for. That doesn't make "altered" wrong, but the USMLE still assesses "lack of."