Synthetic nucleosides
Synthetic nucleosides are a group of drugs used to treat many vi-ral syndromes that can occur
in an immunocompromised patient,including herpes simplex virus (HSV) and
cytomegalovirus (CMV).
Drugs in this class include:
·
acyclovir
·
famciclovir
·
ganciclovir
·
valacyclovir
·
valganciclovir.
Acyclovir sodium, used to treat HSV, is an
effective antiviral drug that causes minimal toxicity to cells. A derivative of
acy-clovir, ganciclovir has potent antiviral activity against HSV and CMV.
Famciclovir is used to treat acute herpes zoster,
genital herpes, and recurrent HSV infections in the HIV-infected patient.
Valacy-clovir is used to treat herpes zoster, genital herpes, and herpes
labialis. Valganciclovir is used to treat CMV retinitis in the patient with
acquired immunodeficiency syndrome (AIDS).
Each of these antiviral drugs travels its own route
through the body.
When given orally, acyclovir absorption is slow and
only 10% to 30% complete. It’s distributed throughout the body and metabo-lized
primarily inside the infected cells; the majority of the drug is excreted in
urine.
Famciclovir is less than 20% bound to plasma
proteins. It’s exten-sively metabolized in the liver and excreted in urine.
Ganciclovir is administered I.V. because it’s
absorbed poorly from the GI tract. More than 90% of ganciclovir isn’t
metabolized and is excreted unchanged by the kidneys.
Valacyclovir is converted to acyclovir during its
metabolism and has pharmacokinetic properties similar to those of acyclovir.
Val-ganciclovir is metabolized in the intestinal wall and liver to
ganci-clovir; however, interchanging the two drugs isn’t effective.
To be effective, acyclovir, famciclovir, and
ganciclovir must be me-tabolized to their active form in cells infected by HSV.
Acyclovir enters virus-infected cells, where it’s
changed through a series of steps to acyclovir triphosphate. Acyclovir
triphosphate inhibits virus-specific DNA polymerase, an enzyme necessary for
viral growth, thus disrupting viral replication.
·
On entry into CMV-infected cells, ganciclovir is converted to
ganciclovir triphosphate, which is thought to produce its antiviral activity by
inhibiting viral DNA synthesis.
·
Famciclovir enters viral cells (herpes simplex 1 and 2, varicella
zoster), where it inhibits DNA polymerase, viral DNA synthesis and, thus, viral
replication.
·
Valacyclovir rapidly converts to acyclovir; acyclovir then be-comes
incorporated into viral DNA and inhibits viral DNA poly-merase, thus inhibiting
viral multiplication.
·
Valganciclovir is converted to ganciclovir, which inhibits repli-cation
of viral DNA synthesis of CMV.
Acyclovir is used to treat infection caused by
herpes viruses, in-cluding HSV types 1 and 2 and the varicella-zoster virus.
Oral acy-clovir is used primarily to treat initial and recurrent HSV type 2
in-fections.
I.V. acyclovir is used to treat:
§ severe initial HSV type 2 infections in a
patient with a normal immune system
§ initial and recurrent skin and mucous
membrane HSV type 1 and 2 infections in an immunocompromised patient
§ herpes zoster infections (shingles) caused by
the varicella-zoster virus in an immunocompromised patient
§ disseminated varicella-zoster virus in an
immunocompromised patient
§ varicella infections (chickenpox) caused by
the varicella-zoster virus in an immunocompromised patient.
Ganciclovir is used to treat CMV retinitis in an
immunocompro-mised patient, including a patient with AIDS or other CMV
infec-tions such as encephalitis.
Famciclovir is used to treat acute herpes zoster,
genital herpes, and recurrent HSV infections in a patient with HIV.
Valganciclovir is used to treat CMV retinitis, and
valacyclovir is ef-fective against herpes zoster, genital herpes, and herpes
labialis.
Synthetic nucleosides may interact with these
drugs.
§ Probenecid reduces kidney excretion and
increases blood levels of ganciclovir, valganciclovir, valacyclovir,
famciclovir, and acy-clovir, increasing the risk of toxicity.
§ Taking ganciclovir with drugs that are
damaging to tissue cells, such as dapsone, pentamidine isethionate,
flucytosine, vincristine, vinblastine, doxorubicin, amphotericin B, and
co-trimoxazole, in-hibits replication of rapidly dividing cells in the bone
marrow, GI tract, skin, and sperm-producing cells.
§ Imipenem-cilastatin increases the risk of
seizures when taken with ganciclovir or valganciclovir.
§ Zidovudine increases the risk of
granulocytopenia (reduced number of granulocytes, a type of white blood cell)
when taken with ganciclovir. (See Adverse
reactions to synthetic nucleo-sides.)
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