Antiherpes Agents:
Overview:
Antiviral drugs targeting herpes viruses are designed to inhibit the replication of these viruses, which include herpes simplex virus (HSV) and varicella-zoster virus (VZV). These drugs are essential in managing and treating infections caused by herpes viruses.
Types of Antiherpes Agents:
Nucleoside Analogues:
Acyclovir: Acyclovir is a prototypical antiviral drug effective against HSV and VZV. It is a nucleoside analogue that inhibits viral DNA synthesis by competing with the natural nucleoside and becoming incorporated into the growing viral DNA chain, leading to chain termination.
Valacyclovir: Valacyclovir is a prodrug of acyclovir, meaning it is converted into acyclovir in the body. It is often used for the treatment of genital herpes, shingles, and cold sores.
Famciclovir: Another prodrug, famciclovir is converted to penciclovir, which inhibits viral DNA polymerase. It is used for the treatment of herpes zoster and recurrent genital herpes.
Nucleotide Analogues:
Cidofovir: Cidofovir is a nucleotide analogue that inhibits viral DNA polymerase. It is used in severe cases of cytomegalovirus (CMV) and acyclovir-resistant HSV infections.
Protein Kinase Inhibitors:
Foscarnet: Foscarnet is a non-nucleoside analogue that inhibits viral DNA polymerase and reverse transcriptase. It is used in the treatment of acyclovir-resistant HSV and CMV infections.
Mechanism of Action:
Most antiherpes agents interfere with viral DNA synthesis. Nucleoside analogues are incorporated into the growing DNA chain, leading to premature termination, while nucleotide analogues act as chain terminators directly. Protein kinase inhibitors disrupt the phosphorylation process crucial for viral DNA synthesis.
Side Effects:
Common side effects of antiherpes agents include nausea, headache, and diarrhea. More severe side effects are rare but may include kidney dysfunction, especially with prolonged use.
Drug Resistance:
The emergence of drug-resistant strains, particularly in immunocompromised patients, is a concern. Combination therapy and close monitoring are strategies employed to mitigate resistance.
Anti-influenza Agents:
Overview:
Anti-influenza agents are crucial for managing influenza, a highly contagious respiratory infection caused by influenza viruses. These drugs aim to reduce the severity and duration of symptoms and prevent complications.
Types of Anti-influenza Agents:
Neuraminidase Inhibitors:
Oseltamivir (Tamiflu): Oseltamivir inhibits the neuraminidase enzyme, preventing the release of newly formed viral particles from infected cells. It is effective against both influenza A and B viruses.
Zanamivir (Relenza): Zanamivir is another neuraminidase inhibitor delivered through inhalation. It also prevents the release of new virions from infected cells.
Adamantanes:
Amantadine: Amantadine inhibits the M2 ion channel, inhibiting the release of viral genetic material into the host cell.
2. 01.
02.
Viruses are the ultimate expression of
obligate intracellular parasitism. They not
only take nutrition from the host cell but
also direct its metabolic machinery to
synthesize new virus particles. Viral
chemotherapy, therefore was considered
impossible, as it would require interference
with cellular metabolism in the host.
Introduction
However, in the past 50 years virus
directed enzymes have been identified in
the infected cell and some viruses have
few enzymes of their own which may have
higher affinities for some antimetabolites
or inhibitors than the regular cellular
enzymes.
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3. In addition, drugs have been developed
which target virus specific steps like cell
penetration, uncoating, reverse
transcription, virus assembly or maturation
and release from host cell, etc.
Introduction
Another stumbling block is that
in majority of acute infections viral
replication is already at its peak when
symptoms appear. To be effective,
therefore, therapy has to be started in the
incubation period, i.e. has to be
prophylactic or preemptive.
03.
04.
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6. MOA
This deoxiguanosine analogue requires a virus specific
enzyme for conversion to the active metabolite that
inhibits DNA synthesis and viral replication.
Acyclovir is preferentially taken up by the virus infected
cells. Because of selective generation of the active
inhibitor in the virus infected cell and its greater
inhibitory effect on viral DNA synthesis, acyclovir has low
toxicity for host cells: a several hundred-fold
chemotherapeutic index has been noted.
It is a synthetic, purine nucleoside analogue that has antiherpes
activity. It is more effective against HSV-1 and HSV-2 than
varicella zoster virus (VZV) infections.
Acyclovir
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7. Pharmacokinetics of Acyclovir
Only about 20% of an oral dose of acyclovir is absorbed. It is little plasma
protein bound and is widely distributed attaining CSF concentration that
is 50% of plasma concentration. After topical application systemic
absorption is negligible, but it penetrates cornea well. Acyclovir is
primarily excreted unchanged in urine, both by glomerular filtration and
tubular secretion; plasma t1⁄2 is 2- 3 hours.
Renal impairment necessitates dose reduction.
It is a highly potent antiherpes drug. It has high therapeutic index with
low toxicity to host cells.
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8. Therapeutic Uses of Acyclovir
1. GENITAL HERPES: Oral/intravenous/topical acyclovir is effective in
genital herpes simplex infections. It is used for primary and recurrent
infections; high doses of acyclovir are needed for recurrent infections.
It reduces the frequency and severity of herpetic lesions.
2. HERPETIC ENCEPHALITIS: Intravenous acyclovir is the drug of
choice for encephalitis caused by HSV.
3. Herpes simplex keratitis: Acyclovir is used topically in herpetic
keratoconjunctivitis.
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9. 4. Mucocutaneous HSV: Acyclovir is used orally or topically in the
treatment of stomatitis, herpes labialis and ulcers in mouth. It is used
intravenously in immunocompromised patients.
5. Herpetic whitlow (nail-bed infection): Oral acyclovir is useful for the
prevention and treatment of whitlow.
6. CHICKENPOX: Acyclovir reduces the duration of illness if started early
in patients at risk of severe illness and immunocompromised
individuals.
7. Herpes zoster: Acyclovir (oral/topical/i.v.) and valacyclovir (oral) are
effective.
Therapeutic Uses of Acyclovir
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10. Adverse Effects of
Acyclovir
Acyclovir is usually well tolerated. Nausea, vomiting,
diarrhoea and headache are the other side effects.
High doses may cause neurotoxicity with tremor,
confusion, disorientation and convulsions. On topical
use, it can cause irritation and burning.
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12. Idoxuridine
Idoxuridine is a thymidine analogue that acts against DNA viruses. It
inhibits viral replication. Idoxuridine is used topically for HSV
keratoconjunctivitis. The adverse effects are local irritation, itching,
pain and swelling of lids.
Valganciclovir
It is a prodrug of ganciclovir. It has better bioavailability than
ganciclovir.
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13. The important features of
some of the antiherpetic
agents are given in the
table.
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