Antiviral Agents

1
Antiviral Agents

• Restricted spectrum
• No standardized in-vitro susceptibility tests
• Most inhibit replication. Cure depends on host
  immune system to eradicate. If patients are
  immunocompromized, may have recurrences.
• Many need to be activated by viral and cellular
  enzymes before exerting antiviral effect.
  Activity of enzymes and concentration of
  substrates will influence the efficacy.

2
Classification

• Purine and Pyrimidine Analogues (Herpes, CMV,
  HIV, Resp. Syncitial)
• Non-nucleoside inhibitors of reverse
  transcriptase (HIV)
• Direct inhibitor of DNA polymerase and RT
  Foscarnet
• Protease Inhibitors (HIV)
• Interferon-alpha (Hep. BC, Herpes)
• Others Amantadine, Rimantadine (Influenza)

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Nucleoside AnaloguesGeneral Mechanism of Action

• Taken up by cells
• Converted by viral and cellualr enzymes to the
  triphosphate form
• The triphosphate form inhibits
• DNA polymerase
• Reverse transcriptase
• RNA polymerase
• Or it may get incorporated into growing DNA
  leading to abnormal proteins or breakage.

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Acyclovir and Valacyclovir (prodrug, better
availability)

• A Guanine analogue with antiviral for Herpes
  group only

Acyclovir
AcycloGMP
AcycloGTP
Thymidine kinase
Cellular kinases
Viral 200x affinity of mammalian

• Inhibits viral DNA polymerase selectively
• Incorporated into DNA and terminates synthesis

Resistance 1. ? activity of thymidine kinase 2.
altered DNA polymerase
Toxicity 1. Encephalopathy 2. Renal Insuficiency
Use 1. H. simplez I and II 2. H. zoster and
Varicella, not good for CMV
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Ganciclovir

• Mechanism like Acyclovir
• Active against all Herpes viruses including CMV
• Low oral bioavailability given I.V.
• Most common adverse effect bone marrow
  suppression (leukopenia 40, thrombocytopenia
  (20) and CNS effects (headache, behavioral,
  psychosis, coma, ocnvulsions).
• 1/3 of patients have to stop because of adverse
  effects
• Drug of choice for CMV infections retinitis,
  pneumonia, colitis

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Acyclovir
Ganciclovir
Guanine
7
Other Nucleoside Analogues

• Vidarabine
• Poor solubility, give i.v. with big volume of
  fluids (2.5 L) ? risk of fluid overload
• Toxicity GI Bone marrow Hypokalemia
  inappropriate ADH secretion (psychosis painful
  neuropathy
• Not a drug of choice for anything. Replaced by
  Acyclovir because of toxicity and problems in
  administration.

• Idoxuridine and Trifluridine
• Topical agents for Herpes keratitis
• Trifluridine also for CMV and others
• Trifluridine better for H. simplex II
  keratoconjuctivitis
• Ribavirin
• Aerosol inhibits replication of Influenza A B
  and RCV
• Triphosphate inhibits RNA polymerase
• Anemia due to hemolysis and BM suppression

8
Foscarnet

• An inorganic pyrophosphate analog
• Active against Herpes (I, II, Varicella , CMV),
  inlcuding those resistant to Acyclovir and
  Ganciclovir.
• Direct inhibition of DNA polymerase and RT
• Nephrotoxicity (25) most common ADR
• Hypocalcemia (chelates divalent cations)
• Others hypokalemia, hypomagnesemia
• Use CMV retinitis and other CMV infections
  instead of ganciclovir. H simplex resistant to
  Acyclovir. HIV.

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Anti-retroviral Agents

• Zidovudine (AZT)
• Cellular enzyme phosphorylate to the triphosphate
  form which inhibits RT and causes chain
  termination
• Adverse effect
• Granulocytopenia and anemia 45 in AIDS but 5
  if asymptomatic HIV
• Severe headache, nausea, insomnia, myalgias
• ?mortality opportunistic infections, gain
  weight, better quality of life, delays signs and
  symptoms of AIDS

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Other Retroviral RT Inhibitors

• Other nucleoside analogs didanosine, stavudine,
  zalcitabine same as AZT but can cause peripheral
  neuropathy and pancreatitis. Can be used with AZT
  for enhanced effect and less toxicity.
• Non-nucleoside RT inhibitors e.g. neviparine.
  Noncompetitive binding to RT and direct
  inhibition at a site different from AZT and
  others. May be active against AZT-resistant
  strains. Can be used in combination. Main
  adverse effect is rash (75).

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Protease Inhibitors

• Produce non-infectious particles or virions
• Reduces the number of new rounds of infection in
  susceptible cells
• To be effective must be prolonged, profound and
  constant.
• Pharmacokinetics important to maintain constant
  concentrations within the effective range.
• Metabqolic adverse effects (DM, hyperglycemia)
  and GI (diarrhea, pain vomiting).

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Protease Inhibitors
Protease action
Panel C shows the translational products of the
HIV gagpol gene and the sites at which the gene
product is cleaved by the virus-encoded protease.
p17 denotes capsid protein, p24 matrix protein,
and p7 nucleocapsid p2, p1, and p6 are small
proteins with unknown functions. The arrows
denote cleavage events catalyzed by the
HIV-specific protease.
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Fig. 3. HIV-1 virion forms. (a) Particles
assembling and budding at the cell membrane. (b)
An immature virus particle. (c) Mature forms of
HIV-1.
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Other Drugs

• Amantadine
• Prevents uncoating (?) /or assembly
• CNS Toxicity due to dopaminergic action
• Prophylaxis of Influenza A during epidemics.
• If used within 48 hours may help cure Influenza
  infection
• Rimantadine analog with less CNS toxicity

• Interferons
• Antiviral, anticancer and immunomodulating
• Several sites of action in viral cycle but mainly
  inhibit translation of viral proteins
• Toxicity flu-like syndrome, BM suppression CNS
• Hepatitis B and C