7. Antivirals Flashcards
Amantadine / Rimantadine - MOA
Block viral penetration / uncoating (M2 ion channel protein)
- Also causes Dopamine release from intact nerve terminals.
“A MAN 2 DINE takes off his COAT”
Amantadine / Rimantadine - Clinical Use
Prophylaxis and treatment of Influenza A –> Recent CDC report that 100% of all influenza A now resistant –> no longer used.
- PARKINSON’S
“Amantadine blocks influenza A and causes problems with the cerebellA”
Amantadine / Rimantadine - Toxicities
Ataxia, dizziness, slurred speech
“Amantadine blocks influenza A and causes problems with the cerebellA”
- Rimantadine does not cross BBB - Less CNS side effects.
Amantadine / Rimantadine - Resistance
Mutated M2 protein
Zanamivir / Oseltamivir - MOA
Inhibit Influenza neuraminadase –> prevent release of progeny virus.
Zanamivir / Oseltamivir - Clinical Use
INFLUENZA A and B
Ribavirin - MOA
Inhibits synthesis of guanine nucleotides by competitively inhibiting IMP dehydrogenase
Inhibit RNA genome replication
Ribavirin - Clinical Use
RSV
- CHRONIC HEPATITIS C
Ribavirin - Toxicities
Hemolytic anemia
-Severe teratogen
Acyclovir - MOA
Monophosphorylated by HSV/VZV thymidine kinase –> Guanisine analog –> preferentially inhibits viral DNA via chain termination (Cellular enzymes make a triphosphate).
Acyclovir - Clinical Use
HSV (mucocutaneous, genital, and encephalitis), VZV, EBV
- Prophylaxis in immunocompromised
- No effect on latent forms of HSV and VZV
- Valacyclovir is prodrug of Acyclovir with better bioavailability
- For Herpes Zoster use Famciclovir
Acyclovir - Toxicities
Few serious side effects, possible nephrotoxicity
Acyclovir - Resistance
Lack of viral thymidine kinase
Ganciclovir - MOA
5’-Monophosphate formed by CMV viral kinase –> Guanosine analog –> preferentially inhibits viral DNA via chain termination (Cellular enzymes make a triphosphate).
Ganciclovir - Clinical Use
CMV especially in immunocompromised
- Valganciclovir is prodrug of Ganciclovir with better bioavailability
Ganciclovir - Toxicities
Leukopenia, Neutropenia, Thrombocytopenia, renal toxicity
- More toxic to host enzymes than Acyclovir
Ganciclovir - Resistance
Mutated CMV DNA polymerase or lack of viral kinase
Foscarnet - MOA
Viral DNA polymerase inhibitor that binds to the pyrophosphate binding site of the enzyme.
- does not require activation by viral kinase.
“FOScarnet is a pyroFOSphate analog”
Foscarnet - Clinical Use
CMV RETINITIS in immunocompromised when Ganciclovir fails.
Foscarnet - Toxicities
Nephrotoxicity
Foscarnet - Resistance
Mutated DNA polymerase
Cidofovir - MOA
Preferentially inhibits viral DNA polymerase
- Does not require phosphorylation by viral kinase
Cidofovir - Clinical Use
CMV retinitis in immunocompromised patients
- Acyclovir resistant HSV
- Long half life
Cidofovir - Toxicities
Nephrotoxicity
- Coadminister with Probenacid
HIV Therapy
HAART
- Initiated when patient presents with AIDs defining illness, low CD4 (<500), or a high viral load.
- 3 drug regimen
- 2 NRTIs + 1 NNRTI
- 2 NRTIs + 1 protease inhibitor
- 2 NRTIs + 1 integrase inhibitor
Protease Inhibitors - Available Drugs
Lopinavir Atazanavir Darunavir Fosamprenavir Saquinavir Ritonavir
” -navir “
Protease Inhibitors (“-navir”) - MOA
Inhibit HIV protease –> Prevent cleavage of HIV protein products into their functional parts –> Prevent maturation of new virus.
- Ritonavir can boost other drug concentrations by inhibiting P450
“NAVIR (never) TEASE a proTEASE”
Protease Inhibitors (“-navir”) - Toxicities
Hyperglycemia, GI intolerance, lipodystrophy
NRTIs - Available Drugs
Tenofovir (TDF) Emtricitabine (FTC) Abacavir (ABC) Lamuvudine (3TC) Zudovudine (ZDV, formerly AZT) Didanosine (ddI) Stavudine (d4T)
NRTIs (Tenofovir, Zidovudine, etc..) - MOA
Competitively inhibit addition of nucleotides
- Lack a 3’ OH
- Chain terminators
- All except Tenofovir (a nucleotide) must be phosphorylated by thymidine kinase to be active
ZDV is used for general prophylaxis and during pregnancy to reduce risk of fetal transmission.
“Have you DINEd (-vuDINE) with my NUCLEar (NUCLEosides) family?”
NRTIs (Tenofovir, Zidovudine, etc..) - Toxicities
Bone marrow suppression (Can be reversed with G-CSF and EPO)
- Peripheral neuropathy, lactic acidosis
- ZDV can cause megaloblastic anemia.
NNRTIs - Available Drugs
Nevirapine
Efavirenz
Delaviridine
” -vir- “
NNRTIs (Nevirapine, Efavirenz, Delaviridine) - MOA
Bind reverse transcriptase at site different from NRTIs.
- Do not require phosphorylation to be active
NNRTIs (Nevirapine, Efavirenz, Delaviridine) - Toxicities
Bone marrow suppression (Can be reversed with G-CSF and EPO)
- Peripheral neuropathy, rash
Integrase Inhibitors - Available Drugs
Raltegravir
Integrase Inhibitors (Raltegravir) - MOA
Inhibit HIV genome integration into host cell chromosome by reversibly inhibiting HIV integrase.
Integrase Inhibitors (Raltegravir) - Toxicities
Hypercholesterolemia
Interferons - Available Drugs
IFN-a
IFN-b
IFN-g
Interferons - MOA
Glycoproteins normally synthesized by virus infected cells that block replication of both DNA and RNA viruses.
Interferons - Clinical Use
IFN-a - Chronic Hep. B and C, Kaposi’s sarcoma
IFN-b - MS
IFN-g - NADPH oxidase deficiency
Interferons - Toxicities
Neutropenia
