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Antiviral drugs, Preferred combined regimens for HCV, IFN-alpha:, Adefovir…
Antiviral drugs
Antiviral drugs can act at any step of viral replication.
Viral replication involves fusion of the virus to host cell membrane and penetration inside the cell.
Then uncoating occurs and early proteins like DNA polymerase are synthesized.
The nucleic acids DNA or RNA are then synthesized
and after that late proteins(final functional proteins)
are synthesized and processed.
After packaging and assembly viral particles are released with the help of neuraminidase
and cause infection of other cells.
Drugs can act at any of these steps to inhibit viral replication.
Preferred combined regimens for HCV
Sofosbuvir/ledipasvir
Sofosbuvir/
daclatasvir
Sofosbuvir/
velpatasvir
Sofosbuvir/velpatasvir/ voxilaprevir
Glecaprevir/
pibrentasvir
Grazoprevir/elbasvir
IFN-alpha:
• Preferred agent
• Approved for adult patients with compensated liver disease and evidence of viral replication and liver inflammation
• Administered SC weekly for 48–52 weeks
it acts by JAK-STAT pathway to increase antiviral proteins
and also promotes the formation of Natural killer cells NK cells.
It is used in chronic HBV infections.
It can also be used with ribavirin in acute HCV infections and prevents its progression to chronic disease.
Pegylated IFN-alpha 2a and 2b are superior to conventional IFN alpha 2a and 2b.
Intralesional IFNs are useful for verruca vulgaris and condyloma acuminata (imiquimod; an immunomodulator is also effective).
used in Kaposi sarcoma (in patients with HIV, other malignancies, multiple sclerosis)
Contraindicated in advanced liver disease and in pregnancy
Adefovir, lamivudine, and Telbivudine
Adefovir
Lamivudine
Telbivudine
• Alternative agents due to high incidence of HBV resistance with monotherapy
• Indefinite treatment for patients with cirrhosis
Oseltamivir and zanamivir:
these drugs act as neuraminidase inhibitors and prevent the virion release by causing clumping of mature virions.
These drugs are effective against both influenza A and influenza B.
Oseltamivir is an oral prodrug can cause nausea and vomiting
whereas zanamivir is administered by inhalational route(bronchospasm is important side effect)
Neuropsychiatric disorders including suicidal tendency have been associated with oseltamivir and zanamivir.
These can be used prophylactically to prevent influenza during epidemics.
Oseltamivir is drug of for bird flu H5N1 as well as swine flu by H1N1.
peramivir is a newer drug in this drug that can be administered intravenously.
Laninamivir is a long-acting inhaled neuraminidase inhibitor effective oseltamivir resistant strains.
Entecavir:
Preferred agent
• Approved for individuals ≥2 years old
• Indefinite treatment for patients with cirrhosis
it is the newer HBV viral DNA polymerase inhibitor.
It is effective against HBV resistant to lamivudine
and has become the first line of choice for chronic HBV infection.
Should be given in empty stomach.
Use higher dose for decompensated cirrhosis and patients with lamivudine
or telbivudine resistance
Ribavirin
May cause hemolytic anemia
• Teratogenic
• Wide tissue distribution
• Long half-life (7–10 days)
• Dose adjustment needed for renal impairment
Used in combination with other HCV regimens to boost therapeutic efficacy
it has a wide antiviral spectrum and can be given orally.
It is used with IFN-alpha in chronic HCV infection.
Although it affords no benefit in respiratory syncytial virus(RSV) infections, however some authorities still recommend its use in immunocompromised children for this purpose.
MOA of acyclovir
It is activated first by a virus specific kinase(thymidine kinase) to form acyclovir monophosphate.
Virus develops resistance due to mutation of this kinase.
And then by host kinases to form acyclovir triphosphate.
This product competitively inhibits the action of DNA polymerase by competing with GTP
and also gets incorporated into the DNA
and causes chain termination.
Ganciclovir:
it is active against CMV and HSV and acts by inhibiting DNA polymerase.
First phosphorylation step in this case is also virus specific.
Ganciclovir is used only intravenously whereas valganciclovir has good oral absorption.
Ganciclovir is the drug of choice for CMV infections including retinitis.
Dose limiting adverse effect is myelosuppression.
Its bone marrow suppressive action is additive to other myelosuppressive drugs like zidovudine.
CNS side effects(headache to convulsions) also occur quite commonly.
Docosanol
10% topical cream for labial herpes
is a long chain saturated alcohol that can be used topically as a cream for herpes labialis.
It prevents the entry of the virus in cell by inhibiting the fusion of the virus envelope with the host cell membrane.
Anti-influenza drugs:
These include amantadine, rimantadine, oseltamivir and zanamivir.
Amantadine and rimantadine: these drugs preventing uncoating of influenza A virus not influenza B.
Inhibitors of viral M2 protein function
these drugs decrease the duration of symptoms of influenza if used prophylactically.
Rimantidine is longer acting than amantadine.
Most common adverse effects of these drugs
are gastrointestinal symptoms and minor CNS side effects.
Amantadine is also effective for the treatment of parkinsonism.
Remdesivir
Remdesivir is indicated for adults and pediatric patients (12 years of age and older and weighing at least 40 kg) for the treatment of COVID-19 requiring hospitalization.
acts by inhibiting RNA-dependent
RNA polymerase (RdRp)
Anti-herpes drugs:
most of these drugs are antimetabolites
and inhibits viral DNA polymerase after bioactivation by kinases.
Acyclovir and its congeners:
it is a guanosine analogue active against herpes simplex HSV-1 and 2.
Acyclovir is not active against CMV infections.
Therapeutic uses
Acyclovir can be used topically, orally or intravenously.
It has very short t1/2 and require multiple daily dosing.
It is primarily excreted by kidneys.
it is used for the treatment of mucocutaneous and genital herpes
and also for the prophylaxis of herpes infection in AIDS and immunocompromised patients.
Chicken pox and herpes zoster infections
Parenteral administration of acyclovir
Parenteral administration of acyclovir for serious herpes infections
cause nephrotoxicity and neurotoxicity as principal dose limiting toxicities
but it doesn’t cause bone marrow suppression.
Precautions
It is essential to maintain hydration while the patient is on acyclovir therapy
because dehydration increases its nephrotoxic potential.
Valacyclovir
has a long half life and gets converted to acyclovir by hepatic metabolism.
Famciclovir and penciclovir
Famciclovir is a prodrug that gets converted to penciclovir(also developed as a separate drug)
and acts via similar mechanism.
Cidofovir
Cidofovir is activated exclusively by host cell kinases
and is active against HSV, CMV, adenovirus and papilloma, polyoma and pox virus. I
ts diphosphate product has prolonged t1/2.
dose limiting toxicity is nephrotoxicity.
Probenecid and IV saline can decrease nephrotoxicity.
Ocular toxicity including uveitis and iritis another complication.
Considered as potential human carcinogen.
Foscarnet
is not antimetabolite and doesn’t require intracellular activation by viral or cellular kinases.
Used for IV for CMV infections.
Nephrotoxicity 30 percent incidence, symptomatic hypomagnesemia and hypocalcemia increased by contamitant pentamidine
and CNS problems are the major adverse effects.
Other drugs
Other drugs:
vidarabine, idoxuridine, trifluridine, fomivirsen
and docosanol(alcohol exclusively found in breast milk)
are other drugs that can be used for herpes infection.
Fomivirsen
is the first antisense oligonucleotide
and is active against CMV retinitis by intravitreal route resistant to other drugs.
It can cause iritis, vitreitis and changes in intraocular pressure.
Idoxuridine
is used only topically for keratoconjunctivitis by HSV.
Trifluridine
• More active than idoxuridine in HSV ocular infections
Inhibitor of Viral Cap-Dependent Endonuclease (blocks initiation of mRNA synthesis)
Baloxavir marboxil
Treatment of acute uncomplicated flu in patients ≥12 years and at risk of complications
• As a postexposure preventative against developing influenza
Drugs active against hepatitis B
virus are interferon alpha, lamivudine, ribavirin, entecavir, adefovir and telbivudine.
Goal of therapy is chronic HBV is to sustain suppression of HBV replication
whereas in HCV it causes viral eradication.
Lamivudine:
it is a nucleoside reverse transcriptase inhibitor used in the treatment of HIV infections.
Low dose of this drug can be used alone or in combination with IFN-alpha for chronic HBV infections.
Because it has longer intracellular t1/2 in HBV than in HIV.
DOC
DOC for chronic HBV is entecavir whereas for HCV both acute and chronic DOC is peg-IFN-alpha + ribavirin
Adefovir:
it acts as an antimetabolite for HBV but nephrotoxicity is dose limiting adverse effect.
It can also cause lactic acidosis with hepatomegaly and steatosis.
Tenofovir disoproxil fumarate
• Preferred agent
• Approved for individuals ≥2 years old
• Indefinite treatment for patients with cirrhosis
Tenofovir alafenamide fumarate
• Preferred agent
• Approved for ages 18 and older
• Indefinite treatment for patients with cirrhosis
Newer drugs for hepatitis C virus:
Three groups of new drugs have been approved for HCV.
All of these are effective orally.
These groups include HCV protease NS3A/4 inhibitors,
RNA polymerase NS5A inhibitors
and RNA polymerase NS5B inhibitors.
NS5B inhibitors
Sofosbuvir, beclabuvir and dasabuvir
NS5A inhibitors
Ledipasvir, elbasvir, ombitasvir and daclatasvir, Velpatasvir, ravidasvir, odalasvir and samatasvir
Protease inhibitors
Boceprevir, telaprevir, simprevir, grazoprevir, asunaprevir and paritaprevir, glecaprevir
Anti-hepatitis drugs