Download ANTIVIRAL AGENTS

ANTIVIRAL AGENTS
1
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
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The free living virus particle (i.e. outside its host) is termed as
Virion
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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:
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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:
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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:
1.
2.
3.
4.
5.
6.
7.
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.
2.
3.
4.
5.
6.
7.
8.
Attachment
Membrane fusion
Release of viral DNA through nuclear pores
Transcription of viral mRNA
Synthesis of viral proteins by host cell’s ribosomes
Replication of viral DNA by viral polymerases
Assembly of virus particles
Budding and release of progeny virus
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Replication cycle of RNA virus
1.
2.
3.
4.
5.
6.
7.
8.
9.
Attachment
Endocytosis
Influx of H+ through M2 protein
Fusion of the viral envelope with the endosomes membrane and entry of viral RNA into
the nucleus
Synthesis of viral mRNA by viral RNA polymerase
Translation of viral mRNA by host cell’s ribosomes
Replication of viral RNA, using viral RNA polymerase, via cRNA replicative form
Assembly of virus particles
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
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Able to interfere with viral nucleic acid synthesis and/or regulation
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Able to interfere with ability of virus to bind to cells
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Some drugs stimulate the body’s immune system

Best responses to antiviral drugs are in patients with competent
immune systems
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Antiviral Agents- CLASSIFICATION
[1] Anti-Herpes:
• Acyclovir
• Valacyclovir
• Ganciclovir
• Penciclovir
• Cidofivir
• Fomivirsen
• Idoxuridine
• Trifluridine
• Docosanol
[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
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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
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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
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Mechanism of
Action
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Therapeutic use
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Adverse Effects
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Acyclovir is an acyclic guanine nucleoside analog
Valacyclovir is the ester prodrug of acyclovir
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
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
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
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Mechanism of
Action
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Therapeutic use
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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
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Adverse Effects
cytidine nucleotide analog
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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
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
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Mechanism of
Action
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Therapeutic use
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Adverse Effects
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Famciclovir is an ester prodrug of penciclovir
Penciclovir is an acyclic guanine nucleoside analog
Triphosphate form competitively inhibits viral DNA polymerase
Inhibit DNA chain elongation (no chain termination)
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
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Oral famciclovir: Headache, diarrhoea, urticaria, rash, confusion
Penciclovir is mutagenic at high concentrations
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Fomivirsen
Nature
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Phosphorothioate oligionucleotide
Mechanism of
Action
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Complimentary to m-RNA sequence of CMV, hence inhibit its replication
Inhibit viral binding to cell
Therapeutic use
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Adverse Effects
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Active against CMV strains resistant to ganciclovir, foscarnet, and cidofovir
 Given by intravitreal injection for patients unresponsive to other therapies for CMV
retinitis
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Occular: irrititis, cataract, increased IOP
Increased risk of inflammatory reactions
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Foscarnet
Nature
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Mechanism of
Action
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Therapeutic use
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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
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Adverse Effects
Inorganic pyrophosphate analog
CMV retinitis (i.v.)
CMV pneumonia and viraemia
Ganciclovir and acyclovir-resistant HSV and VZV infections
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
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Ganciclovir is an acyclic guanine nucleoside analog
Valganciclovir is the ester prodrug of ganciclovir
Mechanism of
Action
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Triphosphate form competitively inhibit DNA chain
Therapeutic use
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Adverse Effects
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Chronic suppression of CMV retinitis (i.v.)
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Intraocular sustained-release ganciclovir implant (VITRASERT) is more effective in
supressing Retinitis
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Benificial in infants with congenital CMV disease
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CMV infections in Organ transplant recipients
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HSV keratitis (ophthalmic gel)
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Myelosuppression (Higher risk with Zidovudin)
Neutropenia (Treated with Recombinant G-CSF)
Eosinophilia
Thrombocytopenia
GI disturbances
Anemia
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Doscosanol
Nature
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Therapeutic use
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Long-chain saturated alcohol
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
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Mechanism of
Action
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Iodinated thymidine analog
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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
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Approved only for topical treatment of HSV keratitis
Adverse Effects
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Pain
Pruritis
Inflammation
Edema involving the eye
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Trifluridine
Nature
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Fluorinated pyrimidine nucleoside
Mechanism of
Action
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Monophosphate irreversibly inhibits thymidylate synthase
Triphosphate competitively inhibits thymidine triphosphate incorporation into DNA
Inhibit DNA synthesis
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Therapeutic use
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FDA approved for treatment of keratoconjunctivitis and keratitis owing to HSV types
1 and 2
 Adenovirus infection
Adverse Effects
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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
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Mechanism of
Action
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Therapeutic use
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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
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Adverse Effects
Both are tricyclic amines
Rimantadine is a methyl derivative of Amantadine
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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
Mainly CNS: Insomnia, confusion, seizure (less frequent with Rimantadine)
Arrhythmia
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Oseltamivir
Nature
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Mechanism of
Action
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Therapeutic use
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Adverse Effects
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Sialic acid analog
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 neuraminidase’s active site
and inhibits its activity, leading to viral aggregation at the cell surface and
reduced virus spread within the respiratory tract
Treatment and prevention of influenza A and B virus infections
 Inhibits amantadine- and rimantadine-resistant influenza A viruses
Nausea, abdominal discomfort and less often emesis probably owing to local
irritation
 GI complaints (usually mild)
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Zanamivir
Nature
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Mechanism of
Action
Potently
Therapeutic use
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Adverse Effects
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Sialic acid analog
and specifically inhibits the neuraminidases of influenza A and B viruses
Treatment and prevention of influenza A and B virus infections
Best drug to protect against household transmission
Whizzing
Bronchospazm
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ANTI-hepetitis VIRUS AGENTS
Adefovir
 Ribavirin
 Lamivudin
 Palivizumab
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Adefovir
Nature
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Acyclic adenosine nucleotide analog
Mechanism of
Action
Cellular enzymes
Therapeutic use
approved
Adverse Effects
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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.
for treatment of chronic HBV infections
This also includs lamivudine-resistant HBV strains
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: α, β and γ
Mechanism of
Action
Interferes
Therapeutic use
Chronic
Adverse Effects
Acute
with viral replication at multiple steps: penetration, mRNA synthesis,
assembly of viral particles, release etc.
Also itself synthesize certain Antiviral proteins
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
influenza like syndrome: fever, chills, headache, myalgia, arthralgia, nausea,
vomiting, and diarrhea (resolved within 12 hrs)
Myellosupression
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Lamivudine
Nature
Cytidine
Mechanism of
Action
Triphosphate
Therapeutic use
Enhanced
Adverse Effects
No
nucleoside analog
form potently inhibits the DNA polymerase / Reverse
transcriptase of HBV and DNA polymerase of HIV
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
marked adverse effects
Generally well tolerated
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Ribavirin
Nature
Purine
Mechanism of
Action
Inhibits
Therapeutic use
In
Adverse Effects
Aerosolized
nucleoside analog with a modified base and D-ribose sugar
viral mRNA synthesis
Interferes with the synthesis of GTP
Inhibit viral cell replication in both DNA and RNA viruses
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
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
[2] NTRTI
[1] NRTI
 Zidovudine
 Tenofovir
 Stavudine
 Didanosine
 Lamivudine
 Abacavir
 Zalcitabine
[3] NNRTI
[4] PI
 Efavirenz
 Saquinavir
 Nevirapine  Ritonavir
 Delavirdine  Indinavir
 Nelfinavir
 Amprenavir
 Lopinavir
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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:
Viral RNA
REVERSE
TRANSCRIPTASE
Proviral DNA
Incorporated into host
cell chromosome
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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:
Viral RNA
REVERSE
TRANSCRIPTASE
Proviral DNA
Incorporated into host
cell chromosome
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These compounds inhibit both HIV-1 and HIV-2 and several have broadspectrum 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]
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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:
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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 γ
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
Zidovudin
SPECTRUM
HIV-1, HIV-2
USES/COMMENTS
FDA-approved for the treatment
of adults and
children with HIV infection
lymphotrophic
Preventing mother-to-child transmission
viruses (HTLV) I and II Recommended for postexposure prophylaxis
in HIV-exposed healthcare workers
human T-cell
Didenosine
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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
Stavudine
HIV-1, HIV-2
Zalcitabine
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Lamivudine
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USES/COMMENTS
Bioavailability
is not affected by food
A sustained-release formulation that can be
given once daily is FDA-approved
HIV-1, HIV-2
HBV
Food does not
affect bioavailability
distinctive toxicity: oral ulceration and
stomatitis
HIV-1, HIV-2
HBV
oral
bioavailability is >80% and is not affected
by food
one of the least toxic antiretrovirals
Frequently employed in three-drug regimens
with other nucleoside analogs, protease
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inhibitors, and/or NNRTIs
Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors [NRTI]
Therapeutic uses:
DRUG
SPECTRUM
Abacavir
HIV-1
Tenofovir
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HIV-1, HIV-2
HBV
USES/COMMENTS
oral
bioavailability is >80% and is not affected
by food
Most imp A/E: a unique and potentially fatal
hypersensitivity
Widely used in coformulations with
zidovudine or lamivudine
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:
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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 enzyme’s 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
Nevirapine
USES/COMMENTS
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
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by 50% with a high fat meal.
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.
2.
3.
Brunton L., Parker K., Blumenthal D., Buxton L., Goodman
and Gillman’s Manual of Pharmacology and Therapeutics;
New York: McGraw Hill; 2008; P. 814-912.
Harrison TR.,Kasper DL., Braunwald E., Fauci AS., Hauser SL.,
Longo DL. et al.; Harrison’s Principles of Internal Medicine.
New York: McGraw Hill; 2005; p.1035-1040.
Rang HP., Dale MM., Ritter JM., Flower RJ., Rang and Dale’s
Pharmacology, China: Elsevier publishers; 2007; p. 679-683.
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