Multi-Systems: Antiviral Agents Flashcards
(2) Anti-herpes-viral drugs that are Guanosine analogs that
inhibit Nucleic Acid Synthesis?
Acyclovir (HSV, VZV)
Ganciclovir (CMV)
Mechanism of Acyclovir and Ganciclovir?
- Acts as a Chain terminator and Viral DNA Polymerase Inhibitor (HSV-enzyme required to activate)
- Guanosine analog w/ Acyclic Sugar
- Phosphorylated by Viral Thymidine Kinase
- -> acylcoGMP –> acycloGTP
- Valacyclovir + H2O –> Acyclovir + Valine
- Valganciclovir + H2O –> Ganciclovir + Valine
Clinical use of Acyclovir and Ganciclovir?
-
Acyclovir
- HSV-1, HSV-2
- VZV
- EBV
-
Ganciclovir
- CMV
- HHV-6, HHV-7
Resistance to Acyclovir and Ganciclover?
- Deleted or Mutated - Viral Tyrosine Kinase
- Resistant - Viral DNA Polymerase
- No effect during latent infection because Viral Tyrosine Kinase is not expressed
Drugs that work on CMV?
- Ganciclovir (Guanosine analog)
- Foscarnet (Viral DNA polymerase inhibitor)
(2) Anti-herpes-viral, Viral DNA polymerase inhibitors that stop Nucleid Acid Synthesis?
- Foscarnet (CMV)
- Cidofovir (HSV* - Acyclovir resistant)
Mechanism of Foscarnet?
- An inorganic pyrophospate analog that Inhibits Viral DNA polymerase w/out requireng activation via Phosphorylation by Viral Kinases.
- Effective against resistant strains of HSV, VSV, and CMV
Clinical use of Foscarnet?
- Acyclovir-resistant HSV and VZV
-
Ganciclovir-resistant CMV
- Produces less Bone Marrow suppression than Ganciclovir
SEs of Foscarnet?
- Nephrotoxicity
- Foscarnet acts as a Potent Chelator of divalent Cations
- -> decreased ionized Ca2+, Mg2+
- -> Symptomatic Hypocalcemia w/ normal Serum Ca2+
Resistance to Foscarnet?
- Foscarnet binds to the pyrophosphate binding site of the DNA polymerase
- -> Mutations in DNA Polymerase that prevent binding
(2) Antiviral drugs that Block the
Influenza A M2 Protein Channel
–> Preventing Uncoating of Influenza virion
–> Req’d for Infection
- Amantadine
- Rimantadine
Mechanism of Amantadine and Rimantadine?
- M2 channel conducts Protons from the Endosome into the Virion
- -> Acidification of the Interior and Dissociation of the Matrix protein from Viral ribonucleoproteins (RNPs)
- Amantadine / Rimantadine prevent Virion from fusing w/ the Endosomal membrane and stops from Releasing contents into Cytoplasm
Clinical use of Amantadine and Rimantadine?
- Influenza A infections
- No longer used though due to increased Resistance
- Resistance arises rapidly via Single-point mutation of M2 protein
(1) Hepatitis Anti-viral, Guanine nucleotide Synthesis that Inhibits Nucleic Acid Synthesis?
- Ribavirin
Mechanism of Ribavirin?
- Guanosine analog that is Phosphorylated by Cellular enzymes
- Inhibits Syn. of Guanine Nucleotides by competitively inhibiting Inosine Monophosphate Dehydrogenase
- Inhibits IMP dehydrogenase
- -> Impaired Purine synthesis
- Inhibits Viral RNA polymerase and 5’ cap formation on mRNAs
Clinical use of Ribavirin?
- Chronic HCV Infection (in combination w/ IFN-α)
SEs of Ribavirin?
- Hemolytic anemia when administered IV
- Severe Teratogenic
- Oncogenic
- Gonadotoxic
Small polypeptide (18 kd) that binds to a cellular receptor
and Induces a Antiviral Cellular State?
- IFN-α
Mechanism of IFN-α?
-
Binds to Cellular Receptor and Induces a Antiviral Cellular State
- Phosph. of EF 2 –> Inhibit Peptide Chain Initiation
- Ribonuclease Activation –> degrade Viral mRNA
- Phosphodiesterase exp –> degrade tRNAs
- -> inhibit Peptide Chain Elongation
- Increase Natural killer cell lytic function
- Increase exp. of MHC Class I molecules
Clinical use of IFN-α?
- Chronic Hepatitis B and Hepatitis C Infections
-
Anti-tumor effect on various cancers
- Melanoma
- Hairy cell leukemia
- Kaposi’s Sarcoma
SEs of IFN-α?
-
Flu-like Symptoms
- Fever
- Myalgias
- Malaise
- Neutropenia
- Thrombocytopenia
(2) Drugs that Reversibly Inhibit Neuraminidase (NA)
of Influenza A and B and impairs budding of Virions?
- Zanamivir
- Oseltamivir
SEs of Zanamivir and Oseltamivir?
- Bronchospasm
- Oseltamivir (Tamiflu) is a prodrug that is converted by the Liver to an Active neuraminidase Inhibitor after Oral Administartion
- Used for Treatment and Prophylaxis of Influenza A and Influenza B Infections.
Mechanism of Enfuvirtide?
- Polypeptide Fusion inhibitor
- Binds to the First Heptad-repeat (HR1) in the
- *gp41** subunit of the HIV envelope glycoprotein and
- *Prevents** the Conformational changes Req’d for the Fusion of Viral and Cellular membranes
- HIV is prevented from establishing infection in the Target Cell.
Clinical use of Enfuvirtide?
- HIV infection
- Salvage regimens to treat Multi-drug-resistant HIV
(3) Drugs that are Fusion Inhibitors?
- Maraviroc (HIV - CCR5 as a co-receptor)
- Enfuvirtide (HIV - gp41 HRI region)
- Palivizumab (RSV)
Mechanism of Maraviroc?
- This entry inhibitor Binds to the CCR5 Receptor on
- *Macrophages**, T cells, and Dendritic cells
- Prevents HIV from using CCR5 as a co-Receptor
- Blocks entry of CCR5-trophic HIV into cells
Clinical use of Maraviroc?
- HIV Infection
- Primarly to salvage regiments of multi-drug-resistant HIV
- Prior to intiation of Therapy, a Viral tropism assay should be done to Exclude CXCR4 or dual trophic HIV Infection
SEs of Maraviroc?
- Cardiovascular
- Myocardial Ischemia
- Myocardial Infarction
Mechanism of Raltegravir?
- An Integrase inhibitor that reversibly
- *Inhibits HIV Integrase** –> Preventing the HIV genome from being inserted into the Host cell Chromosome.
Clinical use of Raltegravir?
- HiV infection
(5) Drugs used for HSV?
- Acylovir
- Ganciclovir
- Foscarnet
- Cidofovit
- Trifluridine
(1) Drug used for EBV?
- Acyclovir - Oral Hairy Leukoplakia only
- Anti-viral therapy is not indicated for **Infectious Mononucleosis
- ->**They will break out in a Full-Body Head to Toe Rash
(4) Drugs used for VZV?
- Acyclovir
- Ganciclovir
- Foscarnet
- Cidofovir
(3) Drugs used for CMV?
- Ganciclovir
- Foscarnet
- Cidofovir
(5) Drugs used for HBV?
- Tenofovir
- Entecavir
- Telbivudine
- Lamivudine
- INF-α
(2) Drugs used for Influenza A?
- Zanamivir
- Amantadine
(1) Drug used for Influenza B?
- Zanamivir
(1) Drug for RSV?
- Ribavirin
(2) Drugs for HCV?
- Ribavirin
- IFN-α
(6) Drugs that Inhibit HIV’s Reverse Transcriptase (RT):
AZT (Azidothymidine) - ?
(Nucleoside RT Inhibitors - NRTIs)
“SEAL-DZ”
- Stavudine (d4T)
- Emtricitabine (FTC)
- Abacavir (ABC)
- Lamivudine (3TC)
- Didanosine (ddl)
- Zidovudine (ZDV) –> Used for general Porphylaxis and During Pregnancy to decrease risk of Fetal Transmission
Mechanism of AZT?
- Nuclear analog of Thymidine –> Phosphorylated by Cellular Enzymes –> Zidovudine Triphosphate
- -> Inhibits HIV’s Reverse Transcriptase (RT)
- NRTI’s lack the Hydroxyl group at 3’ Position req’d for addition of Further Nucleotides
- -> Chain Termination when Incorporated into DNA
Clinical use of AZT?
- HIV-1 and HIV-2
- Decrease incidence of Maternal-fetal HIV Transmission
(w/ combination treatment) - Post-HIV exposure Prophylasix (needlestick, sexual)
SEs of AZT?
- Myelosuppression
- Increased MCV –> used to verify compliance
- **Mitochondrial toxicity
- -> Lactic acidosis
- -> Hepatic acidosis**
- -> Peripheral Fat Wasting
(3) Drugs that Inhibit HIV and HBV Reverse Transcriptase?
And acts as a Chain Terminator when
Incorporated into Viral DNA?
“CAdT”
- Cidofovir
- Adelovir Dipivoxil
- Tenofovir (TDF)
Mechanism of Tenofovir?
- Nucleotide analog of Adenosine
- Addition of Two more Phosphate groups by Cellular enzymes
- -> Inhibitor of HIV and HBV Reverse Transcriptase
- Also, acts as a Chain Terminator when incorporated into Viral DNA
Clinical use of Tenovir?
- HIV Infection
- Chronic HBV infection
- Including HBV strains resistant to Lamivudine
SE of Tenovir?
-
Nephrotoxicity
- Especially w/ Adefovir and Cidofovir
- Nucleotide analogs (NOT nucleoside analogs) are actively secreted by and are Toxic to the PCVT (Kidney)
- Co-administration of Probenecid decreases Toxicity (by preventing drug accumulation in Renal tubular cells) and Increases Serum Drug levels
- Severe“Rebound” Heptatitis can occur upon discontinuation if HBV infection persists
- CONTRAINDICATED: Pregnancy (development and Bone abnormalities)
(4) Drugs that Inhibit HIV’s Reverse Transcriptase (RT)?
(Non-nucleoside Reverse Transcriptase Inhibitor - NNRTI)
“NEED”
- Nevirapine
- Efavirenz
- Etravirine
- Delaviradine
Mechanism of NNRTI’s?
- Binds w/ High Affinity to and Inhibits HIV’s Reverse Transcriptase (RT)
- Does not require Phosphorylation to be active or complete w/ Nucleotides
- HIV-2 RT is not inhibited
Clinical use of NNRTI’s?
- HIV-1
SEs of NNRTI’s?
-
Neuropsychiatric effects
- Feeling “Hung-over”
- Bizarre and Vivid Dreams
- CONTRAINDICATED - Pregnancy (Teratogenic)
(9) Drugs that Inhibit the HIV Protease that is responsible for Cleaving the two polyprotein products of HIV mRNA?
(gag and gag-pol polyproteins)
“F-SALT-RIND”
- Fosamprenavir
- Saquinavir
- Atazanavir
- Lopinavir
- Tipranavir
- Ritonavir
- Indinavir
- Nelfinavir
- Darunavir
SEs of HIV protease inhibitors?
- GI Distress
-
Lipodystrophy
- Glucose Intolerance
- Hyperlipidemia
- Myocardial Infarction (small)
What is special about Ritonavir?
- Ritonavir is a PI that potentially inhibit CYP450
- -> multiple drug interactions
- Co-administered w/ other Protease Inhibitors give w/ Ritonavir to “Boost” their serum levels
Used topically for HSV-1 and HSV-2 Eye Infections?
- Trifluridine
- Thymidine analog
- Phosphorylated by both Viral and Cellular Thymidine Kinases
- Breackage and Faulty protein production
- Inhibits DNA Synthesis
