Antiviral Drugs Flashcards
Respiratory Viral infection Treatment:
Infuenza A, B and Respiratory Syncytial Virus (RSV)
Neuraminidase inhibitors
Inhibitors of Viral uncoating
Synthetic Guanosine Analogue
Neuraminidase inhibitors:
- Oseltamivir
- Zanamivir
Inhibitors of Viral uncoating:
- Amantadine,
- Rimantadine
Synthetic Guanosine Analogue:
- Ribavirin
Neuraminidase inhibitors - MOA
- Effective against
- When is administration best
Neuraminidase inhibitors: Oseltamivir, Zanamivir
- Analogs/inhibitors of sialic acid substrate for neuramindase*
- Inhibit release of virus
- Effective against BOTH Type A and B Infuenza*
- Administration is best prior to exposure as prophylaxis
- Admin within 24-48hrs after infection - modest effect on symptoms.
NOTE: 2015-2016 influenza season
- Osetamivir and zanamivir are the only twi agents recommended for use!!
Neuraminidase Inhibitors PK/AE:
Oseltamivir: orally active prodrug (hydrolyzed in Liver)
Zanamivir: Not orally active (inhaled, intranasal)
AE:
- Oseltamivir: GI discomfort, nausea due to oral route (alleviated when taken with food)- 1 year up
- Zanamivir: airway irritation (avoid in severe asthma, COPD)- 7 years up
Ion channel blockers MOA
- Effective against
- When is administration best
Amantadine - widely distributed and crosses BBB not extensively metabolized and excreted into urine where it may accumulate
Rimantadine - not widely distributed, metabolized and eliminated in urine.
- Block viral membrane protein, M2 (H+ channel)
- channel is required for fusion of viral with cell
membrane to endosome (requirement for viral uncoating)
- oral
1. Exclusively active against Influenza A virus
2. Equally effective in prophylaxis and treatment
NOT effective for treatment of current strains and not. used
Ion channel blockers AE/CI:
Amantadine: CNS - insomnia, dizziness, ataxia, leading ti hallucinations, seizures
Rimantidine: fewer problems
Both: GI intolerance
CI:
- Monitor amantadine in psychiatric patients, cerebral atherosclerosis, renal impairment, epilepsy
- Pregnancy, nursing (FDA Category C)
upto 50% people are naturally resistant
Purine/pyrimidine analogs MOA
- Active against?
- Combo’d with?
Ribavirin (Nucleoside anolgue GUANOSINE)
- Converted to Ribavirin-triphosphate which inhibits guanosine triphosphate formation nd prevents viral mRNA capping.
- Inhibits RNA-dependent RNA polymerase resulting in inhibition of viral protein synthesis
- Active against broad spectrum of RNA and DNA viruses (eg RSV, HCV, Lassa fever)
- used in combo with IFNa for HCV Tx.
Ribavirin PK/AE
Oral IV and aerosolized
Distrbution significantly prolonged in RBC (16-40 days)
AE:
- Dose dependent transient hemolytic anemia (can bind to RBC).
- GI (nausea, anorexia)
- CNS (fatigue, headache, insomnia)
Ribavirin CI:
Pregnancy (Cat. X) extrememly teratogenic
Tx for Hepatic Viral infections Hep A,B,C,D, and E:
Interferon
Nucleotide/Nucleoside analogs
Protease Inhibitors
Interferon - IFNa Nucleotide/Nucleoside analogs - Lamivudin, Entecavir, Ribavirin Protease Inhibitors - Boceprevir, Teleprevir
INFa MOA:
- Naturally occuring, inducible glycoproteins/ cytokines
- Do Not target viral gene products directly
- Inhibit RNA and DNA synthesis by activating / Inducing protein expression that inhibit virus infection eg, PKR
INFa PK/AE
Not orally active because its naturally occuring
uptake and metabolism by liver and kidney
usually pegylated to improve PK profile
AE:
- Flu like (fever, chills, myalgias and GI disturbances)
- Fatigue and mental depression
- interferes w/ hepatic drug metabolism. Can cause toxic accumulation of theophylline
- May potentiate zidovudine induced myelosuppression
INFa
Clinical Applications: Diseases it treats?
- HCV (combo w/ ribavirin)
- HBV, condyloma acuminata, hairy cell leukemia, kaposi’s sarcoma
Hepatic Anti-viral drugs
Nucleoside / Nucleotide Analogs
Lamivudine
Entecavir
- Must be phosphorylated by cellular enzymes to triphosphate (active) form.
- Actions are suppressive rather than curative
Lamivudine
Active against:
MOA:
Hep B and HIV
- Triphosphate form inhibits HBV and HIV reverse transcriptase.
- Monophosphate for incorporates into DNA (by HBV polymerase) resulting in chain termination.
- well tolerated
Entercavir
Active against:
MOA:
- effective against Lamivudine-resistant strains of HBV and HIV*
- phosporylated form competes w/ natural substrates for viral polymerase.
- Subsquent inhibition of polymerase blocks reverse transcriptase activity.
Monitor after discontinuation in case of exacerbation of severe hepatitis***
Protease inhibitors
Boceprevir, Teleperir
- Tx of HCV in adult patients who have been previously untreatd or failed tx. w/ IFNa and ribavirin
- Combo’d wt, IFNa and ribavrin
MOA: Bind reversibly to nonstructural protein 3 (NS3) serine protease and inhibit replication of HCV
Commonly reported AE reactions in adults due to protease inhibitors:
fatigue anemia nausea headache dysgeusia
Tx of herpes viral infections
Herpes can form latent infection. Available drugs are for replicating virus only
Purine and pyrimidine analogs:
-ovir [acyclovir, valacyclovir, cidofovir, Ganciclovir, Valganciclovir, Penciclovir, Trifluridine
Foscarnet
Acyclovir
DOC?
commonly used for?
Prototypic antiherpetic therapeutic agent
Activity against: herpes simplex virus (HSV) Types 1 and 2, VZV, EBV (HSV4).
DOC in HSV Encephalitis*
- Commonly used for genital herpes infections and prophylactically in immuncompromised and transplant patients.
- CMV is resistant at clinically achievable levels (does not encode thymidine Kinase)
- Valacyclovir = Prodrug of acyclovir
Acyclovir MOA
- 3 phosphorylation steps for activation
- Monophosphorylated by herpes virus-encoded enzyme (thymidine kinase)
- Host cell enzymes complete phosporylation to di and triphosphate forms.
- Competes w/ GTP; once incorporated into DNA causes chain termination and inhibition of viral DNA polymerase
Resistance is rare in immunocompetent hosts. occurs by
- deficient thymidine kinases
- altered viral DNA polymerase w/ decreased affinity for acyclovir.
Acyclovir - PK
- IV, oral or topical
- Valacyclovir has greater oral bioavailability than acyclovir
- Partially metabolized thus can accumulate w/ renal failure.
Acyclovir AE
topical: local irritation
oral: headache, diarrhea, nausea and vomiting
IV: acute renal failure. Risk can be minimized by slow infusion and prioir hydration of patient.
Gancyclovir
DOC?
- Valganciclovir = pro-drug w/ greater oral bioavailability
- analog of acyclovir (8-20 X activity against CMV)
- DOC for CMV retinitis and CMV prophylaxis in immunocompromised
MOA:
Phosphorylated by viral (UL97) and cell kinases
DNA chain terminator and DNA polymerase inhibitor
Gancyclovir PK
Gancyclovir (IV)
Valgancycovir (oral) undergoes rapid hydrolysis in intestines and liver to gancyclovir
Urine excretion
Gancyclovir AE/CI
Myelosuppresion
Severe dependent neutropenia
CI:
Pregancy (FDA Cat. C)
Cidofovir whats special about it? Major use? Activation? MOA?
Special because does not require phosphorylation by viral kinases.
- Major use is tx. of CMV-induced retinitis in HIV/AIDS
- Require activation by host cell kinases
- effective against HSV and gancyclovir resistant HSV.
MOA:
- DNA chain terminator and DNA polymerase inhibitor
Cidofovir PK/AE
IV, intravitreal and topical
must be co-administered with probenecid (blocks renal tubular secretion)–> increased time for effects
AE: Nephrotoxicity
Penciclovir
Active against HSV 1-2 and VZV (cold sores)
Used for the topical tx of HSV (cold sores)
Penciclovir
MOA?
penciclovir
MOA: monophosporylated by viral thymidine kinase
- further phosphorylation occurs to give active triphosphate form.
- Inhibits HSV DNA polymerase/ chain terminator
- active against HSV-1, 2 and VZV
- Used for the topical tx. of HSV (cold sores)
Penciclovir PK/AE
topical only
AE:
Dermatologic: mild erythema
Trifluridine
DOC
MOA?
Effective against HSV-1, 2 and vaccina virus.
DOC for HSV keratoconjunctivitis and recurrent epithelial keratitis
MOA: Triphosphate form incorporated into viral DNA causing fragmentation
Trifluridine - PK/AE
Ophthalmic ointment (too toxic for systemic) t1/2=12min (apply frequently)
AE: Transient irritation of eye and palpebral (eyelid) edema
Foscarnet
Organic analog of inorganic pyrophosphate
Does not require phosphorylation!!
Used for CMV retinitis in immunocompromised patients, acyclovir-resistant HSV and SMV retinitis and gancilovir-resistant CMV and VZV.
Fodscarnet MOA
resistance?
Structural analog of anion pyrophosphate that selectively inhibits the pyrophosphate binding site on viral DNA polymerases
resistance:
point mutation in polymerase
Foscarnet PK/AE
IV only
-LAST RESORT
AE:
Nephrotoxicity*
Electrolyte disturbances (Ca+2, Mg+2, K+, PO4)*
Anemia
Genital ulceration (mainly men)
CNS: Hallucinations, seizures, headache (25%)
