Antiviral

Antiviral Drugs

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Virus Structure

There are many types of virus with varying shape and structure. All virus have a central core of either DNA or RNA surrounded by a coat of regularly packed protein units. No nucleus or cytoplasm like bacteria.
* Diagram of an AIDS Virus

Viruses

Intracellular parasites Enter host, bind to receptors on cell membranes Use cellular metabolic activities for replication May be DNA or RNA viruses

Viruses

DNA viruses incorporate into chromosomal DNA, produce new viruses RNA viruses must be converted to DNA by reverse transcriptase in order to replicate Induce antibodies and immunity

CLASSIFICATION OF VIRUSES: DNA----envelope: Herpes, poxvirus Non envelope: adenoviruses RNA-----Envelope: Retrovirus (HIV) Non envelope : Polio, Retro virus

Virus Replication

The virus uses the cell mechanism to replicate itself
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1- Anti Herpes virus agentsAntiviral Drugs - Acyclovir

Acyclovir is an antiviral drug used to treat Herpes Simplex
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Acyclovir and Valacyclovir

Acyclovir’s clinical use is limited to herpes viruses. Acyclovir is most active against HSV-1 , approximately half as active against HSV-2, a tenth as potent against varicella-zoster virus (VZV) and Epstein-Barr virus (EBV), and least active against cytomegalovirus (CMV) and human herpes virus(HHV-6).

MECHANISMS OF ACTION

Acyclovir’s selective inhibition of viral DNA synthesis depends on interaction with two distinct viral proteins: (inhibition of HSV viral DNA polymerase and thymidine kinase )

Side EFFECTS

Topical acyclovir may cause mucosal irritation and transient burning when applied to genital lesions. Oral acyclovir infrequently is associated with nausea, diarrhea, rash, or headache and very rarely with renal insufficiency or neurotoxicity. Valacyclovir also may cause headache, nausea, diarrhea, nephrotoxicity,and CNS symptoms

THERAPEUTIC USES

Herpes Simplex Virus Infectionsoral acyclovir (200 mg five times daily or 400 mg three times daily for 7–10 days) and valacyclovir (1000 mg twice daily for 7–10 days) significantly reduce virus symptoms, and time to healing.

Varicella-Zoster Virus Infections If begun within 24 hours of rash onset, oral acyclovir is efficacious in varicella of children and adults. Other Viruses Acyclovir is ineffective in established CMV infections but has been used for CMV prophylaxis in immunocompromised patients.

Cidofovir Fomivirsen Famciclovir and Penciclovir Ganciclovir and Valganciclovir

Idoxuridine
topical treatment of HSV keratitis, herpes labialis, genitalis, and zoster. Adverse reactions include pain, pruritus, inflammation, and edema involving the eye or lids; allergic reactions occur rarely. Resistance to idoxuridine develops readily.

2- ANTI-INFLUENZA AGENTSAmantadine and Rimantadine

Both agents specifically inhibit the replication of influenza A viruses. Rimantadine is 4–10 times more active than Amantadine.Mechanism of action and Resistance Amantadine and Rimantadine inhibit an early step in viral replication, probably viral uncoating; for some strains, they also have an effect on a late step in viral assembly.

side effects of amantadine and rimantadine are GI and CNS complaints, including : nervousness, light-headedness, difficulty concentrating, insomnia, and anorexia or nausea. CNS side effects occur but are significantly less frequent with rimantadine.


Therapeutic uses Amantadine and Rimantadine are effective for the prevention and treatment of influenza A virus infections. Seasonal prophylaxis : is ~70–90% protective against influenza A illness.

3- Anti Hepatitis Agent Adefovir

Adefovir dipivoxil enters cells and is deesterified to adefovir. THERAPEUTIC USES Adefovir dipivoxil is approved for treatment of chronic HBV infections

MECHANISMS OF ACTION

Cellular enzymes convert adefovir to the diphosphate, which competitively inhibits viral DNA polymerases and reverse transcriptases and also serves as a chain terminator of viral DNA synthesis. Side effect; nephrotoxicity

Interferons

CLASSIFICATION AND ANTIVIRAL ACTIVITY Interferons (IFNs) possess antiviral, immunomodulating. There are three major classes of human interferon's with antiviral activity: a, b, and g. Clinically used recombinant IFNs a.

MECHANISMS OF ACTION

induction of host cell enzymes that inhibit viral RNA translation, ultimately leading to the degradation of viral mRNA and tRNA.

Side effects

fever, chills, headache, myalgia, arthralgia, nausea, vomiting, and diarrhea. Dose-limiting toxicities of systemic IFN are myelosuppression; neurotoxicity (autoimmune disorders including thyroiditis; and rarely, cardiovasculareffects with hypotension. Elevations in hepatic enzymes and triglycerides, alopecia, and pneumonia may occur.

THERAPEUTIC USES

Recombinant, natural, IFNs are approved in the U.S. for treatment of chronic HCV (Hepatitis C Virus) infection, chronic HBV (Hepatitis B Virus) infection, other malignancies. In genital warts

Ribavirin Lamivudine

4- Antiretroviral Agent and Treatment of Human immunodeficiency viruses (HIV) INFECTION
Human immunodeficiency viruses (HIVs) : chronic persistent infection with gradual onset of clinical symptoms.


AIDS Definition
AIDS ( Acquired Immune Deficiency Syndrome) is caused by a retrovirus that contains RNA rather than DNA. This specific virus invades particular cells, that are within the immune system making the body unable to fight off infections.
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Drugs used to HIV infection Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

The HIV-encoded, RNA-dependent DNA polymerase, also called reverse transcriptase, converts viral RNA into proviral DNA that then is incorporated into a host cell chromosome. Inhibitors of this enzyme are either nucleoside/nucleotide analogs drugs or nonnucleoside inhibitors drugs .

Drugs used to HIV infection Nucleoside and Nucleotide Reverse Transcriptase Inhibitors

Like all available antiretroviral drugs, nucleoside and nonnucleoside reverse transcriptase inhibitors prevent infection of susceptible cells but have no impact on cells that already harbor HIV. Nucleoside and nucleotide analogs must enter cells and undergo phosphorylation to generate synthetic substrates for the enzyme

Side effects

anemia, granulocytopenia, myopathy, peripheral neuropathy, and pancreatitis. Zidovudine (AZT) Cellular enzyme phosphorylate to the triphosphate form which inhibits RT (reverse transcription) and causes chain termination

Antiviral Drugs - AZT

* AZT combines with the enzyme that the HIV virus uses to build DNA from RNA and clogs up its active site. It acts as a reverse transcriptase inhibitor. Since only Retro-Viruses, such as HIV, use this enzyme,
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AZT was the first antiviral drug used to effectively treat HIV-AIDS

Adverse effect: Granulocytopenia and anemia. Severe headache, nausea, insomnia, myalgia

Other Retroviral RT Inhibitors

Other nucleoside analogs: didanosine, Stavudine, Zalcitabine:

Influenza Virus Neuraminidase Inhibitors

Neuraminidase is important in the final stages of virion budding from the cellinhibit enzyme – prevent completion of buddingOseltamivir – anti-influenza drug

Drug Examples

Tamiflu- Prevents the mature viruses from leaving the cell It is a neuraminidase inhibitor, it works on both influenza A and B. Neuraminidase is an enzyme found on the virus which cleaves sialic acid from cell membrane, leading to a more effective release of viruses.
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Observed During Clinical Practice for Treatment (Neurologic): seizure, confusion

Concerns *H1N1 is already resistant to two to four common anti-viral drugs (Amantadine , Rimantadine ) Treatment * The supply of the two non-resistant drugs are (Oseltamivir-Tamiflu and Zenamivir-Relenza). available Relenza and Tamiflu antiviral drugs to treat the swine influenza virus cases.