ANTIVIRAL DRUGS

What is a Virus?

• It is an obligate intracellular parasite that makes

use of host’s genetic machinery to produced new
virus particles
• is an infectious microbe consisting of a
segment of nucleic acid (either DNA or
RNA) surrounded by a protein coat.
ANTIVIRAL DRUGS
• an agent effective against viruses
• an agent that maybe useful in early stages of some virus infections or
to prevent recurrences or reactivation in chronic infections
• Constraints in using:
• the number of infectious particles per cell, or multiplicity w/c can
determine if an antiviral agent have a therapeutic or prophylactic
effect.
• most antiviral agents have less efficacy against a large number of
infectious particles, whereas they have greater effect against fewer
infectious particles. Thus, antiviral agents have limited efficacy when
the disease is symptomatic
• Concomitant toxicity to mammalian cells and the virus
Structure, Classification and Replicative Cycles of Viruses

Two general types of Viruses:

• Deoxyribonucleic acid (DNA). -double stranded in animal DNA viruses
• Ribonucleic acid (RNA) -single stranded in animal RNA viruses

Phases of Viral Replication:

• Absorption
• Penetration and Uncoating
• Synthesis
• Assembly
• Release
DNA viruses
• -usually replicate by causing transcription of the genome to specific viral messenger
RNA (mRNA), w/c is subsequently translated using host cell mechanisms into virus-
related proteins.
Small positive-stranded RNA viruses
• -use their genome as mRNA for translation and virus-related protein synthesis
Larger negative-stranded RNA viruses
• -contain an anticoded genome and must be transcribed into a positive strand for
translation
• -usually contain a virus-specific replicase for the initial transcription
Retroviriade
• -unique, requiring a virus-specific reverse transcriptase to produce a DNA
intermediate form w/c progeny RNA and specific mRNA are produced.
Replicative cycle for a positive-stranded RNA:
1. Attachment: the virus particle attaches to the host cell membrane.
2. Viropexis: the virus penetrates the cell membrane.
3. Uncoating: the protein coat of the virus opens and the viral nucleic acid
is released in the host cell cytoplasm
4. Translation: polyribosomes form after viral RNA attaches to ribosomes
and begins to translate the nucleic acid sequence into proteins
5. Complementary strand formation: the RNA-dependent and RNA-
polymerase combines with a strand of input viral RNA to synthesize a
complementary strand to the input RNA
Replicative cycle for a positive-stranded RNA:
6. Replicative form: the double stranded form of the complementary strand
serves as a template for viral RNA production
7. Transcription: a new single stranded RNA is produced by two RNA
polymerases. The new single stranded RNA can serves as a message for a
protein synthesis or as a template for production of more RNA, or it may
become incorporated into mature virus
8. Assembly: the new RNA and structural protein combined or are
assembled into a mature virus, w/c is released from the cell
VIRAL REPLICATION REQUIREMENTS
 CLASSIFICATION OF ANTIVIRAL DRUGS
• ENTRY SITE DRUGS-

• TRANSCRIPTION DRUGS

• ASSEMBLY DRUGS

• HOST RESISTANCE DRUGS

I.Entry Site Drugs
• Attachment and penetration of virus into the host cell often
requires the specific interaction of viral coat proteins w/
receptor proteins of the host cell membrane

• Analog viral binding proteins can bind host cell receptor

proteins thereby competing with actual viral particle from
binding
I. Entry Site Drugs
Amantadine hydrochloride
• -prevents penetration and uncoating of several RNA membrane viruses in cell
culture (e.g. Myxoviruses, Paramyxoviruses, and Togaviruses)
• -absorbs slowly but quite efficiently
• -had a half life of 15 hours
• -drug is recovered in urine following oral administration
• -appears to have its great potential as a chemoprophylactic agent against sensitive
strains of influenza virus
II. Transcription Analog Drugs
Idoxuridine
• -most extensively tested halogenated pyrimidine nucleoside
• -its preparation includes .5% ophthalmic ointment and .1% ophthalmic solution
• -its major use has been in human herpes simplex keratitis
• -has the ability to incorporate bogus DNA and it also inhibits synthesis synthesis of DNA
• -cell cultured- effective against herpesvirus and poxvirus

• Toxicity:
• -noted most in cells having a rapid turnover (e.g. mucosal, epidermal, and cellular components
of blood)
III. Transcription: Synthesis DNA Drugs
A. Acyclovir
• -has antiviral activity against herpes virus
• -effective against herpes simplex virus types I and II
• -in vitro- is more than 100 times more active than vidarabine and 10 times
more active than idoxuridine against herpes simplex virus type I
• -wide margin of safety for an antiviral drug
• -300-3000 times more toxic for herpesvirus that for mammalian cells
III. Transcription: Synthesis DNA Drugs
IV Administration -5mg/kg
• -produce peak concentration of 10µg acyclovir/ml plasma
• -value declined to 0.7µg/ml at 8hours in human studies
• -had a half life of 2.5 hours
• -eliminated in the urine via glomerular filtration and tubular secretion
Acyclovir Na (Zovirax)
• -available as 200mg capsules
• -20% is bioavailable after oral administration
• -5% ophthalmic ointment and powder is also available
III. Transcription: Synthesis DNA Drugs
B. Cytarabine
• -analog for cytosine deoxyribose
• -had an activity against herpesvirus, poxvirus, vaccinia
and rabies
• -topical activity against herpesvirus hominis and
vaccinia keratitis
• -systemic antiviral activity is not established
III. Transcription: Synthesis DNA Drugs
C. Vidarabine
• -have adenine instead of cytosine
• - phosphorylated to nucleotides and inhibit viral DNA polymerase
• - mammalian DNA synthesis is also inhibited but to a lesser degree
• -active in in vitro against vaccinia viruses, herpes simplex virus, cytomegalovirus and
varicella zoster virus
• -available as a suspension for injection at 200 mg/ml and as a 3% ophthalmic
ointment
• - effective as idoxuridine against herpes simplex keratoconjunctivitis but less
irritating.
IV. Translation Drug
Methisazone
• Considered the best antiviral candidate of the N –
substituted analogs of isatin
• - antiviral activity in cell culture against poxvirus and
adenoviruses
• Active also against mouse encephalitis caused by vaccinia
and variola major viruses
• Can be given orally becauseof its low solubility
• Little is know about pharmacokinetic or efficacy as
chemotherapeutic agent
V. Protein Synthesis Drugs
• Inhibit the synthesis of both viral and host cellular
proteins
• Thus, toxicity limits their therapeutic value.
VI. Maturation Drug
• Composed of some antibiotic with antiviral activity
and glucose analogs
• Potential for future use in animal viral disease i.e
ortho, paramyxo, and herpes viruses
VII. Host Resistance
A. Interferon
• Proteinaceous substance released from mammalian cells with
the ability to cause other cells to resist a viral infection
• Important part of natural defense mechanism
• Antiviral activity is related to production of a second protein
• Either inhibits activity of RNA dependent polymerase brought
into the cell by a virus or attenuates ribosomes so they cannot
read viral RNA
• Phylogenetically related and species specify in its ability to
protect cell from RNA and DNA viruses.
VII. Host Resistance
B. Gamma Globulin
• -concentrated solution of antibodies extracted fro
normal blood
• -Effective for preventing various viral infection in
humans ( eg. Infectious hepatitis,measles,
Poliomyelitis, chicken pox)
• - also use as anjunctive treatment for bacterial
infection that do not respond well to antibacterial
therapy.
VII. Host Resistance
C. Host Modulators
• -group of drugs is composed of poly I – poly C, levamisole, inosiplex,
stimulating substances in vaccines
• - poly I – poly C is a commonly drugs of this group

Polyriboinosinic acid – polyribocytidilic

• Important inducer in interferon
• Will protect culture cells from a viral challenge
• In larger amounts it will both protect cells and cause release of
interferon
• Poly I – poly C related to a rapid increase in interferon concentrations
and protective effect against local or systemic viral infection when
administered topically or syste
 Dosages of Antiviral Drugs
Drug Preparation Dose, Route, and Frequency Indication
Idoxuridine 0.1% ophthalmic solution 1 drop, topical, every 5–6 hr
0.5% ophthalmic solution 1 drop, topical, every 1–2 hr

1 drop, topical, every 2 hr initially (2 days), then 3–8 Ocular herpesvirus

Trifluridine 1% ophthalmic solution
times daily infection

0.4–1 cm ointment, topical, every 5–6 hr; 3–6 times Ocular herpesvirus
Vidarabine 3% ophthalmic solution
daily infection
200 mg/mL suspension for
10–30 mg/kg/day, IV, as CRI for 12–24 hr
injection

Acyclovir 200-mg capsules or tablets 200 mg, PO, qid, every 4 hr, or 5 times daily Feline herpesvirus

5% cutaneous ointment Cover lesion, topical, every 3 hr, 6 times daily

80 mg/kg/day (mixed with peanut butter), PO, for 7–

200 mg/5 mL suspension Pacheco’s disease in birds
14 days

500 mg/vial powder 250–500 mg/m2, IV, tid, infused over at least 1 hr

Ganciclovir 500 mg/vial powder 2–5 mg/kg, IV, bid-tid

Susceptible viral
Ribavirin 11 mg/kg/day, IV, for 7 days
infections
Ribavirin 11 mg/kg/day, IV, for 7 days Susceptible viral infections

Using SPAC-2 nebulizer only, inhalation, 8–

6 g/100 mL vial powder
18 hr period daily

10 mg/mL syrup; 10 mg/mL

Zidovudine 5–20 mg/kg (cats), PO or SC, bid-tid FIV, FeLV
injection

100 mg total (human), PO, once to twice

Amantadine 100- and 500-mg capsules
daily

Syrup 10 mg/mL 100 mg/day total (juveniles), PO

Rimantadine 200–300 mg/day total (human), PO

3 × 106 IU/person/day, SC, IM; 0.5–5

Interferon α-2 3 × 106 IU/vial FeLV-associated disease
U/kg/day, PO; 100,000 U/kg/day, SC

1 U/day, PO FeLV appetite stimulant

15–30 U, PO, IM, SC, once daily on alternate

FIP, FIV
weeks

CRI = constant-rate infusion; FeLV = feline leukemia virus; FIP = feline infectious peritonitis; FIV = feline immunodeficiency virus
 AGENTS TO TX HSV (HERPES SIMPLEX VIRUS ) AND VZV (VARICELLA-
ZOSTER VIRUS) INFECTIONS
• ACYCLOVIR
• is most extensively studied, acyclic guanosine derivative
• oral form bioavailability is15-20%,
• IV form is available
• PO – shorten the duration of symptoms in 1st episodes of genital herpes
• IV – tx for herpes simplex encephalitis, neonatal HSV infection and
serious HSV or VZV infection
• Topical –less effective
• VALACYCLOVIR
• L-valyl ester of acyclovir
• Oral bioavailability is 54 – 70%, elimination half life is 2.5-3.3 hrs
• Tx for 1st or recurret genital herpes,suppression of frequently recurring
genital herpes,1 day tx for orolabial herpes, tx for varicell and herpes
zoster
• FAMICYCLOVIR
• diacetyl ester prodrug of 6 deoxypenciclovir, an acyclic guanosine
analog
• PO –tx of first and recurrent genital herpes, for chronic daily suppression
of genital herpes,tx for herpes labialis & tx for acute zoster
Other Anti-herpes agents
A.PENCICLOVIR
• Active metabolite of famciclovit, used as topicl
• Penciclovir cream shortens theduration of recurrent herpes labialis
and genitalis
B.DOCONASOL-used as topical cream

C.TRIFLURIDINE-used in tx of acyclovir resistant HSV

****VALOMACICLOVIR – under study/clinocal evaluation tx of acute

VZV(shingles) infection and acute EBV(infectious mononucleosis)
 AGENTS FOR TX OF CMV (CYTOMEGALOVIRUS)
• GANCICLOVIR

• VALGANCICLOVIR

• FOSCARNET

• CIDOFOVIR
 ANTIRETROVIRAL AGENTS
1.NUCLEOSIDE & NUCLEOTIDE REVERSE TRANSCRIPTASE
INHIBITORS
Abacavir,Didanosine,Emtricitabine,lamivudine,Stavudine,Te
nofovir,
Zalcitabine,Zidovudine

2.NONNUCLEOSIDE REVERSE TRANSCRIPTERASE INHIBITORS

Delaviridine,Efavirenz,Etravirine,Nevirapine

3.PROTEASE INHIBITORS

Atazanavir,Fosamprenavir,Indinavir,Lopinavir,Nelfinavir,Ritonavir,S
aquinavir,Tipranavir
 ANTERETROVIRAL AGENTS
• 4.ENTRY INHIBITORS
Enfuvirtide,Mariviroc

• 5.INTEGRASE STRAND TRANSFER INHIBITORS

Raltegravir
 ANTIHEPATITIS AGENTS
• 1.INTERFERON ALFA

A.FOR HEPATITIS B VIRUS INFECTION

Adefovir Dipivoxil,Entecavir,Lamivudine,Telbivudine,Tenofovir

B.FOR HEPATITIS C VIRUS INFECTION

Pegylated interferon alfa combined with ribavirin
 Anti influenza Agents
• Oseltamiir & Zanamivir

• Amantadine & rimantadine

Other antiviral agents
• Interferons

• Palivizumab

• Imiquimod