anti viral agents
DESCRIPTION
ANTI VIRAL Agents. Kaukab Azim, MBBS, PhD Modified by: iSRAA. Viruses. Features of Antiviral Drugs Purine or pyrimidine analogs Prodrugs must be phosphorylated Antivirals have a narrow spectrum of action - PowerPoint PPT PresentationTRANSCRIPT
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ANTI VIRAL Agents
Kaukab Azim, MBBS, PhDModified by: iSRAA
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Viruses
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Features of Antiviral Drugs•Purine or pyrimidine analogs•Prodrugs must be phosphorylated•Antivirals have a narrow spectrum of action•Inhibit active replication; do not kill latent viruses, need host immune response •Resistance is common•Synergistic effects when given together•Efficacy relates to con. in infected cells •Start therapy early for optimal efficacy
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A good antiviral drug will
Interfere with a viral specific function
Only kill virus-infected cells
Prevent viral replication
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Sites Of Anti Viral Drug Action
Enfuvirtide, maraviroc
Indinavir
Oseltamivir
Reltegravir
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Classes
• Class I Antinfluenza agents• Class II Antiherpetic agents• Class III Antiviral for HBV & HCV• Class IV Antiretroviral therapy (ART)• Class V Agents against human Papiloma
virus and RSV
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Viruses susceptible to drug therapy
DNA Viruses1. Herpes virus (HSV 1 & HSV 2)2. Varicella Zoster (VZV)3. Cytomegalovirus (CMV)4. Hepatitis B virus
RNA Viruses1. Hepatitis C2. HIV (Retro virus)3. Respiratory syncytial virus4. Influenza A & infl. B
viruses
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Treatment of Influenza AAMANTADINE
• MOA: Inhibits uncoating no penetration• Uses: Prophylaxis & treatment, influenza A• It used to be active against influenza A, but not influenza
B. As in recent past seasons, there is a high prevalence (>99%) of influenza A resistant to amantadine. Therefore it is no longer recommended for Influenza A
• S/E: CNS: insomnia & restlessness Livedo reticularis
• dose in renal dysfunction• Good alternative to a vaccine in the elderly or in immuno
compromised patients
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OSELTAMIVIR: Tamiflu• Prophylaxis and treatment of Influenza A and B• Neuraminidase inhibitor• Flu virus attaches to host cell membrane –
hemagglutinin on viral envelope binds to sialic acid moiety in glycoprotein of cell membranes
• Neuraminidase enzyme cleaves viral attachment• Neuraminidase inhibitor keep the virus tethered
to the host cell membrane; prevent it from being released and thus spreading to other cells
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OSELTAMIVIR: Tamiflu
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Treatment of HSV, VZV and CMV
• Acyclovir• Ganciclovir• Foscarnet • 1st two are purine analogs• Acyclovir and Ganciclovir are prodrugs• Compete with dGTP for viral DNA- polymerase
& inhibit viral DNA synthesis • Foscarnet acts directly on DNA polymerase
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ACYCLOVIR: guanine analogMOA: Inhibits HSV replication
Acyclovir
Acyclo-MP
Acyclo-DP
Acyclo-TP(ACTIVE DRUG)
Viral thymidine kinase
Cell kinase
Cell kinase
Incorporated into growing DNA strand
Chain termination
Stops viral replication
Competes with dGTP for viral
polymerase
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USES of ACYCLOVIR
• Genital Herpes: 1st episode viral shedding, duration of symptoms
• Orolabial herpes: Topical/ oral acyclovir (penciclovir)
• Herpes encephalitis: Acyclovir I/V
• Varicella zoster: Oral, till all lesions encrusted I/V in disseminated CNS or Visceral infection
• Cytomegalovirus: Prophylaxis only (prevent CMV infection in transplant ptns)
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Use in pregnancy:
• For 1st episode of genital Herps to prevent neonatal herpes (H.pneumonia)
Side effects:
• Nephrotoxic (reversible crystalline nephropathy)
• Encephalopathy (rare)
Resistance:
• Mutations occur in the thymidine kinase gene causing an enzyme that does not phosphorylate acyclovir
• Occurs more in HIV+ive people
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GANCICLOVIR• 1st drug effective against CMV
Uses: Cytomegalovirus (CMV):
• Acute infection (retinitis, pneumonia in AIDS)
• Prophylactic (in transplant patients, AIDS)
S/E:
• Bone marrow toxicity (granulocytopenia & thrombocytopenia)
Drug Interactions:
• DO NOT give with ZIDOVUDINE (overlappingmyelosuppression toxicities)
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When acyclovir is effective as CMV prophylaxis why gancyclovir is used?
1. To treat lung, colon infection2. Good in AIDS ptns3. Has less teratogenicity
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FOSCARNET (alternate to Ganciclovir for CMV)
• Not a prodrug!
• Uses; CMV infections, Acyclovir-resistant HSV encephalitis
• MOA; Directly inhibits DNA polymerase
• Side Effect: • Renal function, hypocalcaemia, teratogenic, mutagenic &
carcinogenic drug
• Drug Interactions:• Cyclosporine (renal toxicity),
• Pentamidine (hypocalcaemia),
• Imipenem (seizures)
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RIBAVIRIN:
Respiratory Syncytial Virus (given by aerosol only)
Hepatitis C
MOA:
• Synthetic analogue of nucleoside;
• Inhibits GTP synthesis
• Inhibits 5̀ capping of viral mRNA,
• Inhibits RNA- dependent RNA polymerase
• S/ E: Headache, insomnia, anemia, teratogenesis
• Uses: Severe RSV infection with serious underlying respiratory, CV problems or immuno compromised
• C.I: Pregnancy
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HEPATITIS B: Lamivudine (ARV drug) • Inhibits HBV-DNA polymerase & HIV- reverse-
transcriptase by competing with dCTP • Uses:
1. Chronic Hepatitis B infection with evidence of active viral replication
2. HIV infection
• SE: N/V, headache, insomnia, fatigue
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HEPATITIS B: INTERFERONs
• Interferon -2b & INF- : Cytokine• Broad spectrum antivirals, Immuno modulator
activity, Antiproliferative actions; • Reduces progression of liver disease in HBV• S/E: Many, Flu-like syndrome, Bone marrow
suppression
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A 10-days old baby girl/ an AIDS ptn with low CD+4/ or bone marrow transplant pt. is suffering from RSV pneumonitis,
what is the treatment of choice?
1. Lamivudine2. Ribavirin3. Oseltamivir
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HEPATITIS C: Peg-interferon Ribavirin
PAPILLOMAVIRUS:
• Imiquimod
• For topical treatment of perianal & external genital warts
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Stages in Retrovirus development
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Why Body Defenses Disappear
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Anti retroviral agents• 4-5 big classes
1) Protease Inhibitors 2) Nucleoside reverse transcriptase Inhibitors 3) Non-nucleoside reverse transcriptase inhibitors 4) Fusion Inhibitors
5) Integrase inhibitors
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Retrovirus & Anti retroviral agents
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Drugs in different classes
NRTIs Non NRTIS Protease inhibitors
Zidovidine Nevirapine Saquinavir
Didanosine Delavirdine Indinavir
Stavudine Efavirenz Ritonavir
Lamivudine Atazanavir
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ART• Antiretroviral therapy (ART) is begun when:
– Symptomatic disease is present, regardless of CD+4 count and viral load
OR– Patient has CD+4 < 350 cells/mm3 with any value of
RNA copies per milliliterOR
– Plasma HIV RNA viral load>10,000-20,000/ml
• HIV infection associated with lots of symptoms. Malaise, fever, blood disorders, neurological, opportunistic infections etc. difficult to separate these effects from the side effects of the drugs
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Zidovudine (NRTIS)• Inhibit reverse transcriptase – prevent conversion
of viral RNA to DNA• All NRTIs nucleoside analogs e.g. Zidovudine
(azidothymidine- AZT) a thymidine analog• NRTIs: narrow therapeutic window, dose limiting
toxicities (mainly due to mitochondrial toxicity and inhibition of cellular DNA polymerases)
• In toxicity– withdraw drug until symptoms clear or become tolerable OR the drug has to be discontinued
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AZT
AZTmonophosphate
AZT diphosphate
AZT triphosphate
Thymidine kinase (host)
Thymidylate kinase
Cell Kinase
Incorporated into
Viral DNA strand
Chain elongation is terminated at thymidine residues
(lack of 3’-OH group)
No viral DNA formed
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Resistance• Major cause of treatment failure• Likelihood of resistance:
- duration of therapy
- Advancing disease• Due to point mutations in reverse transcriptase
enzyme• 33% patients on monotherapy with AZT become
resistant within a year
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NRTIs MAJOR TOXIC EFFECT
Zidovudine Bone marrow suppression, myopathy & lactic acidosis (LA)
Lamivudine LESS TOXIC THAN ABOVE
Didanosine NEUROPATHY, Hepatitis, LA, PANCREATITIS
Abacavir HYPERSENSITIVITYREACTIONS, MYOPATHY
Stavudine NEUROPATHY, Hepatitis, LAPANCREATITIS (no myopathy)
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NON NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)
•Nevirapine•Delavirdine•Efavirenz
MOA:
• Bind directly to reverse transcriptase
• Allosteric inhibition of enzyme function
• Blocks transcription of viral RNA to DNA
Note: They are NOT pro drugs!
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Pharmacokinetics Of NNRTIs
• Well absorbed orally
• Enter CNS (nevirapine more than the others)
• Metabolized in the liver by cytochrome P450 enzymes
• Excreted by the kidney
• Lot of potential (cyp450) for drug interactions
Toxicity: • Relatively low toxicity, also affect lipid profile. Toxicities
do not overlap with NRTIs
• Major toxicity: Skin rashes
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Protease Inhibitors (Do not need to be prodrugs)
• Saquinavir
• Indinavir
• Ritonavir
MOA:
• Blocks the protease enzyme
• HIV protease cleaves newly synthesized polyproteins at the appropriate places to create the mature protein components of an infectious HIV virion.
• Can inhibit cell to cell spread of the virus
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ToxicitySaquinavir:
• GIT disturbances
Indinavir:
• “trunkal obesity” (Cushing-like syndrome)
• Nephrolithiasis (kidney stones)
• Hemolytic anemia
Ritonavir:
• Paresthesias
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FUSION INHIBITORS Enfuvirtide, Maraviroc
MOA:
• Prevents the fusion of HIV with the host cell membrane
Uses:
• To treat AIDS which is progressing despite HAART
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INTEGRASE INHIBITOR
• Integration of viral DNA into host DNA• First approved HIV-integrase inhibitor. • Raltegravir - integrase inhibitor• Use: Detectable viremia & treatment failure in
ptn with triple class experience• Short term efficacy
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Adherence
• It is currently recommended that antiretroviral therapy be initiated with 2 NRTIs in combination with an NNRTI, PI, or integrase inhibitor.
• A major determinant of degree and duration of viral suppression
• Poor adherence associated with virologic failure• Optimal suppression requires 90-95% adherence• Suboptimal adherence is common
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CONCLUSIONSART:
Delays disease progressionProlongs survivalReduces maternal to child transmission.
BUT: Therapy is still suboptimalComplete suppression of viral replication
has not been achieved.Drugs are toxicResistance is a major problem
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