Introduction to Autonomic Nervous System Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)
Antiviral agents Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)
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Transcript of Antiviral agents Pawitra Pulbutr M.Sc. In Pharm (Pharmacology)
Antiviral agents
Pawitra PulbutrPawitra Pulbutr
M.Sc. In Pharm (Pharmacology)M.Sc. In Pharm (Pharmacology)
วั�ตถุ�ประสงค์�เชิ�งพฤต�กรรมวั�ตถุ�ประสงค์�เชิ�งพฤต�กรรม
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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