Antiviral drugs

Antiviral drugs, Antiviral therapy ,,anti-herpes virus -Idoxuridine, Trifluridine, Acyclovir, Valacyclovir, Famciclovir, Ganciclovir, Valganciclovir, Cidofovir, Foscarnet, Fomivirsen.,anti-influenza virus-Amantadine, Rimantadine, Oseltamivir, Zanamivir.
,anti-hepatitis virus/nonselective antiviral drugs ,primarily for hepatitis b -Ex-Lamivudine, Adefovir dipivoxil, Tenofovir,primarily for hepatitis c-Ribavirin, Interferon α ,anti-retrovirus ,nucleoside-Zidovudine (AZT), Didanosine, Stavudine, Lamivudine, Abacavir, Emtricitabine, Tenofovir (Nt RTI) reverse transcriptase inhibitors -Nevirapine, Efavirenz, Delavirdine, Anti viral drugs
,nrtis ,nonnucleoside reverse transcriptase inhibitors ,nnrtis ,protease inhibitors ,entry (fusion) inhibitor ,ccr5 receptor inhibitor ,integrase inhibitor.-Ritonavir, Atazanavir, Indinavir, Nelfinavir, Saquinavir,
Amprenavir, Lopinavir
Entryy of virus in cell,AIDS,
Herpes group of DNA viruses, Virus cycle, Virus infected cell
Snehal chakorkar. (Pharmacology)

1. Antiviral Drugs
Miss Snehal S. Chakorkar (M.pharm)
Dept Of Pharmacology
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2. Introduction
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Viruses are simple small (20-30nm)
microorganisms that consist of either
double-or single-stranded DNA or
RNA enclosed in a protein coat called
a capsid.
Antiviraltherapybasedon;
Identificationofvirusdirectedenzymesintheinfectedcell
whichmayhavehigheraffinitiesforsomeantimetabolites;
targetthatenzyme.
Targetspecificstepslikecellpenetration,uncoating,reverse
transcription,virusassemblyormaturation,etc.
Virusesareparasitismbecausetheynotonlytakenutrition
fromthehostcellbutalsodirectitsmetabolicmachineryto
synthesizenewvirusparticles.

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Virus life history:
Virus have no metabolic machinery of their own. They attach
and penetrate the host cell.
Replication in DNA virus:
Viral DNA
In cell transcription in to mRNA
Host cell RNA polymerase
Virus specific protein
Viral DNA, coat & envelope
Enter in host cell
Reaction Catalyzed by
Translation of mRNA in
Formation of
Replication in RNA virus:
Release Enzymes within virion
mRNA from viral RNA
Sometimes viral RNA serves as
own mRNA
Synthesize
Viral RNA
Enter in host cell

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Classification
1.Anti-Herpes virus:
Ex-Idoxuridine, Trifluridine, Acyclovir, Valacyclovir,
Famciclovir, Ganciclovir, Valganciclovir, Cidofovir, Foscarnet,
Fomivirsen.
2. Anti-Influenza virus:
Ex-Amantadine, Rimantadine, Oseltamivir, Zanamivir.
3. Anti-Hepatitis virus/Nonselectiveantiviral drugs:
a) Primarily for hepatitis B: Ex-Lamivudine, Adefovir
dipivoxil, Tenofovir
b)Primarily for hepatitis C:Ribavirin, Interferon α
Continue on next

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4. Anti-Retrovirus:
(a)Nucleoside reverse transcriptase inhibitors (NRTIs):
Ex-Zidovudine(AZT), Didanosine, Stavudine, Lamivudine, Abacavir,
Emtricitabine, Tenofovir(NtRTI)
(b) Nonnucleosidereverse transcriptase inhibitors (NNRTIs):
Ex-Nevirapine, Efavirenz, Delavirdine
(c) Protease inhibitors:
Ex-Ritonavir, Atazanavir, Indinavir, Nelfinavir, Saquinavir,
Amprenavir, Lopinavir
(d) Entry (Fusion) inhibitor: Ex-Enfuvirtide
(e) CCR5 receptor inhibitor: Ex-Maraviroc
(f) Integraseinhibitor: Ex-Raltegravir

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A. Anti-herpes virus drugs
These are drugs active against the Herpes group of
DNA viruses which include Herpes simplex virus-1 (HSV-
1), Herpes simplex virus-2 (HSV2), Varicella-Zoster virus
(VZV), Epstein-Barr virus (EBV), and Cytomegalovirus (CMV).
Ex-Idoxuridine, Trifluridine,
Acyclovir, Valacyclovir,
Famciclovir, Ganciclovir,
Valganciclovir, Cidofovir,
Foscarnet, Fomivirsen

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Acyclovir: It is deoxiguanosineanalogue.
Mechanism of Action:
Acyclovir (Prodrug)
Acyclovir monophosphate
Acyclovir triphosphate
Inhibits herpes virus DNA
polymerase competitively
Herpes virus specific thymidinekinase
Cellular kinases
Gets incorporated in viral DNA
and stops lengthening of DNA
strand. The terminated DNA
inhibits DNA-polymerase
irreversibly.

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Pharmacokinetics:
Absorption:20% of an oral dose of acyclovir is absorbed.
Distribution: little plasma protein bound, CSF concentration that
is 50% .Penetrates cornea.
Metabolism: In l liver.
Excretion: unchanged in urine, both by glomerularfiltration
and tubular secretion; plasma t½ is 2–3 hours.
Renal impairment necessitates dose reduction

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Use: Used in treatment of
1.Genital Herpes simplex
2.MucocutaneousH. Simplex
3.H. simplex encephalitis
4.H. simplex (type I) keratitis
5.Herpes zoster
6.Chickenpox
1
2
3
4
5
6

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1.Genital Herpes simplex:
It caused by type-2 virus; can be treated by topical, oral or
parenteralacyclovir.
Primary treatment with 5% ointment is applied locally 6 times
a day for 10 days.
Late and more severe cases should receive oral therapy (1 g/day in
5 divided doses or 400 mg TDS for 10 days).
2. MucocutaneousH. simplex
type-1 virus disease. Infection of lips and gums; Spreading lesions
may be treated with 10 day.
3.H. simplex encephalitis(type-1 virus):
Acyclovir 10 to 20 mg/kg/8 hr i.v. for >10 days.

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4. H. simplex (type I) keratitis:
Though acyclovir eye ointment acts slower than idoxuridineeye
drops, blindness can be prevented.
5.Herpes zoster:
The varicella-zoster virus is less susceptible to acyclovir. As
such, higher doses are needed and it should be used only in
immunodeficientindividuals or in severe cases: 10 mg/kg/8 hr
i.v. for 7 daysprevents symptomatic relief and faster healing of
lesions.
6. Chickenpox:
Acyclovir (15 mg/kg/day i.v. ×7 days) is the drug of choice.
reduces fever, eruptions, hastens healing and prevents visceral
complications.

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Adverse effects
1.After topical: Stinging and burning sensation after each
application.
2.After Oral: headache, nausea, malaise and some CNS effects
are reported.
3.After Intravenous: Rashes, sweating, emesis and fall
in BP occur.
4. After discontinuation: Drug reversible neurological
manifestations (tremors,lethargy, disorientation,hallucinations,
convulsions and coma)
5. No teratogenicpotential has been noted.

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B. Anti-influenza virus drugs
Theterminfluenzareferstoillnesscausedby
influenzavirus.Thisiscommonlycalledtheflu,but
manydifferentillnessescauseflu-likesymptomssuch
asfever,chills,achesandpains,cough,andsore
throat.
Influenzavirusinfectioncancausedifferentillness
patterns,rangingfrommildcommoncoldsymptoms
totypicalflu.

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Amantadine
It is tricyclicamine not related to any nucleic acid
precursor.
Mechanism of Action:
It inhibits replication of influenza A virus (a myxovirus). Activity
is strain specific; influenza B is not affected.
H5N1 (avian influenza/bird flu) and H1N1 (swine flu) strains of
influenza A are resistant in most areas.
It act on anearlystep (possibly uncoating) as well as at a
late step (viral assembly) in viral replication.
Resistance: caused due to mutation of amino acid
substitutions in the M2 protein.

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Uses:
1. Prophylaxis of influenza A2: The epidemic strain of virus is
known to be sensitive to amantadine, should prophylactic
use be considered.
Amantadinedoes not interfere with antibody response to influenza
vaccination; so amantidineand vaccination are given in combination.
Amantadinenot recommended in UK, either for prophylaxis or for
treatment of influenza.
2. Treatment of influenzal(A2) illness: When we observe
therapeutic effect (reduction in fever, congestion, cough and quicker
recovery) drug is given immediately.
3. Parkinsonism: Due to anticholinergicproperty used in treatment
of parkinsonism.

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Adverse effects: Like
CNS effects: Nausea, anorexia, insomnia, dizziness,
Psychological effect:nightmares, lack of mental
concentration, rarely hallucinations,
Local effect: Ankle edemaoccurs due to local
vasoconstriction.
Contraindications:
Epilepsy and other CNS disease;
Gastric ulcer,
Pregnancy.

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C. Anti-hepatitis virus /
nonselectiveantiviral drugs:
Several antiviral drugs are relatively virus nonselectiveand
inhibit viruses belonging to different classes; even cover both
DNA and RNA viruses.
While hepatitis B virus (HBV) is a DNA virus which, like
retroviruses, can integrate into host chromosomal DNA to
establish permanent infection.
The hepatitis C virus (HCV) is a RNA virus, which does not
integrate into chromosomal DNA, does not establish noncurable
infection, but frequently causes chronic hepatitis.
Lamivudine, a nucleoside analogue, is active
against HVB as well as HIV, and is described
with antiretroviral drugs.

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Adefovirdipivoxil:(Primarily for hepatitis B)
It is a monophosphateanalogue of Adenosine mono phosphate
which is active against Hepatitis B Virus and some other DNA as
well as RNA viruses,
Adefovir
Adefovirdiphosphate
HBV DNA polymerase compared to
host cell DNA polymerase
phosphorylatedto
high affinity for
Inhibition of enzyme DNA polymerase andadefovir
itself gets incorporated in the viral DNA
termination of the DNA chain
resulting
Antiviral activity
Mechanism of
Action:

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Uses:
chronic hepatitis B, including lamivudine-resistant cases and those
having concurrent HIV infection.
Side effects:
Sore throat, headache, weakness, abdominal pain and flu
syndrome. Nephrotoxicityoccurs at higher doses and in those with
preexistingrenal insufficiency.
Lactic acidosis is a risk in patients receiving anti-HIV drugs.

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Interferon α: (Primarily for hepatitis C):
low molecular weight glycoprotein cytokines produced by host
cells in response to viral infections, TNFα, IL-1 and some other
inducers.
Three types of human IFNs (α, β and γ) are known to have
antiviral activity.
IFNα2A and IFNα2B produced by recombinant technology
administered by i.m. or s.c. injection

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Interferon receptors are JAK -STAT
tyrosine protein kinasereceptors
phosphorylatecellular proteins
activation
nucleus and induce transcription of ‘interferon inducedproteins
antiviral effects
exert
affect viral replication at multiple steps viral penetration, synthesis of
viral mRNA, assembly of viral particles and their release is direct or
indirect suppression of viral protein synthesis
migrate to
Resulting in
Mechanism of Action:

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Uses:
1.Chronic hepatitis B.
2.Chronic hepatitis C.
3.AIDS-related Kaposi’s sarcoma.
4.Condylomaacuminata.
5.H. simplex, H. zoster and CMV.
6.Other uses. 3
5
4

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1. Chronic hepatitis B: IFNα2Α 2.5−5 ΜU/m2
or IFNα2Β 5−10 ΜU given 3 times per week for 4–6 months.
2. Chronic hepatitis C: IFNα2Β 3ΜU 3 times weekly for
6–12 months has produced remission in 50–70% patients.
3. AIDS-related Kaposi’s sarcoma: IFN is used
to treat AIDS related Kaposi’s sarcoma, but not to treat HIV as
such. However, interferon accentuates haematological toxicity of
zidovudine.
4. Condyloma acuminata:caused by papilloma
virus is usually treated with topical podophyllin.
Intralesionalinterferon injection may be used in refractory cases.

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5. H. simplex, H. zoster and CMV: For these
infections in immunocompromisedpatients, interferon is
inferior to acyclovir/ganciclovir.
It may be used as second line/adjuvant drug.
6. Other uses : Interferonsare also used in chronic
myeloid leukaemia, follicular lymphoma, cutaneous T-cell
lymphoma and multiple myeloma.
Interferon is not effective orally. Clinical utility of s.c. or i.m.
injected interferon is limited by substantial adverse effects.

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Adverse effects:
Flu-like symptoms—fatigue, aches and pains, malaise, fever,
dizziness, anorexia, nausea, taste and visual disturbances develop
few hours after each injection, but become milder later.
Neurotoxicity—numbness, neuropathy, altered behaviour, mental
depression, tremor, sleepiness, rarely convulsions.
Myelosuppression: dose dependent neutropenia, thrombocytopenia.
Thyroid dysfunction (hypo as well as hyper).
Hypotension, transient arrhythmias, alopecia
and liver dysfunction.

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D. Anti-retrovirus drugs
These are drugs active against human immunodeficiency virus
(HIV) which is a retrovirus.
They are useful in prolonging and
improving the quality of life
postponing complications of (AIDS)
but do not cure the infection.
The clinical efficacy of antiretrovirus
drugs is monitored primarily by plasma
HIV-RNA assays and CD4 lymphocyte
count carried out
at regular intervals.

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HIV Virus
HIV is a single stranded RNA retrovirus which uniquely carries out
reverse transcription of proviralDNA from viral RNA
(normally RNA is transcriptedfrom DNA) with the help of a viral
RNA-dependent DNA polymerase (reverse transcriptase).
HIV primarily infection attack on is the CD4+ helper T
lymphocyte, later macrophages and some other cell.
When population of CD4 cells declines markedly (<200 cells/μL),
cell mediated immunity (CMI) is lost and opportunistic infections
resulting death of patient.

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Ref: Rang and dale (Text book of pharmacology)

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Drug Target:
The two established targets for anti-HIV drug attack are:
(a) HIV reverse transcriptase: Which transcripts HIV-RNA into
proviralDNA.
(b) HIV protease: Which cleaves the large virus directed
polyproteininto functional viral proteins.
In addition, some newer targets being exploited are:
• Fusion of viral envelope with plasma membrane of CD4 cells
through which HIVRNA enters the cell.
• Chemokinecoreceptor(CCR5) on host cells which provide
anchorage for the surface proteins of the virus.
• HIV-integrase: Viral enzyme which integrates the proviral
DNA into host DNA.

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A. Nucleoside reverse transcriptase inhibitors (NRTIs):
Zidovudine(AZT),
The first anti-retrovirus (ARV) drug zidovudine(thymidine
analogue )was available for use in 1987.
Zidovudine
Zidovudinetriphosphate
viral reverse transcriptase enzyme
phosphorylatedin the host cell
selectively inhibits
Zidovudinethus prevents infection of new cells by
HIV, but has no effect on proviralDNA that has
already integrated into the host chromosome

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Pharmacokinetics:
Absorption:Rapid absorption, but bioavailability is ~65%.
Distribution: Plasma protein binding is 30% and CSF level is
~50% of that in plasma. It crosses placenta and is found in milk.
Metabolism:hepatic glucuronidation.
Excretion:urine
Adverse effects: Like,
Common:Anaemia and neutropenia.
Dose related toxicity: Nausea, anorexia, abdominal pain,
headache, insomnia and myalgia.
Long term toxicity: Myopathy, pigmentation of nails, lactic
acidosis, hepatomegaly, convulsions and encephalopathy.

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Uses:
Zidovudineis one of the two optional NRTIs used by NACO for
its first line triple drug ARV regimen.
Immune status is improved and opportunistic infections become
less common.
AZT also reduces neurological manifestations of AIDS and new
Kaposi’s lesions do not appear.
beneficial effects are limited from a few months to a couple of
years after which progressively non-responsiveness develops.
Now a days triple therapy is more effective than double therapy.
Two NRTIs or one NRTI + one NNRTI

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B.Nonnucleosidereverse transcriptase inhibitors
(NNRTIs): Ex-Nevirapine, Efavirenz, Delavirdine
These are the nucleoside unrelated compounds which directly
inhibit HIV reverse transcriptase without the need for intracellular
phosphorylation.
They are non-competitive inhibitors.
They are more potent than AZT on HIV-1, but do not inhibit HIV-2
But if used alone resistance is developed.

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C.Retroviralprotease inhibitors (PIs)
From large viral polyprotein;aspartic protease enzyme produces
structural proteins and enzymes (including reverse transcriptase
and integrase) of the virus in the infected cell.
It 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.
Retroviral protease inhibitors (PIs)
Bind to the active sit of protease molecule
Cleaving function(broken into various functional
components )
interfere
Prevent further rounds of infection.

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Uses:
Viral resistance developed within months due to selection of
resistant mutants so Combination of NRTIs with PIs is advised.
Adverse effects:
Gastrointestinal intolerance, asthenia, headache, dizziness, limb
and facial tingling, numbness and rashes.
Lipodystrophy(abdominal obesity, buffalo hump with wasting of
limbs and face),
Dyslipidaemia(raised triglycerides and cholesterol) which may
necessitate hypolipidaemicdrugs, and insulin resistance.
Diabetes may be exacerbated. Indinavircrystalisesin urine and
increases risk of urinary calculi.

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Binding, fusion, entry sequence of retrovirus:
1)Thebindingof HIV surface proteingp120to the CD4
receptor.
2)Aconformational changeingp120, which both
increases its affinity for a co-receptor and exposesgp41.
3)The binding ofgp120to aco-receptoreitherCCR5 or
CXCR4.
4)The penetration of thecell membraneby gp41, which
approximates the membrane of HIV and theT celland
promotes theirfusion
5) Theentryof the viral core into the cell
Entry inhibitors work by interfering with one aspect of
this process.

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D.Entry(fusion) inhibitor: Ex-Enfuvirtide
Enfuvirtide(HIV-derived synthetic peptide)
HIV-1 envelope transmembraneglycoprotein (gp41) (This
is responsible for fusion of viral and cellular membranes)
Entry of the virus into the cell is blocked
Which causes
Prevention of Fusion of the two membrances
binding to
After binding
Enfuvirtideactive against HIV-1 but not active against HIV-2.
Problems associated with therapy is injections are painful and
cause local nodules/cysts.
The cost and inconvenience.

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E.CCR5 receptor inhibitor: Ex.Maraviroc
Maraviroc
Host cell CCR5 receptor
blocks
The HIV envelope contains globular glycoprotein gp120 which is
bind to cell membrane receptor ieCCR5 chemokinereceptor (most
HIV are CCR5-tropic) then attach to the CD4 site of host cell
Anti retroviral action
It has no effect on HIV strains that are CXCR4 receptor
tropic (CXCR4 is an alternative chemokinereceptor which
also can bind gp120), or dual CCR5/ CXCR4 tropic.

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F. Integraseinhibitor: Ex Raltegravir
HIV-proviralDNA
transcriptedin the cytoplasm of host cell
Translocation to
nucleus along with an integraseenzyme
Infection to host cell
Raltegravir
Block
Uses:
It is active against both HIV-1 and HIV-2
Adverse Drug Reaction:
nonspecific; myopathyis a potential toxicity.
However, raltegraviris a new drug; efficacy and safety need to be
established.

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HIV TREATMENT PRINCIPLES AND GUIDELINES
Refer next slide

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Reference:
Rang H.P. and Dale M.M.: Pharmacology, Churchill
Livingstone, Edinbergh.
KatzungB.G.: Basic and Clinical Pharmacology, Lange
Medical Publications, California.
Craig C.R. and StitzelR.E.: Modern Pharmacology, Little
Brown and Co., Boston.
Bowman W.C. and Rand M.J.: Textbook of Pharmacology,
Blackwell Scientific Publications, Oxford.
P.N Bennett & M J Brown: Clinical Pharmacology,
Churchill Livingstone, Edinburgh.
TripathiK.D.: Essentials of Medical Pharmacology, Jaypee
Brothers, Medical Publishers, New Delhi.

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