Transcript Treatment of Varicella-Zoster Virus Infections

In the Name of Allah,
the Beneficent,
the Merciful
ANTIVIRALS
Azam Bakhtiarian
Dept. of Pharmacology
Viruses, what are they?
• Viruses are all parasites of the living
• They use the cell’s materials to build
themselves
Viruses
• Unable to replicate on
their own
• Assemble to viruses
once in host cell
• DNA virus made of
DNA and protein coat
• RNA virus made of
RNA and protein
Viral Life Cycle at the
Cellular Level
1. Entry of genetic information
2. Replication of genetic information
3. Assembly and release of virions
Viruses
• Steps for Viral Replication
– 1) adsorption and penetration into cell
– 2) uncoating of viral nucleic acid
– 3) synthesis of regulatory proteins
– 4) synthesis of RNA or DNA
– 5) synthesis of structural proteins
– 6) assembly of viral particles
– 7) release from host cell
•
»
•
DRUGS FOR
INFLUENZA
Amantadine
•
•
•
•
Rimantadine
Active against influenza type A, not type B
Inhibit viral uncoating
increase lysosomal pH
Oral, long half-life; amantadine excreted
renally
• Can prevent influenza A
• Can treat influenza A if used early
M2 inhibitors: Mechanism
Neuraminidase
Hemagglutinin
RNA
H+
H+
H+
H+
X
M2 inhibitors
M2 protein
(only on type A)
• M2 channel allows acidification
of virus
• Initiates uncoating of viral RNA
• Allows viral replication
• M2 inhibitors block this action
Amantadine
Use: Flu prophylaxis , Anti – Parkinson
SE: CNS (nervousness, dizziness, slurred speech, insomnia,
hallucination, depression)
GI (anorexia, nausea, constipation)
↓dosage with renal problems
NEURAMINIDASE INHIBITORS
Zanamivir (Relenza); Oseltamivir (Tamiflu)
• Block release of new virions from infected
cells.
• Inhibit influenza A and B .
• Zanamivir is a powder given by oral
inhalation, can cause bronchospasm;
Oseltamivir is given by mouth, cause N,V.
• Less toxic than the older agents, but are
more expensive
Antiviral agents for
influenza:
two classes of drugs
• Matrix protein (M2) inhibitors
– amantadine and rimantadine
– inhibit virus uncoating
– influenza A only
• Neuraminidase inhibitors
– oseltamivir and zanamivir
– inhibit release of virus from infected
cells
– active against all known strains of
influenza
DRUGS FOR
INFLUENZA
• INHIBITORS OF VIRAL UNCOATING:
Amantadine and Rimantadine
Active against influenza type A
• NEURAMINIDASE INHIBITORS
Zanamivir (Relenza); Oseltamivir (Tamiflu)
Active against influenza type A&B
DRUG FOR RSV
& INFLUENZA
• Ribavirin is a guanosine analog that is
phosphorylated by host cell .
• Inhibit the viral RNA-dependent RNA
polymerase of influenza A and B,
respiratory syncytial virus, and HIV-1.
• Hemolytic anemia (Systemic Therapy)
• Bronchospasm (Aerosol Therapy)
DRUGS FOR RSV
• Palivizumab
• is a humanized monoclonal antibody
directed against the F glycoprotein
on the surface of RSV.
• For the prevention of RSV infection
in high-risk infants and children such
as premature infants .
• Adverse effect : elevation in serum
aminotransferase levels.
DRUGS FOR
HSV OR VZV
ACYCLOVIR
(Zovirax)
• Spectrum: HSV-1 > HSV-2 > VZV > EBV >> CMV
• Mechanism:
– HSV thymidine kinase produces mono-P
– Host completes phosphorylation to tri-P
– Triphosphate inhibits viral DNA polymerase and acts
as chain terminator
• Resistance: TK (important) , VDP
• Route: IV, oral (20% bioavailability), or topical
• Excretion: Renal
Mechanism of Resistance
Acyclovir
• Alteration in viral thymidine kinase
• Alteration in viral DNA polymerase
• Cross-resistance with valacyclovir,
famciclovir, and ganciclovir
ACYCLOVIR
(Zovirax)
Herpes
Herpes
(topical): 5% ointment
reduces viral shedding/improves
healing
SE: burning, stinging
(PO): 200mg q 4 h for 10 days
shortens clinical course/ ↓pain
SE: N/V, diarrhea, rash
Acyclovir - Clinical Use
•Herpes Simplex Virus:
– Genital - primary, recurrent, and suppressive
– Orolabial - suppressive
– HSV encephalitis - drug of choice, prevents
death
•Varicella-Zoster Virus:
– Immunocompromised
– Chickenpox
– EBV: Oral hairy leukoplakia in AIDS
•CMV: Protective at renal or marrow
transplantation
Orolabial Herpes Simplex Virus
Chickenpox
(Varicella-Zoster
Virus)
Oral Hairy Leukoplakia
in AIDS (Epstein-Barr Virus)
Newer Oral Anti-Herpes Drugs
• Prodrugs that are converted to active agents when passing
through intestinal wall or liver, to achieve higher levels than
oral acyclovir
– Valacyclovir (Valtrex): prodrug of acyclovir (48%)
• recurrent genital herpes
• genital herpes suppression
• in preventing CMV after organ transplantation
• SE: In AIDS patients receiving high-dosage of Val
thrombotic thrombocytopenic purpura and hemolyticuremic
syndrome.
Newer Oral Anti-Herpes Drugs
Famciclovir (Famvir): prodrug of penciclovir (70%)
- active against HSV-1, HSV-2, VZV, EBV, and HBV.
- phosphorylation by the virus-specified thymidine kinase
- inhibition of the viral DNA polymerase
- Penci-3P has lower affinity for the viral DNAP than AC3P
- SE: headache, diarrhea, and nausea
incidence of mammary adenocarcinoma was also increased
In female rats receiving famciclovir for 2 years.
Famciclovir - Clinical Use
•Herpes Simplex Virus:
– Genital - primary, recurrent, and suppressive
– Varicella-Zoster Virus:
– Immunocompromised
– acute herpes zoster (shingles).
– associated with a shorter duration of
postherpetic neuralgia.
Trifluridine-Herpes Drugs
Spectrum: HSV-1 , HSV-2
Mechanism: inhibits viral DNA synthesis (host)
after phosphorylation by host Enz
Used in:
Acyclovir Resistance HSV-infection
keratoconjunctivitis,
Epithelial keratitis
Route:
Topical (1% Sol.)
(No systemic use)
DRUGS FOR
CMV
Ganciclovir
(Cytovene)
• Useful for CMV but also covers HSV, VZV
• Triphosphate inhibits viral DNA polymerase
• Intravenous for therapy of disease;
oral for maintenance or prophylaxis
• Renal excretion
• For CMV retinitis (especially);
also for colitis, Pneumonitis
Approval of oral valganciclovir is a major advance
Ganciclovir
(Cytovene)
SE: Bone marrow depression
Neutropenia
Anemia
Rash, fever
N/V
Liver dysfunction
Cidofovir
• is a cytosine nucleotide analog with in vitro
activity against CMV, HSV-1, HSV-2, VZV, EBV
• Phosphorylation of cidofovir to the active
diphosphate is independent of viral enzymes.
• inhibiting DNA synthesis
• IV for the treatment of CMV retinitis.
• Prevent nephrotoxicity : admin. + probenecid
which blocks active tubular secretion
SE: neutropenia and metabolic acidosis (Rare)
Fomivirsen
• is an oligonucleotide that inhibits CMV
through an antisense mechanism.
• inhibiting virus replication.
• No cross-resistance with ganciclovir,
cidofovir, foscarnet
• in patients with AIDS and patients who are
intolerant of or unresponsive to alternative
therapies.
Drugs used for
Opthalmological Infections by
HSV & CMV
• Cidofovir: active against retinitis
CMV & HSV, acyclovir-Resis
Fomiversin: against retinitis CMV
• Trifluridine: treatment of herpetic
keratitis (topical) , acyclovir-Resis
Retinitis
in
left eye
(CMV)
Foscarnet
(Foscavir)
• Analogue of pyrophosphate
• Inhibits viral DNA polymerase
• Intravenous route only
• Renal excretion
• Very toxic – Nephrotoxic, hallucination, seizures
• For CMV retinitis, acyclovir-resistant HSV or VZV
Therapy for Herpes Viruses
• Herpes simplex or zoster
– Acyclovir
– Foscarnet, trifluridine,
Cidofovir
• Cytomegalovirus
– Ganciclovir
– Foscarnet, Fomivirsen
DRUGS FOR
HIV
Drugs for HIV Infection
• Reverse Transcriptase (RT) Inhibitors
– Nucleoside (or tide) RT inhibitors (NRTIs)
• First there was AZT alone
• Then there was AZT and ddI and ddC
• Now there is AZT, ddI,ddC, d4T, 3TC, ABC, FTC
(and Tenofovir (TDF), a nucleotide RT inhibitor)
– Non-nucleoside RT inhibitors (NNRTIs)
• First there was nevirapine, Delavirdine, Efavirenz
• Protease Inhibitors
– There are now 8, which have revolutionized the
care of people with HIV infection
Zidovudine
(Azidothymidine, AZT,
ZDV, Retrovir)
• Mechanism:
– Phosphorylated by host enzymes
– Tri-P inhibits viral DNA polymerase
– Acts as chain terminator
• Resistance is common with continued use
• Oral or IV, gets into CSF, short half-life
• Can diminish perinatal transmission (the 26% risk
drops to 8%) when given in the latter part of
pregnancy and to the infant for 6 wks
Zidovudine
(Azidothymidine, AZT,
ZDV, Retrovir)
Side Effects:
Bone marrow depression
Anemia, thrombocytopenia
N/V, Liver problems
Tremors, confusion, anxiety
Drug interactions
• Increased serum levels of AZT:
probenecid, phenytoin, methadone,
fluconazole, valproic acid, and
lamivudine, either through inhibition
of first-pass metabolism or
decreased clearance.
• AZT decrease phenytoin levels
Nucleoside Analogue RT Inhibitors
• Zidovudine (AZT, ZDV, Retrovir)
• Didanosine (dideoxyinosine, ddI, Videx)
• Zalcitabine (dideoxycytidine, ddC, Hivid)
• Stavudine (d4T, Zerit)
• Lamivudine (3TC, Epivir)
• Abacavir (ABC, Ziagen)
• Emtricitabine (FTC, Emtriva)
• Tenofovir (TDF, Viread) - Actually a nucleotide
• AZT causes neutropenia, anemia, myopathy
• ddI causes pancreatitis
• ddI, ddC, d4T cause peripheral neuropathy
• Abacavir can cause a fatal hypersensitivity rxn
• All can cause fatal lactic acidosis, steatosis
Non-Nucleoside RT Inhibitors
• Binds to a site on the HIV RT and blocks
DNA polymerase activity.
• Resistance occurs rapidly if used alone
• Three are FDA-approved
– Nevirapine (Viramune) **
– Delavirdine (Rescriptor)
– Efavirenz (Sustiva)
** can prevent perinatal transmission
Protease Inhibitors
• Block virion maturation
• More potent than RT inhibitors
• Resistance occurs rapidly if used alone
• Many drug interactions via hepatic enzymes
• Inhibitors of CYP3A *
• 8 are FDA-approved:
- Saquinavir (Fortovase)*
- Ritonavir (Norvir)*
- Indinavir (Crixivan)*
- Nelfinavir (Viracept)*
- Amprenavir (Agenerase)*
- Fosamprenavir (Lexiva)
- Lopinavir / Ritonavir (Kaletra)* - Atazanavir (Reyataz)
Fusion Inhibitors
• First one approved in 2003
• Enfuvirtide (T-20, Fuzeon)
• Acts early to block virus entry
• Painful SC injections twice daily
• Costs $20,000 per year
• Clinical role likely to be limited
APPROVED ANTIRETROVIRAL DRUGS
Target (Class)
Reverse
Transcriptase
( N R T I 's )
( N N R T I 's )
Protease
( P I 's )
Entry
3
Generic
Brand
Manufacturer
Date
Zidovudine (AZT,ZDV)
Didanosine (ddI)
Zalcitabine (ddC)
Stavudine (d4T)
Lamivudine (3TC)
AZT / 3TC
Abacavir (ABC)
AZT / 3TC / ABC
Tenofovir (TDF) *
Emtricitabine (FTC)
Nevirapine (NVP)
Delavirdine (DLV)
Efavirenz (EFV)
Saquinavir (SQV-hard gel)
Saquinavir (SQV-soft gel)
Ritonavir (RTV)
Indinavir (IDV)
Nelfinavir (NFV)
Amprenavir (APV)
Lopinavir/Ritonavir (LPV/r)
Atazanavir (ATV)
Fosamprenavir (FPV)
Enfuvirtide (T-20)
Retrovir
Videx
Hivid
Zerit
Epivir
Combivir
Ziagen
Trizivir
Viread
Emtriva
Viramune
Rescriptor
Sustiva
Invirase
Fortovase
Norvir
Crixivan
Viracept
Agenerase
Kaletra
Reyataz
Lexiva
Fuzeon
GlaxoSmithKline
Bristol-Myers Squibb
Hoffman-La Roche
Bristol-Myers Squibb
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
GlaxoSmithKline
Gilead
Gilead
Boehringer Ingelheim
Pharmacia & Upjohn
Bristol-Myers Squibb
Hoffman-La Roche
Hoffman-La Roche
Abbott
Merck
Agouron
GlaxoSmithKline
Abbott
Bristol-Myers Squibb
GlaxoSmithKline
Hoffman-La Roche
1987
1991
1992
1994
1995
1997
1998
2000
2001
2003
1996
1997
1998
1995
1997
1996
1996
1997
1999
2000
2003
2003
2003
20 Unique Agents
23 Drugs
9 Companies
17 Years
HAART
• Highly active antiretroviral therapy
• A combination of stavudine and
nevirapine
• Reducing plasma HIV RNA levels
• Increasing CD4 cell counts,
• Tolerability, and convenience.
• Close monitoring of viral load and CD4
cell counts is critical to trigger appropriate
changes in therapy.
DRUGS FOR
Hepatitis
Lamivudine( 3TC)
•
•
•
•
•
•
3 ThiaCytidine (3TC)
Cytosine analogue
Interferes with viral DNA polymerase
Highly active against HIV-1
Active against HBV
Toxicity: Pancreatitis, Lactic acidosis
– Hepatomegaly with steatosis
Hepatitis B
• Response to lamivudine is more
rapid than to interferon.
• with HBV DNA levels decreasing by
97% after 2 weeks of therapy.
Hepatitis B
•
•
•
•
Adefovir developed for treatment of HIV
at lower and less toxic doses, for HBV
is a nucleotide analog.
phosphorylated by cellular kinases to the
active diphosphate metabolite
• competitively inhibits HBV DNA Pol.
results in chain termination after
incorporation into the viral DNA.
Ribavirin
• Synthetic guanosine analogue
• Once phosphorylated
• Interferes with Transcription of viral
RNA
• Ribavirin capsules in combination
with subcutaneous interferon alfa-2b
are effective for chronic HCV.
Interferons
• Endogenous proteins
• induce host cell enzymes that inhibit
viral RNA translation and cause
degradation of viral mRNA and tRNA
• 3 classes: IFN-, IFN- and IFN-g
• IFN- for HBV and HCV virus
Interferon Alfa
Adverse Effects
•
•
•
•
A flu-like syndrome
thrombocytopenia,
granulocytopenia,
elevation in serum aminotransferase
levels, induction of autoantibodies,
• nausea, fatigue, headache,
arthralgias, rash, alopecia, anorexia,
hypotension, and edema.
Hepatitis C
• Pegylated interferon alfa-2a and
pegylated interferon alfa-2b
• In these (PEG) moiety is attached to
interferon by a covalent bond.
Reduced clearance and sustained
absorption results in an increased
T1/2 and steadier drug conc. allowing
for less frequent dosing.
AVAILABLE ANTIVIRAL DRUGS
For RNA Amantadine / Rimantadine Influenza A
Viruses Zanamivir / Oseltamivir
Influenza A and B
Ribavirin
RSV, HepC
For DNA Idoxuridine / Trifluridine / Vidarabine HSV keratitis
Viruses Acyclovir
HSV, VZV, ?EBV
Penciclovir
HSV
Valacyclovir / Famciclovir HSV, VZV
Ganciclovir / Valganciclovir CMV, (HSV, VZV)
Foscarnet
CMV, HSV, VZV
Cidofovir, Fomivirsen
CMV
Lamivudine, Adefovir
Hep B
For HIV 11 different reverse transcriptase inhibitors
8 different protease inhibitors, 1 fusion inhibitor
AVAILABLE ANTIVIRAL DRUGS
For RNA Amantadine / Rimantadine
Viruses Zanamivir / Oseltamivir
Ribavirin
For DNA Idoxuridine / Trifluridine / Vidarabine
Viruses Acyclovir
Influenza A
Influenza A and B
RSV, HepC
HSV keratitis
HSV, VZV, ?EBV
Penciclovir
HSV
Valacyclovir / Famciclovir HSV, VZV
Ganciclovir / Valganciclovir CMV, (HSV, VZV)
Foscarnet
CMV, HSV, VZV
Cidofovir, Fomivirsen
CMV
Lamivudine, Adefovir
HepB
For HIV 11 different reverse transcriptase inhibitors
8 different protease inhibitors, 1 fusion inhibitor
Misc.
7 interferon alfas for HepC, HepB, HHV8, Papillomav.
Potential Future Antiretrovirals
• Entry inhibitors
– Attachment inhibitors: soluble CD4 or antibodies
– Coreceptor inhibitors: to block CXCR4 or CCR5
– Fusion inhibitors: to block final step of entry
• Integrase inhibitors to block integration
• Tat inhibitors to block viral gene expression
• Zinc-finger inhibitors to block nucleocapsid
during assembly of new virions
• Vaccination (preventive and/or therapeutic)
PAYAN
• Protease Inhibitors
• During the later stages of the HIV growth cycle,
the Gag and Gag-Pol gene products are
translated into polyproteins and then become
immature budding particles. Protease is
responsible for cleaving these precursor
molecules to produce the final structural proteins
of the mature virion core. By preventing cleavage
of the Gag-Pol polyprotein, protease inhibitors
result in the production of immature,
noninfectious viral particles.
New therapies
• once-daily dosing, smaller pill size, lower
incidences of adverse effects, new viral targets,
and activity against virus that is resistant to other
agents.
• Agents under evaluation or reformulation for
once-daily dosing include stavudine and
nevirapine. The NRTI agents amdoxovir and
emtricitabine, the NNRTI agents DPC-083 and
TMC- 125, and the protease inhibitors atazanavir,
tipranavir, and fosamprenavir (the prodrug of
amprenavir) are among the new agents currently
in development. In addition, new drug classes
such as entry inhibitors and integrase inhibitors
are under clinical investigation.
Sites of Drug Action