Antiviral agents

Pawitra PulbutrPawitra Pulbutr

M.Sc. In Pharm (Pharmacology)M.Sc. In Pharm (Pharmacology)

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VirusVirus

• Intracellular parasite

• Nucleic acid + protein coat = Nucleocapsid

• Infective particle = Virion

• No metabolic machinery

• Host cells is needed for viral replication

ชิน�ดื้ข้องไวัร�ส โรค์/ อาการแสดื้งI.DNA virus1.Poxvirus2.Herpesvirus3.Adenovirus4.PapillomavirusII. RNA virus1.Orthomyxovirus2.Paramyxovirus3.Rubellavirus4.Rhabdovirus5.Picornavirus6.Retrovirus7.Arenavirus8.Hepadenavirus9.Arbovirus

Small poxChickenpox, Shingles, Cold soresSore throat, conjunctivitisWarts

InfluenzaMeasles, MumpsGerman measlesRabiesColds, Meningitis, PoliomyelitisAIDSMeningitis, Lassa feverSerum hepatitisArthropod-borne encephalitis

Viral replication

Attachment• receptor of receptor of NTs, cytokines, NTs, cytokines, hormoneshormones

• HIV … CD4 RCHIV … CD4 RC

Early Early regulatory regulatory protein = protein =

polymerase polymerase enzymeenzyme

Viral DNA/ Viral DNA/ RNA RNA

synthesissynthesis

Structural Structural protein protein

synthesissynthesis

Blocked by enfuvirtide

(in HIV)

Antiviral agents

Antiherpes & Anticytomegalovirus Antiherpes & Anticytomegalovirus agentsagents

Antiretroviral agentsAntiretroviral agents

Antiinfluenza agentsAntiinfluenza agents

Antihepatitis virus agents Antihepatitis virus agents

Antiherpes & AnticytomegalovirusAcyclovirAcyclovir

• acyclic guanosine derivativeacyclic guanosine derivative

• HSV-1, HSV-2, VZVHSV-1, HSV-2, VZV

• CMV, EBV, HHVCMV, EBV, HHV

• Mechanism of actionMechanism of action

ACV

ACV -P

Viral Viral thymidine thymidine

kinasekinase

Host kinaseHost kinase

ACV-PP

ACV-PPP

Active Active formform

Mechanism of actionMechanism of action

o Acyclovir triphosphateAcyclovir triphosphate

o Inhibit DNA polymeraseInhibit DNA polymerase … competitive … competitive

o Incorporate into DNA and Incorporate into DNA and Chain terminationChain termination

Mechanism of resistanceMechanism of resistance

• Alteration of Alteration of viral thymidine kinase ***viral thymidine kinase ***

• Cross resistance with Cross resistance with valacyclovir, valacyclovir, famcyclovir, ganciclovirfamcyclovir, ganciclovir

• No cross resistance with No cross resistance with foscarnet, foscarnet, cidofovir, trifluridinecidofovir, trifluridine

• Alteration of DNA polymeraseAlteration of DNA polymerase

Clinical usesClinical uses

Route of administratio

n

Use Recommended Adult dosages

Oral Genital herpes treatment

200 mg 5 times daily or 400 mg q 8 h

HSV proctitis treatment 400 mg q 8 h

Genital herpes suppression

400 mg q 12 h or 200 mg q 8 h

Varicella 800 mg qid

Zoster 800 mg 5 times daily

Anti-CMV prophylaxis in organ transplantation

200 mg q 8 h or 800 mg q 12 h

Intravenous Herpes encephalitis 5 mg/ kg q 8 h

Varicella or zoster in an immunosuppressed host

10 mg/ kg q 8 hTopical … Primary HSV infection .. Less effective

GanciclovirGanciclovir

• Acyclic guanosine analogAcyclic guanosine analog

• Active in Active in triphosphate formtriphosphate form

GAN GAN-P• phosphotransferase UL 97 in CMV infected***

• viral thymidine kinase in HSV infected

Mechanism of actionMechanism of action

• Inhibit DNA polymeraseInhibit DNA polymerase

• Inhibit DNA elongationInhibit DNA elongation

Antiviral activityAntiviral activity

CMV, HSV, VZV, EBV, HHV-8CMV, HSV, VZV, EBV, HHV-8

Very good activity to CMV***Very good activity to CMV***

ResistanceResistance

UL 97 gene mutationUL 97 gene mutation

DNA polymerase mutationDNA polymerase mutation

thymidine kinase mutationthymidine kinase mutation

Cross resistance with Cross resistance with Cidofovir, Cidofovir, AcyclovirAcyclovir

P’kineticsP’kinetics

• Low oral bioavailabilty … 6-9%

• Renal excretionClinical uses….CMVClinical uses….CMV

Route of administratio

n

Use Recommended adult dosages

IV CMV retinitis Induction: 5 mg/ kg q 12 hMaintenance: 5 mg/ kg /day

Oral CMV retinitis treatment or prophylaxis

1 g q 8 h

Intraocular implant

CMV retinitis 1 implant q 5-8 monthsOthers… CMV colitis, CMV esophagitis, CMV

pneumonitis

ADRsADRs

• myelosuppression***myelosuppression*** esp. neutropenia

• CNS S/E… headache, changes in mental status, seizures

• Mitogenic to mammalian cells

• Carcinogenic & Embryotoxic in animals

Antiretroviral agentsAntiretroviral agents

Human Immunodeficiency Human Immunodeficiency Virus (HIV)Virus (HIV)

RNA virusRNA virus

Human Immunodeficiency Human Immunodeficiency Virus (HIV)Virus (HIV)

RNA virusRNA virus

AIDSAIDS

(Acquired Immune Deficiency (Acquired Immune Deficiency Syndrome)Syndrome)

AIDSAIDS• CD4 infectedCD4 infected

• Immune deficiencyImmune deficiency

• Opportunistic infectionOpportunistic infection

• Pneumocystic carinii Pneumocystic carinii Pneumonia Pneumonia (PCP)(PCP)

• Toxoplasma gondii … Toxoplasma gondii … ToxoplasmosisToxoplasmosis

• Mycobacterium avium complex (MAC)Mycobacterium avium complex (MAC)

• Mycobacterium tuberculosisMycobacterium tuberculosis

• Viral infection … CMVViral infection … CMV

• Fungal infection … Cyrptococcal meningitis, Fungal infection … Cyrptococcal meningitis, Oral candidiasisOral candidiasis

• TumorTumor

• Organ dysfunction … Brain, CVS, KidneyOrgan dysfunction … Brain, CVS, Kidney

• Finally … DEATHFinally … DEATH

Antiretroviral agents

Nucleoside reverse Nucleoside reverse transcriptase inhibitors transcriptase inhibitors (NRTIs)(NRTIs)

Non nucleoside reverse Non nucleoside reverse transcriptase inhibitors transcriptase inhibitors (NNRTIs)(NNRTIs)

Protease inhibitors (PIs)Protease inhibitors (PIs)

Fusion inhibitors (FIs)Fusion inhibitors (FIs)

Nucleoside reverse trancriptase inhibitorsNucleoside reverse trancriptase inhibitors

Mechanism of actionMechanism of action

• Inhibit HIV reverse transcriptaseInhibit HIV reverse transcriptase

• Incorporate into viral DNA … Chain Incorporate into viral DNA … Chain terminationtermination

• Active in Active in triphosphatetriphosphate formform• Zidovudine (Azidothymidine, Zidovudine (Azidothymidine, AZT)AZT)

• Didanosine (ddI)Didanosine (ddI)

• Zalcitabine (ddC)Zalcitabine (ddC)

• Stavudine (d4T)Stavudine (d4T)

• Lamivudine (3TC)Lamivudine (3TC)

• Abacavir (ABC)Abacavir (ABC)

• Emtricitabine (FTC)Emtricitabine (FTC)

NRTIsNRTIs

Thymidine Cytosine

Cytosine

Adenosine

Guanosine

Thymidine

TenofovirTenofovir

Non-nucleoside reverse transcriptase Non-nucleoside reverse transcriptase inhibitorsinhibitors

• NevirapineNevirapine

• DelavirdineDelavirdine

• EfavirenzEfavirenz

Mechanism of actionMechanism of action

• Inhibit reverse transcriptase enzyme at different Inhibit reverse transcriptase enzyme at different pointpoint

• No DNA incorporation*No DNA incorporation*

• No phosphorylation neededNo phosphorylation needed

• Use in combination with other group … Use in combination with other group … rapid rapid resistanceresistance

• No cross resistance with NRTIs or PIs**No cross resistance with NRTIs or PIs**

Protease Inhibitors (PIs)Protease Inhibitors (PIs)

• Inhibit Protease Enzyme … essential for mature structural protein

• Easy resistance … Use in combination

• **Major ADRs*Major ADRs*

• Altered body fat distribution … buffalo hump, truncal obesity, facial & peripheral atrophy

• Insulin resistance

• Hyperlipidemia, Hypertriglyceridemia

• Spontaneous bleeding in hemophilia

Protease Inhibitors (PIs)Protease Inhibitors (PIs)

• SSaquinaviraquinavir

• RRitonaviritonavir

• IIndinavirndinavir

• NNelfinavirelfinavir

• AAmprenavirmprenavir

• LLopinavir … opinavir … New New agentsagents

• FFosamprenavirosamprenavir

• AAtazanavirtazanavir

Fusion inhibitorFusion inhibitorFusion inhibitorFusion inhibitor Novel class of ARV use in HIV infectionNovel class of ARV use in HIV infection Enfuvirtide (FuzeonEnfuvirtide (Fuzeon®, T-20)®, T-20) Linear 36 aa synthetic peptideLinear 36 aa synthetic peptide Inhibit HIV fusion with CD4+ cellInhibit HIV fusion with CD4+ cell Bind to HR1 in gp 41 at viral glycoprotein Bind to HR1 in gp 41 at viral glycoprotein

envelopeenvelope Inhibit conformational change of Inhibit conformational change of

envelopeenvelope Inhibit HIV fusion Inhibit HIV fusion No cross resistance with other classNo cross resistance with other class Reserve >>> last option to be used***Reserve >>> last option to be used***

HAART; Highly Active AntiRetrovirus HAART; Highly Active AntiRetrovirus TherapyTherapy

• 3 Antiretrovirus in combinations

• NNRTIs based regimen NNRTIs based regimen

• NNRTIs + 2 NRTIs

• Efavirenz + 2 NRTIs (3TC + AZT/ Tenofovir/ d4T)

• PIs based regimenPIs based regimen

• PI + 2NRTIs

• Lopinavir/ RNV (kaletra®)+ 2NRTIs (3TC + AZT/ d4T)

• Triple NRTIs regimenTriple NRTIs regimen >>> 3 NRTIs

• ABC + 3TC + AZT/ d4T

Four drug regimenFour drug regimen

• 3 NRTIs + 1 PIs or NNRTIs3 NRTIs + 1 PIs or NNRTIs

• May be more effective in high viral load > May be more effective in high viral load > 100,000100,000

GPO vir® in ThailandGPO vir® in Thailand

S30 = d4T 30 + 3TC 150 + Nevirapine 200 S30 = d4T 30 + 3TC 150 + Nevirapine 200 mgmg

S40 = d4T 40 + 3TC 150 + Nevirapine 200 S40 = d4T 40 + 3TC 150 + Nevirapine 200 mg mg

Factors affecting anti-retroviral Factors affecting anti-retroviral regimenregimen

• P’kinetic profile

• Potency

• ADRs

• Tolerability

• Resistance

• Life style

• Drug interaction

• Advantage VS Disadvantage of ARV agents

• AZT + Ganciclovir … bone marrow suppression

• ddI + dapsone … altered absorption

• Clarithromycin …Enzyme inhibitor

• Rifampin … Enzyme inducer

Anti-influenza agents

• M2 InhibitorsM2 Inhibitors

• Amantadine

• Rimantadine

• Neuraminidase Neuraminidase inhibitorsinhibitors

• Zanamivir

• Oseltamivir

Amantadine and RimantadineAmantadine and Rimantadine

• Cyclic amine

• Mechanism of actionMechanism of action

• Inhibit viral uncoating

• Bind at M2 proteinM2 protein

• Effective to Influenza A only**Influenza A only**

• Easy mutation of M2 protein… drug resistance

Neuraminidase inhibitorsNeuraminidase inhibitors

• Zanamivir & OseltamivirZanamivir & Oseltamivir• Neuramidinase … essential for viral release & Neuramidinase … essential for viral release & viral penetrationviral penetration

• Effective both Influenza A & B**Effective both Influenza A & B**

• ZanamivirZanamivir

• Intranasal powder for inhalation.. Low oral bioavailability

• Rapid renal clearance

• OseltamivirOseltamivir

• Oral … prodrugprodrug … Activate in gut & liver into Oseltamivir carboxylate … active form

Viral hepatitisViral hepatitis

Hepatitis AHepatitis A Hepatitis BHepatitis B Hepatitis CHepatitis C Hepatitis DHepatitis D Hepatitis EHepatitis E

Interferon Interferon (IFN)(IFN)

PeginterferonPeginterferonRibavirinRibavirinLamivudine Lamivudine

(3TC)(3TC)AdefovirAdefovir

Anti-hepatitis agentsAnti-hepatitis agents

• Interferons … Interferons … IFN IFN αα, IFN , IFN ββ, IFN , IFN γγ .. .. Endogeneous proteinEndogeneous protein

• IFN IFN use in chronic hepatitis B & use in chronic hepatitis B & hepatitis C hepatitis C

• LamivudineLamivudine >>> chronic hepatitis B >>> chronic hepatitis B

• Adefovir Adefovir >>> chronic hepatitis B>>> chronic hepatitis B

• RibavirinRibavirin >>> chronic hepatitis C >>> chronic hepatitis C

PEG IFNPEG IFN Pegylated interferon Pegylated interferon Conjugated with polyethylene glycol Conjugated with polyethylene glycol

(PEG)(PEG) Longer half-life >>> 45 hrs … Once a Longer half-life >>> 45 hrs … Once a

weekweek Less clearanceLess clearance PEG IFN PEG IFN -2b (PEG Intron®)-2b (PEG Intron®)

Chronic hepatitis CChronic hepatitis C MonotherapyMonotherapy

1.0 1.0 g/ kg/ wk SC for 1 yearg/ kg/ wk SC for 1 year Combined with Combined with ribavirinribavirin

1.5 1.5 g/ kg/ wk SC + Ribavirin 800 mg/ dayg/ kg/ wk SC + Ribavirin 800 mg/ day PEG Intron powder for injectionPEG Intron powder for injection PEG Intron RedipenPEG Intron RedipenTMTM

Ribavirin (Rebetol®)Ribavirin (Rebetol®)

• Guanosine analogGuanosine analog

• Activate by phosphorylation

• Expected mechanism of actionExpected mechanism of action

• Inhibit Inhibit guanosine triphosphateguanosine triphosphate synthesissynthesis

• Inhibit RNA dependent RNA polymerase

• Hep C, Influenza A, B, Parainfluenza, RSV, Paramyxovirus

Adefovir dipivoxilAdefovir dipivoxil

Hepsera®Hepsera® Diester prodrug of adefovir Diester prodrug of adefovir Adefovir diphosphate = active Adefovir diphosphate = active Inhibit HBV DNA polymerase**Inhibit HBV DNA polymerase** Incorporate into DNA & chain Incorporate into DNA & chain

terminationtermination Active for HBV including lamivudine Active for HBV including lamivudine

resistanceresistance Clinical use >>> Clinical use >>> Active chronic Active chronic

hepatitis B infection in adultshepatitis B infection in adults 10 mg OD for 1 year10 mg OD for 1 year

Antiviral agentsAntiviral agents Antiherpes & Anti-CMVAntiherpes & Anti-CMV

Acyclovir & derivativesAcyclovir & derivatives Ganciclovir, FoscarnetGanciclovir, Foscarnet

AntiretrovirusAntiretrovirus NRTIsNRTIs NNRTIsNNRTIs PIsPIs FIsFIs

AntiinfluenzaAntiinfluenza M2 inhibitorsM2 inhibitors Neuraminidase inhibitorsNeuraminidase inhibitors

Antihepatitis Antihepatitis IFN/ PEG IFNIFN/ PEG IFN RibavirinRibavirin AdefovirAdefovir