Antivirals Flashcards
Ganciclovir
Similar to acyclovir except monophosphate is put on by CMV protein kinase and host enzymes make it a triphosphate and inhibits DNA synthesis and elongation
Uses: CMV retinitis, CMV prophylaxis for transplant recipients
Side effect: bone marrow suppression
Enfuvirtide
Use: For HIV-1 and HIV treatment-experienced patients who have failed multiple regimens
MOA: binds to gp41 subunit of HIV glycoprotein and blocks conformational changes required for membrane fusion to CD4+ cells
Side effects: local injection site reactions, diarrea, nausea, fatigue, later option when other regimens have failed
Non-nucleoside reverse transcriptase inhibitors
Efavirenz
bind at different site distinct from enzyme catalytic site
All are active as given
Maraviroc
chemokine CCR5 antagonist (on human cells to prevent interaction with HIV gp120)–> blocks entry into HIV cells
Use: treatment of CCR5-tropic HIV-1
effective for strains resistant to other drugs (CCR-5 tropic strains tend to predominate early in infection)
Side effects: hepatotoxicity, CV events
Oseltamivir
Influenza A and B treatment/ prophylaxis (greatest benefit if given in first 48 hours of symptoms)
Mechanism: prodrug given orally and activated in liver and compettively inhiits influenza neuraminidases (interfere with viral release and penetration)
side effects: nausea, vomiting, diarrhea, bronchitis
Hepatitis B
Lamivudine
Tenofovir
Interferon alpha
Tenofivir
MoA: monophosphate prodrug phosphorylated by cell enzymes to triphosphate form and compet inhibitor of reverse transcriptase domain of hep B polymerase so cause DNA chain termination
Use: Hep B
Side effects: GI upset
Cytomegalovirs Prophylaxis/Infection
Ganciclovir
Foscarnet
HIV therapeutic failure
failure to maintain adherence
resistant strains
Ribavirin
Interfere with viral mRNA synthesis by :
Mono-P form inhibits inosine 5’-P dehydrogenase and thus GMP and GTP synthesis
Tri-P form inhibits GTP dependent capping of viral mRNA (so gets degraded)
Uses: aerosol use for young children with severe RSV infections and oral capsules for hepatitis C (combined with PEG interferon alpha and other drugs)
Side effects: aerosol use precipitates and clog resp equipment and pulmonary function deterioration and rash
also anemia and bone marrow suppression with Oral and IV use
Inhibition of Nucleic Acid Synthesis
Trifluridine
Acyclovir
Famciclovir
Penciclovir
Protease Inhibitors
Lopinavir
Ritonavir
Use: in combination with inhibitors of RT (HIV 1 and HIV 2)
and significantly decrease viral blood load
MOA: prevent viral aspartic protease from cleaving Gag-pol polypeptide into separate functional proteins
competitive inhibitor
results in non-infectious viral particles
Toxicity: diabetes, alterations in lipid metabolism (increased triglycerides and cholesterol), fat redistribution, alters metabolism of many other drugs (potent CYP3A inhibitors)
Acyclovir
Guanosine analog without cycle of ribose
activated only in virus infected cells and phosphorylates the acyclovir 40-100X faster in infected cells
Inhibits herpes DNA polymerase 10-30X more effectively than host cell DNA polymerase
Competes with doxy-GTP for DNA polymerase (chain termination)
Side Effects: generally well tolerated, rash, itching, nausea, vomiting, headache, fatigue
Abacavir
NRTI
Nucleoside Analog
Triphosphorylated form inhibits RT and cause DNA chain termination
Adverse effects: hypersensitivity (associated with HLA-B*57-1 allele) and if develops then stop drug immediately
Amantadine
Influenza A prophylaxis
Therapy: reduces fever in 50% of patients and illness duration by 1-2 days
resistance is common
Best in crowded environments
MOA: blocks viral uncoating by interfering with influenza A M2 protein (ion channel)
Side Effects: CNS effects
Penciclovir
Similar to acyclovir
Use: recurrent herpes of lips and face
topical administration
Lamivudine (3TC)
Nucleoside analog inhibitor of RT and in triphosphate form competitively inhibits RT and cause DNA chain termination (AZT resistance strains are 3TC sensitive and 3TC resistant strains are AZT sensitive)
Use: synergisitic with AZT against HIV
Side effects: nausea, diarrhea, rash
Hepatitis C
Ribavirin Interferon alpha Simeprevir Sofosbuvir Ledipasvir
Treat: interferon alpha +ribavirin for Hep C treatment
HCV drug combinations
2 or more drugs with different mechanisms
avoid Interferon alpha when possible
Genotype appropriate therapy
Side Effects Tolerance
Lamivudine
MOA: nucleoside analog (no phosphates) and phosphorylated by cell enzymes to triphosphate form and competitively inhibits reverse transcriptase domain of hep B polymerase (CAUSE DNA CHAIN TERMINATION)
Use: hepatitis B
Side effects: nausea, diarrhea
Famciclovir
Prodrug activation to penciclovir-triP (active) which is very similar to acyclovir and inhibits viral DNA polymerase
Uses: acute herpes zoster (shingles which is latent chickenpox virus) localized and
Foscarnet
Inhibits CMV DNA polymerase by biding to pyrophosphate binding site
Does not require conversion to triphosphate form to be active
Uses: CMV retinitis, acyclovir resistant herpes virus (thymidine kinase mutations)
Side Effects: renal damage, electrolyte imbalance, seizures
Emtricitabine (FTC)
NRTI
Analog of lamivudine
Same mechanism and resistance as 3TC
Zidovudine
NRTI
Thymidine nucleoside analog phosphorylated by cell enzymes to AZT-triphosphate which competitively inhibits RT and acts as a chain terminator
Side Effects: bone marrow suppression (neutropenia and anemia), avoid drugs which inhibit glucoronyltransferases, myopathy
Raltegravir
Inhibitor of HIV integrase
Use: HIV-1 treatment and works on virus resistant to other drugs
Mechanism: HIV-1 integrase activity inhibited so HIV-1 DNA can’t integrate into chromosomes
Side effects: potential for severe/fatal skin and hypersensitivity reactions
Strategies to inhibit viral adsorption and penetration
Immunization
Amantadine
Oseltamivir
Fusion Inhibitors
Enfuvirtide
Efavirenz
NNRTI- binds at different site than NRTI and disrupt RT
Multi-drug therapy for HIV
Side effects: rash, CNS/psychiatric symptoms, nightmares, vivid dreams
Tenofovir
NRTI
unlike AZT: adenosine monophosphate prodrug hydrolyzed to tenofovir phosphonate
similariity to AZT: triphosphate form inhibits RT by competing for incorportate into DNA, causing chain temrination
Uses: combination therapy for HIV
side effects: overall, well tolerated
Trifluridine
Thymidine analog
Interferes with DNA synthesis
Use: Opthalmic use and treatment of herpes simplex type 1 and 2
Integrase Inhibitors
Raltegravir
Interferon alpha
Approved use: condyloma acuminata (venereal warts), hepatitis B and C and given with other drugs (pegylation decreases clearance) with better kinetics and less frequent dosing
Side effects: flu-like syndrome, leukopenia, bone marrow suppression, neurotoxicity, myalgia
Lopinavir
Protease Inhibitor
Protease inhibitor
Immunization
active- vaccination
passive- injection of immune globulin (antibodies)
Simeprevir
Better pharmacokinetics and side effects (new generation)
Reversible inhibitor of hepatitis C NS3/NS4A protease (cleavage of polyprotein to make individual proteins) so no cleavage of polyprotein and infectious virus not made
Use: hepatitis C genotype 1 and in combination with other drugs
Side effects: rash, nausea, itching, CYP3A interactions
Nucleoside analtog reverse transcriptase inhibitors (NRTI)
Zidovudine Lamivudine Abacavir Tenofovir Emtricitabine Side effects: lactic acidosis, hepatic steatosis
Ledpasvir
Inhibits NS5A phosphoprotein
Use: Given with sofosbuvir for HCV genotypes (1,4,5,6)
Three forms of Acyclovir
Intravenous–> systemic HSV (disseminated neonatal, encephalities) and severe genital herpes
Oral–> primary genital herpes and primary herpetic gingivostomatis
Topical–> primary genital herpes
CCR5 Antagonists
Maraviroc
Sofosbuvir
Nucleoside (uridine) analog prodrug
Triphosphate form inhibits HCV NS5B RNA polymerase and is incorporated into viral RNA to cause chain termination
Uses: all hep C genotypes, given with anti-HCV drugs
Side effects: substrate of P-glycoprotein so avoid potent inducers of this
Ritonavir
Protease Inhibitor Booster
Used to boost levels of other protease inhibitors (blocks metabolism by CYP3A by inhibiting it)
avoid other drugs metabolized by CYP3A
