Antiviral Drugs Flashcards
What are the major sites of antiviral Drug action?
1. Viral attachment and entry
Blocked by:
Enfuvirtide (HIV)
Maraviroc (HIV)
Docosanol (HSV)
Palivizumab (RSV)
2. Viral Penetration
Blocked by:
Interferon-a (HBV, HCV)
3. Uncoating of viral proteins
Blocked by:
Amantadine, Rimantadine (Influenza)
4. Nucleic acid synthesis
Blocked by:
NRTIs (HIV, HBV)
NNRTIs (HIV)
Acyclovir (HSV)
Foscarnet (CMV)
5. Late Protein synthesis and processing
Blocked by:
Protease Inhibitors (HIV)
6. Viral release
Blocked by:
Neuraminidase inhibitors (Influenza)
Amantadine
Used for prophylaxis of Influenza A
- *Inhibits M2 proton channel** (unique to viruses)
- -> prevents acidification necessary for uncoating
- Toxicities are those expected from a dopamine agonist
(originally deeloped as an anti-parkinson drug)
Rimantidine is an alpha-mehtyl derivative of Amantadine with similar mode of action
- May shorten duration of illness if taken after symptoms present
Maraviroc
Inhibits HIV attachment
Inhibits bindign of gp120 to CCR5
Enfuvirtide
Inhibits HIV attachment
Synthetic peptide
- Locks gp41 in extended conformation
–> No fusion of viral envelop and cell membrane
Docosanol
Topical treatment against HSV
(abreva)
–> prevents attachment and penetration of virus
Palivizumab
Humanized mAb against coat protein of RSV for high-risk patients
- Prevents attachment and penetration
Triflundine
Treatment for herpes keratitis treatment
Inhibits thymidylate synthase
(very toxic)
Ribavirin
Inhibits purine biosynthesis
Interferes with RNA metabolism needed for viral replication; widely active with DNA and RNA viruses
Aerosolized delivery for RSV (especially infants)
Hepatitis C (in combination with IFN-alpha)
Acyclovir
Acyclovir is a pro-drug that is phosphorylated by viral Thymidine Kinase
Then cellular kinases convert it to acycloguanosine triphosphate (acyclo GTP) which is incorporated into infected DNA
–> acyclo GTP doesn’t have the hydroxyl group required to make phosphodiester bonds
Ganciclovir
Another nucleoside analog (like acyclovir) that is most useful against CMV
What are the types of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) for HIV?
Azidothymidine/Zidovudine
Stavudine
Lamivudine - used with IFN-a to treat HBV and pregnant women (lower side effects)
Zalcitabine
Didanosine
Abacavir
Emtricitabine - fluorinated analog of lamivudine
Azidothymidine (AZT, zidovudine)
Prodrug converted by cellular kinases into AZT-TP in which Reverse Transcriptase has and increased affinity for, making it more specific to infected cells
- -> many Side Effects:
i. e. Anemia, granulocytopenia
Short 1/2 life
–> frequent dosing required
Didanosine
Nucleoside RT inhibitor
Side effect: pancreatitis
Abacavir side effects
Nucleoside RT inhibitor for HIV
Hypersensitivty rxns
hepatosplenomegaly
–> especially in HLA-B*5701 patients
–> used only after genotyping
What are the nucleoside RT inhibitors for HBV only?
Entecavir (guanosine analog)
Telbivudine (thymidine analog)
–> not effective against HIV
–> effective against HBV RT/DNA polymerase
What are the available Nucleotide Reverse Transcriptase Inhibitors?
Tenofovir
Cidofovir
Adefovir
Tenofovir
Nuceotide analog
Nucleoside phosphonate that is converted to the di- and tri-phosphate in resting cells
–> this gets around the problem of initial phosphorylation
Competitively inhibits HIV RT, causes chain termination
(approved for HBV as well)
reduced renal function over time
Cidofovir
Nucleotide RTI
** Inhibitory effect on viral DNA polymerase**
used for ganciclovir/foscarnet-resistant CMV and acyclovir-resistant HSV
Doesn’t require virally coded enzymes for phosphorylation
Adefovir
Nucleotide RTI
Used against HBV
Potential for lactic acidosis
What are the available Non-nucleoside RT inhibitors?
Nevirapine - recommended against pregnant patients, Stevens Johnson syndrome possible, risk fo hepatotoxicity
Rilpivirine
Etravirine
Delavirdine
Efavirenz
Efavirenz
NNRTI for HIV
Once a day dosing
Fewer serious toxic side effects (nightmares)
NOT to be used during pregnancy
Foscarnet
Inorganic pyrophosphate analog
Inhibits HSV and CMV DNA polymerase
Used for treatment of ganciclovir-resistant CMV retinitis
IV only
Side effects:
Nephrotoxicity
Hypocalcemia
What are the available integrase inhibitors?
Raltegravir
Elvitagravir - newer inhibitor; only used in combination therapy
What are the available protease inhibitors?
Fosamprenavir
atanazavir
darunavir
indinavir
Lopinavir*
Nelfinavir
Ritonavir*
Saquinavir
Tipranavir
Telaprevir** (inhibits HCV serine protease)
Boceprevir** (inhibits HCV serine protease)
*Recommended for pregnant patients
**Beware drug interactions!
Does resistance to one protease inhibitor mean resistance to all?
Not necessarily
protease inhibitors each have different sites of action, thus making them variable in resistance
–> sequencing of viral protease can help predict resistance to various inhibitors
Side effects of protease inhibitors
Increased LDL
Decreased HDL
Increased Triglycerides
–> Lipodystrophies
Hyperglycemia (insulin resistance)
*Atanazavir has lower incidence of lipodystrophies
Why are Interferons used for antiviral treatment?
IFN-alfa has antiviral activity (hepatitis B and C)
Transcription inhibition
Translation Inhibition
Protein Processing Inhibition
Virus Maturation Inhibition
–> most effective against C when used in combination with:
Ribavirin (Nucleoside RTI) and Protease Inhibitors
–> pegylated forms have improved pharmacokinetics
What are available neuraminidase inhibitors?
How is use of Anti-Retroviral Therapy determined for HIV patients?
CD4 Count is the major indicator (
–> best predictor of disease progression
Regardless of CD4 Count:
History of AIDS-defining illness
Pregnant women
HIV-associated nephropathy
Hepatitis B coinfection, when HBV treatment is indicated
Acute opportunistic infections
Age >50yrs
HIV Viral load is not a determinant in ART
When would deferral of ART be considered for HIV?
Clinical or personal factors may support deferral
- When there are significant barriers to adherence
- if co-morbidities complicate or prohibit ART
- “Elite controllers” and long-term nonprogressors
What are potential risks of early ART for HIV?
ARV-related side effects and toxicities
Drug resistance (attributable to ART failure)
Inadequate time to learn about HIV, treatment, and adherence
Increase in total time on ART; greater chance of treatment fatigue
Current ART may be less effective or more toxic than future therapies
Transmission of ARV-resistant virus, if incomplete virologic suppression
Pill Fatigue –> increases risk of developing resistance
What are the benefits of early ART for HIV?
Maintain higher CD4 count; prevent irreversible immune system damage
Decrease risk of HIV-associated complications
Decrease risk of nonopportunistic conditions and non-AIDS associated conditions
Decrease risk of HIV transmission
What are the ART options for HIV?
2 NRTIs + a Protease Inhibitor*
2 NRTIs and a NNRTI* (PI sparing regimen)
2 NRTIs + and Integrase Strand Inhibitor*
*Denotes backbone agent of regimen; most powerful
