Antiviral And Antiaids Agents Notes

Antiviral And Antiaids Agents Introduction

Antiviral drugs are a class of medication used specifically for treating viral infections. Viruses are not quite proper living thing, consist of a genome and sometimes a few enzymes stored in a capsule made up of protein and rarely covered with lipid layer. They are the smallest of all self- replicating organisms able to pass through filter that retain the smallest bacteria.

Virus conducts no metabolic process on their own. They invade the host cell, which may be bacteria, animal or plant cell. The virus turns the biochemical system of the host cell to its own purposes completely subverting the infected cell.

Viral diseases include influenza, rabies, poliomyelitis, yellow fever, ornithosis, mumps, measles, ebola human immunodeficiency syndrome, herpes, warts and small pox.

Virus does not possess cell wall. It consists of one or more of linear or helical strands of either DNA or RNA enclosed in a shell of protein known as capsid. The capsid is composed of several sub-units known as capsomers. In certain cases, capsid may be surrounded by an outer protein or lipoprotein envelope.

Viral life cycle varies with species, but they all share a general pattern can be sequenced as follows:

Virus

↓

Adsorption

↓

Penetration

↓

Uncoating
↓

Transcription

↓

Reverse transcriptase

↓

Translation

↓

Assembly

↓

Release

• Adsorption: Attachment of virus to the host cell.
• Penetration: Penetration of virus into the cell.
• Uncoating: The genetic material or viral genome (DNA or RNA) passes into the host- cell, leaving the capsid covering outside of the host cell.
• Transcription: Production of viral mRNA from the viral genome.
• Translation: Viral genome enters the cytoplasm or nucleoplasma and direct or utilizes the host nucleic acid machinery for the synthesis of new viral protein and also for the production of more viral genome. The viral protein modifies the host cell and allows the viral genome to replicate by using host and viral enzyme. This is often the stage at which the cell is irreversibly modified and eventually killed.
• Assembly of the viral particle: New viral coat protein assembles into capsid and viral genomes.
• Release of the mature virus from the cells by budding process or rupture of the cell and repeat of the process, in fresh host cell. Since the host cell machinery is totally utilized for production of new virions, the normal cell function ceases at the time of replication.

The best time to attack virus is as early as possible in its life cycle that is exactly what vaccines do. Vaccines consists of a weakened or killed version of pathogen, though more recently subunit vaccine have been devised that consists strictly of protein targets from the pathogens. They stimulate the immune system without doing serious harm to the host and so when the real pathogens attack the subject, the immune system responds to it quickly and blocks it. Vaccines have an excellent effectiveness, but they are of limited use in treating a patient who has already been infected. That’s where antiviral drug come in

Because of unique properties of virus and the need for host cell metabolic activities, antiviral agents have been developed to act at various stages in the viral replication cycle, such as attachment, replication and release of the virus.

General approaches for treating the virus infection by antiviral agents are:

• Interference of virus attachment to the host.
• Inhibition of virus associated enzymes.
• Inhibition of transcription process.
• Inhibition of translation process.
• Interference with viral regulatory process.
• Interference with viral glycosylation, phosphorylation, etc.,
• Interference with assembly of viral protein.
• Interference with release of virus from cell surface membrane

Antiviral And Antiaids Agents Classification

• Antiviral drug can be classified as:
  • Purine nucleoside and nucleotides: eg. Acyclovir, Valacyclovir, Ganciclovir, Vidarabin, Abacavir, Famciclovir, Penciclovir.
  • Pyrimidine nucleoside and nucleotides: eg. Iodoxuridine, Trifluridine Cidofovir.
  • Thio-semicarbazone : eg. Methisazone.
  • Adamantane amines : eg. Amantadine, Rimantadine, Somantadine.
  • Interferons
  • Miscellaneous agents : eg. Foscarnet sodium, Ribavirin.
• According to the enzyme inhibition, it can also be classified as:
  • Inhibitor of DNA polymerase :eg. Iodoxuridine, Trifluridine, Vidarabin, Acyclovir.
  • Reverse transcriptase inhibitors : eg. Zidovudine, Zalcitabine, Didanosine, Stavudine, Lamivudine, Abacavir.
  • Nucleoside antimetabolite : eg. Ribavirin.
  • Non-nucleoside reverse transcriptase inhibitors: eg. Nevirapine, Efavirenz, Delaviridine.
  • HIV protease inhibitors : eg. Atazanavir, Saquinavir, Ritonavir, Indinavir, Nelfinavir, Amprenavir, Lopinavir.
  • Neuroamidase inhibitors : eg. Oseltamivir, Zanamivir.
• According to treatment protocol it is classified as
  • Treatment of respiratory virus infections
    • Adamantane derivatives : eg. Amantadine, Rimantadine.
  • Treatment of herpes and cytomegalovirus infections.
    • Purine nucleotides : eg. Acyclovir, Ganciclovir, Vidarabine.
    • Pyrimidine nucleotides : eg. Trifluridine, Idoxuridine.
    • Phosphorus derivatives : eg. Foscarnet sodium.
  • Treatment of Human Immunodeficiency Virus (HIV) infection
    • Reverse Transcriptase inhibitors
      • Purine derivatives : eg. Didanosine.
      • Pyrimidine derivatives : eg. Zidovudine, Stavudine.
      • Non-nucleotides : eg. Nevirapine, Delavirdine, Efavirenz.
    • Protease inhibitors : eg. Saquinavir, Indinavir, Ritonavir, Nelfinavir, Amprenavir, Lopinavir.
    • Integrase inhibitor : eg. Zintevir.

Purine Nucleoside and Nucleotide

Acyclovir (Acivir, Cyclovir, Zovirax)

Synthesis

Mechanism of Action: Acyclovir is a synthetic analogue of deoxy guanosine in which the carbohydrate moiety is acyclic. The mode of action of Acyclovir consists of the following consecutive mechanism:

• Conversion to active Acyclovir monophosphate within cells by viral thymidine kinase. This phosphorylation reaction occurs faster in infected cell than normal cell, because Acyclovir is a poor substrate for the normal cell thymidine kinase. Acyclovir monophosphate is further converted into di and triphosphate by a normal cellular enzyme guanosine monophosphate kinase.
• Acyclovir triphosphate inhibits viral DNA polymerase by competing deoxy guanosine triphosphate. The triphosphate drug is also incorporated into viral DNA where it acts as a chain terminator; because it has 3′- hydroxy group, like cyclic sugar, 3′ 5′- phosphodiester bond can be formed. It acts as suicide inhibitor because the terminated DNA template containing Acyclovir as ligand binds irreversibly with DNA polymerase and inactivates. It is a drug of choice in both prophylaxis and treatment of herpes simplex virus.

ADR: Nausea, vomiting, head ache, diarrhea and rash.

Dose: 200mg five times daily every 4hrs for 5 to 10 days or 400mg five times daily for 5 days in severely patients.

Use: It is effective against several DNA viruses including Herpes Simplex Virus (HSV) 1 & 2 and also against Varicella Zoster Virus (VZV). An advantage is that uninfected human cell are unaffected by the drug. It is used for short term treatment of shingles and chicken pox caused by VZV.

DNA Synthesis Replication

Ganciclovir (Ganguard, Vitrasert, Cytovene)

It is an analogue of Acyclovir, with an additional hydroxy methyl group on the acylic side chain.

Synthesis

Mechanism of Action: It is phosphorylated to monophosphates by viral and cellular kinase and then to di- and triphosphate by cellular enzymes. The triphosphate is a competitive inhibitor by incorporating deoxyguanosine triphosphate into DNA and it inhibits DNA polymerase selectively.

ADR: Leucopenia, neutropenia, thrombocytopenia, hematological disturbances, bone marrow depression and GI disturbances

Dose: 5mg/kg every 12 hrs for 14 to 21 days. Available only as i.v infusion because of its poor oral bioavailability.

Use: It is active in the treatment of cytomegalovirus (CMV), herpes simplex virus (HSV) and vesicular stomatitis virus (VSV).

Abacavir (Abavir, Abamune, Abec)

ADR: Anorexia, head ache, nausea and diarrhea.

Dose: 300mg bid or 600mg once daily.

Use: It is used in combination with other drugs for the treatment of HIV and AIDS.

Famciclovir (Famdrex, Microvir)

Famciclovir is a prodrug of Penciclovir. It possesses antiviral activity due to inhibition of DNA polymerase.

ADR: Dizziness, head ache and diarrhea.

Dose: 200 mg tid or 750mg once daily for 7 days.

DNA Synthesis Replication

Use: It is used against acute herpes zoster and genital herpes. It is active against HSV, and VZV.

Valacyclovir (Valtrex, Zelitrex)

Valacyclovir is a prodrug of Acyclovir. It is L-valyl ester of Acyclovir. In order to increase the oral bioavailability of Acyclovir, it is converted into ester form. The prodrug is converted into Acyclovir in human by the hydrolase enzyme present in the liver and gut. As Acyclovir, it is active against HSV-1, VZV and CMV (Cytomegalovirus)

ADR: Vertigo, confusion, dizziness, edema and arthralgia.

Dose: For the treatment of herpes zoster (shingles), the usual dose is 1gm three times a day for 7 days. For the treatment of an initial episode of herpes, the usual dose is 1gm twice daily for 10 days. For the treatment of recurrent herpes, the usual dose is 500mg twice daily for 5 days.

Use: It is used in the treatment of herpes zoster in immuno compromised patients.

Pyrimidine Nucleoside and Nucleotide

Idoxuridine (Toxil)

It is a nucleoside containing halogenated pyrimidine and is an analogue of thymidine.

Synthesis

Mechanism of Action: It acts as antiviral agent against DNA virus. Idoxuridine is phosphorylated by thymidine kinase to active triphosphate. This phosphorylated drug inhibits the DNA polymerase which is necessary for the synthesis of viral DNA. The ability of idoxuridylic acid substitute for deoxythymidic acid in the synthesis of DNA may be due to the similar Vander-Waal’s radii of iodine (2.15A°) and the thymidine methyl group (2.0A°).

ADR: Irritation or inflammation of the eye or eyelids.

Dose: One drop of 0.1% solution can be instilled in the affected eye(s) every hr. Continue treatment for at least 7 days.

Use: It is used for the topical treatment of herpes simplex virus (HSV) keratitis, which causes blindness. Idoxuridine in dimethyl sulfoxide is used in mucocutaneous HSV infection.

Thio Semicarbazone Derivatives

Methisazone (Marboran)

Synthesis

Mechanism of Action: Methisazone interferes with the translation of mRNA messages into protein synthesis on the cell ribosomes, thereby resulting a defect in protein inclusion into the virus. It is active against poxvirus, including variola and vaccinia.

ADR: Fever, chills, flu symptoms, a slow or irregular heartbeat and trouble breathing.

Dose: Its prophylactic dose is 3gm twice daily at 4 – 6 hrs intervals.

Use: It finds prophylactic value against small pox and alastrim. In conjunction with y globulin it is active against eczema vaccinatum and vaccinia gangraenosa.

Adamantane amine

Adamantane inhibits influence type A infection. These agents interfere with influenza type A replication by preventing the early stage of viral uncoating and disturbing the late stage of viral assembly.

 

Amantadine (Symmetral)

Amantadine is a symmetric tricyclic primary amine that inhibits penetration of RNA virus particle.

Synthesis

The tertiary halide is incapable of dehydrohalogenation, but with even a weak base like CH3CN, it undergoes SN, reaction and gives corresponding acetamido derivatives.

DNA Synthesis Replication

ADR: Depression, anxiety, hallucinations, confusion, anorexia and dry mouth.

Dose: 100mg twice a day in adults for influenza A virus and dose can be increased from 200mg to 400mg for Parkinsonian patients.

Use: Amantadine is used in the treatment of Parkinson’s disease. It is effective against influenza type A virus, parainfluenza and some RNA virus.

Rimantadine (Flumadine)

It is more effective against influenza A virus. It interferes with virus uncoating by inhibiting the release of specific protein.

ADR: Dizziness, dry Mouth, headache, loss of appetite and abdominal pain.

Dose: 100mg twice daily.

Use: It is used for prevention of infection caused by various strains of influenza virus A.

Miscellaneous Agents

Foscarnet sodium (Carnet, Foscavir)

Mechanism of Action: Foscarnet sodium is an inorganic pyrophosphate analogue that inhibits replication in herpes viruses and retroviruses. It is a reversible, non competitive inhibitor at the pyrophosphate binding site of the viral DNA polymerase and reverse transcriptase. They inhibit the cleavage of pyrophosphate from deoxy nucleotide triphosphate and incorporation of nucleoside triphosphate into DNA. Foscarnet does not require bio activation by viral or cellular enzymes.

ADR: Renal Impairment, Vomiting, Diarrhea, Headache and Seizures.

Dose: 60 mg/kg for every 8hrs for 14 to 21 days.

Use: Foscarnet is used in the treatment of cytomegalovirus retinitis in patient with AIDS.

Ribavirin (Ribavin, Ribamac)

Ribavirin is a purine nucleoside analogue with a modified base and a D-ribose sugar moiety.

Synthesis

Mechanism of Action: It is bio-activated by viral and host cellular kinase to give monophosphate (RMP) and triphosphate (RTP). Ribavirin monophosphate inhibits inosine monophosphate dehydrogenase, thereby preventing the conversion of inosine monophophate to xanthine monophosphate, which is required for the synthesis of guanosine triphosphate. RTP inhibits viral RNA.

ADR: Increased serum bilirubin, uric acid and hemolytic anemia, reticulocytosis and anorexia.

Dose: 800mg daily.

Use: It is used in the treatment of influenza types A and B, hepatitis, genital herpes and Lassa fever.

Anti-HIV Agents

Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). Both HIV-1 and HIV-2 cause AIDS, but HIV-1 is found worldwide. HIV is one of the human T-cell lymphotropic retrovirus which infect and kills helper (CD4) T-lymphocytes resulting in the loss of cell mediated immunity and the host will develop opportunistic infections. While there is no permanent cure of AIDS without prevention or elimination of HIV infection, AIDS patients can prolong their life, if early diagnosed and treatment started.

Reverse Transcriptase (RT) Inhibitors

Reverse transcriptase is RNA-dependent DNA polymerase. The drugs inhibiting RT interferes with replication of HIV and stops the synthesis of infective viral particle. They are further classified into nucleoside and non-nucleoside RT inhibitors.

At the early stage of HIV-1 is reverse transcription, whereby genomic RNA from the virus is converted into a cDNA-RNA complex, then into double stranded DNA ready for integration into the host chromosome. The enzyme that catalyzes this set of reaction is reverse transcriptase (RT). To synthesis this complex RT requires purine and pyrimidine nucleoside and nucleotides.

Therefore a variety of chemical modification of natural nucleoside has been investigated. Such modification resulted in active drugs. Removal of the 3′- hydroxy group of the deoxynucleoside resulted in deoxy adenosine; dideoxy cytidine and didehydro dideoxy thymidine. Replacement of 3′-deoxy with an azido group has given 3′- azido thymidine and 3′- azido uridine.

All these drugs have similar mechanism of action in that their incorporation into viral DNA will ultimately lead to chain terminating blockage due to lack of a 3′- hydroxyl, needed for the DNA propagation.

Didanosine (Dinex, Dinosin)

Didanosine is a purine dideoxy nucleoside, which is an analogue of inosine. It differs from inosine by having hydrogen atom in place of 2′ and 3′ hydroxy groups on the ribose ring. It is a prodrug which is bio-activated to dideoxyadenosine triphosphate, which is a competitive inhibitor of reverse transcriptase (RT). Due to the absence of 3′-hydroxy group it causes chain termination. It inhibits HIV RT and exerts a virustatic effect on the retroviruses.

Synthesis

ADR: Pancreatitis, peripheral neuropathy and diarrhea.

Dose: 400mg daily as a single dose or in two divided doses.

Use: It is recommended for treatment of patients with advanced HIV infections.

Zidovudine (Zidovir, Zilion, Zidine)

Zidovidine is an analogue of thymidine in which the azido group is substituted at 3rd – carbon atom of the dideoxyribose moiety. It is active against RNA tumor viruses that are causative agent of AIDS and T-cell leukemia.

Synthesis

Mechanism of Action: Retroviruses possess a reverse transcriptase or RNA-directed DNA- polymerase that directs the synthesis of DNA copy (proviral DNA) of the viral DNA genome that is duplicated, circulated and incorporated into DNA of the infected cell. The drug enters the host cell by diffusion and is phosphorylated by cellular thymidine kinase. Thymidylate kinase then converts monophosphate into di- and triphosphate. Zidovudine triphosphate competitively inhibits reverse transcriptase. The 3′- azido group prevents the formation of a 3′ 5′- phosphodiester bond, which causes DNA chain termination.

ADR: Nausea, severe head ache, myalgia and insomnia.

Dose: 600mg daily in divided doses, in combination with other anti-retroviral agents.

Use: It is used for the treatment of AIDS and AIDS related complex. Because it crosses blood brain barrier, it has favorable effect on neurological symptoms of AIDS.

Stavudine (Virostav, Stag)

It is an unsaturated pyrimidine nucleoside that is related to thymidine. It differs from thymidine by replacement of the 3′- hydroxyl group with a hydrogen atom and a double bond in the 2′ and 3′ positions on the deoxy ribose ring.

Mechanism of Action: Stavudine is bio-activated by cellular enzymes to a triphosphate. The triphosphate competitively inhibits the incorporation of thymidine triphosphate into retro viral DNA by reverse transcriptase.

ADR: Head ache, nausea, vomiting and asthenia.

Dose: 30 to 40mg to be taken every 12 hrs.

Use: It is given for the treatment of patients with AIDS who are intolerant of or refractory to approved therapies.

Lamivudine (Lamda, lamivir)

Lamivudine is a synthetic nucleoside analogue that differs from 2′, 3′- dideoxy cytidine (ddc) by the substitution of sulfur atom in place of methylene group at 3′ position of the ribose ring. The (+) enantiomer is more active than (-) enantiomer.

Synthesis

Mechanism of Action: It exerts virustatic effect against retroviruses by competitively inhibiting HIV- RT after intracellular conversion of the drug to its active form.

ADR: Abdominal pain, nausea, vomiting and insomnia.

Dose: 100mg once daily.

Use: It is used in combination with ZDV for the treatment of disease caused by HIV infection.

Non-Nucleoside RT inhibitors

Non-nucleoside reverse transcriptase inhibitors (NNRTI) are used with nucleoside drug to obtain synergistic activity. These drugs do not require bio-activation by kinase to yield phosphate esters. They are not incorporated into the growing DNA chain. Instead, they bind to an allosteric site that is distinct from the substrate- binding site of reverse. transcriptase. The inhibitor can bind either free or substrate-bound enzyme, interfering with the action of both.

Such binding inactivates the enzyme, so that it cannot form the enzyme substrate complex at its normal rate. The tricyclic compounds Nevirapine, Delaviridine, Efavirenz are approved for use in combination with NRTIs for the treatment. of HIV infections.

Efavirenz (Efavir, Efferven)

ADR: Rash including Stevens-Johnson syndrome and erythema multiforme. CNS effects like dizziness and head ache.

Dose: 600mg once daily. Using at bed time is recommended during first 2 to 4 weeks of therapy to improve tolerability.

Use: It is a non-nucleoside RT inhibitor that is effective against HIV-1.

Nevirapine (Nevimune, Nevipan, Neve)

Nevirapine is a dipyrido diazepinone derivative which binds directly to RT. Thus, it blocks RNA and DNA dependent polymerase activities.

ADR: Skin rash, nausea, vomiting and headache.

Dose: 200mg once daily for first 14 days. Increase to 200mg bid if rash does not develop.

Use: It exhibits retroviral effect against AZT- resistant HIV strains. It is recommended for HIV infected patients who have experienced clinical or immunological deterioration.

HIV Protease Inhibitors

HIV protease is an enzyme that is essential for viral growth. The inhibitors act on HIV protease and prevent post-translation processing and budding of immature viral particles from the infected cell.

Atazanavir (Atazor)

ADR: Taste disturbances, abdominal pain, anorexia, increased appetite and flatulence.

Dose: 400mg once daily, with Ritonavir 100mg.

Use: It is used to treat infection of HIV and like other protease inhibitor; it is used only in combination with other HIV medications.

Saquinavir (Saquin)

Saquinavir mesylate is a carboxamide derivative, specifically designed to inhibit HIV-protease.

ADR: Nausea, vomiting and diarrhea.

Dose: 1gm bid when taken with Ritonavir 100mg bid. Alternatively, 400mg bid with Ritonavir 400mg bid.

Use: It is used in the treatment of advanced HIV infection in selected patients.

Indinavir (Indease, Indivan)

Indinavir is a pentanoic acid amide derivative.

ADR: Flank pain, abdominal pain, nephrolithiasis and malaise.

Dose: 800mg for every 8hrs.

Use: A synthetic peptide analogue that is specific inhibitor of HIV-1 and 2 protease.

Ritonavir (Ritomax, Ritovir, Norvir)

ADR: Syncope, orthostatic, hypotension, dry mouth and mouth ulcer.

Dose: 300mg bid for one day. May be increased gradually by 100mg bid over a period of up to 14 days to 600 mg bid.

Use: It is a peptidomimetic inhibitor of HIV-1 and HIV-2 protease.

Nelfinavir (Nelfin, Nelvir)

ADR: Hyperglycemia, dyslipidemia and diarrhea.

Dose: 1.25gm bid or 0.75gm tid.

Use: It is generally used in combination with other antiretroviral agents. It inhibit both HIV-1 and HIV-2 protease.

Lopinavir (Kaletra, Aluvia)

ADR: Abdominal pain, head ache, diarrhea, nausea and vomiting

Dose: 400mg every 12 hrs in fixed combination with 100mg Ritonavir.

Use: It is used in the treatment of AIDS.

Neuroamidase inhibitors

Oseltamivir (Tamiflu)

ADR: Nausea, vomiting, abdominal pain, insomnia, bronchitis and vertigo.

Dose: 75mg twice daily for 5 days.

Use: It is used to treat Influenza A and B.

Zanamivir (Relenza)

ADR: Acute bronchospasm, headache, gastrointestinal problems and severe skin rashes.

Dose: 10mg twice daily for 5 days.

Use: It is used to treat influenza A and B.