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. B&C, Herpes)
Others: Amantadine, Rimantadine (Influenza)

3. Nucleoside Analogues General 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.

4. 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

5. 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…

6. 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.

9. 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

10. 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).

11. 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).

12. 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.

13. 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.

14. 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