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ANTIVIRAL AGENTS
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Virus Replication &
Pharmacological Intervention
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Therapeutic Overview for
Treatment of Viral Infections
1. Block viral attachment to cells (fusion inhibitors)
2. Block uncoating of virus (ion channel blockers)
3. Inhibit viral DNA/RNA synthesis (Polymeraseinhibitors)
4. Inhibit viral protein synthesis (Protease inhibitors)
5. Inhibit viral release (Neuraminidase inhibitors)
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ANTIVIRAL DRUGS
Antiherpetic drugs. Acyclovir- oral or IV Ganciclovir Foscarnet
Anticytomegalovirus drugs Ganciclovir Foscarnet
Antihepatitis drugs Interferon Pegylated interferon Ribavirin
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INTERFERON :
Mechanism of action: Antiviral, immunomodulatoryand antiproliferative (affect synthesis of both RNA andproteins). Given SC or IM
Uses: Antiviral uses:
Hepatitis B and C acute infection. Reduces the risk of
cirrhosis, malignancy. Combination with ribavirin is more effective in chronic
hepatitis C infection
Antimalignant uses: hairy cell leukemia, Kaposi sarcoma,
malignant melanoma
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INTERFERON :
Adverse effects Flu like syndrome (headache, fever, chills, myalgias,
malaise)
Transient increased transaminases. During chronic therapy:
Neurotoxicities (mood disorders, depression,somnolence, confusion, seizures).
Myelosuppression- thrombocytopenia
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ACYCLOVIR
Mechanism of action: Acyclovir inhibits viral DNA synthesis
Uses:
Herpes simplex:
Oral:
Primary infection and recurrences of genital and labialherpes
Long term suppressive therapy of genital herpes simplex inpatients with more than 6-8 recurrence /year
IV: Serious infections due to herpes simplex virus Encephalitis Neonatal HSV infection
Varicella zoster infection: patients with severe disease
Herpes Zoster infection
Adverse effects:
Oral acyclovir: Nausea, diarrhea, headache
Intravenous acyclovir: Nephrotoxicity & neurologic toxicity
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Acyclovir: Inhibition of Viral DNA
synthesis
1. Competitively inhibits DNA polymerase
2. Terminates DNA elongation (no 3 hydroxyl)
3. Irreversible binding between DNA polymerase and interrupted DNA chain
NB:viral DNA polymerase more sensitive to pppACV than cellular DNA polymerase
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Valacyclovir
The L-valyl ester of acyclovir
It is rapidly converted to acyclovir after oral
administration, achieving serum levels threeto five times greater than those achievedwith oral acyclovir.
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Acyclovir (ACV)
An acyclic guanosine derivative
Pharmacological effects:
Against HSV-1 and HSV-2 and against varicella-zoster virus, Epstein-Barr virus andcytomegalovirus.
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Mechanism:
Three phosphorylation steps for activation. First converted to the monophosphate derivative by thevirus-specifiedthymidine kinase;selective activation
Then to the di- and triphosphate compounds by hostscellular enzymes.
Acyclovir triphosphate inhibits viral DNA synthesis bytwo mechanisms:
Competitive inhibition of deoxyGTP for the viral DNApolymerase, with binding to the DNA template as an
irreversible complex; Incorporation into the viral DNA chain termination
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Resistance HSV or VZV alteration in either the viral thymidine
kinase or the DNA polymerase resistance
Cross-resistance to valacyclovir,famciclovir, and
ganciclovir. Agents such asfoscarnet, cidofovir, and trifluridine do
not require activation by viral thymidine kinase and thushave preserved activity against the most prevalent
acyclovir-resistant strains.
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Pharmacokinetics Available in oral, intravenous, and topical formulations.
Oral bioavailability is 15-20%.
Plasma protein binding is low, diffuses into most tissuesand body fluids.
Cleared primarily by glomerular filtration and tubularsecretion.
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Clinical uses
Treatment ofHSV infection first selection
Topical acyclovir is much less effective than oral therapy forprimary HSV infection. It is of no benefit in treatingrecurrences.
VZV is less susceptible to acyclovir than HSV, high doses arerequired.
Adverse reactions
Nausea, diarrhea, headach Intravenous infusion renal insufficiency or neurologic
toxicity
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Ganciclovir
An acyclic guanosine analog
Against CMV is up to 100 times greater than
that of acyclovir. Adverse reactions:
Myelosuppression, particularly neutropenia
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GANCICLOVIR
Mechanism of action: Inhibition of viral DNAPolymerase
Uses: Prevention & treatment ofcytomegalo virus
infections (CMV retinitis, esophagitis, colitis orpneumonitis) seen commonly in HIV infected pts.
Adverse effects:
Bone marrow suppression
Hepatic dysfunction
Seizures, behavioral disturbances
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FOSCARNET
Mechanism of action: Inhibition of viral DNApolymerase
Uses: Prophylaxis and treatment of CMV infection
Acyclovir resistant strain of herpes virus
Adverse effects: Nephrotoxicity
CNS toxicities: headache, seizures,hallucinations
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Trifluridine
Trifluorothymidine, Fluorinated pyrimidine nucleoside.
Against HSV-1, HSV-2, vaccinia, and some adenoviruses.
Incorporation of trifluridine triphosphate into both viral
and cellular DNA prevents its systemic use. Therapy for keratoconjunctivitis and for recurrent
epithelial keratitis due to HSV-1 and HSV-2.
Topical application, alone or in combination with interfonalfa, has been used successfully in treatment ofacyclovir-resistant HSV infections.
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Vidarabine, ara-A
Adenosine analog
Against HSV, VZV, CMV, HBV and some RNAviruses.
Phosporylated intracellular by host enzymes toform ara-ATP, incorporated into both viral and
cellular DNA. excessive toxicity
Rapidly metobolized to hypoxanthinearabinoside.
Instability and toxicity limited its clinical utility.
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Topical application for acute keratoconjunctivitis,
superficial keratitis, and recurrent epithelialkeratitis due to HSV-1 and HSV-2.
Intravenous for treatment ofHSV encephalitis,
neonatal herpes, and VZV infection inimmunocompromised patients.
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Idoxuridine
Competitive inhibition of thymidylic acidsynthase block DNA synthesis.
No effect on RNA virus.
Only topical application because of its greaterside effects in systemic application.
Treatment ofocular or dermal infections due
to herpesvirus or cowpox virus, especiallyacute epithelial keratitis due to herpesvirus.
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Lamivudine (3TC)
Cytosine analog
Against HIV-1, synergistic with a variety ofantiretroviral nucleoside analogs, including
zidovudine and stavudine. Treatment ofchronic hepatitis B infection.
Oral bioavailability exceeds 80% and is not food-dependent.
The majority of lamivudine is eliminatedunchanged in the urine.
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Ribavirin (Virazole)
Guanosine analog.
Phosphorylated intracellularly by host cell enzymes.
Mechanism: to interfere with the synthesis of guanosine
triphosphate, to inhibit capping of viral messenger RNA,and to inhibit the viral RNA-dependent RNA polymeraseof certain viruses.
Ribavirin triphosphate inhibits the replication of a widerange ofDNA and RNA viruses, including influenza A and
B, parainfluenza, respiratory syncytial virus,paramyxoviruses ,HCV, and HIV-1.
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RIBAVIRIN
ACTION: Effective against influenza A and B,parainfluenza, respiratory syncytial virus, paramyxoviruses,HCV and HIV-1.
Therapeutic uses: Hepatitis C infection- given with With INF .
Severe respiratory syncytial virus bronchitis or pneumoniain infants and children used as nebuliser
Influenza A and B, parainfluenza.
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RIBAVIRIN
Adverse effects:
Dose dependent hemolytic anemia.
Fatigue, irritation, depression, insomnia Rash, pruritus, cough
Nausea.
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Antiviral agents for influenza:
two classes of drugs
Matrix protein (M2) inhibitors
amantadine and rimantadine
inhibit virus coating
influenza A only
Neuraminidase inhibitors
oseltamivir and zanamivir
inhibit release of virus from infected cells
active against all known strains of influenza
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M2 inhibitors: Mechanism
Neuraminidase
Hemagglutinin
RNA
M2 protein
(only on type A)H+
H+
H+
H+
X
M2 inhibitors
M2 channel allows acidificationof virus
Initiates uncoating of viral RNA
Allows viral replication
M2 inhibitors block this action
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ZANAMIVIR & OSELTAMIVI
Used for: Influenza A and B virus infection
Mechanism of action : Inhibitneuraminidase of host cell membraneinhibits the release of virus particleswhich remain stuck to infected cell
Zanamivir: by inhalation or intranasally.Avoided in asthma or COPD
Oseltamivir: oral
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Inhibition of viral release
(Influenza Virus)
Zanamivir
Structural analogue of Sialic Acid
Inhibits neuraminidases Rationale: Normally virus attaches via
interaction between haemagglutinin andsialic acid moieties present on many cellmembrane GPs.
On viral egress haemagglutinin present onnascent virions also bind to sialic acidmoieties preventing release.
viral neuraminidase (envelope boundenzyme) cleaves sialic acid from membraneGPs, freeing virions.
I hibiti f i l ti I Ch l
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Inhibition of viral uncoating: Ion Channel
Inhibitors (Amantadine, Rimantadine)
Influenza A virus
M2: proton channel
HA: haemagglutinin
NA: neuraminidase
Virus enters by receptor
mediated endocytosis
2 events:
Conformational change
in haemagglutinin
permits fusion with
endosomal membrane
M2 channel opens and
virion matrix protein
dissociates releasing
ribonucleoprotein
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AMANTADINE AND RIMANTADINE
Mechanism of action: Inhibition of viral uncoating
Clinical uses:i. Influenza A:
Prophylactic against influenza A virus infection in highrisk individuals: elderly and immuno-suppressedpopulation
Shorten clinical illness in those who acquired theinfection.
ii. Also used in parkinsonism.
Adverse effects:CNS toxicity: Dizziness, ataxia, slurred speech
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Simplified Structure of HIV
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Viral Life Cycle: HIV
(retrovirus)
Notes
Gp120 binds to cells
expressing CD4 orchemokine receptors egCCR5
Viral entry depends ongp41 which folds resultingin fusion of HIV and targetcell membranes
Cellular RNA polymerasescopy DNA into mRNA andgenomic viral RNA
Proteases cleave viralpolyproteins (maturation)to yield key viral proteins: Gag: proteins that
determine viral core(matrix proteins)
Pol: reverse transcriptase& integrase
Env: envelope protein thatdetermines viral tropism(specificity for host)
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USES OF ANTIRETROVIRAL DRUGS
1. In HIV infected patient : Delay progression of the disease & decrease
incidence of opportunistic infection.Antiretroviral drugs are used in different
combinations: Highly active antiretroviral therapy(HAART).Initiate treatment with three drugs: Two nucleosidereverse transcriptase inhibitors plus an inhibitor ofHIV protease or Non nucleoside reverse
transcriptase inhibitor
2. Prophylaxis against infection through accidentalneedle sticks
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USES OF ANTIRETROVIRAL DRUGS
3. Reduce the incidence of vertical transmission ofHIV from mother to new born
Zidovudine:
is given to the mother orally between 14-34 weeks of gestation
intravenous during labor
syrup to neonate from birth through 6
weeks of age . Nevirapine : a single oral intrapartum dose
followed by a single dose to the new born -superior to zidovudine.
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ADVERSE EFFECTS OF HAART
1. NRTIS: lactic acidosis, severe hepatomegaly with steatosis
2. Protease inhibitors: Lipodystrophy
Facial & limb lipoatrophy
Abnormal accumulation of body fat: Increased abdominal girth Breast enlargement Buffalo hump.
Hyperlipidemia Insulin resistance and diabetes mellitus Nausea, vomiting and paresthesia
3. Immune reconstituation syndrome Appears in first few weeks of therapy. Unmasking of subclinical co-infection: tuberculosis, leprosy Worsening or appearance of a new opportunistic infection.
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Selective toxicity of Antiretrovirals
Reverse transcriptase Inhibitors: ((NRTIs: )) Zidovudine: Myelosuppression Didanosine: Pancreatitis, Peripheral neuropathy
((NNRTIs)) : Nevirapine: AR: Hepatotoxicity, Severe skin reaction
Protease inhibitors: Atazanavir: Hyperbilirubinemia
Indinavir: Kidney stone
Entry blockers:
Enfuvirtide (SC inj): Protease inhibitors:
Atazanavir: AR: Hyperbilirubinemia Indinavir: AR: Kidney stone
Entry blockers:
Enfuvirtide (SC inj): AR: local reactions local reactions
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ViralRNA
double helixDNA
Incorporated
intohostgenome
reverse
transcriptaseHIV integrase
transcriptiontranslation
PolyproteinsFinal
structural
proteins
HIV protease
Drugs
NRTIsNNRTIs
PIs
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HIV
Human immunodeficenecy virus : Is a retrovirus.
It is a RNA virus. After entering the host cells, itundergoes reverse transcription into DNA.
Mechanism of action of antiretroviral agents:1. They act by inhibition of viral enzymes
i. Reverse transcriptase inhibitors: inhibit reverse
transcriptase which convert Viral RNA into DNA Nucleoside reverse transcriptase inhibitors: e.g,
Zidovudine, Didanosine Non nucleoside reverse transcriptase inhibitors: e.g.
Nevirapine
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HIV (continue)
ii. Protease inhibitors: inhibit protease which help inthe formation of mature virus particles: e.gAtazanavir, Indinavir
iii. Integrase inhibitor: raltegravir
2. Fusion inhibitors: prevents entry of HIV into CD4cells: e.g. Enfuvirtide
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Mechanism of Action
Competitive inhibition of HIV-1 reversetranscriptase;
Incorporated into the growing viral DNA
chain cause termination Drugs requires intracytoplasmic activation--
- phosphorylation triphosphate form
Most have activity against HIV-2 as well asHIV-1.
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Nucleoside Antiviral Agents
Including Purine-nucleoside and Pyrimidine-nucleoside
Drugs requires intracytoplasmic activation---
phosphorylation triphosphate formcompetitive inhibition of viral DNApolymerase.
Incorporated into the growing viral DNAchain cause termination
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Zidovudine
Azidothymidine , AZT
Deoxythymidine analog
anti-HIV-1 and HIV-2
Well absorbed from the gut and distributed tomost body tissues and fluids, including thecerebrospinal fluid.
Eliminated primarily by renal excretionfollowing glucuronidation in the liver.
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Decrease the rate of clinical disease progression
and prolong survival.
Treatment HIV-associated dementia andthrombocytopenia.
Reduce the rate ofvertical (mother-to-newborn)transmission of HIV.
Adverse effect: myelosuppression anemia or
neutropenia; gastrointestinal intolerance,headachs, insomnia
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Zalcitabine (ddC)
Cytosine analog
Anti-HIV-1
Zalcitabine + Zidovudine + one proteaseinhibitor
Long intracellular half-life of 10hs.
Dose-dependent peripheral neuropathy.
Contraindication to use with other drugs thatmay cause neuropathy.
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Stavudine
Thymidne analog (d4T), not used with AZTbecause AZT may reduce the phosphorylation ofd4T.
Anti-HIV-1 and HIV-2
High oral bioavailability (86%) that is not food-dependent.
Plasma protein binding is negligible, meancerebrospinal fluid concentrations are 55% of
those of plasma. Excretion is by active tubular secretion and
glomerular filtration.
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Adverse effects:
Dose-limiting toxicity is a dose-related peripheralsensory neuropathy.
Pancreatitis, arthralgias, elevation in serumaminotransferases.
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Didanosine (ddI)
Synthetic analog of deoxyadenosine
Plasma protein binding is low (
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Adverse effects: Dose-dependent pancreatitis
Painful peripheral distal neuropathy
Diarrhea
Hepatitis
Esophageal ulceration
Cardiomyopathy
Central nervous system toxicity (headach, irritability,insomnia)
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Nonnucleoside reverse
transcriptase inhibitors Including delavirdine, nevirapine, efavirenz. Bind directly to a site on the viral reverse
transcriptase that is near to but distinct from the
binding site of the NRTIs.
Neither compete with nucleoside triphosphatesnor require phosphorylation to be active.
The binding to the enzymes active site results inblockade of RNA- and DNA-dependent DNApolymerase activities.
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Specific activity against HIV-1.
Cross-resistance among this class of agents.
The rapid emergence of resistance prohibitsmonotherapy with any of the NNRTIs.
No cross-resistance between the NNRTIs and theNRTIs or the protease inhibitors.
Oral bioavailability is high.
Metabolized by the CYP3A P450 isoform, excreted
in the urine. Adverse effects: skin rash
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Inhibition of viral
maturation HIV Protease inhibitors: Ritonavir, saquinavir
Inhibit cleavage of the gag/pol HIV polyprotein
Therefore, viral particles which bud from infected
cells are immature and non-infectious
Interaction with P450 (CYP3A4)
Inhibitors of P450 enhance SE of protease inhibitors
P450 inducers can lower plasma levels of PIs andencourage viral resistance
Nucleoside Reverse
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Nucleoside Reverse
Transcriptase Inhibitors (NRTIs)
Zidovudine (AZT): thymidine analogue Excellent substrate for cellular thymidine kinase (HIV no TK)
No selectivity at activation, accumulates in most dividingcells
No 3 OH group, contains N3 obligatory chain terminator
pppAZT more potent competitive inhibitor of HIV reversetranscriptase than cellular RT
Lamivudine (3TC): cytidine analogue L-stereoisomer which contains a S atom
chain terminator & competitive inhibitor of RT
ppp3TC inhibits HIV RT > cellular RT
Also used in chronic HepB where evidence of viral replication
Least toxic of NRTIs
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Protease inhibitors
Including ritonavir, nelfinavir, saquinavir, indinavirand amprenavir.
Gag and Gag-Polgene
Polyproteins,Immature budding particles
translate
Final structural proteins,Mature virioncore
protease
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Combination therapy with other agents is
recommended to avoid emergence of resistance,because of specific genotypic alterations.
Adverse effect: Syndrome of altered body fat distribution (buffalo
hump and truncal obesity, with facial and peripheralatrophy)
Insulin resistance
Hyperlipidemia
i i i f i
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Inhibition of viral
maturation HIV Protease inhibitors: Ritonavir, saquinavir
Inhibit cleavage of the gag/pol HIV polyprotein
Therefore, viral particles which bud from infected
cells are immature and non-infectious
Interaction with P450 (CYP3A4)
Inhibitors of P450 enhance SE of protease inhibitors
P450 inducers can lower plasma levels of PIs andencourage viral resistance
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