ANTIVIRAL

DRUGS
(NONRETROVIRAL)

B.Dian Novita, dr., MKed.

diannovitakrisdianto@yahoo.co.id
Antiviral drugs

 Viruses have no cell wall and made up of nucleic acid

components
 Viruses containing envelope – antigenic in nature
 Viruses are obligate intracellular parasite
 They do not have a metabolic machinery of their own
– uses host enzymes
 Certain viruses multiply in the cytoplasm but others
do in the nucleus
 Most multiplication take place before diagnosis made
The major site of
Antiviral drug action
Antiviral drugs

 Many antiviral drugs are Purine/Pyrimidine analog

 Many antiviral drugs are Prodrugs. They must be
phosphorylated by viral or cellular enzymes in
order to become active.
 Anti-viral agents inhibits active replication so the
viral growth resumes after drug removal
Anti-viral drugs

 Current anti-viral agents do not eliminate

non-replicating or latent virus
 Effective host immune response remains
essential for the recovery from the viral
infection
 Clinical efficacy depends on achieving
inhibitory conc. at the site of infection within
the infected cells
 Stages of viral replication

 Cell entry – attachment

- penetration
 Uncoating
 Transcription of viral genome
 Translation
 Assembly of virion components
 Release
Stages of Virus Replication and Possible
Targets of Action of Antiviral Agents (1)
Stages of Virus Replication and Possible
Targets of Action of Antiviral Agents (2)
Stages of Virus Replication and Possible
Targets of Action of Antiviral Agents (3)
Nomenclature of Antiviral Agents (1)
Nomenclature of Antiviral Agents (2)
Agents to treat
HSV & VZV

 Acyclovir / Valacyclovir
 Famciclovir /
Penciclovir
 Ganciclovir / Cidofovir
 Foscarnet
 Trifluridine /
Idoxuridine /
Vidarabine
Phosphorylate Acyclovir

Acyclovir triphosphate
Acyclovir & Congeners :

 guanine nucleoside analogs

 Acyclovir distributes widely in body fluids (vesicular
fluid, aqueous humor & CSF
 Valacyclovir is a prodrug (substrate for intestinal &
renal peptide transporters) of Acyclovir with better
bioavailability
 Famciclovir is diacetyl ester prodrug of Penciclovir and
has greatest bioavailability
 Penciclovir is used only topically whereas Famciclovir
can be administered orally
Mechanism of action of Acyclovir
and congeners :

 All drugs are phosphorylated by a viral

thymidine-kinase, then metabolized by host cell
kinases to nucleotide analogs.
 The analog inhibits viral DNA-polymerase
 Only actively replicating viruses are inhibited
 Acyclovir is thus selectively activated in cells
infected with herpes virus
 Uninfected cells do not phosphorylate acyclovir
Antiviral spectrum :

 Acyclovir: HSV-1, HSV-2, VZV, Shingles.

 Ganciclovir / Cidofovir : CMV
 Famciclovir : Herpes genitalis
 Foscarnet : HSV, VZV, CMV, HIV
 Penciclovir : Herpes labialis
 Trifluridine : Herpetic keratoconjunctivitis
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
GANCICLOVIR & VANGANCICLOVIR

 an acyclic guanine nucleoside analog that

inhibits viral DNA synthesis
 Valganciclovir is the L-valyl ester prodrug of
ganciclovir
 against all herpesviruses, especially CMV
 Use for retinitis in immunocompromised
patients & for prevention of CMV disease in
transplant patients
Adverse effects of Acyclovir &
Ganciclovir

 Nausea, vomiting and diarrhea

 Nephrotoxicity - crystalluria, haematuria,
renal insufficiency
 Testicular toxicity
 Myelosuppression – Neutropenia and
thrombocytopenia – Ganciclovir
FOSCARNET …1

PHARMACOLOGY OF FOSCARNET
 Foscarnet is an inorganic pyrophosphate
analog
 It directly inhibits viral DNA and RNA -
polymerase and viral inverse transcriptase
(it does not require phosphorylation for
antiviral activity)
FOSCARNET …2

 HSV-1, HSV-2, VZV, CMV and HIV.

 Oral bioavailability ~ 10-20%
 Distribution to all tissues including CNS
 Administration: IV

Adverse effects of Foscarnet

 Hypocalcemia and hypomagnesemia (due to chelation of
the drug with divalent cations) are common.
 Neurotoxicity (headache, hallucinations, seizures)
 Nephrotoxicity (acute tubular nephrosis, interstitial
nephritis)
FOSCARNET …3

Therapeutic uses of Foscarnet

 It is an alternative drug for
 HSV infections (acyclovir resistant /
immunocompromised patient )
 CMV retinitis (ganciclovir resistant /
immunocompromised patient )
Therapeutic uses :

Acyclovir is the drug of choice for:

 HSV Genital infections
 HSV encephalitis
 HSV infections in immuno-compromised patient

Ganciclovir is the drug of choice for:

 CMV retinitis in immunocompromised patient
 Prevention of CMV disease in transplant patients
VIDARABINE …1

PHARMACOLOGY OF VIDARABINE
 Vidarabine is a nucleoside analog.
(adenosine)
Antiviral spectrum of Vidarabine :
HSV-1, HSV-2 and VZV.
Its use is limited to HSV keratitis only
VIDARABINE …2

 The drug is converted to its triphosphate

analog which inhibits viral DNA-polymerase.
 Oral bioavailability ~ 2%
 Administration: Ophthalmic ointment
 Used in HSV keratoconjunctivitis in
immunocompromised patient.
 Anemia and SIADH are adverse effects.
TRIFLURIDINE

PHARMACOLOGY OF TRIFLURIDINE
 Trifluridine is a Pyrimidine nucleoside analogs
- inhibits viral DNA synthesis.
Antiviral spectrum Trifluridine :
 HSV-1, HSV-2 and VZV.
 Use is limited to Topical - Ocular HSV
Keratitis
Respiratory viral infections

Influenza –
 Amantadine / Rimantadine
 Oseltamivir / Zanamavir
(Neuraminidase inhibitors)
RSV bronchiolitis –
 Ribavirin
Amantadine and Rimantadine :
Influenza

 Prevention & Treatment of influenza A

 Inhibition of viral uncoating by inhibiting
the viral membrane protein M2
 Influenza A virus
 Amantadine has anti-parkinsonian effects.
Amantadine

Pharmacokinetics of Amantadine
 Oral bioavailability ~ 50-90%
 Amantadine cross extensively BBB whereas
Rimantadine does not cross extensively .
 Administration: Oral
Oseltamivir / Zanamavir …1

Neuraminidase inhibitors : Influenza

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.
Oseltamivir / Zanamavir …2

 These are effective against both types of

influenza A and B.
 Do not interfere with immune response to
influenza A vaccine.
 Can be used for both prophylaxis and acute
treatment
 Oseltamivir is orally administered.
 Zanamavir is given intranasal.
 Risk of bronchospasm with zanamavir
Anti-viral drugs
RIBAVIRIN …1

PHARMACOLOGY OF RIBAVIRIN
 Ribavirin is a guanosine analog.
 Inhibition of RNA polymerase
Antiviral spectrum : DNA and RNA viruses
are susceptible, including influenza,
parainfluenza viruses, RSV, Lassa virus
RIBAVIRIN …2

Ribavirin : RSV
 Distribution in all body tissues, except CNS
 Administration : Oral, IV, Inhalatory in RSV.
 Anemia and jaundice are adverse effects
 Not advised in pregnancy.
RIBAVIRIN …3

Therapeutic uses Ribavirin

Ribavirin is the drug of choice for:
 RSV bronchiolitis and pneumonia in
hospitalized children (given by aerosol)
 Lassa fever
Ribavirin is an alternative drug for:
 Influenza, parainfluenza, measles virus
infection in immunocompromised patients
Hepatic Viral infections :

 Interferons
 Lamivudine – cytosine analog – HBV
 Entecavir – guanosine analog – HBV –
lamivudine resistance strains
 Ribavirin – Hepatitis C (with interferons)
INTERFERONS …1

Interferons (IFNs) are natural proteins

produced by the cells of the immune systems
in response to challenges by foreign agents
such as viruses, bacteria, parasites and tumor
cells.
 Antiviral, immune modulating and
anti-proliferative actions
 Three classes of interferons – α , β, γ
INTERFERONS …2

 α and β interferons are produced by all the

cells in response to viral infections
 γ interferons are produced only by T
lymphocyte and NK cells in response to
cytokines – immune regulating effects
 γ has less anti-viral activity compared to α
and β interferons
INTERFERONS …3
Mechanism of action of Interferons :
 Induction of the following enzymes:
1) a protein kinase which inhibits protein
synthesis
2) an oligo-adenylate synthase which leads to
degradation of viral mRNA
3) a phosphodiesterase which inhibit t-RNA
The action of these enzymes leads to an
inhibition of translation
INTERFERONS …4

Antiviral spectrum : Interferon α

 Includes HBV, HCV and HPV.
 Anti-proliferative actions may inhibit the
growth of certain cancers - like Kaposi
sarcoma and hairy cell leukemia.
INTERFERONS …5

Pharmacokinetics : Interferons
 Oral bioavailability: < 1%
 Administered Intralesionally, S.C, and I.V
 Distribution in all body tissues, except CNS
and eye.
 Half lives: 1-4 hours
INTERFERONS …6

Adverse effects of Interferons

 Acute flu-like syndrome (fever, headache)
 Bone marrow suppression (granulocytopenia,
thrombocytopenia)
 Neurotoxicity (confusion, seizures)
 Cardiotoxicity - arrhythmia
 Impairment of fertility
 INTERFERONS …7
Therapeutic uses Interferons
 Chronic hepatitis B and C (complete disappearance is
seen in 30%).
 HZV infection in cancer patients (to prevent the
dissemination of the infection)
 CMV infections in renal transplant patients
 Condylomata acuminata (given by intralesional
injection). Complete clearance is seen ~ 50%.
 Hairy cell leukemia (in combination with
zidovudine)
 AIDS related Kaposi’s sarcoma
Antiretroviral
Therapy
Principles of HIV Chemotherapy

 direct toxic effects of HIV on host cells, mainly

CD4+ T-lymphocytes
 associated with long-term suppression of HIV
replication (as measured by decreased plasma
HIV RNA) & repletion of peripheral CD4 cells
 goal of therapy is to suppress virus replication
as much as possible for as long as possible
Nucleoside and Nucleotide
Reverse Transcriptase Inhibitors
Pharmacokinetic Properties of
Nucleoside Reverse Transcriptase
Inhibitors
ZIDOVUDINE

 a synthetic thymidine analog

 potent in vitro activity against a broad spectrum of
retroviruses including HIV-1, HIV-2, and human T-
cell lymphotrophic viruses (HTLV) I and II
 active in lymphoblastic and monocytic cell lines,
less active in chronically infected cells
 has no impact on cells already infected with HIV
 the drug is more potent in activated than in resting
lymphocytes
STAVUDINE

 a synthetic thymidine analog reverse

transcriptase inhibitor
 active in vitro against HIV-1 and HIV-2
 use in HIV-infected adults and children,
including neonates
 Lamivudine improves the long-term virologic
response to stavudine
LAMIVUDINE

 a cytidine analog reverse transcriptase

inhibitor that is active against HIV-1, HIV-2,
and H
 one of the least toxic antiretroviral drugs and
has few significant adverse effects
 approved for HIV in adults and children ≥3
months of age
 Drug(s) of Alternative
Virus Diseases drugs
choice
Inf. Rimantadine
Influenza Amantadine
A
Pneumonia, Ribavirin
RSV
bronchiolitis (aerosol)

HSV Genital herpes Acyclovir Foscarnet

Keratitis Idoxuridine
Trifluridine
Conjunctivitis Vidarabine
Encephalitis Acyclovir
Neonatal HSV
Acyclovir Vidarabine
infection
Herpes infections in
immuno- Acyclovir Foscarnet
compromised host
 In normal host No therapy
VZV
In immunocompro-
mised host, or during Acyclovir Foscarnet
pregnancy

CMV Retinitis Ganciclovir Foscarnet

AIDS Zidovudine ± Didanosine,

HIV
HIV antibody protease Stavudine
positive with CD4 inhibitors
count < 500/mm3

HBV Hepatitis B, C Interferons

HCV
THANK YOU