Anti-viral drugs By Dr.Mohamed Abd ALMoneim Attia

Structure of the virus  They are not cells & having no metabolic machinery of their own, they are obligate intracellular parasites,i.e they have to use the metabolic process of the host cell which they enter & infect. Types of Virus:  DAN viruses usually enter the host cell nucleus & direct the generation of new viruses.  RNA viruses direct the generation of new viruses,usually without involving the host cell nucleus ( the “flu “ virus is an exception in that it does involve the host cell nucleus)  RNA retroviruses (e.g., AIDS virus,T cell leukemia virus) contain an enzyme, reverse transcriptase, which integrates into host DNA and makes a DNA copy of the viral RNA (produces viral DNA from RNA). This copy is integrated into the host cell genome & direct the generation of new virus particles.

ANTIVIRAL DRUGS RNA Viruses  Poliovirus  Rhinovirus  Mumps, measles  Yellow fever  Dengue fever  Influenza  HIV DNA Viruses  Papilloma  Zoster  Adenovirus  Epstein-Barr  Cytomegalovirus  Herpes simplex

STEPS OF VIRAL INFECTION AND REPLICATION  Phase 1: Attachment and penetration: The viruses attach and bind to the host cell membrane. Specific receptor sites on the host cell are recognized by corresponding areas on the specific virus. Then, the receptor- virus complex penetrates the cell and is encapsulated by host cell cytoplasm.

Phase 2: Uncoating: The protein coat of the virus is dissolved liberating free DNA or RNA i.e. the viral genome. Phase 3: Synthesis of viral components: The genome of the virus is duplicated and viral proteins are synthesized. At this time, host synthesis of nucleic acid and or protein is inhibited because the synthetic processes of host cell are directed for synthesis of viral components. Phase 4: Assembly of the virus particle and their release from the cell: The viral genome is encapsulated by viral protein. The mature virus is then released from cell.

Sites of Drug Action

ANTI-VIRAL DRUGS Classification : A)Anti-HIV drugs : B)Other anti-viral drugs.

1. Virion binding - CD4, chemokines 2. Reverse transcriptase- RNA to DNA 3. Integration of viral DNA 4. Replication of viral RNA 5.Protease 6.Assembly of virions 7.Release X AZT Replication of HIV Human Pharmacology, ed. by Brody et al. nRTIs nnRTIs X Protease inhibitors

Viral RNA double helix DNA Incorporated into host genome reverse transcriptase HIV integrase transcription translation Polyproteins Final structural proteins HIV protease Drugs NRTIs NNRTIs PIs

Highly Active Antiretroviral Therapy  The term Highly Active Antiretroviral Therapy (HAART) is used to describe a combination of three or more anti-HIV drugs.  Four approved classes of drugs in the HAART regimens:  NRTI (Nucleoside Reverse Transcriptase Inhibitors)  NtRTI (Nucleotide Reverse Transcriptase Inhibitors)  NNRTI ( Non-Nucleoside Reverse Transcriptase Inhibitors)  PI (Protease Inhibitors)  Entry Inhibitors  Integrase Inhibitors

Currently Available Drugs  Nucleoside analogue reverse transcriptase inhibitors –Zidovudine –Lamivudine –Emcitrabine  Nucleotide … –Tenofovir

Currently Available Drugs  Non-nucleoside reverse transcriptase inhibitors –Nevirapine –Efavirenz  Fusion Inhibitors –Enfuvirtide –Maraviroc

Currently Available Drugs Protease Inhibitors Protease Inhibitors Indinavir Indinavir Ritonavir Ritonavir Saquinavir Saquinavir Integrase inhibitors: Raltegravir Raltegravir

Zidovudine :  -it is analogue of thymidine.  -it is an active inhibitor of reverse transcriptase in retroviruses-such as HIV virus.  -it is phosphorylated by cellular enzymes to the triphosphate form,in which it competes with equivalent cellular triphophates which are essential substrates for the formation proviral DNA by viral reverse transcriptase

Unwanted effects of zido…  -anemia & neutropenia with long term administration ( administration of erythropioten & GM-CSF may alleviate these problems.  -GIT upset.  -skin rash,fever,headache,insomnia.  -abnormalities of liver function.

Inhibition of post-translational events Protease inhibitors  E.g Saquinavir, ritonavir,indiavir & -Host mRNAs code directly for functional proteins. -Host mRNAs code directly for functional proteins. -In HIV, the RNA is translated into biochemicaly inert poly-proteins. -In HIV, the RNA is translated into biochemicaly inert poly-proteins. -A virus –specific protease (not present in the host cell) converts poly-protein into various structural & functional proteins. -A virus –specific protease (not present in the host cell) converts poly-protein into various structural & functional proteins.

-They are all given orally. -They are all given orally. -they are given in combination with reverse transcriptase inhibitors. -they are given in combination with reverse transcriptase inhibitors. Side effects : - GIT upset (nausea,vomiting & diarrhea) - GIT upset (nausea,vomiting & diarrhea) -Raised concentration of liver enzymes. -Raised concentration of liver enzymes. -Metablic abnormalities e.g insulin resistance,++blood glucose & hyperlipidemia -Metablic abnormalities e.g insulin resistance,++blood glucose & hyperlipidemia

Why Does Treatment Fail?  NON-ADHERENCE  Intolerance  Infection with a resistant virus

Other anti-virals 1-Anti-Influenza Agents  Amantadine  Rimantadine  Zanamivir  oseltamivir

2-Antiherpes Agents  Acyclovir- prototype  Valacyclovir  Famciclovir  Penciclovir  Trifluridine  Vidarabine

3-Anti-Cytomegalovirus Agents  Gancyclovir  Valgancyclovir  Cidofovir  Foscarnet  Fomivirsen

4-Anti-Hepatitis Agents  Lamivudine - Nucleoside Reverse Transcriptase Inhibitor (NRTI)  Adefovir - Nucleotide Inhibitor  Interferon Alfa  Pegylated Interferon Alfa  Ribavirin

ANTIVIRAL DRUGS I. INHIBITION OF ATTACHMENT TO OR PENETRATION OF HOST CELL: GAMMA GLOBULINS (Immuno Globulins) It is a fraction obtained from the plasma of normal individuals and rich in antibodies against viral antigen. The antibody present in gamma globulins is directed against superficial envelope of susceptible virus and block its penetration into the host cell (phase 1 inhibitor). Therapeutic uses: Intramuscular injection given during the early infection stage can partially alleviate the progression of measles, poliomyelitis, rabies and hepatitis. Protection lasts for 2-3 weeks and injection can be repeated every 2-3 weeks. It confers a passive immunity to the virus.

II. INHIBITION OF VIRAL UNCOATING: II. INHIBITION OF VIRAL UNCOATING: AMANTADINE: Amantadine is a synthetic antiviral compound. It has antiparkinsonial effect. Mechanism of action: Amantadin is a phase 1 and 2 inhibitor. It inhibits penetration of the virus to host cell and impairs the ability of the virus to uncoat its RNA in host cell. Therapeutic uses: Amantadine is useful in the prevention and treatment of diseases caused by type A2 (Asian) influenza virus. It is used prophylactically during epidemics for high risk patients such as elderly or those with other underlying disease. Also, it is used for treatment of an already established influenza-A2 infection to reduce severity of the disease.

III. INHIBITION OF SYNTHESIS OF VIRAL COMPONENTS (Non-structural protein, DNA and RNA) RIBAVIRIN Ribavirin is a synthetic purine nucleoside that possesses broad antiviral inhibitory activity against respiratory syncytial, herpes simplex and influenza viruses. Mechanism of action: Ribavirin has antimetabolite activity, which interfere with synthesis of viral messenger RNA and ribonucleic protein synthesis.

ACYCLOVIR It is a synthetic nucleoside that have potent antiviral activity against most herpes viruses and is particularly effective against the herpes simplex virus. Mechanism of action:It is transformed by viral enzyme into triphosphate derivative, which inhibits DNA polymerase necessary for DNA viral replication. This drug shows selective activity against virus only. Therapeutic uses: For treatment of genital herpes. Treatment of herpes keratoconjunctivitis. herps simplex encephalitis. herpes zoster.

Ganciclovir: It is similar to acyclovir used for treatment of cytomegalovirus. IDOXURIDINE It is pyrimidine analogue that inhibits DNA synthesis. The drug has host cytotoxicity and can not be used to treat systemic viral infection. It is used topically in treatment of herpes simplex infection of eyelid, conjunctiva and cornea.

VIDARABINE It is pyrimidine analogues.It acts by inhibiting viral DNA polymerase so; impair the early step of viral DNA synthesis. Therapeutic uses: Vidarabine is used for treatment of herpes simplex viruses. It has some efficacy in treatment of herpes zoster and chicken pox infection and varicella infections in immunocompromised patients. ZIDOVUDINE It is synthetic pyrimidine analouge, used for management of patients with symptomatic human immunodeficiency virus (HIV) infection. Mechanism of action: inhibition of reverse transcriptase enzyme

INTERFERONS They are natural antiviral glycoproteins. They were called so because they interfere with replication of the virus in tissue culture. Interferons are of three major classes: alpha synthesized by leucocyte, beta produced by fibroblasts and gamma formed by lymphocytes. The exogenous interferon used clinically is alpha interferon produced by using recombinant DNA technology.

Mechanism of action: The natural interferons attach to surface receptor on the membrane of infected cell and then inhibit synthesis of protein and DNA that block viral replication. Also interferon blocks viral assembly and release. Interferon is able to suppress cell proliferation. Interferon has immunomodulating effects. It enhance phagocytosis by macrophages and increases the cytotoxicity exerted by lymphocytes

Therapeutic uses: Treatment of viral infections, especially, chronic hepatitis B and C viruses and prevents chronic liver toxicity, AIDS and genital (venereal) warts. Human cancer shows some response to interferon e.g. certain leukemias, lymphomas and laryngeal papillomatosis.

Adverse effects: 1-Flu-like symptoms: Fatigue, depression, muscle weakness, weight and appetite loss, and change in thyroid function and cardiotoxcity. 2-High dose or chronic therapy causes bone marrow suppression, neurotoxicity and progressive fatigue. 3-Plasma concentration of hepatic enzymes increase. 4-The metabolism of other drugs can be reduced by interferon action on microsomal enzyme.

IV. INHIBITION OF ASSEMBLY OR RELEASE OF VIRAL PARTICLES: RIFAMPIN It inhibits poxviruses by preventing the assembly of enveloped mature particles. It is not used in treatment of human poxvirus infection but topical application can inhibit human vaccinia lesions (Rifampin has antibacterial action).

Group of vesicles on erythematous base scattered within a dermatome ( flank )

Grouped vesicles with erythematous base on the skin surface of the face ( especially the lips – typically on the vermillion border )..

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