Anti-Viral Drugs I Flashcards by Joel Glotfelty

The genomes of non-retroviruses are made of either

DNA or RNA

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What are 3 examples of DNA viruses?

Herpes, Varicella, and Cytomegalovirus

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Replicate inside host nuclei using virus-encoded machinery

DNA viruses

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In DNA viruses, the viral genome is transcribed and translated by

Host proteins

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A DNA virus that replicates through an RNA intermediate

HBV

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What are two examples of RNA viruses?

Influena and Hepatitis A and C

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(-)RNA genome serves as template for viral mRNA production

Influenza

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In influenza, the genome is copied into a

(+) RNA intermediate

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This (+) RNA intermediate is then used to produce more

(-) RNA genomes

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(+) RNA genome is used directly as mRNA. The genome is copied to a (-) RNA intermediate, which is used to produce more (+) RNA genomes

Hepatitis

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Analogs of naturally occurring nucleosides inhibit viral

DNA replication

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All compete with natural nucleotides for binding viral DNA polymerase

Nucleoside analogs

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Requires HSV thymidine kinase (TK) for first phosphaste

Acyclovir

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Guanosine derivative that functions as a viral DNA replication inhibitor

Acyclovir

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Acyclovir undergoes monophosphorylation by viral

Thymidine Kinase (HSV-TK)

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Phosphorylation traps acyclovir within

Infected cells

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The triphosphate form competes with dGTP to bind viral DNA polymerase

-Also acts as chain terminator

Acyclovir

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Resistance to acyclovir is due largely to mutations in

HSV-TK and viral DNA polymerase

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HSV-TK mutations cause cross-resistance to other drugs activated by

HSV-TK

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A derivative of acyclovir that has increased bioavailability of the drug

Valacyclovir

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Limited by renal insufficiency and CNS effects

-Use slow infusion rate

IV acyclovir

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No evidence of teratogenic or carcinogenic effects despite nucleoside structure

Acyclovir

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Drug Treatments for Herpes Simplex Virus (HSV) and Varicella Zoster Virus (VZV) are

Nucleoside analogs (acyclovir)

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Which drugs do we use to treat Cytomegalovirus (CMV)?

Valganciclovir, ganciclovir, and letermovir

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Valganciclovir and ganciclovir are both

Guanosine derivatives

The valyl protecting group in valganciclovir is removed at the

Intestinal wall

Taken orally

Valganciclovir

Given by IV

Ganciclovir

Ganciclovir is a prodrug that must be

Triphosphorylated

Adds the first phosphate to ganciclovir

Viral UL97 kinase

Binds viral polymerase competitively and causes chain termination

Ganciclovir

Ganciclovir resistance is caused by mutations in the viral

UL97

Approved in 2017 for CMV suppression during hematopoietic stem cell transplant (HSCT)

Letermovir

Inhibits the CMV DNA terminus complex required for viral packaging

Letermovir

Cleaves viral concatemers after DNA replication into monomers

Letermovir

Letermovir is an inhibitor and inducer of

CYP3A4 and other P450s

Contraindicated for use with pimozide, ergot alkaloids

Letermovir

Letermovir is also contraindicated for use with pitavastatin or simvastatin when co-administered with

Cyclosporine

Recommended treatments for first clinical episode for HSV and VZV

Acyclovir, valacyclovir, and famciclovir

Recommended first-line treatments for CMV in immunocompromised patients

Valganciclovir, ganciclovir, and letermovir

For influenza, we want early treatment within

48 hours of illness onset

This early treatment within 48 hours of illness onset shortens the duration of fever and illness symptoms by about a

Day

Sialic residues on host receptors bind viral hemagglutinin causing viral particles to

Aggregate

Cleaves these sialic residues, thereby permitting viral escape

Viral Neuramidase

These drugs are sialic acid, transition-state analogs that inhibit viral neuraminidase activity

Neuramidase inhibitors

Zanamivir, Oseltamivir (tamiflu), and Peramivir are the three

Neuramidase inhibitors

Reduce viral escape from infected cells, preventing infection of others

Neuramidase inhibitors

Neuramidase inhibitors work on the neuraminidase of both

Influenza A and B

Resistance to neuramidase inhibitors appears with mutations in the

Neuraminidase gene or hemagglutinin

A prodrugthat is taken orally. Activated by esterasesin GI or liver

Oseltamivir

An inhaled drug to overcome low oral bioavailability

Zanamivir

Administered as single IV dose (versus 5 days of Oseltamivir)

Peramivir

Virus enters cell by endocytosis. Particles arrive in endosomes, which are

Acidic

Low pH cleaves hemagglutinin on viral surface and activation of the viral

M2 ion channel

Bind to the M2 protein and block viral acidification and unsheathing

Amantadine and Rimantidine

Amantadine and rimantidine are not effective against

Influenza B

Well absorbed by oral administration -Very large Vd

Amantadine and Rimantadine

Excreted unmetabolized in urine. Levels rise with renal insufficiency

Amantidine

Metabolized by hydroxylation, conjugation and glucuronidation before excretion

Rimantidine

There are reports of HBV reactivation during treatment of

HCV

Chain terminator of HCV NS5B polymerase -Part of first ALL oral treatment for HCV

Sofosbuvir

Uridinechain terminator of the NS5B RNA-dependent RNA polymerase

Sofosbuvir

Once daily pill. No induction of P450s

Sofosbuvir

Sofosbuvir is a substrate for the p-glycoprotein drug

Efflux pump

Abnormal slow heartbeat may occur in patients taking sofosbuvir-based drugs along with

Amiodarone

Coformulated with pibrentasvir (NS5A drug) as fixed dose oral Mavyret

Glecaprevir

A pan-genomic drug that is more than 92% effective and requires only 8 weeks of treatment

Glecaprevir

Maintains activity against NS3/4A variants that are resistant to other drugs

Grazoprevir

Coformulatedwith elbasvir (NS5A drug) as fixed dose oral Zepatier

Grazoprevir

Coformulated with sofosbuvir (NS5B drug) and velpatasvir (NS5A drug) as fixed-dose oral Vosevi

Voxilaprevir

Approved for use with patients who were treated previously with other HCV drugs that failed

Vosevi

A structural protein of HCV with no enzymatic function

NS5A protein

Binds NS5A tightly and blocks viral RNA replication and packaging

Ledipasvir

A coformulationof ledipasvirand sofosbuvirwas approved in 2014 for

Genotype 1

Principle drug interactions are associated with sofosbuvir component because it is a substrate for

P-glycoprotein

Coformulated with grazoprevir (NS3/4A drug) as fixed dose oral Zepatier -More than 94% Effective for genotypes 1 and 4.

Elbasvir

Coformulated with sofosbuvir (NS5A drug) as fixed-dose oral Epclusa

Velpatasvir

Over 90% effective for ALL genotypes

Velpatasvir

More than 94% effective for genotypes 1 and 4

Elbasvir

Coformulated with glecaprevir as fixed-dose oral Mavyret

Pibrentasvir

Considered a first-line treatment for HBV

PEG-IFN

Also first-line treatments, and have fewer associated side effects and restrictions

Nucleoside analogs

Human proteins with antiviral, immunmodulating, and anti-proliferative actions

Interferon (IFN)

Activate JAK-STAT signal transduction pathway, activating IFN responsive genes

Interferons

IFN-induced major histocompatability antigens enhance the lytic effects of

Cytotoxic T-lymphocytes

What are the 4 sites of interferon-mediated viral inhibition?

1. ) Transcription inhibition 2. ) Translation inhibition 3. ) Protein processing inhibition 4. ) Viral maturation

Linked to polyethylene glycol (PEG), which increases its half-life from 2-3 to 54 hours. Allows less frequent injections

IFN

Up to 1/3 of people taking IFNs must stop early due to

Side effects

Dose-limiting toxicities are myelosuppression with granulocytopeniaand thrombocytopenia

IFN side effects

Contraindicated for hepatic decompensation, autoimmune disease, severe heart disease, kidney disease, poorly controlled psychiatric conditions

IFN

IFN reduces P450 metabolism of

Other drugs

What are 2 drugs that target nucleic acid synthesis in HBV

Entecavir and Tenofovir

Guanosine nucleoside analog recently approved by FDA for HBV. -Prodrug that is tri-phosphorylated inside cells

Entecavir

Drug is chain terminator for HBV RT -Inhibits both first and second strand synthesis

Entecavir

Entecavir's distortion of DNA end blocks further

Synthesis

With entecavir, with discontinuation of treatment, we have to watch for

Rebounding

Resistance to entecavir requires -Thus we have not seen much resistance yet

2 mutations

Was first drug of this class for HBV and it is still in wide-spread use

Lamivudine

Anti-Viral Drugs I Flashcards

(98 cards)