How do antiviral drugs act

Resistance to administered IFN has not been documented although neutralizing antibodies to recombinant IFNs have been reported. The clinical importance of this latter observation is unknown. Side effects are frequent with IFN both standard and pegylated administration and are usually dose limiting. Influenza-like symptoms i. Leukopenia is usually modest, not clinically relevant, and reversible upon discontinuation of therapy.

Increased ALT levels may also occur as well as nausea, vomiting, and diarrhea. At higher doses of IFN, neurotoxicity is encountered, as manifested by personality changes, confusion, attention deficits, disorientation, and paranoid ideation. Lamivudine is phosphorylated to the triphosphate metabolite by cellular kinases. The triphosphate derivative is a competitive inhibitor of the viral reverse transcriptase. Peak serum concentrations of 1. Lamivudine is eliminated by the kidneys unchanged by both glomerular filtration and tubular excretion, and dosages should be adapted to creatinine clearance.

Lamivudine is effective as monotherapy for the treatment of chronic HBV infection and in combination with other antiretroviral drugs for treatment of HIV infection. Elevated serum ALT levels have been shown to predict a higher likelihood of HBeAg loss in patients with chronic hepatitis B treated with lamivudine. Resistance to lamivudine monotherapy develops within 6 months of therapy. It will be curious to know if lamivudine at higher doses will affect the incidence of resistance.

These mutants have a reduced replication capacity compared with the wild type HBV virus. Lamivudine resistance is managed by sequential treatment with either adefovir or entecavir. However, the advantage of sequential treatment compared to de novo combination therapy is questionable. Lamivudine has an extremely favorable toxicity profile. This may be partly because lamivudine does not affect mitochondrial DNA synthesis and its poor inhibition of human DNA polymerases.

Adefovir dipivoxil, bis pivaloyloxymethyl ester of 9- 2-phosphonylmethoxyethyl adenine, is an orally bioavailable prodrug of adefovir, a phosphonate acyclic nucleotide analogue of adenosine monophosphate. Adefovir is monophosphorylated and is not dependent on initial phosphorylation by viral nucleoside kinases to exert its antiviral effect.

The phosphorylation to the di- and triphosphate metabolites is by cellular kinases. It has activity against HIV, hepadnaviruses and herpesviruses. It has a long intracellular half-life of 18 h allowing for a once-daily dose.

Clearance of adefovir is by renal excretion. Its pharmacokinetics is substantially altered in subjects with moderate and severe renal impairment. The efficacy of adefovir has been assessed in patients with HBeAg positive and negative disease and other settings in the spectrum of chronic hepatitis B infection. It is also useful for the treatment of lamivudine-resistant HBV infection. Nephrotoxicity is the major side effect of higher doses of adefovir.

It causes a proximal convoluted tubule lesion characterized by a rise in urea and creatinine. Other dose-related clinical adverse events have been gastrointestinal events, including nausea, anorexia and diarrhea. These are usually mild, intermittent and self-limited without the need for concomitant medications or dose interruption. Entecavir 2-amino-1,9-dihydro[ 1 S ,3 R ,4 S hydroxy hydroxymethyl methylenecyclopentyl]-6H-purinone , monhydrate is a guanosine nucleoside analogue.

Entecavir is efficiently phosphorylated by cellular kinases to the active triphosphate metabolite. The HBV polymerase binds preferentially to entecavir triphosphate, and entecavir triphosphate does not affect human mitochondrial DNA synthesis. The effect of entecavir on human cellular polymerase is minimal. Studies prior to approval of entecavir for HBV treatment suggested that entecavir did not have anti-HIV activity at clinical relevant concentrations.

However, recent studies have suggested an anti-HIV activity of entecavir at drug concentrations in the low nanomolar range. Entecavir is well absorbed after oral administration achieving peak plasma concentrations between 0. Entecavir is not a substrate of the cytochrome P CYP enzyme system. It is eliminated primarily in the urine through glomerular filtration and tubular secretion.

The intracellular half-life of the triphosphate metabolite in vitro studies is about 15 h. The prevalence rate of resistance to entecavir in HBV-treatment naive is about 1. Most adverse events in the phase III studies were mild and comprised of headache, upper respiratory tract infections, cough, fatigue, pharyngitis, abdominal pain, and gastrointestinal upset.

The most common laboratory abnormality was ALT level greater than five times the upper limit of normal. Monitoring for long-term toxicity is needed. Telbivudine is phosphorylated by cellular kinases to the triphosphate metabolite, which competes with naturally occurring thymidine triphosphate for viral DNA elongation. In contrast to other nucleoside analogue, such as lamivudine, telbivudine preferentially inhibits anticomplement or second-strand DNA, whereas lamivudine triphosphate preferentially inhibits the complement DNA synthesis.

Preliminary studies have shown a potent inhibition of HBV replication with a safe profile and no effect on mitochondrial metabolism. In addition, telbivudine triphosphate is not a substrate for human DNA polymerase and thus will not induce genotoxicity. Telbivudine is rapidly absorbed after oral dosing with peak plasma concentration achieved within 1—3 h, the absolute oral bioavailability of telbivudine is not known. However, a presence of a second, slower elimination phase was observed with intensive sampling in healthy volunteers up to h post-dosing.

In the second year of the study, telbivudine was found to be superior to lamivudine. Using the two drugs in combination was no more effective than telbivudine monotherapy. HBeAg-positive, Lamivudine-resistance HBV strains have a high level of cross resistance to telbivudine.

Most of the adverse effects of telbivudine reported in clinical studies were mild to moderate. The most common were elevated creatinine phosphokinase CPK , an enzyme present in muscle tissue and a marker for the breakdown of muscle tissue, upper respiratory tract infection, fatigue, headache, abdominal pain, and cough. Clevudine was recently approved in South Korea for the treatment of hepatitis B after demonstration of potent anti-hepatitis B activity in phase II and III clinical trials.

It is likely to be licensed for hepatitis B treatment in other countries. Clevudine is efficiently phosphorylated by cellular kinases to clevudine-triphosphate in target cells. The mechanism of action is mainly inhibition of viral plus-strand DNA synthesis. Clevudine is well absorbed after oral administration with estimated long half-life of 44—60 h. Clevudine is approved for treatment of chronic hepatitis B infection in South Korea.

In a randomized, placebo-controlled phase III study in South Korea, chronic HBeAg-positive patients who received 30 mg of clevudine once daily for 24 weeks maintained a 3.

A unique characteristic of clevudine is the slow rebound of viremia after cessation of treatment. In vitro studies suggest that there may be cross-resistance with lamivudine-resistant HBV mutants. In animal studies resistance occurred in the B domain of the polymerase gene, within 12 months of treatment. In clinical trials, clevudine was well tolerated without any serious adverse events reported. Long-term toxicity has to be closely monitored. Current antiviral agents either inhibit hepatitis B replication, or invoke an immune response, which may be necessary but not sufficient to effect viral control.

Moreover, antiviral resistance remains a concern with long-term therapy, the search for novel agents, and treatment strategies with minimal or no resistance and good long-term safety profile are the focus of ongoing research.

Another challenge is the management of hepatitis B in individuals with HIV coinfection. Appropriate combination regimens for individuals with coinfections are expected in the near future; target treatment of HBV to alter the outcome and take into account the impact of HBV treatment on HIV.

HPV infection induces the hyperproliferation of epithelial cells, leading to a broad spectrum of human diseases, ranging from benign warts self-limiting to malignant neoplasms. In general, there is no virus-specific effective systemic therapy available. Furthermore, treatment of disease with current therapies has not been shown to reduce the rates of transmission.

With time, this prophylactic vaccine is expected to reduce the incidence of HPV infections, particularly, infections due to the vaccine types HPV6, 11, 16, and IFNs have antiproliferative, antiviral, and immunomodulatory properties. They are more effective if used in combination with either local surgery or podophyllotoxin. Intralesional therapy is painful, systemic therapy is associated with influenza-like symptoms such as fever and myalgia.

Furthermore, IFN treatment is expensive and there is limited efficacy. This is an immunomodulator approved by the FDA for topical treatment of external and perianal genital warts. The adverse effects are; application site reactions irritation, pruritus, flaking, and erosion , and systemic effects including fatigue and influenza-like illness.

Podophyllotoxin is the main cytotoxic ingredient of podophyllin, a resin used for many years for topical treatment of warts. The exact mechanism of action is unknown. Podophyllotoxin 0. Adverse effects include irritation of the adjacent skin, local erosion, ulceration and scarring.

The current therapies are not targeted antiviral therapies. They result in the physical removal of the lesion or the induction of nonspecific inflammation, thereby inducing a bystander immune response. There is urgent need to develop specific and effective antiviral agents for HPV infections. The enteroviruses include nearly 70 serotypes of closely related pathogens that cause a wide spectrum of human illness, from mild nonspecific fever to common upper respiratory infections, aseptic meningitis, severe myocarditis, encephalitis, and paralytic poliomyelitis.

Certain patients, including antibody-deficient individuals, bone marrow recipients, and neonates, may develop potentially life-threatening enterovirus infections for which therapeutic options have been limited.

There are case series of the use of immune serum globulin and pleconaril for serious enteroviral infections. Pleconaril failed to secure FDA approval because of its induction of CYP 3A enzyme activity, and the potential for drug interactions, particularly the interference with oral contraceptives. The viral capsid structure, which is the target of pleconaril, is relatively conserved among the picornaviruses.

Pleconaril has broad spectrum and potent activity against enteroviruses and rhinoviruses. This high level of bioavailability was achieved by the substitution of trifluoromethyl on the oxadiazole ring that reduces its degradation in the liver by enzymes involved in oxidative processes.

Pleconaril also readily penetrates the blood-brain barrier. In a phase I trial of pleconaril for treatment of common cold, there was a significant reduction in rhinorrhea of about 1.

Subsequent trials confirmed a modest reduction in length of symptoms for common cold in patients treated with pleconaril. Patients with compromised humoral immunity, such as those with agammaglobulinemia, who contract enteroviral infections may develop chronic meningitis and meningoencephalitis, often with a fatal outcome.

There are case reports of the efficacy of pleconaril in these patients. For treatment of enteroviral meningitis, two large studies showed a marginal statistical improvement in a clinical score in the pleconaril-treated groups. A subsequent small study of 21 infants with proven enteroviral meningitis in the United States did not have enough power to show unequivocal benefit with pleconaril.

Resistance to pleconaril has been reported in some serotypes of enteroviruses, however, the mechanism is not well understood. Pleconaril is generally well tolerated. The most common adverse events are headache, diarrhea, and nausea. Long-term use of pleconaril is associated with an increase in menstrual irregularities in women. Pleconaril has not been licensed for treatment of enteroviral infections; there is an urgent need to identify alternative drugs that might be effective.

There are several investigational compounds; however, none has reached phase I clinical trial. Combinations of drugs are likely to offer the best chance of cure and protection from enterovirus infections in the future. Drug combinations are, in principle, aimed at obtaining synergism between the compounds, while reducing the likelihood of the development of drug resistance virus, and minimizing toxicity.

Fixed-dose combinations and once-daily dosage forms of many anti-HIV agents are available. The antiviral activity of maraviroc against HIV-2 has not been evaluated. Peak plasma concentrations of maraviroc are attained at 0.

It is principally metabolized by the cytochrome P system to metabolites that are essentially inactive against HIV The terminal half-life in healthy subjects is 14—18 h. Maraviroc is approved for use in combination with other anti-HIV agents for the treatment of adults with CCR5-tropic HIV-1, who are treatment-experienced with evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.

The resistance profile in treatment-naive and treatment-experienced subjects has not been fully characterized. The clinical relevance of these mutations is not known.

The most common adverse events reported with maraviroc were cough, fever, upper respiratory tract infections, rash, musculoskeletal symptoms, abdominal pain, and dizziness.

The product label includes a warning about liver toxicity hepatoxicity and a statement about the possibility of heart attacks. Enfuvirtide, a linear amino acid synthetic peptide with the N-terminus acetylated and the C-terminus is a carboxamide, is the first licensed agent in the class of fusion inhibitors.

Enfuvirtide interferes with the entry of HIV-1 into cells by inhibiting fusion of viral and cellular membranes Figure 2. Enfuvirtide binds to the first heptad-repeat HR1 in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes required for the fusion of viral and cellular membranes. The IC 50 of enfuvirtide for baseline clinical isolates ranged from 0. Enfuvirtide is administered twice daily by subcutaneous injection.

The absolute bioavailability is Following 90 mg bid dosing of enfuvirtide subcutaneously in combination with other antiretroviral agents in HIV-1 infected subjects, the median T max was 4 h ranged from 4 to 8 h. Enfuvirtide is catabolized by proteolytic enzymes.

It is not metabolized by hepatic CYP isoenzyme systems. There are no known clinically significant interactions between enfuvirtide and other medications. Enfuvirtide is used with other anti-HIV agents to treat HIV-1 infection in patients who are treatment-experienced and have detectable viral loads even though they are taking anti-HIV agents. HIV-1 isolates with reduced susceptibility to enfuvirtide have been selected in vitro.

Genotypic analysis of these resistant isolates showed mutations that resulted in amino acid substitutions at the enfuvirtide binding HR1 domain positions 36—38 of the HIV-1 envelope glycoprotein gp In clinical trials, HIV-1 isolates with reduced susceptibility to enfuvirtide have been recovered from subjects failing enfuvirtide-containing regimen. Most of the isolates with decreased in susceptibility to enfuvirtide of greater than fourfold exhibited genotypic changes in the codons encoding gp41 HR1 domain amino acids 36— HIV-1 clinical isolates resistant to nucleoside analogue reverse transcriptase inhibitors, non-nucleoside analogue reverse transcriptase inhibitors, and protease inhibitors are susceptible to enfuvirtide in cell culture.

The most common adverse effects of enfuvirtide are injection site reactions. Other symptomatic side effects may include insomnia, headache, dizziness, and nausea. Several cases of hypersensitivity have been described. In phase III studies, bacterial pneumonia was seen at a higher rate in patients who received enfuvirtide than in those who did not receive enfuvirtide.

Eosinophilia is the primary laboratory abnormality seen with enfuvirtide administration. Zidovudine is initially phosphorylated by cellular TK and then to its diphosphate by cellular thymidylate kinase. The triphosphate derivative competitively inhibits HIV reverse transcriptase, and functions as a chain terminator. Zidovudine inhibits HIV-1 at concentrations of approximately 0. In addition, it inhibits a variety of other retroviruses. Synergy has been demonstrated against HIV-1 when zidovudine is combined with didanosine, zalcitabine, lamivudine, nevirapine, delavirdine, saquinavir, indinavir, ritonavir, and other compounds.

It was the first drug to be licensed for the treatment of HIV infection, and still is used in combination with other drugs as initial therapy for some patients.

Zidovudine is available in capsule, syrup, and intravenous formulations. Peak plasma levels are achieved approximately 0. Zidovudine penetrates cerebrospinal fluid, saliva, semen, and breast milk and it crosses the placenta. Zidovudine is used in combination with other anti-HIV agents.

The single most important usage of zidovudine in the last decade has been the peripartum three-part zidovudine regimen, which has decreased the incidence of transmission of HIV infection from pregnant women to their infants. Zidovudine has been associated with skeletal and cardiac muscle toxicity, including polymyositis. Nausea, headache, malaise, insomnia, and fatigue are common side effects. Didanosine is activated by intracellular phosphorylation.

It is then converted to diphosphate by adenylate kinase and subsequently by creatine kinase or phosphoribosyl pyrophosphate synthetase to the triphosphate. The triphosphate metabolite is a competitive inhibitor of HIV reverse transcriptase and a chain terminator.

The spectrum of activity of didanosine is enhanced by synergism with zidovudine and stavudine as well as the protease inhibitors. Didanosine is acid labile and has poor solubility. A mg oral dose achieves peak plasma concentrations of 0.

It is metabolized to hypoxanthine and is cleared primarily by the kidneys. It is given as two mg tablets buffered tablets twice a day or as one mg capsule delayed-release capsule once a day. Lipoatrophy, lactic acidosis and diabetes have been observed in patients on antiretroviral regimens containing didanosine.

The peak plasma concentrations following an oral dose of 0. It is administered orally at 2. Pancreatitis can occur, but does so infrequently. Other zalcitabine-related side effects include nausea, vomiting, headache, hepatotoxicity, and cardiomyopathy.

Its mechanism of action is similar to that of zidovudine. Peak plasma concentrations of approximately 1. Stavudine penetrates CSF and breast milk. It is excreted by the kidneys unchanged and, in part, by renal tubular secretion.

Stavudine is a highly potent inhibitor of HIV-1 replication in vitro. However, its use has been limited by delayed toxicity, notably peripheral neuropathy and myopathy caused by mitochondrial damage. The principal adverse effect of stavudine therapy is the development of peripheral neuropathy. The development of this complication is related to both dose and duration of therapy. Inhibition of mitochondrial DNA synthesis is proposed to induce depletion of cellular mitochondrial DNA and it is ultimately responsible for the delayed toxicity observed with the use of stavudine and other nucleoside reverse transcriptase inhibitors NRTIs.

Neuropathy tends to appear after 3 months of therapy and resolves slowly with medication discontinuation. Other side effects are uncommon. Fatal and nonfatal pancreatitis have occurred during therapy when stavudine was part of a combination regimen that included didanosine.

Redistribution and accumulation of body fat lipoatrophy have been observed in patients receiving stavudine as part of their antiretroviral regimen. Lamivudine is a competitive inhibitor of the viral reverse transcriptase. Lamivudine is used in combination with other anti-HIV agents.

It is also formulated in combination with zidovudine, or with zidovudine and abacavir as fixed-dose combination tablet. This may largely be attributed to the low affinity of lamivudine for human DNA polymerases, and the lack of active lamivudine metabolites in the mitochondrial compartment of cells.

In pediatric studies, pancreatitis and peripheral neuropathies have been reported. Abacavir sulfate, 1 S ,4 R [2-amino cyclopropylamino -9 H -purinyl]cyclopentenemethanol, is a structural analogue of the purine guanine. The phosphorylation pathway of abacavir differs from that of all other nucleoside analogues.

The first step in the conversion of abacavir to its active metabolite, carbovir triphosphate, is phosphorylation to abacavir monophosphate by adenosine phosphotransferase. This step is followed by deamination by a cytosolic enzyme to form carbovir monophosphate, which undergoes two subsequent phosphorylations, to the diphosphate by guanylate kinase and to the triphosphate by nucleoside diphosphate kinase and other enzymes.

However, there is no significant difference between the levels of activity of abacavir IC 50 0. After single or multiple doses, C max is attained after a mean of 0.

The intracellular carbovir triphosphate was measurable throughout the h study period, with the highest levels found between 6 and 8 h.

This finding suggests a long half-life for carbovir triphosphate within cells. The main route of excretion is renal. Abacavir is used in combination with other anti-HIV agents. Science writer Amber Dance lives in the Los Angeles area. Already a subscriber? Sign in. Thanks for reading Scientific American.

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Continue reading with a Scientific American subscription. That leads to conformational changes that distort the position of the DNA binding sites in the enzyme and lead to halt in DNA polymerization. Non-nucleotide inhibitors are non-competitive inhibitorsof reverse transcriptase. Such drugs are Efavirenz and Nevirapine. Resistance occurs to all drug groups. The mechanisms for resistance against the nucleoside nucleotide inhibitors are two.

The first one is due to mutations in the N-terminal polymerase domain of the reverse transcriptase that makes it less likely to incorporate the analogues. The second mechanism is caused by mutations in the transcriptase that allow the removal of the incorporated inhibitor and hence restart of DNA replication.

Resistance to the non-nucleotide inhibitors is caused by mutations in the inhibitor binding site of the enzyme.

Such mutations prevent the binding of the inhibitor to the enzyme. Protease inhibitors target viral proteases which are key enzymes for the completion of viral maturation. Proteases are enzymes that have the ability to cut proteins into peptides. They are used by some viruses e. This allows the completion of the assembly step in the viral life cycle where the proteins and the viral RNA come together to form virion particles ready to exit the cell.

HIV protease with bound protease inhibitor : The drug is ritonavir depicted here with a white molecule in the middle of the enzyme structure. The design of protease inhibitors, that could be used to battle HIV, started soon after the discovery of the virus.

The first approved protease inhibitor drug was released on the market in , only 10 years after the discovery of HIV. These drugs are an inseparable part of an HIV therapy. Natural protease inhibitors are found in Shiitake mushrooms. The experimental protease inhibitor drugs Zmapp and Brincidofovir are currently being tested to treat the ebola virus disease. Protease inhibitors are short peptide-like molecules that are competitive inhibitors of the enzyme.

When such a peptide gets into the enzyme active site, the protease is unable to cut the linkage and gets inactivated. This leads to a lack of cleavage of the polypeptide chains of two crucial viral proteins, Gag and Pol, which are essential structural and enzymatic proteins of HIV. Their absence blocks the formation of mature virion particles.

Saquinavir is the first clinically used peptide-like inhibitor. Some protease inhibitors do not mimic peptides in their structure. One such drug is Nelfinavir. In general, protease inhibitors exhibit the unusual side effect of fat storage in non-typical organs and tissues. The reasons for this are still unclear. Valganciclovir prodrug of ganciclovir with greater oral availability.

In influenza A and B , administration of neuraminidase inhibitors within 2 days of symptom onset is vital to reduce the duration of illness and alleviate symptoms. Expand all sections Register Log in. Trusted medical expertise in seconds. Find answers fast with the high-powered search feature and clinical tools. Try free for 5 days Evidence-based content, created and peer-reviewed by physicians.

Read the disclaimer. Antiviral agents. Summary Antivirals are a class of medications that are used to treat viral infections. Overview of the viral replication cycle and targets of antiviral drug Viral replication cycle Target Antiviral drug Fusion with host cell Attachment CCR5-antagonist e. Analysis of mutations in the gene encoding cytomegalovirus DNA polymerase in a phase 2 clinical trial of brincidofovir prophylaxis.

J Infect Dis. Function of human cytomegalovirus UL97 kinase in viral infection and its inhibition by maribavir. Rev Med Virol. The human cytomegalovirus UL97 protein is a protein kinase that autophosphorylates on serines and threonines..

J Virol. Updated: August 27, Accessed: December 3, Katzung B,Trevor A. Basic and Clinical Pharmacology. Rimantadine: Drug information. In: Post TW, ed.