Flashcards in Anti-Viral (NON-HIV) Drugs Deck (55)
DRUG CLASS 1: anti-DNA viruses
What is the mechanism of the drug treatments for HSV and CMV?
Nucleoside analogs that competitively bind VIRAL DNA POLYMERASE -> Most are chain terminators and inhibit viral DNA replication
Which two anti-HSV and anti-CMV drugs are so toxic that they can ONLY be used as TOPICAL agents?
How do the nucleoside analog drugs get converted to its active form?
Pro-drug form needs to be phosphorylated by HOST PT kinases -> Triphosphorylated form = active form
What is the one exception among the anti-HSV and anti-CMV drugs requiring host kinase for active phosphorylation?
ACYCLOVIR - Requires VIRAL thymidine kinase (TK) for the first phosphorylation event
Mutations of developing resistance to ACYCLOVIR
1) Mutations in the binding site of VIRAL DNA POLYMERASE
2) Mutations in VIRAL THYMIDINE KINASE - necessary for first phosphorylation
What are the drug treatments for Herpes Simplex Virus (HSV) and Cytomegalovirus (CMV) - DNA VIRUSES?
What is the chemical composition of ACYCLOVIR?
COMPETITIVE substrate (against dGTP) for VIRAL DNA Polymerase
How does ACYCLOVIR specifically get concentrated inside PARTICULARLY in viral-infected cells?
1st phosphorylation event is by VIRAL thymidine kinase (HSV-TK)
Then the 2nd and 3rd phosphorylation events by host kinases -> Gets trapped inside the virus
What is the chemical composition of CIDOFOVIR?
Competitive substrate (against dCTP) for VIRAL DNA Polymerase
How does CIDOFOVIR get activated within BOTH virus-infected and non-infected cells?
ONLY 2 PHOSPHORYLATION events by host kinases
Mechanism of CIDOFOVIR
CMP analog that competitively binds (against dCTP) for VIRAL DNA polymerase -> No 3'OH elongation -> Chain termination
Mechanism of resistance development for CIDOFOVIR
Mutations in the VIRAL DNA Polymerase
What does the CMP analog state of CIDOFOVIR imply in terms of pharmacoDYNAMICS?
Low oral bioavailability - because it is a charged molecule
Which agent is given commonly with CIDOFOVIR to increase its levels in pt? Name two reasons why.
REASON 1: Blocks tubular transport of cidofovir -> Reduces renal clearance
REASON 2: Reduces associated nephrotoxicity
Which is the most broad-spectrum anti-viral drug in that it blocks all 3: HIV RT + VIRAL DNA polymerase + VIRAL RNA polymerase
What is the chemical composition of FOSCAVIR?
Phosphate + Carboxylate moieties
Mechanism of resistance development against FOSCAVIR
Mutations in VIRAL DNA Polymerase
Why is FOSCAVIR also preferred with regards to resistance?
Retains its anti-DNA pol activity against GANCICLOVIR/CIDOFOVIR resistant strains
What are the three toxicities associated with FOSCAVIR administration?
1) NEPHROTOXICITY: Due to its negative charge (3-)
2) PENILE ULCERS: High levels of ionized urine
3) CNS TOXICITIES: Headache, hallucinations, seizures
DRUG CLASS 2: anti-Influenza (RNA - strand virus, orthomyxovirus)
What are the two subclasses?
SUBCLASS 1: Neuraminidase Inhibitors (Prevents viral escape)
SUBCLASS 2: Adamantanes - M2 protein Inhibitors (Prevents viral uncoating/unsheathing -> Prevents viral entry)
What are the 3 Neuraminidase inhibitors and routes of administration?
OSELTAMIVIR (Tamiflu) - Oral
ZANAMIVIR - Inhaled
PERAMIVIR - IV (single IV dose versus 5 days of oseltamivir)
What is the chemical composition of OSELTAMIVIR + ZANAMVIR + PERAMIVIR?
Sialic acid transition state analogs that INHIBIT viral neuraminidase activity
Mechanisms of resistance development in OSELTAMIVIR + ZANAMIVIR + PERAMIVIR
Mutations in neuraminidase gene OR hemagglutinin (HA)
Describe the prodrug -> activated drug conversion of OSELTAMIVIR
Prodrug taken orally -> Activated by ESTERASES (GI/liver)
Name the 2 Adamantane drugs that prevent M2 protein and thus Influenza viral entry
What is the specific mechanism of action of AMANTADINE + RIMANTADINE?
Binds and inhibits by clogging the M2 protein (H+/ion pore) -> Inhibits viral uncoating/unsheathing for its entry into host cell
What is the mechanism of developing resistance against AMANTADINE + RIMANTADINE?
Mutation in viral M2 protein
* Currently most circulating strains are all resistant to this and currently waiting for a strain to emerge for which we can use the adamantanes *
DRUG CLASS 3: anti-Hepatitis C (RNA virus, + sense)
What is the overall goal/benchmark for anti-hepatitis therapy?
SUSTAINED virologic response (SVR)
* Often times, the virologic response may be suppressed only temporarily due to a small pool of infected cells that emerges thereafter *
Does a vaccine exist for Hepatitis C? How about Hepatitis B?
Hep B- YES
Hep C - NO