Nonselective Antiviral Drugs

NONSELECTIVE ANTIVIRAL DRUGS

Ribavirin This purine nucleoside analogue has broadspectrum antiviral activity, including that against influenza A and B, respiratory syncytial virus and many other DNA and double stranded RNA viruses. Its mono and triphosphate derivatives generated intracellularly inhibit GTP and viral RNA synthesis and have other sites of action as well. No viral resistance to ribavirin has yet been observed.

Oral bioavailability of ribavirin is ~50%. It is partly metabolized and eliminated in a multiexponential manner; accumulates in the body and persists months after discontinuation.

Administered orally or i.v. ribavirin has been used in influenza A/B and measles in immunosuppressed patients as well as for herpes virus infections, acute hepatitis, but is not a first line drug for any of these. Combined with interferon α, ribavirin is the standard treatment for chronic hepatitis C. Nebulized ribavirin has been used for respiratory syncytial virus broncholitis in infants and children, particularly those with congenital heart disease, prematurity or other high risk conditions. It has also shown efficacy in some rare viral infections.

Dose: 200 mg QID (children 10 mg/kg/day).

VIRAZIDE, RIBAVIN 100, 200 mg caps, 50 mg/5 ml syr.

Prominent toxic effects are anaemia, haemolysis, CNS and g.i. symptoms. It is also teratogenic. The aerosol can cause irritation of mucosae and bronchospasm.

Adefovir dipivoxil It is the diester prodrug of AMP analogue adefovir which is active against hepatitis B virus (HBV) and some other DNA viruses. Esterases in the intestine and liver release the active drug during absorption to attain oral bioavailability of ~60% in terms of adefovir, which is then distributed in whole body water. On entering cells, adefovir (a monophosphate) is phosphorylated to the diphosphate which has high affinity for HBV DNA polymerase. This enzyme is inhibited and adefovir itself gets incorporated in the viral DNA resulting in termination of the DNA chain. While plasma t½ of adefovir is ~7 hours (due to renal excretion), intracellular t½ of the diphosphate is upto 18 hours.

Adefovir is indicated in chronic hepatitis B, including lamivudineresistant cases and those having concurrent HIV infection. There is no cross resistance between adefovir and lamivudine. Clinical, biochemical (liver function tests), histological, serological and virological response occurs in nearly 50% patients within 1 year. More cases respond with continued treatment. The optimum duration of treatment is uncertain at present.

Dose: 10 mg/day; ADESERA, ADFOVIR 10 mg tab.

At 10 mg/day dose adefovir is well tolerated. Side effects are sore throat, headache, weakness, abdominal pain and flu syndrome. Nephrotoxicity occurs at higher doses and in those with preexisting renal insufficiency. Lactic acidosis is a risk in patients receiving antiHIV drugs.

Interferon α

Interferons are low molecular weight glycoprotein cytokines produced by host cells in response to viral infections and some other inducers. They have nonspecific antiviral as well as other complex effects on immunity and cell proliferation. Interferons bind to specific cell surface receptors and affect viral replication at multiple steps: viral penetration, synthesis of viral mRNA, assembly of viral particles and their release, but the most widespread effect is direct or indirect suppression of viral protein synthesis, i.e. inhibition of translation. Interferon receptors are JAKSTAT tyrosine protein kinase receptors which on activation phosphorylate cellular proteins. These then migrate to the nucleus and induce transcription of ‘interferon-induced-proteins’ which exert antiviral effects.

Interferons inhibit many RNA and DNA viruses, but they are host specific: those produced by another species have poor activity in man. Three types of human interferons (α, β and γ) have been produced by recombinant DNA technology. Only interferon α_2A and α_2B have antiviral activity.

After i.m./s.c. injection, interferon is distributed to tissues and is degraded; may be detectable in plasma for 24 hours. However, cellular effects are longer lasting and it is generally administered thrice weekly. Complexed with polyethylene glycol (pegylated interferon), it is absorbed more slowly—exerts more sustained effects, permiting weekly administration and improving clinical efficacy.

ALFERON: Interferon α_2A 3MU/vial inj.

REALFA2B, SHANFERON, VIRAFERON: Interferon α_2B 3MU, 5MU vials for inj.

Uses

Chronic hepatitis B and C: Interferon causes disappearance of HBVDNA from plasma and improvement in liver function tests/histology in nearly half of the patients. High doses (10 MU) injected thrice weekly for 6 months often produce prolonged remission, but relapses do occur. The newer pegylated interferons produce better and more sustained responses. Addition of ribavirin has the potential to further decrease chances of relapse.

1.            AIDS-related Kaposi’s sarcoma (but not to treat HIV as such). However, interferon accentuates haematological toxicity of zidovudine.

2.         Condyloma acuminata caused by papilloma virus is usually treated with topical podophyllin. Intralesional interferon injection may be used in refractory cases.

3.  H. simplex, H. zoster and CMV infections in immunocompromised patients: interferon is inferior to acyclovir/ganciclovir; may be used as second line/adjuvant drug.

4.       Rhinoviral cold: intranasal interferon is prophylactic, but not beneficial in those already having cold.

Interferons are also used in chronic myelogenous leukaemia and multiple myeloma.

Interferon is not effective orally. Clinical utility of s.c. or i.m. injected interferon is limited by substantial adverse effects.

Adverse Effects

Flulike symptoms—fatigue, aches and pains, malaise, fever, dizziness, anorexia, taste and visual disturbances: develop a few hours after each injection, but become milder later.

Neurotoxicity—numbness, neuropathy, tremor, sleepiness, rarely convulsions. Myelosuppression (dose limiting)—neutropenia, thrombocytopenia.

Thyroid dysfunction (hypo as well as hyper). Hypotension, transient arrhythmias, alopecia and liver dysfunction.