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 AnaloguesGeneral Mechanism of Action

1. Taken up by cells2. Converted by viral and cellualr enzymes to the

triphosphate form3. The triphosphate form inhibits:

1. DNA polymerase2. Reverse transcriptase3. 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 AcycloGTP

Thymidine kinase Cellular kinases

Viral 200x affinityof mammalian

1. Inhibits viral DNA polymerase selectively2. Incorporated into DNA and terminates synthesis

Resistance:1. ↓ activity of thymidine kinase2. altered DNA polymerase

Toxicity:1. Encephalopathy2. Renal Insuficiency

Use:1. H. simplez I and II2. 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…

Guanine

Acyclovir Ganciclovir

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

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).

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.

Protease InhibitorsProtease Inhibitors

Protease action

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