Anti-viral drugsAnti-viral drugs

ByBy

Dr.Mohamed Abd ALMoneim AttiaDr.Mohamed Abd ALMoneim Attia

Structure of the virusStructure of the virus They are They are not cellsnot cells & having & having no metabolicno metabolic machinery of their machinery of their

own, they are own, they are obligateobligate intracellular parasites intracellular parasites ,i.e they have to ,i.e they have to use the metabolic process of the host cell which they enter & use the metabolic process of the host cell which they enter & infect.infect.

Types of Virus:Types of Virus: DAN viruses usually enter the host cell nucleus & direct the DAN viruses usually enter the host cell nucleus & direct the

generation of new viruses.generation of new viruses. RNA viruses direct the generation of new viruses ,usually RNA viruses direct the generation of new viruses ,usually

without involving the host cell nucleus without involving the host cell nucleus ( the “flu “ virus is an ( the “flu “ virus is an exception in that it does involve the host cell nucleus)exception in that it does involve the host cell nucleus)

RNA retroviruses (e.g., AIDS virus ,T cell leukemia virus) RNA retroviruses (e.g., AIDS virus ,T cell leukemia virus) contain an enzyme , contain an enzyme , reverse transcriptase , which reverse transcriptase , which integrates integrates into host DNA and into host DNA and makes a DNA copy of the viral RNA makes a DNA copy of the viral RNA ((produces viral DNA from RNA)produces viral DNA from RNA).. This copy is integrated into the This copy is integrated into the host cell genome & direct the generation of new virus particles. host cell genome & direct the generation of new virus particles.

ANTIVIRAL DRUGSANTIVIRAL DRUGSRNA Viruses

PoliovirusPoliovirus RhinovirusRhinovirus Mumps, measlesMumps, measles Yellow feverYellow fever Dengue feverDengue fever InfluenzaInfluenza HIVHIV

DNA Viruses

PapillomaPapilloma ZosterZoster AdenovirusAdenovirus Epstein-BarrEpstein-Barr Cytomegalovirus Cytomegalovirus Herpes simplexHerpes simplex

STEPS OF VIRAL INFECTION STEPS OF VIRAL INFECTION AND REPLICATIONAND REPLICATION

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

Phase 2: Uncoating: Phase 2: Uncoating: The protein coat of the virus is The protein coat of the virus is dissolved liberating free DNA or RNA i.e. the viral dissolved liberating free DNA or RNA i.e. the viral genome.genome.

  Phase 3: Synthesis of viral components: Phase 3: Synthesis of viral components: The The

genome of the virus is duplicated and viral proteins genome of the virus is duplicated and viral proteins are synthesized. At this time, host synthesis of are synthesized. At this time, host synthesis of nucleic acid and or protein is inhibited because the nucleic acid and or protein is inhibited because the synthetic processes of host cell are directed for synthetic processes of host cell are directed for synthesis of viral components.synthesis of viral components.

  Phase 4: Assembly of the virus particle and their Phase 4: Assembly of the virus particle and their

release from the cell: release from the cell: The viral genome is The viral genome is encapsulated by viral protein. The mature virus is encapsulated by viral protein. The mature virus is then released from cell.then released from cell.

Sites of Drug ActionSites of Drug Action

ANTI-VIRAL DRUGSANTI-VIRAL DRUGSClassification :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. Protease6. Assembly of virions7. Release

X

AZT

Replication of Replication of HIVHIV

Human Pharmacology, ed. by Brody et al.

nRTIsnnRTIs

X

Proteaseinhibitors

ViralRNA

double helix DNA

Incorporated into host genome

reverse transcriptase

HIV integrase

transcription

translation

Polyproteins

Final structural proteins

HIV protease

Drugs

NRTIsNNRTIs

PIs

Highly Active Antiretroviral TherapyHighly Active Antiretroviral Therapy

The term Highly Active Antiretroviral Therapy The term Highly Active Antiretroviral Therapy (HAART) is used to describe a combination of (HAART) is used to describe a combination of three or more anti-HIV drugs. three or more anti-HIV drugs.

Four approved classes of drugs in the HAART Four approved classes of drugs in the HAART regimens:regimens:

NRTI (Nucleoside Reverse Transcriptase Inhibitors)NRTI (Nucleoside Reverse Transcriptase Inhibitors) NtRTI (Nucleotide Reverse Transcriptase Inhibitors)NtRTI (Nucleotide Reverse Transcriptase Inhibitors) NNRTI ( Non-Nucleoside Reverse Transcriptase NNRTI ( Non-Nucleoside Reverse Transcriptase

Inhibitors)Inhibitors) PI (Protease Inhibitors)PI (Protease Inhibitors) Entry InhibitorsEntry Inhibitors Integrase InhibitorsIntegrase Inhibitors

Currently Available DrugsCurrently Available Drugs

Nucleoside analogue reverse transcriptase Nucleoside analogue reverse transcriptase inhibitorsinhibitors– Zidovudine Zidovudine – LamivudineLamivudine– EmcitrabineEmcitrabine

Nucleotide …Nucleotide …– Tenofovir Tenofovir

Currently Available DrugsCurrently Available Drugs

Non-nucleoside reverse transcriptase inhibitorsNon-nucleoside reverse transcriptase inhibitors– Nevirapine Nevirapine – Efavirenz Efavirenz

Fusion InhibitorsFusion Inhibitors– Enfuvirtide Enfuvirtide – MaravirocMaraviroc

Currently Available DrugsCurrently Available Drugs

Protease InhibitorsProtease Inhibitors Indinavir Indinavir

Ritonavir Ritonavir

Saquinavir Saquinavir

Integrase inhibitors:Integrase inhibitors:

RaltegravirRaltegravir

Zidovudine :Zidovudine :

--it is analogue of thymidineit is analogue of thymidine.. --it is an active inhibitor of reverse it is an active inhibitor of reverse

transcriptase in retroviruses-such as HIV transcriptase in retroviruses-such as HIV virus.virus.

-it is -it is phosphorylated byphosphorylated by cellular enzymes to cellular enzymes to the the triphosphate form,in which it competes triphosphate form,in which it competes with equivalent cellular triphophateswith equivalent cellular triphophates which are which are essential substrates for the formation proviral essential substrates for the formation proviral DNA by viral reverse transcriptaseDNA by viral reverse transcriptase

Unwanted effects of zido…Unwanted effects of zido… --anemia & neutropeniaanemia & neutropenia with long term administration with long term administration

( administration of erythropioten & GM-CSF may ( administration of erythropioten & GM-CSF may alleviate these problems.alleviate these problems.

--GIT upsetGIT upset.. --skin rash ,fever ,headache ,insomnia.skin rash ,fever ,headache ,insomnia. -abnormalities of liver function-abnormalities of liver function..

Inhibition of post-translational eventsInhibition of post-translational eventsProtease inhibitorsProtease inhibitors

E.g E.g SaquinavirSaquinavir , , ritonavir,indiavir &ritonavir,indiavir & -Host mRNAs code directly for functional proteins.-Host mRNAs code directly for functional proteins.

-In HIV , the RNA is translated into biochemicaly -In HIV , the RNA is translated into biochemicaly inert poly-proteins.inert poly-proteins.

-A virus –specific protease (not present in the host -A virus –specific protease (not present in the host cell) converts poly-protein into various structural & cell) converts poly-protein into various structural & functional proteins.functional proteins.

-They are all given -They are all given orally.orally. --they are given in combination with reverse they are given in combination with reverse

transcriptase inhibitors.transcriptase inhibitors.

Side effectsSide 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 -Metablic abnormalities e.g insulin

resistance,++blood glucose & resistance,++blood glucose & hyperlipidemiahyperlipidemia

Why Does Treatment Fail?Why Does Treatment Fail? NON-ADHERENCENON-ADHERENCE IntoleranceIntolerance Infection with a resistant virusInfection with a resistant virus

Other anti-viralsOther anti-virals 1-Anti-Influenza Agents 1-Anti-Influenza Agents

AmantadineAmantadine RimantadineRimantadine ZanamivirZanamivir oseltamiviroseltamivir

2-Antiherpes Agents2-Antiherpes Agents

Acyclovir- Acyclovir- prototypeprototype ValacyclovirValacyclovir FamciclovirFamciclovir PenciclovirPenciclovir TrifluridineTrifluridine VidarabineVidarabine

3-Anti-Cytomegalovirus Agents3-Anti-Cytomegalovirus Agents

GancyclovirGancyclovir ValgancyclovirValgancyclovir CidofovirCidofovir FoscarnetFoscarnet FomivirsenFomivirsen

4-Anti-Hepatitis Agents4-Anti-Hepatitis Agents LamivudineLamivudine - -Nucleoside Reverse Transcriptase Nucleoside Reverse Transcriptase

Inhibitor (NRTI)Inhibitor (NRTI)

Adefovir Adefovir --Nucleotide InhibitorNucleotide Inhibitor

InterferonInterferon AlfaAlfa Pegylated Interferon AlfaPegylated Interferon Alfa RibavirinRibavirin

ANTIVIRAL DRUGSANTIVIRAL DRUGSI. INHIBITION OF ATTACHMENT TO OR PENETRATION OF I. INHIBITION OF ATTACHMENT TO OR PENETRATION OF

HOST CELL:HOST CELL:  GAMMA GLOBULINS (Immuno Globulins)GAMMA GLOBULINS (Immuno Globulins)  It is a fraction obtained from the plasma of normal individuals It is a fraction obtained from the plasma of normal individuals

and rich in antibodies against viral antigen. The antibody and rich in antibodies against viral antigen. The antibody present in gamma globulins is directed against superficial present in gamma globulins is directed against superficial envelope of susceptible virus and block its penetration into the envelope of susceptible virus and block its penetration into the host cell (phase 1 inhibitor).host cell (phase 1 inhibitor).

Therapeutic uses: Therapeutic uses: Intramuscular injection given during the early Intramuscular injection given during the early infection stage can partially alleviate the progression of infection stage can partially alleviate the progression of measles, poliomyelitis, rabies and hepatitis. Protection lasts measles, poliomyelitis, rabies and hepatitis. Protection lasts for 2-3 weeks and injection can be repeated for 2-3 weeks and injection can be repeated every 2-3 every 2-3 weeks. It confers a passive immunity to the virus.weeks. It confers a passive immunity to the virus.

II. INHIBITION OF VIRAL II. INHIBITION OF VIRAL UNCOATING:UNCOATING:

  AMANTADINE:AMANTADINE:  Amantadine is a synthetic antiviral compound. It has Amantadine is a synthetic antiviral compound. It has

antiparkinsonial effect. antiparkinsonial effect.   Mechanism of action: Mechanism of action: Amantadin is a phase 1 and 2 inhibitor. It Amantadin is a phase 1 and 2 inhibitor. It

inhibits penetration of the virus to host cell and impairs the inhibits penetration of the virus to host cell and impairs the ability of the virus to uncoat its RNA in ability of the virus to uncoat its RNA in host cell.host cell.

  Therapeutic uses: Therapeutic uses: Amantadine is useful in the prevention and Amantadine is useful in the prevention and

treatment of diseases caused by type A2 (Asian) influenza treatment of diseases caused by type A2 (Asian) influenza virus. It is used prophylactically during epidemics for high risk virus. It is used prophylactically during epidemics for high risk patients such as elderly or those with other underlying patients such as elderly or those with other underlying disease. Also, it is used for treatment of an already disease. Also, it is used for treatment of an already established influenza-A2 infection to reduce severity of the established influenza-A2 infection to reduce severity of the disease. disease.

III. INHIBITION OF SYNTHESIS III. INHIBITION OF SYNTHESIS OF VIRAL COMPONENTSOF VIRAL COMPONENTS

(Non-structural protein, DNA and (Non-structural protein, DNA and RNA) RNA)

RIBAVIRINRIBAVIRIN  Ribavirin is a synthetic purine nucleoside that possesses Ribavirin is a synthetic purine nucleoside that possesses

broad antiviral inhibitory activity against respiratory broad antiviral inhibitory activity against respiratory syncytial, herpes simplex and influenza viruses.syncytial, herpes simplex and influenza viruses.

  Mechanism of action: Mechanism of action: Ribavirin has antimetabolite Ribavirin has antimetabolite

activity, which interfere with synthesis of viral activity, which interfere with synthesis of viral messenger RNA and ribonucleic protein synthesis.messenger RNA and ribonucleic protein synthesis.

ACYCLOVIR ACYCLOVIR It is a synthetic nucleoside that have potent antiviral activity It is a synthetic nucleoside that have potent antiviral activity

against most herpes viruses and is particularly effective against most herpes viruses and is particularly effective against the herpes simplex virus.against the herpes simplex virus.

  Mechanism of action:Mechanism of action: It is transformed by viral enzyme into It is transformed by viral enzyme into

triphosphate derivative, which inhibits DNA polymerase triphosphate derivative, which inhibits DNA polymerase necessary for DNA viral replication. This drug shows selective necessary for DNA viral replication. This drug shows selective activity against virus only.activity against virus only.

  Therapeutic uses: Therapeutic uses:   For treatment of genital herpes. For treatment of genital herpes. Treatment of herpes keratoconjunctivitis. Treatment of herpes keratoconjunctivitis. herps simplex encephalitis.herps simplex encephalitis.herpes zoster.herpes zoster.

  Ganciclovir: Ganciclovir: It is similar to acyclovir used for It is similar to acyclovir used for

treatment of cytomegalovirus.treatment of cytomegalovirus.  IDOXURIDINEIDOXURIDINE  It is pyrimidine analogue that inhibits DNA It is pyrimidine analogue that inhibits DNA

synthesis. The drug has host cytotoxicity and synthesis. The drug has host cytotoxicity and can not be used to treat systemic viral can not be used to treat systemic viral infection. It is used topically in treatment of infection. It is used topically in treatment of herpes simplex infection of eyelid, herpes simplex infection of eyelid, conjunctiva and cornea.conjunctiva and cornea.

VIDARABINEVIDARABINE  It is pyrimidine analogues.It acts by inhibiting viral DNA polymerase so; It is pyrimidine analogues.It acts by inhibiting viral DNA polymerase so;

impair the early step of viral DNA synthesis.impair the early step of viral DNA synthesis.  Therapeutic uses:Therapeutic uses:  Vidarabine is used for treatment of herpes simplex viruses.Vidarabine is used for treatment of herpes simplex viruses.It has some efficacy in treatment of herpes zoster and chicken pox It has some efficacy in treatment of herpes zoster and chicken pox

infection and varicella infections in immunocompromised patients.infection and varicella infections in immunocompromised patients.  ZIDOVUDINE ZIDOVUDINE   It is synthetic pyrimidine analouge, used for management of patients It is synthetic pyrimidine analouge, used for management of patients

with symptomatic human immunodeficiency virus (HIV) infection.with symptomatic human immunodeficiency virus (HIV) infection.  Mechanism of action:Mechanism of action: inhibition of reverse transcriptase enzyme inhibition of reverse transcriptase enzyme

INTERFERONSINTERFERONS

  

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

Mechanism of action:Mechanism of action:  The natural interferons attach to surface The natural interferons attach to surface

receptor on the membrane of infected cell receptor on the membrane of infected cell and then inhibit synthesis of protein and DNA and then inhibit synthesis of protein and DNA that block viral replication. Also interferon that block viral replication. Also interferon blocks viral assembly and release.blocks viral assembly and release.

Interferon is able to suppress cell proliferation.Interferon is able to suppress cell proliferation.Interferon has immunomodulating effects. It Interferon has immunomodulating effects. It

enhance phagocytosis by macrophages and enhance phagocytosis by macrophages and increases the cytotoxicity exerted by increases the cytotoxicity exerted by lymphocyteslymphocytes

Therapeutic uses:Therapeutic uses:

  

Treatment of viral infections, especially, Treatment of viral infections, especially, chronic hepatitis B and C viruses and chronic hepatitis B and C viruses and prevents chronic liver toxicity, AIDS and prevents chronic liver toxicity, AIDS and genital (venereal) warts.genital (venereal) warts.

Human cancer shows some response to Human cancer shows some response to interferon e.g. certain leukemias, interferon e.g. certain leukemias, lymphomas and laryngeal papillomatosis.lymphomas and laryngeal papillomatosis.

Adverse effects:Adverse effects:  1-Flu-like symptoms: Fatigue, depression, muscle 1-Flu-like symptoms: Fatigue, depression, muscle

weakness, weight and appetite loss, and weakness, weight and appetite loss, and change in thyroid function and cardiotoxcity.change in thyroid function and cardiotoxcity.

2-High dose or chronic therapy causes bone 2-High dose or chronic therapy causes bone marrow suppression, neurotoxicity and marrow suppression, neurotoxicity and progressive fatigue.progressive fatigue.

3-Plasma concentration of hepatic enzymes 3-Plasma concentration of hepatic enzymes increase.increase.

4-The metabolism of other drugs can be reduced 4-The metabolism of other drugs can be reduced by interferon action on microsomal enzyme.by interferon action on microsomal enzyme.

IV. INHIBITION OF ASSEMBLY OR IV. INHIBITION OF ASSEMBLY OR RELEASE OF VIRAL PARTICLES:RELEASE OF VIRAL PARTICLES:

  RIFAMPINRIFAMPIN

It inhibits poxviruses by preventing the It inhibits poxviruses by preventing the assembly of enveloped mature particles. It is assembly of enveloped mature particles. It is not used in treatment of human poxvirus not used in treatment of human poxvirus infection but topical application can inhibit infection but topical application can inhibit human vaccinia lesions (Rifampin has human vaccinia lesions (Rifampin has antibacterial action).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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