ANTIVIRAL AGENTS

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ANTIVIRAL AGENTS

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Introduction to Virus

• Virus is a small (20-30 nm) infective agents
  which is an obligate intracellular parasite
• It contain either double- or single-stranded DNA
  or RNA enclosed in a protein coat called a
  Capsid
• A virus depends upon host cell for its metabolic
  processes, such as synthesis of proteins and DNA
• It cannot replicate on its own

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Introduction to Virus

• The virus must attach to and enter a host cell
• It then uses the energy of host cell to
  synthesize protein, DNA and RNA
• The free living virus particle (i.e. outside its
  host) is termed as Virion
• The life cycles of viruses are intimately
  associated with those of their host cells, hence
  it is difficult to find agents that selectively
  inhibit virus replication without damaging human
  cells
• Most drugs can not distinguish between viral
  function and host cell function, hence cause
  toxicity to both

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Types of Virus with examples

• DNA viruses
• poxviruses (smallpox),
• herpesviruses (chickenpox, shingles, cold sores),
• adenoviruses (sore throat, conjunctivitis) and
• papillomaviruses (warts)

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Types of Virus with examples

• RNA viruses
• orthomyxoviruses (influenza),
• paramyxoviruses (measles, mumps),
• rubella virus (German measles),
• rhabdoviruses (rabies),
• picornaviruses (colds, meningitis,
  poliomyelitis),
• retroviruses (acquired immunodeficiency syndrome
  (AIDS), T cell leukaemia),
• arenaviruses (meningitis, Lassa fever),
• hepadnaviruses (serum hepatitis) and
• arboviruses (various fevers, e.g. yellow fever).

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Viral Cell Replication

• Major Steps Involved in Replication are
• Adsorption and penetration into host cell
• Uncoating of viral nucleic acid
• Synthesis of regulatory proteins
• Synthesis of RNA or DNA
• Synthesis of structural proteins
• Assembly of viral particles
• Release from host cell

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Replication cycle of DNA virus

1. Attachment
2. Membrane fusion
3. Release of viral DNA through nuclear pores
4. Transcription of viral mRNA
5. Synthesis of viral proteins by host cells
   ribosomes
6. Replication of viral DNA by viral polymerases
7. Assembly of virus particles
8. Budding and release of progeny virus

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Replication cycle of RNA virus

1. Attachment
2. Endocytosis
3. Influx of H through M2 protein
4. Fusion of the viral envelope with the endosomes
   membrane and entry of viral RNA into the nucleus
5. Synthesis of viral mRNA by viral RNA polymerase
6. Translation of viral mRNA by host cells
   ribosomes
7. Replication of viral RNA, using viral RNA
   polymerase, via cRNA replicative form
8. Assembly of virus particles
9. Budding and release of progeny virus

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Antiviral Agents

• Key characteristics of antiviral drugs
• Able to enter the cells infected with virus
• Able to interfere with viral nucleic acid
  synthesis and/or regulation
• Able to interfere with ability of virus to bind
  to cells
• Some drugs stimulate the bodys immune system
• Best responses to antiviral drugs are in patients
  with competent immune systems

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Antiviral Agents- CLASSIFICATION

• 2 Anti-Influenza
• Amantadine
• Rimentadine
• Oseltamivir
• Zanamivir

• 3 Anti-Hepatitis
• Adefovir
• Ribavirin
• Lamivudin
• Palivizumab

• 4 Anti-Retroviral
• Zidovudine
• Stavudine
• Didanosine
• Lamivudine
• Zalcitabine
• Efavirenz
• Nevirapine
• Delavirdine
• Tenofovir
• Saquinavir
• Indinavir
• Nelfinavir
• Lopinavir

• 1 Anti-Herpes
• Acyclovir
• Valacyclovir
• Ganciclovir
• Penciclovir
• Cidofivir
• Fomivirsen
• Idoxuridine
• Trifluridine
• Docosanol

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ANTI-HERPES VIRUS AGENTS

• Acyclovir
• Valacyclovir
• Ganciclovir
• Penciclovir
• Cidofivir
• Fomivirsen
• Idoxuridine
• Trifluridine
• Docosanol

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Anti-Herpes virus agents

• Herpes simplex virus type 1 (HSV-1) causes
  diseases of the mouth, face, skin, esophagus or
  brain.
• Herpes simplex virus type 2 (HSV-2) causes
  infections of the genitals, rectum, skin, hands
  or meninges.
• Both cause serious infections in neonates.

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Acyclovir and Valacyclovir
Nature Acyclovir is an acyclic guanine nucleoside analog Valacyclovir is the ester prodrug of acyclovir
Mechanism of Action Selective inhibition of viral DNA synthesis by interaction with two viral proteins HSV Thymidine kinase (TK) HSV DNA polymerase Does not affect host DNA synthesis
Therapeutic use Herpes Simplex Virus (HSV) Infection Primary herpetic gingivostomatitis Genital herpes Mucocutanious HSV infection (prophylaxis and treatment) Herpetic keratoconjunctivitis (ophthalmic formulation) Verisella Zoster Virus (VZV) Infection Rash, fever, cutanious lesions Cytomegalo Virus (CMV) Infection CMV retinitis
Adverse Effects Topical mucosal irritation and transient burning when applied to genital lesions. Oral nausea, diarrhea, rash, headache I.V. severe renal insufficiency, nephrotoxicity and CNS side effects
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Cidofovir
Nature cytidine nucleotide analog
Mechanism of Action inhibits viral DNA synthesis by terminating chain elongation metabolized by cellular enzymes to its active diphosphate form which competitively inhibit dCTP a substrate for viral DNA polymerase (of both HSV CMV) A phosphocholine metabolite serves as an intracellular drug reserviour
Therapeutic use Approved to be used in CMV retinitis in HIV infected patients Synergistic in combination with Ganciclovir or Foscarnet Acyclovir resistant Mucocutanious HSV infection (topical gel) Treatment of anogenital warts (topical gel) Foscarnet resistant CMV infection Adenovirus disease in transplant recipient BK virus nephropathy in renal transplant patient
Adverse Effects Nephrotoxicity Proxymal tubular dysfunction including proteinurea, azotemia, glucosurea Cycloplegia due to Occular hypotony Topical application burning, pain, pruritis Considered as potential human carcinogen
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Famciclovir and Penciclovir
Nature Famciclovir is an ester prodrug of penciclovir Penciclovir is an acyclic guanine nucleoside analog
Mechanism of Action Triphosphate form competitively inhibits viral DNA polymerase Inhibit DNA chain elongation (no chain termination)
Therapeutic use Oral famciclovir, topical penciclovir, and intravenous penciclovir are approved for HSV and VZV infections Treatment of genital herpes Reduce HSV recurrences in HIV-infected persons Chronic HBV hepatitis
Adverse Effects Oral famciclovir Headache, diarrhoea, urticaria, rash, confusion Penciclovir is mutagenic at high concentrations
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Fomivirsen
Nature Phosphorothioate oligionucleotide
Mechanism of Action Complimentary to m-RNA sequence of CMV, hence inhibit its replication Inhibit viral binding to cell
Therapeutic use Active against CMV strains resistant to ganciclovir, foscarnet, and cidofovir Given by intravitreal injection for patients unresponsive to other therapies for CMV retinitis
Adverse Effects Occular irrititis, cataract, increased IOP Increased risk of inflammatory reactions
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Foscarnet
Nature Inorganic pyrophosphate analog
Mechanism of Action Reversibly and noncompetitively blocks the pyrophosphate binding site of the HSV DNA Polymerase Also interact directly with HIV Reverse Transcriptase Thus inhibits viral nucleic acid synthesis
Therapeutic use CMV retinitis (i.v.) CMV pneumonia and viraemia Ganciclovir and acyclovir-resistant HSV and VZV infections
Adverse Effects Genital Ulceration Nephrotoxicity Acute tubular necrosis Nephrogenic diabetes insipidus Highly ionized at physiological pH, and metabolic abnormalities are very common, including hypocalcemia, hypophosphatamia, hypomagnesemia, and hypokalemia Thrombophlebitis ECG changes
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Ganciclovir and Valganciclovir
Nature Ganciclovir is an acyclic guanine nucleoside analog Valganciclovir is the ester prodrug of ganciclovir
Mechanism of Action Triphosphate form competitively inhibit DNA chain
Therapeutic use Chronic suppression of CMV retinitis (i.v.) Intraocular sustained-release ganciclovir implant (VITRASERT) is more effective in supressing Retinitis Benificial in infants with congenital CMV disease CMV infections in Organ transplant recipients HSV keratitis (ophthalmic gel)
Adverse Effects Myelosuppression (Higher risk with Zidovudin) Neutropenia (Treated with Recombinant G-CSF) Eosinophilia Thrombocytopenia GI disturbances Anemia
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Doscosanol
Nature Long-chain saturated alcohol
Therapeutic use FDA approved as a 10 OTC cream for the treatment of recurrent orolabial herpes Topical treatment within 12 hours of symptom initiation is only effective
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Idoxuridine
Nature Iodinated thymidine analog
Mechanism of Action Inhibits the in vitro replication of various DNA viruses (HSV and Pox virus) Triphosphate inhibits viral DNA synthesis Lacks selectivity between host cell and viral cell
Therapeutic use Approved only for topical treatment of HSV keratitis
Adverse Effects Pain Pruritis Inflammation Edema involving the eye
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Trifluridine
Nature Fluorinated pyrimidine nucleoside
Mechanism of Action Monophosphate irreversibly inhibits thymidylate synthase Triphosphate competitively inhibits thymidine triphosphate incorporation into DNA Inhibit DNA synthesis
Therapeutic use FDA approved for treatment of keratoconjunctivitis and keratitis owing to HSV types 1 and 2 Adenovirus infection
Adverse Effects Discomfort and edema upon instillation Hypersensitivity reactions and irritation (Rare)
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ANTI-INFLUENZA VIRUS AGENTS

• Amantadine
• Rimentadine
• Oseltamivir
• Zanamivir

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Amantadine and Rimantadine
Nature Both are tricyclic amines Rimantadine is a methyl derivative of Amantadine
Mechanism of Action Inhibit viral uncoating as well as viral assembly Interfere with function of M2 protein of Influenza A virus, which act as ion channel for viral uncoating
Therapeutic use Both are effective for the prevention and treatment of Influenza A infection Seasonal prophylaxis of Influenza A Treatment of Hepatitis-C in combination with Interferon Amantadine treatment of Parkinsonism
Adverse Effects Mainly CNS Insomnia, confusion, seizure (less frequent with Rimantadine) Arrhythmia
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Oseltamivir
Nature Sialic acid analog
Mechanism of Action Influenza neuraminidase cleaves terminal sialic acid residues and destroys the receptors recognized by viral hemagglutinin, which are present on the cell surface, which is essential for virus release from infected cells Oseltamivir causes a conformational change in neuraminidases active site and inhibits its activity, leading to viral aggregation at the cell surface and reduced virus spread within the respiratory tract
Therapeutic use Treatment and prevention of influenza A and B virus infections Inhibits amantadine- and rimantadine-resistant influenza A viruses
Adverse Effects Nausea, abdominal discomfort and less often emesis probably owing to local irritation GI complaints (usually mild)
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Zanamivir
Nature Sialic acid analog
Mechanism of Action Potently and specifically inhibits the neuraminidases of influenza A and B viruses
Therapeutic use Treatment and prevention of influenza A and B virus infections Best drug to protect against household transmission
Adverse Effects Whizzing Bronchospazm
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ANTI-hepetitis VIRUS AGENTS

• Adefovir
• Ribavirin
• Lamivudin
• Palivizumab

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Adefovir
Nature Acyclic adenosine nucleotide analog
Mechanism 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.
Therapeutic use approved for treatment of chronic HBV infections This also includs lamivudine-resistant HBV strains
Adverse Effects Dose related Nephrotoxicity proteinurea, azotemia, glucosurea
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Interferons
Nature Possess antiviral, immunomodulating, and antiproliferative activities They are synthesized by host cells in response to various inducers and stimulate an antiviral state in cells There are three major classes of human interferons with antiviral activity a, ß and ?
Mechanism of Action Interferes with viral replication at multiple steps penetration, mRNA synthesis, assembly of viral particles, release etc. Also itself synthesize certain Antiviral proteins
Therapeutic use Chronic HBV and HCV infection Broad-spectrum antiviral activity against respiratory viruses Papilloma virus infection in genital warts Genital HSV infections, localized herpes-zoster infection, and CMV infections of renal transplant patients
Adverse Effects Acute influenza like syndrome fever, chills, headache, myalgia, arthralgia, nausea, vomiting, and diarrhea (resolved within 12 hrs) Myellosupression
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Lamivudine
Nature Cytidine nucleoside analog
Mechanism of Action Triphosphate form potently inhibits the DNA polymerase / Reverse transcriptase of HBV and DNA polymerase of HIV
Therapeutic use Enhanced antiviral activity against hepadnaviruses when combined with adefovir or penciclovir HBV infection in children Administered before and after liver transplantation to suppress recurrent HBV infection
Adverse Effects No marked adverse effects Generally well tolerated
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Ribavirin
Nature Purine nucleoside analog with a modified base and D-ribose sugar
Mechanism of Action Inhibits viral mRNA synthesis Interferes with the synthesis of GTP Inhibit viral cell replication in both DNA and RNA viruses
Therapeutic use In combination with parenteral IFN is standard treatment for chronic HCV infection Aerosol is approved in the U.S. for treatment of RSV bronchiolitis and pneumonia in hospitalized children, in bonemarrow transplant and higjly immunocompromised patients
Adverse Effects Aerosolized form conjunctival irritation, rash, transient wheezing, and reversible deterioration in pulmonary function Systemic reversible anemia owing to extravascular hemolysis and bone marrow suppression Teratogenic and Gonadotoxic
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ANTI-retro VIRUS AGENTS

• Nucleoside and Nucleotide Reverse Transcriptase
  Inhibitors NRTI
• Non- Nucleoside and Nucleotide Reverse
  Transcriptase Inhibitors NNRTI
• Protease Inhibitor PI

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Anti-Retroviral Agents

• 3 NNRTI
• Efavirenz
• Nevirapine
• Delavirdine

• 2 NTRTI
• Tenofovir

• 4 PI
• Saquinavir
• Ritonavir
• Indinavir
• Nelfinavir
• Amprenavir
• Lopinavir

• 1 NRTI
• Zidovudine
• Stavudine
• Didanosine
• Lamivudine
• Abacavir
• Zalcitabine

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Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors NRTI
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Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors NRTI
Mechanism of Action
REVERSE TRANSCRIPTASE
Proviral DNA
Viral RNA
Incorporated into host cell chromosome

• Nucleoside and nucleotide analogs must enter
  cells and undergo phosphorylation to generate
  synthetic substrates for the enzyme Reverse
  Transcriptase
• Fully phosphorylated analogs block replication of
  the viral genome by
• competitively inhibiting incorporation of native
  nucleotide
• terminating elongation of nascent proviral DNA

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Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors NRTI
Mechanism of Action
REVERSE TRANSCRIPTASE
Proviral DNA
Viral RNA
Incorporated into host cell chromosome

• These compounds inhibit both HIV-1 and HIV-2 and
  several have broad-spectrum activity against
  other retroviruses some are also active against
  HBV and the herpes viruses

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• ZDV zidovudine T
• d4T stavudine T
• ddC dideoxycytidine C
• FTC emtricitabine C

• 3TC lamivudine C
• ABC abacavir G
• ddI didanosine A
• DF disoproxil fumarate A

MP, monophosphate DP,diphosphate TP,
triphosphate AMP, adenosine monophosphate CMP,
cytosine monophosphate dCMP, deoxycytosine
monophosphate IMP, inosine 5'-monophosphate
PRPP, phosphoribosyl pyrophosphate NDR,
nucleoside diphosphate
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Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors NRTI
Adverse Effects

• Selective toxicity of these drugs depends on
  their ability to inhibit the HIV reverse
  transcriptase without inhibiting host cell DNA
  polymerases
• Some are capable of inhibiting human DNA
  polymerase ?
• Toxicities due to inhibition of mitochondrial DNA
  synthesis are frequently observed which are
  anemia, granulocytopenia, myopathy, peripheral
  neuropathy, and pancreatitis

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Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors NRTI
Therapeutic uses
DRUG SPECTRUM USES/COMMENTS
Zidovudin HIV-1, HIV-2 human T-cell lymphotrophic viruses (HTLV) I and II FDA-approved for the treatment of adults and children with HIV infection Preventing mother-to-child transmission Recommended for postexposure prophylaxis in HIV-exposed healthcare workers
Didenosine HIV-1 HIV-2 HTLV-1 Acid labile, and therefore is administered with an antacid buffer. Food decreases bioavailability
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Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors NRTI
Therapeutic uses
DRUG SPECTRUM USES/COMMENTS
Stavudine HIV-1, HIV-2 Bioavailability is not affected by food A sustained-release formulation that can be given once daily is FDA-approved
Zalcitabine HIV-1, HIV-2 HBV Food does not affect bioavailability distinctive toxicity oral ulceration and stomatitis
Lamivudine HIV-1, HIV-2 HBV oral bioavailability is gt80 and is not affected by food one of the least toxic antiretrovirals Frequently employed in three-drug regimens with other nucleoside analogs, protease inhibitors, and/or NNRTIs
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Nucleoside and Nucleotide Reverse Transcriptase
Inhibitors NRTI
Therapeutic uses
DRUG SPECTRUM USES/COMMENTS
Abacavir HIV-1 oral bioavailability is gt80 and is not affected by food Most imp A/E a unique and potentially fatal hypersensitivity Widely used in coformulations with zidovudine or lamivudine
Tenofovir HIV-1, HIV-2 HBV Only nucleotide analog currently marketed for HIV infection FDA-approved as a component of combination HIV therapy for adults in triple drug regimen
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Non-Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors NNRTI
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Non-Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors NNRTI

• Mechanism of Action
• Noncompetitive inhibitors that bind to a
  peripheral site on HIV-1 reverse transcriptase.
• The binding site is a hydrophobic pocket in the
  p66 subunit of reverse transcriptase, distant
  from the active site.
• Occupation of the site by an NNRTI induces a
  conformational change that greatly reduces the
  enzymes activity.
• Because the binding site for NNRTIs is
  strain-specific, the approved agents are active
  against HIV-1 but not HIV-2 or other
  retroviruses.
• They have no activity against host cell DNA
  polymerases.
• NNRTIs do not require intracellular
  phosphorylation for activity.
• Adverse Effect
• Rash and severe hepetitis

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Non-Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors NNRTI
Therapeutic uses
DRUG USES/COMMENTS
Nevirapine FDA-approved for the treatment of HIV-1 infection in adults and children Used to prevent mother-to-child transmission of HIV-1
Delavirdine Least used of the NNRTIs Avoided with potent enzyme inducers
Efavirenz Widely used because of its convenience, effectiveness, and long-term tolerability Predominant adverse effects of CNS dizziness, impaired concentration, dysphoria Teratogenic
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Protease Inhibitors PI

• Mechanism of Action
• Competitively inhibit the action of the viral
  enzyme Aspartyl protease
• This protease is a homodimer consisting of two
  99-amino-acid monomers each monomer contains an
  Aspartate residue that is essential for
  catalysis.
• The preferred cleavage site for this enzyme is
  the N-terminal side of Proline residues,
  especially between Phenylalanine and Proline
• Human aspartyl proteases contain only one
  polypeptide chain and are not significantly
  inhibited by HIV protease inhibitors

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Protease Inhibitors PI

• Mechanism of Action
• These drugs bind reversibly to the active site of
  the protease and prevent proteolytic cleavage of
  HIV gag and pol proteins into essential
  structural and enzymatic components of the virus.
  
• This prevents themetamorphosis of HIV virus
  particles into their mature infectious form

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Protease Inhibitors PI

• Adverse Effects
• Most commonly nausea and vomiting, anorexia,
  diarrhea
• Unique lipodystophy, a metabolic syndrome
  characterized by insulin resistance and
  dyslipidemia

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Protease Inhibitors PI

• Saquinavir
• Inhibits HIV-1 and HIV-2 replication.
• Of all of the HIV protease inhibitors, saquinavir
  inhibits CYP3A4 least potently.
• Administered in combination with ritonavir
• Ritonavir
• Active against HIV-1 and HIV-2.
• Extremely potent inhibitor of CYP3A4 and is
  frequently combined with most of the PI.
• Better tolerated

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Protease Inhibitors PI

• Indinavir
• Food adversely affects indinavir bioavailability
• Unique adverse effects of indinavir are
  crystalluria and nephrolithiasis
• Nelfinavir
• Active against HIV-1 and HIV-2
• Very sensitive to food effects
• Used in HIV-infected patients with significant
  hepatic dysfunction
• Lopinavir
• Inhibits both HIV-1 and HIV-2.
• Only administered in combination with ritonavir
• Should be taken with food because oral
  bioavailability is increased by 50 with a high
  fat meal.

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Entry Inhibitors PI

• Enfuvirtide
• Mechanism of action
• Prevents formation of a six-helix bundle critical
  for membrane fusion and viral entry into the host
  cell
• Inhibits infection of CD4 cells by free virus
  particles, as well as cell-to-cell transmission
  of HIV-1
• Adverse effects
• Injection site reactions including pain,
  erythema, nodules or cysts
• Therapeutic Use
• FDA-approved for use only in treatment of adults
  resistant to other applied HIV-1antiretroviral
  therapy

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References

1. Brunton L., Parker K., Blumenthal D., Buxton L.,
   Goodman and Gillmans Manual of Pharmacology and
   Therapeutics New York McGraw Hill 2008 P.
   814-912.
2. Harrison TR.,Kasper DL., Braunwald E., Fauci AS.,
   Hauser SL., Longo DL. et al. Harrisons
   Principles of Internal Medicine. New York McGraw
   Hill 2005 p.1035-1040.
3. Rang HP., Dale MM., Ritter JM., Flower RJ., Rang
   and Dales Pharmacology, China Elsevier
   publishers 2007 p. 679-683.

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