Antiviral Agents 2009

8/2/2019 Antiviral Agents 2009

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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

Antiviral Agents 2009

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