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Antiviral drug

Antiviral drug

Antiviral drugs are a class of medication used specifically for treating viral infections Like antibiotics for bacteria, specific antivirals are used for specific viruses. Unlike most antibiotics, antiviral drugs do not destroy their target pathogen; instead they inhibit their development.

Antiviral drugs are one class of antimicrobials, a larger group which also includes antibiotic, antifungal and antiparasitic drugs. They are relatively harmless to the host, and therefore can be used to treat infections. They should be distinguished from viricides, which are not medication but destroy virus particles.

Most of the antivirals now available are designed to help deal with HIV, herpes viruses (best known for causing cold sores and genital herpes, but actually causing a wide range of diseases), the hepatitis B and C viruses, which can cause liver cancer, and influenza A and B viruses. Researchers are working to extend the range of antivirals to other families of pathogens.

Designing safe and effective antiviral drugs is difficult, because viruses use the host's cells to replicate. This makes it difficult to find targets for the drug that would interfere with the virus without also harming the host organism's cells.

The emergence of antivirals is the product of a greatly expanded knowledge of the genetic and molecular function of organisms, allowing biomedical researchers to understand the structure and function of viruses, major advances in the techniques for finding new drugs, and the intense pressure placed on the medical profession to deal with the human immunodeficiency virus (HIV), the cause of the deadly acquired immunodeficiency syndrome (AIDS) pandemic.

Almost all anti-microbials, including anti-virals, are subject to drug resistance as the pathogens mutate over time, becoming less susceptible to the treatment. For instance, a recent study published in Nature Biotechnology emphasized the urgent need for augmentation of oseltamivir (Tamiflu) stockpiles with additional antiviral drugs including zanamivir (Relenza) based on an evaluation of the performance of these drugs in the scenario that the 2009 H1N1 'Swine Flu' neuraminidase (NA) were to acquire the tamiflu-resistance (His274Tyr) mutation which is currently widespread in seasonal H1N1 strains. Mechanism of actionAmantadine and rimantadine were the first generation of influenza antiviral agents.1These compounds specificallyblock the ion channel function of the M2 protein of influenza A virus, thus interfering with corresponding specific steps in the viral life cycle. The neuraminidase inhibitors are novel drugs, designed on the basis of the three-dimensional structure of the influenza A and B neuraminidase. The mechanisms of action of the four available specific anti-influenza viral drugs are summarized in.

Figure 1 The mechanism by which antiviral drugs interrupt the replicative cycle of influenza is illustrated. M2 inhibitors prevent the M2-mediated acidification of the interior of the virus while it resides in endosomes and the subsequent uncoating of the viral genome, thus inhibiting viral replication. Neuraminidase inhibitors (NAIs) prevent cleavage of sialic acid residues and thus newly formed virus cannot be released from the cell surface to infect adjacent cells; also, virus particles remain associated to one another.

The M2 channel inhibitors amantadine and rimantadine

At high concentrations (>15 g/ml), amantadine and rimantadine non-specifically raise the pH within cellular endosomes, thus inhibiting or retarding the acid-induced conformational change in the viral HA. However, the required concentrations of the drugs are not generally attainedin vivo. At low, pharmacologically relevant concentrations (250 cells/L or men with CD4 counts of >400 cells/L, unless the benefit clearly outweighs the risk. Monitor liver tests closely for the first 16 weeks of treatment.

Rilpivirine Insomnia

Depression

Elevations in liver function tests

Elevations in serum creatinine

May be less potent if baseline HIV RNA >100,000 copies/mL

Requires acidic gastric environment for adequate absorption:

Must be taken with food.

Contraindicated with proton pump inhibitors.

Other antacid medications and H2 blockers require specific timing if used by persons taking rilpivirine.

Drug reaction

Antiviral drug interactions are a particular problem among immuno-compromised patients because these patients are often receiving multiple different drugs, i.e. antiretroviral drugs and drugs effective against herpesvirus. The combination of zidovudine and other antiretroviral drugs with different adverse event profiles, such as didanosine, zalcitabine and lamivudine, appears to be well tolerated and no relevant pharmacokinetic interactions have been detected. The adverse effects of didanosine and zalcitabine (i.e. peripheral neuropathy and pancreatitis) should be taken into account when administering these drugs with other drugs with the same tolerability profile. Coadministration of zidovudine and ganciclovir should be avoided because of the high rate of haematological intolerance. In contrast, zidovudine and foscarnet have synergistic effect and no pharmacokinetic interaction has been detected. No major change in zidovudine pharmacokinetics was seen when the drug was combined with aciclovir, famciclovir or interferons. However, concomitant use of zidovudine and ribavirin is not advised. Although no pharmacokinetic interaction was documented when didanosine was first administered with intravenous ganciclovir, recent studies have shown that concentration of didanosine are increased by 50% or more when coadministered with intravenous or oral ganciclovir. The mechanism of this interaction has not been elucidated. Lack of pharmacokinetic interaction was demonstrated between foscarnet and didanosine or ganciclovir. Clinical trials have shown that zidovudine can be administered safely with paracetamol (acetaminophen), nonsteroidal anti-inflammatory drugs, oxazepam or codeine. Inhibition of zidovudine glucuronidation has been demonstrated with fluconazole, atovaquone, valproic acid (valproate sodium), methadone, probenecid and inosine pranobex; however, the clinical consequences of this have not been fully investigated. No interaction has been demonstrated with didanosine per se but care should be taken of interaction with the high pH buffer included in the tablet formulation. Drugs that need an acidic pH for absorption (ketoconazole, itraconazole but not fluconazole, dapsone, pyrimethamine) or those that can be chelated by the ions of the buffer (quinolones and tetracyclines) should be administered 2 hours before or 6 hours after didanosine. Very few interaction studies have been undertaken with other antiviral drugs. Coadministration of zalcitabine with the antacid 'Maalox' results in a reduction of its absorption. Dapsone does not influence the disposition of zalcitabine. Cotrimoxazole (trimethoprim-sulfamethoxazole) causes an increase in lamivudine concentrations by 43%. Saquinavir, delavirdine and atevirdine appeared to be metabolised by cytochrome P450 and interactions with enzyme inducers or inhibitors could be anticipated. Some studies showed that interferons can reduce drug metabolism but only a few studies have evaluated the pathways involved. Further studies are required to better understand the clinical consequences of drug interactions with antiviral drugs. Drug-drug interactions should be considered in addition to individual drug clinical benefits and safety profiles.

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