Professional Documents
Culture Documents
Antiviral Agents
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.
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. B&C, Herpes) Others: Amantadine, Rimantadine (Influenza)
Nucleoside Analogues
General Mechanism of Action 1. Taken up by cells 2. Converted by viral and cellualr enzymes to the triphosphate form 3. The triphosphate form inhibits:
1. DNA polymerase 2. Reverse transcriptase 3. RNA polymerase
4. Or it may get incorporated into growing DNA leading to abnormal proteins or breakage.
Acyclovir
and Valacyclovir (prodrug, better availability) A Guanine analogue with antiviral for Herpes group only
Acyclovir
Thymidine kinase Viral 200x affinity of mammalian
AcycloGMP
Cellular kinases
AcycloGTP
1. Inhibits viral DNA polymerase selectively 2. 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
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
Acyclovir
Ganciclovir
Guanine
Ribavirin
Aerosol: inhibits replication of Influenza A & B and RCV Triphosphate inhibits RNA polymerase Anemia due to hemolysis and BM suppression
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.
AntiAnti-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
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).
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.
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.
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