Herpes Antivirals

Question 1

How must acyclovir (ACV) be changed in order to work

Answer 1

Must be phosphorylated 3 times before it can be encorporated into viral DNA

Question 2

Describe process of first phosphorylation of ACV, what does this mean for drug potency

Answer 2

The first round of acyclovir phosphorylation is carried out by thymidine kinase enzymes specific to each virus, meaning HSV has a different specific enzyme than VZV or CMV.

Mutations in this enzyme, and innate conformational differences between the different viruses, determine the potency or effectiveness of the drug, and confer resistance to ACV.

This specificity of the viral thymidine kinase results in ACV being 10x more potent for HSV than for VZV, and having even less activity for CMV, EBV, and HHV-6.

Question 3

Where is ACV active

Answer 3

Because the initial phosphorylation has to be carried out by the viral thymidine kinase, this means only HSV-infected cells activate the drug and accumulate the active metabolite (after first phosphorylation)

Question 4

Acyclovir mechanism of action

Answer 4

Acyclovir triphosphate, the product of the three phosphorylation steps, inhibits viral DNA synthesis in two ways:

1. Competitive inhibition with deoxyGTP for the viral DNA polymerase, resulting in binding to the DNA template as an irreversible complex.
2. Premature chain termination following incorporation into the viral DNA (blocks DNA polymerase).

Question 5

How is low bioavailability of acyclovir overcome

Answer 5

Valacyclovir is a prodrug of ACV that is much better absorbed and then transformed to ACV by the liver. This prodrug strategy to overcome poor bioavailability achieves higher serum levels with fewer doses a day.

Question 6

When is topical ACV not effective

Answer 6

If given topically for an HSV skin infection that is chronic and thus has taken up residence in the sensory ganglia, effectiveness will by definition be limited.

Due to the pathophysiology of the infection, topical ACV cream is substantially less effective than oral therapy for primary HSV infection, and is of no benefit in treating recurrent genital herpes.

Question 7

Where are all herpes antivirals cleared

Answer 7

Kidneys

Question 8

Acyclovir toxicities

Answer 8

The major toxicity of ACV occurs in patients with dehydration or shock who are not getting sufficient perfusion of the kidneys. In these patients, IV acyclovir can crystallize in the renal tubules, resulting in acyclovir rocks instead of kidneys. Please note that acyclovir rocks are not good for making urine or doing any other job of the kidney, and please remember to ensure that any patient getting IV acyclovir is well hydrated first and getting good renal perfusion to avoid this toxicity.

At high doses, confusion, seizures, and hallucinations can be seen

Question 9

What type of drug is trifluridine

Answer 9

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses

Question 10

Trifluridine MOA

Answer 10

It is activated by being phosphorylated intracellularly by host cell enzymes

The drug exerts its mechanism of action by competing with thymidine triphosphate for incorporation by the viral DNA polymerase.

Question 11

What is useful about trifluridine? Drawback?

Answer 11

Because it does not require the initial phosphorylation by the viral thymidine kinases that tend to be mutated or deficient in resistant herpesviruses, it can be useful in ACV-resistant infections whose resistance is due to mutations in viral thymidine kinase.

Unfortunately, also because it does not have the first step in phosphorylation by viral thymidine kinases, this drug acts on infected and noninfected cells and incorporation of trifluridine triphosphate into both viral and host DNA, preventing systemic use.

Question 12

What is docosanol and MOA

Answer 12

It is a saturated 22-carbon aliphatic alcohol used topically that inhibits fusion between the host cell plasma membrane and the HSV envelope, thereby preventing viral entry into cells and subsequent viral replication

Question 13

How is ganciclovir activated (specific enzyme too)

Answer 13

Ganciclovir is another acyclic guanosine analog that requires activation by triphosphorylation before inhibiting the viral DNA polymerase. Initial phosphorylation is catalyzed by a very specific thymidine kinase, the virus-specified protein kinase phosphotransferase UL97 in CMV-infected cells.

Question 14

Gancivlovir MOA

Answer 14

Like acyclovir, the activated compound competitively inhibits viral DNA polymerase use of DeoxyGTP and causes termination of viral DNA elongation.

Its activity against CMV is up to 100 times greater than that of acyclovir, due to the specificity of the viral thymidine kinase, and so ganciclovir is used clinically for CMV rather than other herpesvirus infections.

Question 15

How was bioavailability of ganciclovir improved

Answer 15

a prodrug named Valganciclovir was developed with improved bioavailability and so therapy can now be given orally

Question 16

Ganciclovir toxicities

Answer 16

Myelosuppression is a more prominent side effect than seen with ACV

Neurotoxicity, including peripheral neuropathy, is increased with this drug, usually because it was prescribed for much longer courses than ACV for serious CMV disease or to suppress CMV reactivation

Question 17

Usefulness of cidovfovir

Answer 17

Cidofovir is a cytosine nucleotide analog with in vitro activity against many viruses including CMV, HSV-1, HSV-2, VZV, EBV, HHV-6, HHV-8, adenovirus, poxviruses, polyomaviruses, and human papillomavirus.

In contrast to the other CMV drugs discussed so far, phosphorylation of cidofovir to the active diphosphate does not require viral enzymes, and thus activity is maintained against thymidine kinase mutants of CMV or HSV.

Question 18

CIdofovir MOA

Answer 18

Cidofovir is activated by cellular kinases that add two phosphate groups to the drug to generate its active metabolite.

Cidofovir diphosphate acts both as a potent inhibitor of and as an alternative substrate for viral DNA polymerase, competitively inhibiting DNA synthesis and becoming incorporated into the viral DNA chain , causing chain termination.

Question 19

Pharmakodynamics of cidofovir (half life, dosing)

Answer 19

Active metabolites have a very long half-life, allowing infrequent dosing. Cerebrospinal fluid penetration is poor, making it inappropriate for CNS disease.

Intravenous cidofovir must be administered with high-dose probenecid , which blocks active tubular secretion and decreases nephrotoxicity.

Question 20

Cidofovir toxicities

Answer 20

Renal toxicity that increases as the dose increases, and which may be reduced with prehydration using normal saline.

Protein in the urine, elevation of BUN/creatinine, metabolic acidosis (low serum bicarbonate), and Fanconi’s syndrome (glucose in the urine with a normal serum glucose) may occur. (Fanconi’s syndrome is a rare toxicity so that is one I would remember.)

Other potential really strange adverse effects that are common with the drug include uveitis, ocular hypotony (eye muscles stop working), and neutropenia

Question 21

Can cidofovir be given in pregnancy

Answer 21

No, teratogenic

Question 22

Foscarnet MOA

Answer 22

Foscarnet (phosphonoformic acid) is an inorganic pyrophosphate analog that inhibits herpesvirus DNA polymerase, RNA polymerase, and HIV reverse transcriptase directly without requiring activation by phosphorylation.

Foscarnet blocks the pyrophosphate binding site of these enzymes and inhibits cleavage of pyrophosphate from deoxynucleotide triphosphates, inhibiting DNA formation. The binding site is different than the site used for ganciclovir/valganciclovir and cidofovir.

Question 23

Foscarnet toxicities

Answer 23

Foscarnet has the highest toxicity rate of any of the herpes antiviral drugs. Adverse effects of foscarnet that are different than the other herpes antivirals and relate to the effects of the drug on electrolyte levels in the plasma.

Renal failure

Hypo- or hypercalcemia, hypo- or hyperphosphatemia, hypokalemia, and hypomagnesemia.

Genital ulcerations due to high levels of ionized drug in the urine causing tissue damage. Central nervous system toxicity is reported with the same spectrum of problems as the other herpes antivirals: hallucinations, seizures, delirium. Foscarnet is considered a teratogen, and the drug should not be used in pregnancy.

Question 24

If you have mutation affecting the activity of the UL97 viral thymidine kinase, you will be resistant to _____. This is the _____ common type of mutation. ____ does not require viral enzymatic phosphorylation and so ____ will still work, as will ____.

Answer 24

If you have mutation affecting the activity of the UL97 viral thymidine kinase, you will be resistant to GCV/VGCV. This is the most common type of mutation. CDV does not require viral enzymatic phosphorylation and so CDV will still work, as will FOS.

Question 25

If you have mutation affecting the dNTP (DeoxyGTP) binding site on the CMV DNA polymerase, you will have decreased affinity for ____and _____ and thus resistance to those drugs. The binding site for ____ is not affected and thus it will still work.

Answer 25

If you have mutation affecting the dNTP (DeoxyGTP) binding site on the CMV DNA polymerase, you will have decreased affinity for CDV and GCV/VGCV and thus resistance to those drugs. The binding site for FOS is not affected and thus FOS will still work.

Question 26

If you have mutation affecting the PPI (pyrophosphate) binding site on the CMV DNA polymerase, you will have decreased affinity for _____ and thus it will not work.

Answer 26

If you have mutation affecting the PPI (pyrophosphate) binding site on the CMV DNA polymerase, you will have decreased affinity for FOS and thus it will not work.

Question 27

Acyclovir is chemically similar to what molecule

Answer 27

nucleosides, specifically guanine