Microbiology Msii Temple Antiviral Drugs

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Anti-Viral Meds

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Interferons
Gamma globulins
Amantadine
Rimantadine
Trifluridine
Zanamivir
Oseltamir
Acyclovir
Valcyclovir
Penciclovir
Famciclovir
Ganciclovir
Valganciclovir
Foscarnet
Cidofovir
Ribavirin
Palivizumab

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Antiviral Immunization

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Currently available vaccines include:

Measles
Mumpa
Rubella
Chicken Pox(varicella)
Polio
Hepatitis A
Hepatitis B
influenza.

Adverse resctions vary but may include localized tnederness, erythma, rash, mild flu like symptoms, and rarely anaphylaxis. Generally this is due not to the vaccine itself, but often to one of the fillers/preservatives in the vaccine. One (Thy...?) contains sulfur for example. Note that vaccination is desirable as once a virus has taken hold it may remain latent for life.

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Interferons

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Alfa-2a (Roferon-A), Alfa-2b (Intron A), Alfa-n3 (Alferon).

In vivo interferons are glycoproteins secreted by viral infected cells which will autoregulate proliferation and protein synthesis, and also activate uninfected cells into an antiviral state. The medication alternatives bind to receptors are are taken into infected cells.

Mechanism:
1. Activation of Oligoiadenylate synthetase- increases RNAse activity degrading viral mRNA and stalling protein synthesis.

2. Activates a protein kinase that phosphorylates Elongation initiation factor
2 (EIF-2), inactivating it and stalling protein synthesis.

3. Activates Phosphodiesterase which degrades the terminal nucleotides of tRNA, inhibiting peptide elongation.

In addition it may inhibit viral entry into the cell, replication, and viral particle assembly/release.

Spectrum:
Tx of genital warts, chronic Hep B & C, AIDS-related Karposi's Sarcoma, Malignant melanoma, and Laryngeal papillomatosis. (Imiquimod used topically for external genital and perianal warts.

Pharmacokinetics:
Must be given IV as they are proteins and would not survive the Gi tract.

Adverse Effects:
Flu like, increase pulse, fever, decreased white count, headache, somlolence, malaise, mental confusion

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Gamma Globulin

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Immune globulin USP

Pooled gammaglobulin with antibodies against superficial virus antigens. They are used preventitively.

Spectrum:
Measles, Hepatitis, Rabies, Varicells, Poliomyelitis

Pharmacokinetics:
IM or IV (lasta 2-3 weeks) administration blocks penetration of viruses inthe early incubation stages

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Amantadine (Symmetrel)

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Mechanism:
Interferes with fusion of lysosomes to membrame by increasing lysosomal pH. Thus inhibits uncoating and txfer of viral genome. May also inhibit viral assembly.

Spectrum:
Influenza A

Pharmacokinetics:
Completely absorbed with oral administration. 90% excreted unchanged in urine.

Adverse Effects:
anorexia, nervousness, insomnia, drowsiness, GI upset, hallucinations, seizures (elderly)

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Rimantadine (Flumadine)

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Mechanism:
Interferes wtih fusion of lysosomes to membrame by increasing lysosomal pH. Thus inhibits uncoating and txfer of viral genome. May also inhibit viral assembly.

Spectrum:
Influenza A

Pharmacokinetics:
Completely absorbed with oral administration. METABOLIZED IN THE LIVER. The difference is why we may choose to give this or amantadine, depending on the state of the liver/renal system of the pt.

Adverse Effects:
Less CNS effects than amantadine...

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Trifluridine (Viroptic)

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Fluronated thymadine (Trifluorothymidine)

Mechanism:
Phosphorylated to triphosphage, and then incorporated into viral DNA inhibiting DNA synthesis.

Spectrum:
DNA viruses (e.g. herpes simplex, adenovirus)

Adverse Effects:
mild local effects including irritation and photosensitivity.

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Zanamivir (relenza)

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Effective in reducing the duration or preventing the flu in patients in their families.

Mechanism:
inhibits Neuraminidase (a glycoprotein on the surface of influenza) reducing the release of the virus from infected cells.

Spectrum:
Influenza A and B

Pharmacokinetics:
Inhalation

Adverse Effects:
Inhalation may cause bronchospasm (may be contraindicated in respiratory compromised patients.

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Oseltamir (Tamiflu)

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Effective in reducing the duration or preventing the flu in patients in their families.

Mechanism:
inhibits Neuraminidase (a glycoprotein on the surface of influenza) reducing the release of the virus from infected cells.

Spectrum:
Influenza A and B

Pharmacokinetics:
Oral

Adverse Effects:
GI upset

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Acyclovir (Zovirax)

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(Acycloguanosine, Guanosine analog)

Mechanism:
Phosphorylated by VIRAL thymadine kinase to acycloGMP and then by CELL kinases to acycloGTP, which inhiits viral DN Apolymerase and incorporates in to DNA breaking the chain.

Spectrum:
Herpes Simplex, Varicella Zoster. (@ high doses in vitro CMV and Epstein Barr). Used for primary gential herpes, Oral/IV for serious/recurrent HSV/VZV. Also prophylactically during bone marrow transplant in sero+ individuals, after heart transplant, during immunosupression. Excreted unchanged by the kidney.

Pharmacokinetics:
15-20% bioavailability with oral admin. IV (gives higher levels). Also available topically.

Adverse Effects:
Topical- Burning mild pain; PO/IV- GI, CNS, renal, headache, confusion, tremor rash, thrombophlebitis, and rare seizures.

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Valacyclovir (Valtrex)

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Prodrug hydrolyzed to acyclovir in the liver and intestinal wall. Improves oral bioavailability to 48%. Similar adverse effects, and additinally may cause thrombocytopenia.

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Pencyclovir (Denavir)

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Topical Acyclovir analog used for orolavial herpes.

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Famciclovir (Famvir)

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Prodrug form of pencyclovir used to tx HSV and VZV infections. Increased oral bioavailability.

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Docosanol

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O.T.C. topical acyclovir analog used fo Tx of HSV. Inhibits fusion between HSV envelope and the plasma membrane, thus reducing healing time.

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Gancyclovir (Cytovene)

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Different guanosine analog, works like acyclovir.

Mechanism:
See Acyclovir

Spectrum:
CMV retinitis and other AIDS/immunocompromised related CMV infections(more potent than acyclovir for CMV).

Pharmacokinetics:
IV, Oral, Intraocular implant

Adverse Effects:
bone marrow supression, thrombocytopenia, renal impairment, and seizures. Severity of the adverse reactions may limit duration of use.

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Valgancyclovir (Valcyte)

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analog of Ganciclovir to improve oral bioavailabity.

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Foscarnet (Foscavir)

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Mechanism: non-nucleoside inhibitor of DNA polymerase of Human Herpes Viruses and Varicella Zoster

Spectrum:
CMV, Herpes in AIDS pt's. Acyclovir resistant HSV and VZV

Adverse Effects:
Hypocalcemia, Neurotoxicity, cardiac toxicity, renal toxicity, anemia.

It can be combined with ganciclovir and has less hematologic toxicity than the zidovudine/ganciclovir combination.

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Fomiversen (Vitravene)

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Intravitrial antisense therapy for CMV

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Cidofovir (Vistidine)

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Iv medication for CMV retinitis. It inhibits DNA polymerase and may cause nephrotoxicity. It should be used with caution with other nephrotoxic drugs.

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Ribavirin (Virazole)

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Synthetic guanosine analog.

Mechanism:
Converted to monophosphate which inhibits inosine dehydrogenase, blocks GMP formation and nucleic acid synthesis, also depletes intracellular GTP. Ribavirin-TP supresses mRNA inhibiting protein sythesis.

Spectrum:
Broad against DNA (herpes) and RNA (influenza A/B) viruses, RSV, Hep C, Lassa Fever.

Pharmacokinetics:
Aerosol form given in hospital for RSV, Combined wtih Interferon alfa (rebetron) for tx of Hep C, IV for Lassa fever.

Adverse Effects:
Headache, rash, fatigue, and dyspnea. The oral form is associated with cough, puritis, and depression.

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Palivizumab (Synagis)

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Humanized monoclonal antibody for prevention of RSV, esp used for high risk kids like premature infants. Potentially produces upper resp tract infections, fever, rhinitis, GI upset, and rash.

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Lamivudine

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Tx for HBV. Inhibits HBV DNA polymerase. Entecavir and adeforvir dipivoxil have also been used.

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HIV MEDS (Sterling)

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Zidovudine, Lamivudine, Nelfinavir, analogs

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Herpes Virus MEDS

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Keratitis- Trifluridine
Genital- Acyclovir & Analogs
Encephalitis- Acyclovir
Neonatal- Acyclovir

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Varicella Zoster MEDS

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Acyclovir & Analogs

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Influenza A MEDS

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Amantadine, Rimantadine

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Influenza A/B MEDS

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Zanamivir, Oseltamir

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Chronic HEP B

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Interferons (Pegylated Interferon Alfa), Lamivudine, Adefovir, Telbivudine, Entecavir

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Hep C

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interferons + Ribavirin

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Cytomegalovirus

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ganciclovir, Fosarner, Cidofovir.

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Respiratory Syncitial Virus

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Ribavirin

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Mechanisms of Antiviral Meds

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Mechanisms of Antiviral meds

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HIV Meds (Henderson)

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Microbicides
Surfactants
Non-Ionic detergents
Small Molecules

Entry Inhibitors
Enfuritide
Selzentry

Reverse Transcriptase Inhibitors
Nucleoside Inhibitors
Nucleotide Inhibitors
Non-Nucleotide Inhibitors

End Processing Inhibitors
Dinucleotides
Small Molecules

Protease Inhibitors
Saquinavir
Indinavir
Ritonavir
Peptideamimics

HAART

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Nucleoside Analog Inhibitors of Reverse Transcriptase

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AZT- 3' -azido-3' 1 deoxythymidine, N3 group

DDI- 2'3' -dideoxyinosine, has 2 DDI groups

DDC- α,3' - dideoxycytidine

D4T (Stavudine)- 2'3' -dieoxy-'2', 3' -dideohydrothymidine, uses a double bond

They all work in a similar manner. They are first phosphorylated to the active triphosphate form, and then act as DNA chain termiantors, blocking the addition of normal nucleoside triphosphates by alteration of the 2'-3' linkage. Toxicity is related to their effect on mitochondrial DNA synthesis.

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Non- Nuleoside Inhibitors of Reverse Transcriptase

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Nevirapine- A small molecules that binds to reverse transcriptase and inactivates catalytic sites (possible steric hinderance)

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Protease Inhibitors

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Saquinavir, Indinavir, Ritonavir, Peptidamimics:

These have a modified Proline-Phenalanine (part of the normal recognition sequence) linkage which will sit on the protease clevage site, but is not hydrolyzed and thus not released.

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HIV targets for Antiretroviral Therapy

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Virus receptor and entry: Fusion inhibitors, chemokine receptor blockers

Reverse transcriptase: Inhibitor/DNA chain terminators

RNAase: Inhibitors

Integration: Viral integrase inhibitors

Viral gene expression: Inhibitors of HIV regulatory genes and their products tatand rev

Viral protein synthesis: Enzyme inhibitors, eg protease inhibitors

Viral budding: Interferons (also act at other sites of replication cycle), antibodies, and ligands

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Induction Therapy

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Aimed at activation of infeted memory B cells to cause viral replication and thus viral recognition and destruction through normal medications. It is being attamped throgh administering a combination of Il-2 and AZT.

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Indications for HIV Antiviral therapy

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Symptomatic HIV disease- Therapy recommended for all patients

Asymptomatic, CD4+ cell numbers <500- Therapy recommended

Asymptomatic, CD4+ cell numbers >500- Therapy recommended for patients with >30,000-50,000 HIV RNA copies/ml

Therapy should be considered
patients with >5,000 - 10,000
HIV RNA copies/ml

Asymptomatic, CD4+ cell numbers >500, and <5,000 copies of HIV RNA/ml- No Therapy


Therapeudic sucess is measured as a rise in CD4+ cells and a decrease in viral load.

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Entry Inhibitors

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Enfuritide- a 16 AA peptide that mimicks gp41 fusion region and thus prevents fusion. It is being used as a salvage drug effecting the first part of the viral replication pathway. Reduces viral burden by 50%, but costs %75,000/year.

Selzentry- a small molecule that prevents biding to CCR5 and thus entry, but comes with a black box warning as CCR5 is ubiquitous, so there are significant side effects. Also a salvage drug.