ANTI VIRAL Agents
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Transcript of ANTI VIRAL Agents
ANTI VIRAL Agents
Kaukab Azim, MBBS, PhDModified by: iSRAA
Viruses
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
A good antiviral drug will
Interfere with a viral specific function
Only kill virus-infected cells
Prevent viral replication
Sites Of Anti Viral Drug Action
Enfuvirtide, maraviroc
Indinavir
Oseltamivir
Reltegravir
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
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
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
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
OSELTAMIVIR: Tamiflu
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
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
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)
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
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)
When acyclovir is effective as CMV prophylaxis why gancyclovir is used?
1. To treat lung, colon infection2. Good in AIDS ptns3. Has less teratogenicity
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)
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
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
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
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
HEPATITIS C: Peg-interferon Ribavirin
PAPILLOMAVIRUS:
• Imiquimod
• For topical treatment of perianal & external genital warts
Stages in Retrovirus development
Why Body Defenses Disappear
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
Retrovirus & Anti retroviral agents
Drugs in different classes
NRTIs Non NRTIS Protease inhibitors
Zidovidine Nevirapine Saquinavir
Didanosine Delavirdine Indinavir
Stavudine Efavirenz Ritonavir
Lamivudine Atazanavir
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
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
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
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
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)
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!
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
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
ToxicitySaquinavir:
• GIT disturbances
Indinavir:
• “trunkal obesity” (Cushing-like syndrome)
• Nephrolithiasis (kidney stones)
• Hemolytic anemia
Ritonavir:
• Paresthesias
FUSION INHIBITORS Enfuvirtide, Maraviroc
MOA:
• Prevents the fusion of HIV with the host cell membrane
Uses:
• To treat AIDS which is progressing despite HAART
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
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
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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