Mr. Norazli Ghadin Dr.T.V.Rao MD 1 INTRODUCTION TO MEDICAL MICROBIOLOGY.
11/18/12 Dr.T.V.Rao MD 2 - courseware.cutm.ac.in
Transcript of 11/18/12 Dr.T.V.Rao MD 2 - courseware.cutm.ac.in
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Understanding VirusesUnderstanding VirusesThey are different from other MicrobesThey are different from other Microbes
Viral replicationViral replication
• A virus cannot replicate on its own• It must attach to and enter a host
cell• It then uses the host cell’s energy to
synthesize protein, DNA, and RNA
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Understanding VirusesUnderstanding Viruses
Viruses are difficult to kill because they live inside the cells• Any drug that kills a virus may also kill cells
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Antiviralsavailable for many viral infections
Viruses controlled by current antiviral therapy
• Cytomegalovirus (CMV)• Hepatitis viruses• Herpes viruses• Human immunodeficiency virus (HIV)• Influenza viruses (the “flu”)• Respiratory syncytial virus (RSV)
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Anti-viral drugsAnti-viral drugs• Viruses have no cell wall and made up of
nucleic acid components• Viruses containing envelope – antigenic in
nature• Viruses are obligate intracellular
parasite• They do not have a metabolic machinery
of their own – uses host enzymes
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Anti-viral drugsAnti-viral drugs• Certain viruses
multiply in the cytoplasm but others do in the nucleus
• Most multiplication take place before diagnosis is made
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Anti-Viral drugs• Many antiviral drugs are Purine or
Pyrimidine analogs.• Many antiviral drugs are Prodrugs.
They must be phosphorylated by viral or cellular enzymes in order to become active.• Anti-viral agents inhibits active
replication so the viral growth resumes after drug removal.
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Antivirals how they act Key characteristics of antiviral drugs
Able to enter the cells infected with virus
Interfere with viral nucleic acid synthesis and/or regulation
Some drugs interfere with ability of virus to bind to cells
Some drugs stimulate the body’s immune system
Best responses to antiviral drugs are in patients with competent immune systems
A healthy immune system works synergistically with the drug to eliminate or suppress viral activity
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Antiviral MedicationsAntiviral drugs
Used to treat infections caused by viruses other than HIVAntiretroviral drugs
Used to treat infections caused by HIV, the virus that causes AIDS
Herpes-Simplex Viruses HSV-1 (oral herpes) HSV-2 (genital herpes)
Varicella Zoster Virus Chickenpox Shingles
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Antiviral Drugs: Nonretroviral Mechanism of action
Inhibit viral replication
Used to treat non-HIV viral infections Influenza viruses HSV (herpes simplex virus), VZV (vericella zoster virus) CMV (cytomegalovirus) Hepatitis A, B, C (HAV, HBV, NCV)
Adverse Effects Vary with each drug Healthy cells are often killed also, resulting in serious toxicities
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Anti-viral drugs• Current anti-viral agents do not eliminate
non-replicating or latent virus• Effective host immune response remains
essential for the recovery from the viral infection
• Clinical efficacy depends on achieving inhibitory conc. at the site of infection within the infected cells
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Anti-viral drugsAnti-viral drugsStages of viral replication• Cell entry – attachment
- penetration • Uncoating• Transcription of viral genome• Translation • Assembly of virion components• Release
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Anti-viral drugsAnti-viral drugsAnti-herpes virus agents
• Acyclovir / Valacyclovir• Famciclovir / Penciclovir • Ganciclovir / Cidofovir • Foscarnet • Trif luridine / Idoxuridine /
Vidarabine11/18/12 Dr.T.V.Rao MD 15
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Anti-viral drugsAcyclovir & Congeners :• Valacyclovir is a prodrug of Acyclovir with
better bioavailability.• Famciclovir is hydrolyzed to Penciclovir
and has greatest bioavailability.• Penciclovir is used only topically whereas
Famciclovir can be administered orally.
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Anti-Viral drugsPHARMACOLOGY
OF ACYCLOVIR AND CONGENERS
• Acyclovir, Valacyclovir, Ganciclovir, Famciclovir, Penciclovir all are guanine nucleoside analogs.
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Anti-viral drugsMechanism of action of Acyclovir and
congeners :• All drugs are phosphorylated by a viral
thymidine-kinase, then metabolized by host cell kinases to nucleotide analogs.• The analog inhibits viral DNA-
polymerase• Only actively replicating viruses are
inhibited 11/18/12 Dr.T.V.Rao MD 18
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Anti-viral drugsAnti-viral drugs• Acyclovir is thus
selectively activated in cells infected with herpes virus.• Uninfected cells
do not phosphorylate acyclovir.11/18/12 Dr.T.V.Rao MD 19
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Mechanism of Action of Acyclovir
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Anti-Viral drugsAnti-Viral drugsAntiviral spectrum :• Acyclovir: HSV-1, HSV-2, VZV, Shingles.• Ganciclovir / Cidofovir : CMV• Famciclovir : Herpes genitalis and
shingles• Foscarnet : HSV, VZV, CMV, HIV• Penciclovir : Herpes labialis • Trifluridine : Herpetic keratoconjunctivitis
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Anti-Viral drugsAnti-Viral drugsPharmacokinetics of Acyclovir :• Oral bioavailability ~ 20-30% • Distribution in all body tissues
including CNS • Renal excretion: > 80% • Half lives: 2-5 hours• Administration: Topical, Oral , IV11/18/12 Dr.T.V.Rao MD 22
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Anti-viral drugsAnti-viral drugs
Adverse effects of Acyclovir / Ganciclovir • Nausea, vomiting and diarrhea • Nephrotoxicity - crystalluria,
haematuria, renal insufficiency• Myelosuppression – Neutropenia
and thrombocytopenia – Ganciclovir
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Anti-viral drugsTherapeutic uses :Acyclovir is the drug of choice for:• HSV Genital infections• HSV encephalitis • HSV infections in immunocompromised patientGanciclovir is the drug of choice for:• CMV retinitis in immunocompromised patient• Prevention of CMV disease in transplant patients
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Anti-viral drugsAnti-viral drugsCidofovir :• It is approved for the treatment of CMV
retinitis in immunocompromised patients• It is a nucleotide analog of cytosine – no
phosphorylation required.• It inhibits viral DNA synthesis• Available for IV, Intravitreal inj, topical• Nephrotoxicity is a major disadvantage.
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Anti-viral drugsAnti-viral drugsPHARMACOLOGY OF
VIDARABINE • Vidarabine is a nucleoside analog.
(adenosine) Antiviral spectrum of Vidarabine : HSV-1, HSV-2 and VZV.Its use is limited to HSV keratitis only
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Anti-viral drugsVidarabine• The drug is converted to its triphosphate
analog which inhibits viral DNA-polymerase.
• Oral bioavailability ~ 2%• Administration: Ophthalmic ointmentOphthalmic ointment• Used in HSV keratoconjunctivit is in Used in HSV keratoconjunctivit is in
immunocompromised patient.immunocompromised patient. • Anemia and SIADH are adverse
effects.11/18/12 Dr.T.V.Rao MD 27
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Anti-viral drugsPHARMACOLOGY OF TRIFLURIDINE • Trifluridine is a Pyrimidine nucleoside
analogs - inhibits viral DNA synthesis. Antiviral spectrum Trif luridine :• HSV-1, HSV-2 and VZV. • Use is limited to Topical - Ocular HSV
Keratitis
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Anti-viral drugs
PHARMACOLOGY OF FOSCARNET • Foscarnet is an inorganic
pyrophosphate analog • It directly inhibits viral DNA and RNA
-polymerase and viral inverse transcriptase (it does not require phosphorylation for antiviral activity)
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Anti-viral drugsAnti-viral drugsFoscarnet • HSV-1, HSV-2, VZV, CMV and
HIV.• Oral bioavailability ~ 10-20%• Distribution to all tissues
including CNS• Administration: IV11/18/12 Dr.T.V.Rao MD 30
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Anti-viral drugsAnti-viral drugsAdverse effects of Foscarnet • Hypocalcemia and hypomagnesemia (due
to chelation of the drug with divalent cations) are common.
• Neurotoxicity (headache, hallucinations, seizures)
• Nephrotoxicity (acute tubular nephrosis, interstitial nephritis)
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Anti-viral drugsAnti-viral drugsTherapeutic uses of Foscarnet
• I t is an alternative drug for• HSV infections (acyclovir resistant
/ immunocompromised patient )• CMV retinitis (ganciclovir resistant
/ immunocompromised patient )
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Anti-viral drugsAnti-viral drugsRespiratory viral infectionsInfluenza –• Amantadine / Rimantadine• Oseltamivir / Zanamavir
(Neuraminidase inhibitors)RSV bronchiol it is –• Ribavirin11/18/12 Dr.T.V.Rao MD 33
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Anti-viral drugsAnti-viral drugsAmantadine and Rimantadine :
Influenza• Prevention & Treatment of influenza A• Inhibit ion of viral uncoating by
inhibiting the viral membrane protein M2• Influenza A virus • Amantadine has anti-parkinsonian
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Anti-viral drugsAnti-viral drugsPharmacokinetics of Amantadine
• Oral bioavailability ~ 50-90%• Amantadine cross extensively
BBB whereas Rimantadine does not cross extensively . • Administration: Oral 11/18/12 Dr.T.V.Rao MD 35
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Anti-viral drugsNeuraminidase inhibitors : Influenza
Oseltamivir / Zanamavir • Influenza contains an enzyme
neuraminidase which is essential for the replication of the virus.
• Neuraminidase inhibitors prevent the release of new virions and their spread from cell to cell.
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Anti-viral drugsNeuraminidase inhibitors : Influenza
Oseltamivir / Zanamavir • These are effective against both types of
influenza A and B.• Do not interfere with immune response to
influenza A vaccine.• Can be used for both prophylaxis and
acute treatment.
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Anti-viral drugs
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Anti-viral drugsAnti-viral drugsNeuraminidase inhibitors :
Influenza Oseltamivir / Zanamavir • Oseltamivir is orally administered.• Zanamavir is given intranasal. • Risk of bronchospasm with
zanamavir11/18/12 Dr.T.V.Rao MD 39
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Anti-viral drugsAnti-viral drugs
PHARMACOLOGY OF RIBAVIRIN • Ribavirin is a guanosine analog. • Inhibit ion of RNA polymeraseAntiviral spectrum : DNA and RNA
viruses are susceptible, including influenza, parainfluenza viruses, RSV, Lassa virus
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Anti-viral drugsAnti-viral drugsRibavirin : RSV• Distribution in all body tissues, except
CNS • Administration : Oral, IV, Inhalational
in RSV.• Anemia and jaundice are adverse
effects• Not advised in pregnancy.11/18/12 Dr.T.V.Rao MD 41
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Anti-viral drugsTherapeutic uses RibavirinRibavirin is the drug of choice for:• RSV bronchiolitis and pneumonia in
hospitalized children (given by aerosol)• Lassa fever Ribavirin is an alternative drug for:• Influenza, parainfluenza, measles virus
infection in immunocompromised patients
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Anti-viral drugsAnti-viral drugsHepatic Viral infections :• Interferons• Lamivudine – cytosine analog – HBV • Entecavir – guanosine analog – HBV
– lamivudine resistance strains• Ribavirin – Hepatitis C (with
interferons)
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Anti-viral drugsAnti-viral drugsInterferons Interferons (IFNs) are natural proteins
produced by the cells of the immune systems in response to challenges by foreign agents such as viruses, bacteria, parasites and tumor cells.
• Antiviral, immune modulating and anti-proliferative actions
• Three classes of interferons – α , β, γ
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Anti-viral drugsInterferons• α and β interferons are produced by
all the cells in response to viral infections
• γ interferons are produced only by T lymphocyte and NK cells in response to cytokines – immune regulating effects
• γ has less anti-viral activity compared to α and β interferons
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Anti-viral drugsMechanism of action of Interferons :• Induction of the following enzymes:1) a protein kinase which inhibits protein
synthesis2) an oligo-adenylate synthase which leads to
degradation of viral mRNA3) a phosphodiesterase which inhibit t-RNA The action of these enzymes leads to an
inhibit ion of translation
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Anti-viral drugsAntiviral spectrum :
Interferon α • Includes HBV, HCV
and HPV.• Anti-proliferative
actions may inhibit the growth of certain cancers - like Kaposi sarcoma and hairy cell leukemia.
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Anti-viral drugsPharmacokinetics :
Interferons • Oral bioavailability: <
1% • Administered
Intralesionally, S.C, and I.V
• Distribution in all body tissues, except CNS and eye.
• Half lives: 1-4 hours
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Anti-viral drugsAnti-viral drugsAdverse effects of Interferons • Acute flu-like syndrome (fever,
headache)• Bone marrow suppression
(granulocytopenia, thrombocytopenia)• Neurotoxicity (confusion, seizures)• Cardiotoxicity - arrhythmia• Impairment of fertility
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Anti-viral drugsAnti-viral drugsTherapeutic uses Interferons • Chronic hepatitis B and C (complete disappearance is
seen in 30%).• HZV infection in cancer patients (to prevent the
dissemination of the infection)• CMV infections in renal transplant patients• Condylomata acuminata (given by intralesional
injection). Complete clearance is seen ~ 50%.• Hairy cell leukemia (in combination with zidovudine)• AIDS related Kaposi’s sarcoma
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Virus
Diseases Drug(s) of choice
Alternative drugs
FLU A
Influenza
Amantadine Rimantadine
RSV Pneumonia,bronchiolitis
Ribavirin(aerosol)
HSV
Genital herpes
Acyclovir
Foscarnet
Keratitis
Conjunctivitis
Trifluridine IdoxuridineVidarabine
Encephalitis
Acyclovir
Neonatal HSV
infection
Acyclovir
Vidarabine Herpes infections in
immuno- compromised host
Acyclovir
Foscarnet11/18/12 Dr.T.V.Rao MD 51
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VZV
In normal host
No therapy
In immunocompro-mised host, or during pregnancy
Acyclovir
Foscarnet
CMV
Retinitis
Ganciclovir
Foscarnet
HIV
AIDSHIV antibody positive with CD4 count < 500/mm3
Zidovudine ± protease inhibitors
Didanosine,Stavudine
HBVHCV
Hepatitis B, C
Interferons
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Antiretroviral DrugsHAART - Highly active
antiretroviral therapy
• Includes at least three medications– “cocktails”
• These medications work in different ways to reduce the viral load
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Antiretroviral Drugs• Reverse transcriptase inhibitors (RTIs)– Block activity of the enzyme reverse transcriptase, preventing
production of new viral DNA
• Reverse transcriptase inhibitors (RTIs)– Nucleoside RTIs (NRTIs)– Nonnucleoside RTIs (NNRTIs)– Nucleotide RTIs (NTRTIs)
• Examplesabacavir (Ziagen) delavirdine (Rescriptor)didanosine (Videx) lamivudine (Epivir)stavudine (Zerit) tenofovir (Viread)
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Antiretroviral Drugs• Protease inhibitors
(PIs)– Inhibit the protease
retroviral enzyme, preventing viral replication
– Examples:
amprenavir (Agenerase)indinavir (Crixivan)
nelfinavir (Viracept)ritonavir (Norvir)
saquinavir (Invirase)11/18/12 Dr.T.V.Rao MD 55
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Antiretroviral DrugsAntiretroviral Drugs• Fusion inhibitors– Inhibit viral fusion,
preventing viral replication
– Newest class of antiretroviral drugs
– Example: enfuvirtide (Fuzeon)
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Antiretroviral Drugs• Combinations of multiple
antiretroviral medications are common• Adverse effects vary with each drug
and may be severe−monitor for dose-limiting toxicities• Monitor for signs of opportunistic
diseases11/18/12 Dr.T.V.Rao MD 57