ANTIVIRAL

DRUGS
 Viruses cause a variety of conditions,
ranging from warts, to the common
cold and flu, to diseases such as
chickenpox and measles.

Viruses are intracellular parasites with

INTRODUCTION no metabolic machinery of their own;
they lack both a cell wall and a cell
membrane.

To replicate, viruses must attach to and

enter a living host cell – animal, plant,
or bacterium – and use its metabolic
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process.
 Certain viruses multiply in the
cytoplasm, but others do in the
nucleus.

Viral replication requires DNA or

INTRODUCTION
RNA synthesis.

Most multiplication take place

before diagnosis is made

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STAGES OF VIRAL REPLICATION
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 Nucleosides

-Adenosine

-Thymidine
INTRODUCTION
-Cytidine

-Guanosine

-Uridine

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 • Many antiviral drugs are
Purine or Pyrimidine
analogs.

ANTIVIRAL • Many antiviral drugs are

DRUGS
Prodrugs. They must be
phosphorylated by viral or
cellular enzymes in order to
become active.
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CLASSIFICATION OF ANTIVIRAL DRUGS

1. Anti-Herpes virus
-Idoxuridine

-Acyclovir
-Valacyclovir
-Famciclovir
-Ganciclovir
-Foscarnet
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CLASSIFICATION OF ANTIVIRAL DRUGS
2.Anti-Retrovirus
a)Nucleoside reverse transcriptase inhibitors(NRTIs)

-Zidovudine(AZT)
-Zalcitabine
-Didanosine
-Stavudine
-Lamivudine 8

-Abacavir
CLASSIFICATION OF ANTIVIRAL DRUGS

2.Anti-Retrovirus
b)Non-nucleoside reverse transcriptase
inhibitors(NNRTIs)
-Nevirapine
-Efavirenz
-Delavirdine
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CLASSIFICATION OF ANTIVIRAL DRUGS

2.Anti-Retrovirus
c)Protease inhibitors:
-Ritonavir
-Indinavir
-Lopinavir
-Saquinavir 10
CLASSIFICATION OF ANTIVIRAL DRUGS
2.Anti-Retrovirus
d)Entry Inhibitor
-Enfuvirtide(T-20)
e) CCR-5 receptor inhibitor
-Maraviroc
f) Integrase inhibitor
-Raltegravir
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-Dolutegravir
CLASSIFICATION OF ANTIVIRAL DRUGS

3.Anti-Influenza virus
-Amantadine
-Rimantadine
-Oseltamivir
-Zanamivir
-Peramivir 12
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 ANTI-HIV AGENTS

a)Nucleoside reverse transcriptase inhibitors(NRTIs)

-On the template of single-stranded RNA genome of HIV a double-

stranded DNA copy is produced by viral reverse transcriptase.

-This DNA translocates to the nucleus and is integrated with

chromosomal DNA of the host cell, which then starts transcribing
viral genomic RNA a well as viral mRNA.

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 ANTI-HIV AGENTS
a)Nucleoside reverse transcriptase inhibitors(NRTIs)
Under the direction of viral mRNA, viral regulatory and
structural proteins are produced.
Viral particles assemble and gets matured
They inhibit viral reverse transcriptase enzyme
They exhibit Competitive inhibition.

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 ANTI-HIV AGENTS
Zidovudine is a thymidine analogue(azido-thymidine,AZT)
• After phosphorylation in the host cell-zidovudine triphosphate
selectively inhibits viral reverse transcriptase
• It thus prevents infection of new cells by HIV, but has no effect on
virus directed DNA that has already integrated in to the host
chromosome
• Resistance to AZT occurs by mutation
• Oral bioavailibilty ͂65%
• Crosses placenta and is found in milk
• Paracetamol, probenecid, nephrotoxic and myelosuppressive 18

drugs enhances AZT toxicity

HIV REPLICATION

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 ANTI-HIV AGENTS

• Didanosine- Purine nucleoside

• Stavudine (d4T)- Thymidine analogue

• Lamivudine (3TC)-deoxycytidine analogue

• Abacavir (ABC)-Guanosine analogue

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 ANTI-HIV AGENTS
b)Non-nucleoside reverse transcriptase inhibitors(NNRTIs)
• These are nucleoside unrelated compounds which directly inhibit
HIV reverse transcriptase without the need for intracellular
phosphorylation.
• Their locus of action on the enzyme is also different.
• They are more potent than AZT on HIV-1, but do not inhibit HIV-
2.
• Resistance to these drugs develops by mutation and cross resistance
• Nevirapine(NVP) and Efavirenz(EFV)- modestly induce CYP 3A4,
2D6 enzymes and enhance their own metabolism as well as that of 21
other drugs
ANTI-HIV AGENTS

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 ANTI-HIV AGENTS

c)Protease inhibitors
• Protease enzyme is involved in the production of structural
proteins and enzymes(including reverse transcriptase) of the virus.
• Protease enzyme breaks down large viral polyprotein in to
various functional components.
• This enzyme acts at a late step in HIV replication, i.e. maturation
of the new virus particles when the RNA genome acquires the
core proteins and enzymes
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 ANTI-HIV AGENTS

• Protease inhibitors bind to the protease molecule , interfere

with its cleaving function , and are more effective viral
inhibitors than AZT.
• Because they act at a late step of viral cycle, they are
effective in both newly and chronically infected cells.
• Under their influence HIV-infected cells produce immature
non-infectious viral progeny-hence prevent further rounds of
infection
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• Most prominent adverse effect is gastrointestinal intolerance
ANTI-HIV AGENTS

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 ANTI-HIV AGENTS

• Indinavir (IDV)-it is to be taken on empty stomach; gastrointestinal tolerance

is common; excess fluids must be consumed to avoid nephrolithiasis
• Nelfinavir (NFV)-It is to be taken with meals and bioavailability is erratic
• Ritonavir (RTV)-Potent PI; also a potent CYP3A4 inhibitor.
• Saquinavir (SQV)-Low oral bioavailabilty and thus tablet load is large,
photosensitivity can occur, weak CYP3A4 inhibitor
• Lopinavir (LPV/r) -available only in combination with Ritonavir to improve
bioavailability.

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 ANTI-HIV AGENTS
• Entry (fusion) inhibitor: Enfuvirtide
• This HIV-derived synthetic peptide acts by binding to HIV-
1 envelope transmembrane glycoprotein (gp41) which is
involved in fusion of viral and cellular membranes.

• Fusion of the two membranes is thus prevented and entry

of the virus into the cell is blocked.

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 ANTI-HIV AGENTS
• Entry (fusion) inhibitor: Enfuvirtide
• It is not active against HIV-2.
• No cross resistance with other classes of ARV drugs occurs.
• Administered s.c. twice daily, it is used as add on drug to
an optimized regimen in selected patients who have failed
many earlier regimens and for whom there is no other
treatment option.
• The injections are painful and cause local nodules/cysts.
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 ANTI-HIV AGENTS
• Maraviroc.
• The globular glycoprotein gp120 of the HIV envelope
anchors to the CD4 site of host cell by binding to a cell
membrane receptor, which mostly is the CCR5
chemokine receptor.
• Maraviroc is a novel anti-HIV drug which targets the
host cell CCR5 receptor and blocks it. Attachment of the
virus and subsequent entry of viral genome into the cell
is thus interfered
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 ANTI-HIV AGENTS
• Maraviroc.

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 ANTI-HIV AGENTS
• Maraviroc.
• It is active orally and there is no cross resistance with
any other ARV drug.
• Though a number of side effects are reported,
tolerability in general is satisfactory.
• Since it blocks one of the human chemokine receptor,
there is concern about impaired immune surveillance
and increased risk of infection/malignancy

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 ANTI-HIV AGENTS
• Integrase inhibitor: Raltegravir:
• The HIV-proviral DNA transcripted in the cytoplasm of
host cell translocates to the nucleus along with an integrase
enzyme. The HIV-integrase nicks host chromosomal DNA
and integrates the proviral DNA with it.
• Raltegravir is an orally active drug that blocks this step by
inhibiting the integrase enzyme.
• It is active against both HIV-1 and HIV-2.

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 ANTI-HIV AGENTS
• Integrase inhibitor: Raltegravir:
• Because of its unique mechanism of action, there is no
cross resistance between it and any other ARV drug

• It has shown good efficacy as a component of initial triple

drug regimen along with two NRTIs.

• Side effects are nonspecific; myopathy is a potential

toxicity. It is otherwise well tolerated 33
 HERPES VIRUS

• The herpes simplex virus, also known as HSV, is an infection that

causes herpes.
• Herpes can appear in various parts of the body, most commonly on the
genitals or mouth.
• There are two types of the herpes simplex virus. HSV-1, also known as
oral herpes, can cause cold sores and fever blisters around the mouth
and on the face.
• HSV-2 is generally responsible for genital herpes outbreaks.

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 ANTI-HERPES DRUGS

• Acyclovir / Valacyclovir
• Famciclovir / Penciclovir
• Ganciclovir / Cidofovir
• Foscarnet
• Idoxuridine

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 ANTI-HERPES DRUGS

Acyclovir & Congeners :

• Valacyclovir is an ester prodrug of Acyclovir with better bioavailability.
• Famciclovir is hydrolyzed to Penciclovir and has greatest
bioavailability.
• Penciclovir is used only topically whereas Famciclovir can be
administered orally.
• Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are
guanine nucleoside analogs.

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ANTI-HERPES DRUGS

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 ANTI-HERPES DRUGS

• Acyclovir is thus selectively activated in cells infected with herpes virus.

• Uninfected cells do not phosphorylate acyclovir.
Pharmacokinetics of Acyclovir :
• Oral bioavailability ~ 20-30%
• Distribution in all body tissues including CNS
• Renal excretion: > 80%
• Half lives: 2-5 hours
• Administration: Topical, Oral , IV

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 ANTI-HERPES DRUGS

PHARMACOLOGY OF FOSCARNET
•Foscarnet is an inorganic pyrophosphate analog  
•It directly inhibits viral DNA and RNA -polymerase
and viral reverse transcriptase (it does not require
phosphorylation for antiviral activity)
•HSV-1, HSV-2, VZV(Varicella Zoster Virus),
CMV(Cytomegalovirus) and HIV.
•Oral bioavailability ~ 10-20%
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•Distribution to all tissues including CNS
•
 ANTI-HERPES DRUGS

Therapeutic uses of Foscarnet

• It is an alternative drug for
• HSV infections (acyclovir resistant /
immunocompromised patient )
• CMV retinitis (ganciclovir resistant /
immunocompromised patient )
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 ANTI-HERPES DRUGS
• Idoxuridine:5-iodo-2-deoxyuridine(IUDR)
• First pyrimidine antimetabolite to be used as antiviral drug
• Competes with thymidine gets incorporated in DNA so that
faulty DNA is formed which breaks down easily
• Low virus selectivity and higher local toxicity.
• Trifluridine and vidarabine are other pyrimidine
antimetabolites effective against H.simplex

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 ANTI-INFLUENZA AGENTS
Amantadine and Rimantadine
• Prevention & Treatment of influenza A
• Inhibition of viral uncoating by inhibiting the viral
membrane protein M2
• It also acts on late step i.e viral assembly in viral replication.
• Amantadine has anti-parkinsonian effects
Pharmacokinetics
• Oral bioavailability ~ 50-90%
• Amantadine cross extensively BBB whereas Rimantadine does
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not cross extensively .
• Administration: Oral
ANTI-INFLUENZA AGENTS

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 ANTI-INFLUENZA AGENTS

Neuraminidase inhibitors : Oseltamivir / Zanamavir

• Influenza contains an enzyme neuraminidase which is
essential for the replication of the virus.
• Neuraminidase inhibitors prevent the release of new
virions and their spread from cell to cell.
• These are effective against both types of influenza A and
B.
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