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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. 2. 3.

DNA polymerase Reverse transcriptase 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

AcycloGMP Thymidine kinase

AcycloGTP Cellular kinases

Viral 200x affinity of mammalian

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


Other Nucleoside Analogues Idoxuridine and Trifluridine

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.

• • •

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


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.


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


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).


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 gag–pol 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


Antiviral Agents