Exam 4: Antivirals I Flashcards by TheOneandOnly Ash

What kind of virus is herpes?

Large, double-stranded DNA virus

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The varicella zoster virus (VZV) can cause what 2 conditions?

Chickenpox

Shingles (reactivation)

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What is a potential complication of shingles?

Postherpetic neuralgia (PHN)

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Who should receive Shingrix to prevent from shingles and how many doses?

2 doses

In all immunocompetent adults 50 and older

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Who typically gets infected by cytomegalovirus?

Immunocompromised people

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What is a potential complication of cytomegalovirus?

Cytomegalovirus-retinitis

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What are all of the potential anti-herpes agents?

Acyclovir
Valacyclovir
Cidofovir
Pencyclovir
Ganciclovir
Valganciclovir
Foscarnet

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The anti-herpesvirus agents are all what (structurally)?

Nucleotide analogs

Prodrugs, must be phosphorylated
(chain-terminator) -block DNA replication by blocking phosphodiester bonds

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What is the structure of acyclovir?

Acyclic guanosine derivative

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What is a benefit to using acyclovir for herpes therapy?

it selectively accumulates in infected cells

-low toxicity

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How does acyclovir become active?

Requires 3 phosphorylation events:

-Viral Thymidine Kinase
(1st step, where toxicity comes from)

-Cellular GMP Kinase (HOST KINASE)

-Cellular Kinase (HOST KINASE)

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What step in acyclovir activation causes toxicity?

1st phosphorylation by viral thymidine kinase

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What is an important thing to note with acyclovir activation?

The last 2 phosphorylations are done by host kinases

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Why is acyclovir selective for viral cells?

The first phosphorylation step in its activation can only be done by a viral kinase

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What is the MOA of acyclovir?

Competitive inhibitor of viral DNA polymerase

(Competes with dGTP)

Note that competition occurs at a lower concentration for viral DNA pol than host, which decreases the risk for toxicity

This binds the DNA polymerase to the template irreversible

Acyclovir becomes incorporated into DNA

overall action: CHAIN TERMINATOR
-blocks ability to create the next phosphodiester bond (lacks necessary hydroxyl group)

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What viruses does acyclovir have activity against?

HSV-1
HSV-2
VZV (varicella)

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What are the 2 ways that resistance to acyclovir can develop?

Mutations in viral thymidine kinase
(responsible for first phosphorylation)

Mutations in viral DNA polymerase
(drug is not accommodated as well, not able to inhibit the polymerase as well)

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who is more likely to experience resistance to acyclovir?

Immunocompromised people

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What is the structure of valacyclovir?

L-valyl ester of acyclovir

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What happens to valacyclovir when it enters the body?

It is rapidly converted to acyclovir by esterases in the intestine and liver

-Transported by INTESTINAL amino acid transporters
(does not cross membrane as well as acyclovir)

*oral drug

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How does the efficacy of valacyclovir compare to acyclovir?

Valacyclovir is more efficacious for all indications

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How does the MOA of Famciclovir and Penciclovir differ from Acyclovir and Valacyclovir?

DO NOT CAUSE IMMEDIATE CHAIN TERMINATION

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True or False: Viral kinase mutants show cross-resistance to both penciclovir and acyclovir

True
-resistance to one means resistance to the other

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How does the MOA penciclovir differ from acyclovir?

Penciclovir has a higher affinity for HSV TK than acyclovir

-this means that penciclovir is able to bind better
-levels of penciclovir triphosphate in infected cells are much higher than those of acyclovir triphosphate

*Note that HSV DNA polymerases have a higher affinity for acyclovir giving the 2 drugs similar efficacy

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What are the clinical uses of oral famciclovir?

Primary + Recurrent Genital Herpes Acute herpes zoster

What are the clinical uses of topical penciclovir?

Recurrent herpes labialis

Ganciclovir has a similar structure and the same MOA as what other drug?

Penciclovir

Ganciclovir is better used for what indication than the other drugs listed?

Better substrate for cytomegalovirus kinase

What drug + dosage form is used to treat CMV retinitis?

Ganciclovir IV, oral, and intraocular implants

what drug + dosage form is used for CMV prophylaxis?

Ganciclovir Oral

How does the toxicity of ganciclovir compare to acyclovir?

Toxicity is more severe

What toxicity is associated with ganciclovir?

Myelosuppression

How does resistance to Ganciclovir occur?

Mutations in: CMV kinase CMV DNA pol *note that there is no cross-resistance with other drugs*

What is the structure of Valganciclovir?

Monovalyl ester of ganciclovir *converted to ganciclovir in intestine and liver

What is the benefit of Valganciclovir over Ganciclovir?

Increased bioavailability

What is the indication of Valganciclovir?

CMV retinitis in AIDS patients

What is the structure of Foscarnet?

Inorganic pyrophosphate compound

What is the MOA of Foscarnet?

Inhibits viral DNA polymerase -Blocks pyrophosphate binding site of the viral DNA polymerase -Inhibits cleavage of pyrophosphate from dNTPs -DNA is ultimately unable to translocate

How does Foscarnet differ from the other herpes virus drugs?

*Does not require phosphorylation for activity*

How is foscarnet administered?

IV only (poor oral bioavailability)

Foscarnet is synergistic with which other drug?

Ganciclovir

How can resistance occur against Foscarnet?

Mutations in DNA pol or HIV RT

Foscarnet shows cross-resistance with what drug?

Ganciclovir

Foscarnet does not have cross-resistance with what drug?

Cidofovir

What is the structure of Cidofovir?

Acyclic nucleoside phosphonate analog of cytosine

How does the action of cidofovir differ from other drugs?

It only requires 2 phosphorylations by the cellular kinases Is not virally phosphorylated

What is the activity of cidofovir?

Broad spectrum (covers many viruses)

What is the MOA of cidofovir?

Competitive inhibitor and chain terminator

What is the indication of cidofovir?

CMV retinitis

What is the moa of Letermovir?

Newest anti-herpes drug Non-nucleoside inhibitor (does not have a nucleotide analog structure) Binds the CMV terminase complex *Prevents cleavage and packaging *No effect on protein synthesis or DNA replication

True or False: Letermovir has no cross resistance with other drugs

True

What kind of virus is Influenza?

Negative stranded RNA virus

What are the types of influenza?

A B C

Who does Influenza virus A infect?

Humans + Animals

Who does Influenza virus B affect?

Humans only

What is the main characteristic of Influenza virus C?

Mild/undetectable

Vaccines protect against what type(s) of influenza?

A + B

What are the 2 subtypes of Influenza A?

Hemagglutinin (H1-H16) Neuraminidase (N1-N9)

How does the influenza virus spread?

It takes part of the plasma membrane from the host to create new viral particles

Which part of the influenza virion is critical for viral release from the cell so it can spread/replicate?

NA (neuraminidase)

What drugs are neuraminidase inhibitors?

Oseltamivir Zanamavir Baloxavir Peramivir

How is oseltamivir activated?

Liver esterases (note that this is a prodrug)

Oseltamivir is active against which forms of influenza?

A and B (more A)

What is a limitation to oseltamivir use?

It must be initiated within 48 hours of first symptoms to be useful

Resistance develops more easily against which drug: Oseltamivir or Zanamivir

Oseltamivir (more floppy drug)

Zanamivir can be used for what kinds of influenza?

A and B

What is a unique thing to remember about Zanamivir?

It is an oral inhaler

What is an important side effect of Zanamavir?

Bronchospasm

Who should not receive Zanamavir?

Patients with airway diseases like asthma and obstructive pulmonary disease

What is the structure or Peramivir?

Transition state analog of sialic acid

What is the indication of Peramivir

Influenza A + B

What is the dosage form of Peramivir?

IV or Injectable

Who should receive Peramivir?

Adult patients able to receive IV and based on one or more of the following reasons: -Patient not responding to oral or inhaled therapy -No other route is expected to be dependable/feasible -Clinician judgement

What is the mechanism of Baloxavir?

Inhibits viral cap-snatching (blocks transcription)

What is the indication of Baloxavir?

Influenza within 48 hrs of symptoms -age 12+ only

What are the side effects of Baloxavir?

Diarrhea Bronchitis

What kind of virus is Hepatitis C?

Small, positive-stranded RNA

How is Hepatitis C transmitted?

Blood

How do interferons fight viral infections?

Induce synthesis of cellular proteins

How do ribonucleases fight viral infections?

Degrade viral RNA but not cellular RNA

What is the indication for Interferon alpha (drug)?

Hepatitis C Hepatitis B Human herpes virus Papillomavirus

Interferon alpha should be combined with which drug to improve efficacy?

Ribavirin

what are the Hepatitis C Virus inhibitor drugs?

Ribavirin Grazoprevir Voxilaprevir Glecaprevir Sofosbuvir Ledipasvir Elbasvir Dasabuvir Daclatasvir Velpatasvir Pibrentasvir

How is ribavirin activated?

Phosphorylated by cellular kinases to triphosphate form (Prodrug)

What is the MOA of Ribavirin?

Inhibits Inosine monophosphate dehydrogenase (IMPDH) -reduces GTP levels Directly inhibits viral RNA polymerase -Incorporation into viral RNA leads to an error catastrophe

What are the uses for Ribavirin?

Combination therapy for Hep C Aerosol can be used for RSV pneumonia in children

How do HCV protease inhibitors work?

Mimic substrate structure and locks the protease from being active -this prevents the protease from cleaving its substrate

What drugs act as P2-P4 substrate analog HCV protease inhibitors?

Grazopevir Voxilaprevir Glecaprevir

What are the advantages of using HCV protease inhibitors?

Once daily dosing Well tolerated

How do mutations against HCV protease inhibitors occur?

Mutations in NS3 active site

HCV RNA polymerase inhibitors block what?

NS5B (HCV RNA polymerase)

What drug is a HCV RNA polymerase inhibitor?

Sofosbuvir

How is Sofosbuvir activated?

Converted to monophosphate by liver enzymes Triphosphorylated by nucleotide kinases

How does Sofosbuvir work?

Incorporated into viral RNA chain of HCV Causes chain termination

Which drug is a non-nucleoside RNA polymerase inhibitor?

Dasabuvir

Dasabuvir is not active against what?

HCV genotype 2, 3, 4

What is the MOA of Dasabuvir?

Binds to pal I site of HCV RNA polymerase Prevents conformational changes Blocks nucleotide incorporation into viral RNA

What are the HCV NS5A inhibitors?

Ledipasvir Elbasvir Daclatasvir Velpatasvir Pibrentasvir

What is the role of NS5A?

Required for HCV RNA replication

What is the MOA of the HCV NS5A inhibitors?

Inhibit both viral RNA replication and assembly/release of infectious particles

For HCV inhibitors, the ending -previr indicates what?

HCV NS3 protease inhibitor

For HCV inhibitors, the ending -asvir indicates what?

HCV NS5A inhibitor

For HCV inhibitors, the ending -buvir indicates what?

HCV NS5B inhibitor

What black box warning is associated with HCV direct acting antivirals?

Hepatitis B Virus reactivation

What kind of virus is Hepatitis B?

Partially double-stranded DNA virus -genome includes an RNA intermediate that is converted to viral DNA by reverse transcriptase

What are the anti-HBV drugs?

Tenofovir Lamivudine Entecavir

What are the important points about tenofovir?

-Prodrug -Only needs 2 phosphorylations

What 3 drugs are used for COVID?

Remdesivir Nirmatrelvir Molnupiravir

What are the important points about Remdesivir?

Prodrug IV Approved for COVID

What are the important points about Nirmatrelvir?

Inhibitor of SARS-CoC-2 3C-like protease (3CL^pro) Mild-moderate covid Use within 5 days of symptom onset Peptidomimetic inhibits active site of 3CL^pro *Use ritonavir to boost levels

What are the important points about Molnupiravir?

Prodrug For mild-moderate COVID Mutagenic potential

Exam 4: Antivirals I Flashcards

(111 cards)