Introduction: All Antiviral Drugs are virustatic

Antiviral Drugs for – Herpes viruses

• remember that these are DNA viruses
• Includes HSV 1&2, VZV, CMV, EBV, HHV-6, HHV-7, HHV-8

Specific Drugs

Acyclovir – guanosine analogue

• requires phosphorylation to triphosphate form for activity
• the viral thymidine kinase performs the initial phosphorylation
• Mechanism

Ø  irreversibly binds to viral DNA polymerase

Ø  acts as a chain terminator and inhibitor of viral DNA polymerase

• Absorption

Ø  bioavailability – 10-20%

Ø  CSF levels ~50% that of plasma

• USED FOR: HSV or VZV
• Minimal toxicity

Valaciclovir – guanosine analogue

• PRODRUG of acyclovir
• Increased bioavailability – 50-60%
• Use: VZV, HSV

Famiciclovir – guanosine analogue

• converted to peniciclovir in the intestinal wall and liver
• MOA similar to acyclovir
• Greater bioavailability than acyclovir (75%)
• Penciclovir excreted unchanged in the urine
• Use: VZV, HSV 1 & 2

Ganciclovir – guanosine analogue

• NOT dependent on viral thymidine kinase for initial phosphorylation
• Good CSF penetration
• Use: life threatening CMV disease
• Toxicity: hematologic

Vidarabine – adenosine analogue

• inhibits DNA polymerase; requires phosphorylation
• USE: 1^st one for HSV, now others used; Ophthalmic ointment in herpes keratitis
• Toxicity: HIGH DOSES necessary so GI, CNS, hematologic

Cidofovir – nucleotide analogue

• inhibits viral DNA polymerase
• requires phosphorylation to active form
• long intracellular t^1/2
• USE: significant CMV disease
• Toxicity: renal toxicity

Phosphonoformate – pyrophosphate analogue

• activity against viral DNA polymerase, reverse transcriptase, and RNA polymerase in vitro
• chain terminator
• USE: acyclovir-resistant HSV or VZV, CMV retinitis
• Toxicity: renal, “metabolic”

Idoxuridine, Trifluridine – thymidine analogues

• phosphorylated by BOTH viral and cellular thymidine kinase
• inhibit BOTH viral and cellular DNA synthesis
• USE: ONLY topically in opthalmic prep – HSV keratitis

Fomivirsen sodium – antisense oligonucleotide

• antisense oligonucleotide complementary to immediate-early region of CMV nuclei acid
• inhibits viral replication
• Use: CMV retinitis; only for injection into the eye
• Toxicity: inflammation, increased intraocular pressure

Antiviral Drugs for Respiratory Viruses

• most are RNA viruses (except adenovirus)

Specific Drugs

Ribavirin – guanosine analogue

• competitive inhibitor of DNA and RNA synthesis; unknown MOA
• administrated via aerosol
• oral an IV available
• USE: Pneumonitis due to RSV
• Toxicity: minimal if aerosolized, anemia in IV and oral use

Amantadine – primary amine

• interferes with the release of viral RNA genome into cell
• Use: prophylaxis and treatment of influenza A
• Also used in Parkinson’s patients
• Toxicity: reversible CNS effects, potentiated by antihistamines

Rimantadine -

• same as amantadine, except fewer CNS side effect

Antiviral Drugs for HIV

Zidovudine (AZT) – thymidine analogue

• inhibits reverse transcriptase and acts as a DNA chain terminator
• HISTORY: 1^st line agent for HIV
• Toxicity:

1)     hematologic

2)     lactic acidosis

3)     severe hepatomegaly with steatosis

Didanosine – deoxyadenosine analogue

• RT inhibitor and DNA chain terminator
• Rapidly degraded by acidic pH, must take buffering agent with the oral prep.
• Toxicity

1)     pancreatitis

2)     peripheral neuropathy

Zalcitabine – deoxycytidine analogue

• RT inhibitor and DNA chain terminator
• Use: 2^nd line agent in combo therapy
• Toxicity: peripheral neuropathy

Staduvine – thymidine analogue

• RT inhibitor and DNA chain terminator
• Use: HIV patients intolerant or not responding to alternate therapy
• Toxicity: peripheral neuropathy

Lamivudine – cytidine analogue

• RT inhibitor and DNA chain terminator
• Use in combo therapy – Lamivudine + Zidovudine = Combivir
• Less toxic than other antiretroviral agents; pancreatitis

Abacavir – guanosine analogue

• DNA chain terminator
• Use: combo therapy
• Toxicity: hypersensitivity

Non-Nucleoside RT Inhibitors (NNRTIs)

• Nevirapine
• Delavirdine
• Efavirenz

Ø  non-nucleoside inhibitors

Ø  directly bind to RT

Ø  p450 metabolism

Ø  USE: combo therapy

Ø  Toxicity: rash, Efavirenz with CNS symptoms

Protease Inhibitors

• Sequinavir
• Ritonavir
• Indinavir
• Nelfinavir

Ø  inhibit HIV aspartic protease

Ø  results in production of non-infectious virus

Ø  p450 metabolism

Ø  Use: combo therapy

Ø  Toxicity: diabetes mellitus, GI, liver

Interferon and Immunomodulators in Antiviral Therapy

Immunomodulator – diverse group of biologically active compounds which alter the immune response via direct or indirect interactions with T cells, B cells, or APCs.

Interferons – subset of immunomodulators.  Family of related peptides, produced by cells in response to viral infection or other stimuli

Specific Drugs

Interferon -  a

• mechanism

Ø  multiple mechanisms of antiviral activity

-        includes activation of enzymes blocking viral transcription and translation

• inactivated in GI tract, thus subQ or injected into lesions
• use: therapy of Hep B and C, papillomavirus
• Toxicity: influenza like symptoms, CNS disorders

Tags: Cidofovir, Famiciclovir, Fomivirsen sodium, Ganciclovir, guanosine analogue, Herpes viruses, Idoxuridine, Phosphonoformate, phosphorylation, Ribavirin, Trifluridine, Valaciclovir, Vidarabine

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