2. Overveiw :
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Antiviral Drugs 2
Introduction
Types of viruses
Replicative cycle of virus
Classification of drugs
Individual drugs
Summary
3. Introduction :
◦ Virus is ultramicroscopic infectious parasite
◦ Consist of core genome of nucleic acid ( DNA or RNA), contained in
a protein shell (capsid) & this is surrounded by lipoprotein membrane
(envelope) – “Virion”
◦ Obligate parasites & are inactive outside the host cell
◦ Theses host cells may be mammals, insect or bacteria
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Antiviral Drugs 3
8. 16-Jul-21
Antiviral Drugs 8
Classification of Antiviral drugs :
(Therapeutic)
Anti-Herpes
virus drugs
ldoxuridine
Trifluridine
Acyclovir
Val acyclovir
Famciclovir
Ganciclovir
Valganciclovir
Cidofovir
Foscarnet
Anti-Influenza
virus drugs
Amantadine
Rimantadine
Oseltamivir
Zanamivir
Peramivir
Anti-Hepatitis virus
drugs
For Hepatitis B
Lamivudine
Entecavir
Adefovir
dipivoxil
Tenofovir
Telbivudine
For Hepatitis C
Ribavirin
Interferon α
Sofosbuvir
Simeprevir
Daclatasvir
Ledipasvir
Velpatasvir
9. Anti-Herpes virus drugs
Acyclovir –
An acyclic guanosine derivative
10 times more potent against HSV-1 & HSV-2 than VZV
converted first to the monophosphate derivative- virus specified thymidine
kinase & di- and triphosphate compounds - host cell enzymes
Oral bioavailability is low (15–20%) & is unaffected by food
Cleared through kidney & t1/2 is 2.5–3 hours
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10. Anti-Herpes virus drugs contd..
Uses :
◦ Intravenous acyclovir - treatment of choice for herpes simplex encephalitis,
neonatal HSV infection, and serious HSV or VZV infections
◦ Topical acyclovir cream is less effective than oral therapy for primary HSV
infection
◦ Neonates - oral acyclovir suppression for 6 months following acute treatment
improves neurodevelopmental outcomes
◦ In immunocompromised patients with VZV infection, IV acyclovir reduces the
incidence of cutaneous and visceral dissemination
◦ Resistance to acyclovir can develop in HSV or VZV through alteration in either
the viral thymidine kinase or the DNA polymerase
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Antiviral Drugs 10
Acyclovir –
11. Anti-Herpes virus drugs contd..
Adverse effects :
◦ Oral: drug is well tolerated but headache, nausea, malaise
◦ Intravenous:
Rashe , sweating, emesis and fall in BP occur
Dose-dependent decrease in g. f.r. is the most important toxicity
Reversible neurological manifestations (tremors, lethargy, disorientation,
hallucinations, convulsions and coma)
Not teratogenic
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Acyclovir –
12. Valacyclovir
◦ L-valyl ester of acyclovir
◦ Rapidly converted to acyclovir after first-
pass metabolism resulting in serum levels
that are 3-5 times greater than oral &
intravenous acyclovir
◦ Oral bioavailability is 54–70%
◦ Elimination half-life 2.5–3.3 hours
◦ Drug of choice in herpes zoster
Famciclovir
◦ Ester prodrug of penciclovir
◦ Needs viral thymidine kinase but does not
cause chain termination
◦ Penciclovir triphosphate has lower affinity but
achieves higher intracellular concentrations
◦ Bioavailability - 70%
◦ The intracellular half-life 7–20 hours
◦ Excreted in the urine
◦ Active against HSV-1, HSV-2, VZV, EBV, HBV
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Anti-Herpes virus drugs contd..
13. Anti-Herpes virus drugs contd..
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Antiviral Drugs 13
Agent Treatment of First
Episode
Treatment of Recurrent Episodes Suppression
Genital Herpes
Acyclovir, oral1 400 mg tid × 7–10 days
or 200 mg 5 times daily
800 mg tid × 2 days or 800 mg bid × 5
days
or 400 mg tid × 5 days
400–800 mg bid-tid
Famciclovir, oral 250 mg tid × 7–10 days 1000 mg bid × 1 day or 125 mg bid × 5
days
or 500 mg once then 250 mg bid × 2
days
250–500 mg bid
Valacyclovir, oral 1000 mg bid × 10 days 500 mg bid × 3 days or 1 g qd × 5 days 500–1000 mg qd–bid
Orolabial herpes
Acyclovir, oral 400 mg tid × 7–10 days
or 200 mg 5 times daily
200–400 mg 5 times daily × 5 days 400–800 mg bid–tid
Famciclovir, oral 500 mg tid × 7–10 days 1500 mg once or 750 mg bid 500 mg bid
Valacyclovir oral 1 g bid × 7–10 days 2 g bid × 1 day 500–1000 mg qd
Acyclovir topical (5% cream) 5 times daily . 4 days
Docosanol, topical (10% cream) 5 times daily
Penciclovir, topical (1% cream) Every 2 h while awake
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Antiviral Drugs 14
Severe HSV infection or
HSV infection in the
immunocompromised host
Acyclovir, IV 5–10 mg/kg q8h × 7–14 days
Herpes encephalitis Acyclovir, IV 10–15 mg/kg q8h × 21 days
Neonatal HSV infection Acyclovir, IV 10–20 mg/kg q8h × 14–21 days
Herpetic
keratoconjunctivitis
Ganciclovir(0.15% gel) 5 times daily
Trifluridine (1% solution) Every 2 hr
Varicella infection Acyclovir, oral 20 mg/kg (maximum 800 mg) qid × 5
days
Valacyclovir, oral 20 mg/kg (maximum, 1 g) tid × 5 days
Zoster infection Acyclovir, oral 800 mg 5 times daily × 7–10 days
Famciclovir, oral 500 mg tid × 7 days
Valacyclovir, oral 1 g tid × 7 days
Severe VZV infection or
VZV infection in the
immunocompromised host
Acyclovir, IV 10–15 mg/kg q8h × ≥7 days
Acyclovir-resistant HSV
or VZV infection
Foscarnet, IV 40–60 mg/kg q8h until healed
15. ◦ CMV infections occur in immunosuppression and are typically due to
reactivation of latent infection
◦ Dissemination of infection results in end-organ disease- retinitis, colitis,
esophagitis, central nervous system disease and pneumonitis
◦ Oral valganciclovir has decreased the use of IV ganciclovir, foscarnet &
cidofovir for the prophylaxis and treatment of end-organ CMV disease
◦ Oral valganciclovir has replaced oral ganciclovir
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Anti-cytomegalovirus drugs
16. ◦ Ganciclovir -
◦ analogue of guanosine
◦ virus specific thymidine kinase
◦ higher concentration inside CMV infected
cells is t½ > 24 hrs
◦ bioavailability - < 10%
◦ Mutation- same
◦ Used for prophylaxis and treatment of severe
CMV infections (pneumonia/colitis/retinitis)
in immunocompromised
◦ bone marrow depression, rash, fever,
vomiting, neuropsychic disturbances
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Anti-cytomegalovirus drugs
◦ Valganciclovir –
◦ valyl prodrug of ganciclovir
◦ Oral bioavailablility 60%
◦ Oral valganciclovir is equally effective as
i.v. ganciclovir
◦ Use –
◦ long term suppressive therapy of CMV
retinitis
◦ prophylaxis in transplant/
immunosuppressed patients
◦ Adverse effects- similar to ganciclovir
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Antiviral Drugs 17
Anti-cytomegalovirus drugs
◦ Cidofovir-
◦ analogue of cytidine
◦ does not require viral phosphokinase
◦ remains intracellularly for long periods so
weekly therapy
◦ i. v. infusion with pre and post dose oral
probenecid
◦ Uses-
CMV retinitis in AIDS patients
for acyclovir-resistant mucocutaneous herpes
simplex in immunosuppressed patients
Topically for anogenital “wart”
◦ Foscarnet -
◦ inhibits viral DNA polymerase by blocking
pyrophosphate binding site
◦ Oral absorption – poor, t½ is 4- 8 hr
◦ acyclovir-resistant H. simplex, ganciclovir-
resistant CMV retinitis and other CMV
infections
◦ damages kidney, electrolyte imbalance,
anaemia, phlebitis, tremor, convulsions &
neurological
19. Influenza virus are classified by their core proteins A,B,C species
Influenza A causes pandemics, is classified into 16 H (hemagglutinin) and 9
N (neuraminidase) subtypes based on surface proteins
Subtypes circulating among worldwide H1N1, H1N2, and H3N2
H5N1, H7N9 subtypes rapidly mutate
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Antiviral Drugs 20
Anti-influenza virus drugs
• Oseltamivir
• Zanamivir
• Peramivir
Neuraminidas
e inhibitors
• Amantadine
• Rimantadine
Adamantanes
20. Oseltamivir and Zanamivir – (analogs of sialic acid)
◦ Neuraminidase inhibitors active against both influenza A and B virus
◦ Competitively & reversibly interact with the active enzyme site to inhibit viral
neuraminidase activity resulting in clumping of newly released influenza virions
to each other & inhibit release of progeny
◦ Administered early as replication of virus peaks at 24–72 hours after the
onset of illness
◦ 75 mg twice daily for 5-day within 48 hours after the onset of illness
decreases the duration of symptoms, viral shedding & titer
◦ 75 mg once daily is for prophylaxis after exposure
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Anti-influenza virus drugs
21. ◦ Oseltamivir
◦ Oral
◦ Bioavailability ∼ 80%
◦ Nausea & gastric
irritation (reduced
by taking the drug
with food)
◦ DOC – H1N1, H5N1
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Antiviral Drugs 22
Anti-influenza virus drugs
◦ Zanamivir
◦ Inhalation
◦ concentration in the
respiratory 1000
times more
◦ Causes bronchospasm
◦ 10 mg twice daily for
5 days for treatment
or 10 mg once daily
for prevention
◦ Peramivir
◦ Activity against both
◦ 600-mg IV dose for
acute uncomplicated
influenza in adults
◦ diarrhea,
hypersensitivity
reactions
22. Amantadine & Rimantadine-
◦ Tricyclic amines of the adamantane family
◦ Block the M2 proton (ion channel) of the virus particle and inhibit uncoating of
the viral RNA & thus prevent its replication
◦ Active against influenza A only, Rimantadine is 4-10 times more active than
amantadine
◦ Due to high rates of resistance, no longer recommended for the prevention or
treatment of influenza
◦ Nausea, anorexia, nervousness, difficulty in concentrating, insomnia, light-
headedness, marked behaviral changes, delirium, hallucinations, agitation, and
seizures
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Antiviral Drugs 23
Anti-influenza virus drugs
23. Laninamivir – long acting neuraminidase inhibitor used for oseltamivir
resistant virus
Baloxavir – FDA approved on 24th oct 2018 for influenza given as oral
20mg & 40 mg
IV Zanamivir – phase III trial but showed its not superior to oral
oseltamivir
DAS181 – recombinant fusion protein, FDA approved for parainfluenza
virus infection in transplant recepeint patients, cleaves sialic acid
receptors on virus
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Antiviral Drugs 24
Newer Anti-influenza virus drugs
24. ◦ Hepatitis B virus (HBV) is a DNA virus integrate into host chromosomal DNA
to establish permanent infection
◦ Since virus cannot be eradicated, treatment is aimed as suppression of virus
and its inflammatory & hepatocyte damaging response
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Antiviral Drugs 25
Drugs for hepatitis-B
5 oral
Nucleoside/Nucleotide
analogs
Lamivudine, Adefovir
dipivoxil, Tenofovir
disoproxil, Entecavir,
Telbivudine
2 injectable
Interferon drugs
Interferon alfa-2b,
pegylated IFNalfa-2a
25. ◦ Interferon –
◦ Enhanced production of cytokines in body
◦ Bind to receptors & affect multiple steps- viral penetration, uncoating, m-RNA
synthesis, assembly of virion & release
◦ 3 types – IFN-a, IFN-β, IFN-γ only IFNa2a & IFNa2b produced by
recombinant technology used clinically
◦ Can be given by SC, IM, IV or intralesional route, doesn’t cross BBB
◦ IFN-a2b – for chronic HBV, HCV
◦ Polyethylene glycol with IFNs (pegylated IFN-a2b) once a week SC
◦ Flu-like symptoms, Neurotoxicity, Myelosuppression, Thyroid dysfunction,
Hypotension, reversible liver dysfunction
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Antiviral Drugs 26
Drugs for hepatitis-B
26. ◦ Advantages-
◦ Absence resistant variants
◦ Higher rate of viral load reduction
◦ Disadvantages-
◦ Adverse effects are more frequent & severe
◦ Not used in patients with decompensated disease
◦ Nucleoside/nucleotide analogue have better tolerability and higher
response than the interferons & are now the first line of therapy
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Drugs for hepatitis-B
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Antiviral Drugs 28
Drugs for hepatitis-B
◦ Entecavir –
◦ is an oral guanosine nucleoside analog
◦ inhibits HBV DNA polymerase
◦ bioavailability 100% but is decreased by food
◦ plasma half-life is 128–149 hours so once-daily dosing
◦ Effective than lamivudine or adefovir (resistant cases)
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Antiviral Drugs 29
Drugs for hepatitis-B
◦ Lamivudine-
◦ inhibits HBV DNA polymerase and HIV reverse transcriptase resulting in chain
termination
◦ rapid and potent virus suppression, but limited use because of emergence of
lamivudine resistant HBV isolates
◦ Adefovir and Tenofovir used against lamivudine resistant HBV
◦ Safest
◦ Adefovir dipivoxil-
◦ prodrug of adefovir, approved at lower doses for HBV infection
◦ phosphorylated by cellular kinases to the active diphosphate metabolite which inhibits
HBV DNA polymerase & chain termination
◦ Least active nucleotide analogue against HBV so not a first line drug
◦ Chronic hepatitis B, including lamivudine-resistant cases and concurrent HIV infection
29. ◦ Tenofovir disoproxil –
◦ activity against lamivudine & entecavir-resistant hepatitis virus isolates
◦ Higher rate of virologic response, histologic improvement & lower rate of
emergence of resistance
◦ Tenofovir alafenamide fumarate (TAF) is an oral prodrug of tenofovir with
minimized toxicities
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Antiviral Drugs 30
Drugs for hepatitis-B
◦ Telbivudine-
◦ Thymidine nucleoside analog
◦ Competitively inhibits HBV DNA polymerase & chain termination
◦ Induced greater virologic response than lamivudine & adefovir
◦ Not effective in patients with lamivudine-resistant HBV
31. Drugs for hepatitis-C
◦ Hepatitis C virus (HCV) is a RNA virus, which does not integrate into
chromosomal DNA instead causes frequent chronic hepatitis
◦ The aim of treatment is to attain sustained viral response (SVR) -
undetectable HCV-RNA in blood for at least 6 months after completion of
therapy
◦ Oral ribavirin with injected PegINFa is the standard therapy for HCV
infection
◦ However, first generation direct acting oral antiviral (DAA) drugs
(boceprevir & telaprevir) altered the treatment of hepatitis C
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Antiviral Drugs 33
32. Drugs for hepatitis-C
◦ Interferon – associated with serious adverse effects, longer duration of
treatment, frequent dosing
◦ First generation DAA plus pegIFN plus ribavirin improved effectiveness, but are
replaced by newer DAAs
◦ Main target of all newer DAAs HCV-encoded proteins & so inhibit replication
◦ All given oral, IFN free combinations with or without ribavirin & excreted-feces
◦ Improved efficacy, tolerability, improved dosing schedule & fewer drug-drug
interactions but are expensive combinations
◦ All combinations have excellent safety & low rate of discontinuation due to mild
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Antiviral Drugs 34
Non structural protein (NS)5A
inhibitors
NS5B nucleoside polymerase
inhibitors
NS5B non-nucleoside polymerase
inhibitors
NS 3/4A protease inhibitors
33. ◦ Ribavirin-
◦ Guanosine analogue has broad-spectrum antiviral activity
◦ Active against HCV, influenza A and B, Parainfluenza, respiratory
syncytial virus, HIV
◦ Mono & triphosphate derivatives generated intracellularly by host
kinases interfere GTP synthesis and viral RNA synthesis
◦ Oral bioavailability is - 50% increases with fatty meal
◦ Active against all genotypes of HCV & SVR in 50- 80% cases
◦ Dose-dependent hemolytic anemia, bone marrow depression
◦ Teratogenic
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Antiviral Drugs 35
Drugs for hepatitis-C
34. ◦ Daclatasvir
◦ Orally active NS5A inhibitor blocks HCV-RNA replication & assembly of
progeny virions
◦ Used with sofosbuvir for treatment of HCV genotypes 1, 2, 3
◦ t½ of daclatasvir is 12- 15 hr, no effect of food
◦ Metabolized by CYP3A
◦ SVR upto 90% after 12 week therapy in noncirrhotic but lower response
in cirrhotic
◦ No dose adjustment is required in mild-mod renal/hepatic impairment
◦ Headache, fatigue, abdominal pain, bradycardia, alopecia, anaemia and
rarely allergy
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Antiviral Drugs 36
Drugs for hepatitis-C
NS5A inhibitors:
35. ◦ Ledipasvir
◦ Available in a fixed-dose combination with sofosbuvir for HCV-1,4,5,6
◦ can be used in HIV coinfected
◦ LDV/SOF combination-SVR of 95- 99% cases after 12 weeks in
noncirrhotic & 24 weeks after in cirrhotic
◦ Absorption is dependent on gastric acid & impaired by taking H2
blockers/PPI
◦ t½ 47 hr
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Antiviral Drugs 37
Drugs for hepatitis-C
NS5A inhibitors:
36. ◦ Velpatasvir
◦ Available in a fixed-dose combination with the sofosbuvir
◦ Indicated in all ( 1- 6) genotypes of HCV
◦ Noncirrhotic - SVR of 95- 99% after 12 weeks
◦ Absorption is dependent on gastric acid
◦ t½ 15 hr
◦ Adverse effects - headache, fatigue, weakness and nausea
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Antiviral Drugs 38
Drugs for hepatitis-C
NS5A inhibitors:
37. ◦ Elbasvir
◦ Activity against variants resistant to earlier NS5A inhibitors & HCV 1,6
genotypes
◦ Used with grazoprevir regimen SVR reduced at 12 weeks
◦ Fatigue, headache, nausea & Elevated serum aminotransferases
◦ Ombitasvir
◦ Fixed-dose combination with paritaprevir + ritonavir for-HCV4, & with
dasabuvir + paritaprevir + ritonavir for HCV1
◦ C/I in patients with moderate or severe hepatic impairment
◦ Nausea, pruritus, insomnia & increased serum aminotransferases
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Antiviral Drugs 39
Drugs for hepatitis-C
NS5A inhibitors:
38. ◦ NS5B is an RNA-dependent RNA polymerase necessary for replication of HCV
◦ Enzyme has a catalytic site for nucleoside binding and 4 other sites at which non-
nucleoside compound can bind and cause allosteric alteration
◦ Nucleoside/nucleotide analogs (Sofosbuvir) target the catalytic site & activated
within the hepatocyte through phosphorylation to nucleoside triphosphate, which
competes with nucleotides, resulting in chain termination
◦ Non-nucleoside analogues (Dasabuvir) act at allosteric site
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Antiviral Drugs 40
Drugs for hepatitis-C
NS5B RNA Polymerase inhibitors:
39. ◦ Sofosbuvir
◦ Prodrug which is converted into active form in hepatocytes & then to its
triphosphate nucleotide which inhibits NS58 causes chain termination
◦ Active against all (1-6) HCV in combination with one of the NS5A inhibitors or
simeprevir or ribavirin ± PeglNFa
◦ SVR o f 85%- 99% after 12 weeks in noncirrhotic & upto 93% after 24 weeks
in cirrhotic
◦ Dasabuvir
◦ Non-nucleoside NS5B polymerase inhibitor
◦ Ombitasvir, Paritaprevir, and Ritonavir for HCV-1
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Antiviral Drugs 41
Drugs for hepatitis-C
NS5B RNA Polymerase inhibitors:
40. ◦ Paritaprevir
◦ Ombitasvir and ritonavir HCV-4 & with dasabuvir HCV-1
◦ Grazoprevir
◦ Potent, reversibly binds to HCV NS3/4A protease
◦ Shows activity against resistant variants
◦ Elbasvir for HCV 1 and 4
◦ Not to be administered moderate or severe hepatic impairment
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Antiviral Drugs 42
Drugs for hepatitis-C
NS3/4A Protease inhibitors: (serine protein required for post-
translational processing & transcription)
41. ◦ Simeprevir
◦ Active against HCV-1,4 is used along with sofosbuvir or ribavirin +
PegINFa
◦ Simeprevir - sofosbuvir-SVR in 83- 97% noncirrhotic after 12 weeks
cirrhotic patients after 24 weeks therapy
◦ adverse effects - nausea, headache, dyspnea, fatigue, rashes and
photosensitivity as it contains sulfa moiety
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Antiviral Drugs 43
Drugs for hepatitis-C
NS3/4A Protease inhibitors:
43. Other Antiviral drugs
Palivizumab
◦ Humanized monoclonal antibody – against an epitope in A antigen on F surface
protein of Respiratory syncytial virus
◦ Prevention of RSV infection in high-risk infants and children with
bronchopulmonary dysplasia or congenital heart disease
Aerosolized ribavirin (20 mg/mL for 12–18 hours continuously per day) to
children and infants with severe RSV bronchiolitis or pneumonia
◦ Lumicitabine – RNA polymerase inhibitor, phase II
◦ Ziresovir – viral fusion inhibitor completed phase II
◦ GS-5806 –phase II
◦ ALS-008176 – phase I
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Antiviral Drugs 45
RSV
44. Other Antiviral drugs
Imiquimod -An immune response modifier - effective in the topical
treatment of external & perianal warts (condyloma acuminatum) 5%
cream 3 times weekly
Intralesional injection of IFNa-2b or IFNa-n3 used condylomata
acuminata
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Antiviral Drugs 46
45. Corona virus drugs
Starting in December 2019 in Wuhan (Hubei province, China), a
novel coronavirus (CoV), causing severe acute respiratory syndrome
(SARS)-CoV-2, caused an international outbreak of a respiratory
illness (COVID-19) & is rapidly evolved into a pandemic
Remdesivir –
◦ first drug approved by the FDA May 1, 2020 for treating the SARS-
CoV-2 virus
◦ Adenosine triphosphate analogue competes with RNA chains leads to
delayed chain termination during replication
◦ IV 200 mg OD for 1day & IV 100 mg OD for 5days
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Antiviral Drugs 47
46. Corona virus drugs
Favipiravir –
◦ Pyrazincarboxamide derivative that acts new RNA-dependent RNA
polymerase inhibitor causing chain termination
◦ Oral 1800 mg BD f/b 800 mg BD for 7-14 days
Lopinavir – (800 mg daily in combination with 200 mg)
◦ An antiretroviral protease inhibitor used in combination with ritonavir
in HIV infection
◦ Peptidomimetic HIV type 1 aspartate spartate protease inhibitor that
acts by binding to its catalytic site, thereby, preventing th venting the
cleavage of viral polyprotein precursor
◦ Main difference with respect to the SARS-CoV-2 - cysteine protease
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Antiviral Drugs 48
47. Conclusion :
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Antiviral Drugs 49
◦ The knowledge of mechanism of viral replication provided insight into the
critical steps in viral life cycle
◦ This serves the potential target for antiviral drugs
◦ Antiviral drugs are classified according to virus & to the mechanism
inhibiting viral life cycle
◦ Whereas, some infections require monotherapy & some require multiple drug
therapy
◦ Recent research has focused on identifying agents with greater selectivity,
higher potency & reduced toxicity
48. References:
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Antiviral Drugs 50
Harry W. Lampiris, MD, & Daniel S. Maddix, Pharm D, Chapter 48
Antifungal Agents, Bertram G. Katzung Basic & Clinical Pharmacology
14th Edition; 869.
The pharmacological basis of Therapeutics 13th edition,
Chapter62,Antiviral Agents (Nonretroviral) Edward P. Acosta, 1105.
Principles of pharmacology HL sharma KK sharma 3rd edition, Antiviral
drugs for non-retroviral infections, 789.
https://pubmed.ncbi.nlm.nih.gov
