Agents To Treat HSV & VZV Infections
- Inhibit DNA polymerase enzyme. Chemically acyclic guanosine derivative.
- Active against HSV-1 HSV-2 (herpes simplex virus), EBV (ebstein barr virus), CMV (cytomegalo virus), HHV-6 (herpes human virus) & VZV (varicella zoster virus)
- Highly active against HSV and varicella virus.
- HSV causes cold sores, conjunctivitis, mouth ulcers, genital infections and rarely encephalitis in immunocompromised patients.
a) HSV 1 causes mouth and face, skin and esophagus infections
b) HSV II causes infection of rectum, genitals, hands and skin.
- n VZV causes shingles, chicken pox.
Mechanism of Action
- Highly specific for herpes simplex and varicella zoster.
- Accumulated in the infected cell.
- Infected cell has to be activated by phosphorylation in 3 steps:
- Virus thymidine kinase phosphorylate Acyclovir into monophosphate.
- Host cell kinases convert monophosphate to diphosphate & triphosphate compounds.
- Acyclovir triphosphate inhibits viral DNA synthesis by
- Competitive inhibition of DNA Polymerase
- Incorporation into viral DNA strand, hence lengthening and elongation does not occur.
- Oral, I/V or topical. Highly effective orally.
- Oral bioavailability 15-20%.
- t ½ = 3 hrs. Once administration.
- Widely distributed to all compartments.
- Clearance by glomerular filtration.
- Primary genital herpes, recurrent genital herpes.
- Long term chronic suppression of genital herpes.
- Recurrent herpes labialis
- Herpes proctitis
- Mucocutaneous herpes in immunocompromised patients
- Decreases total number of lesions and duration of varicella and cutaneous zoster infections.
- Prophylactically before organ transplantation, it prevents reactivation of HSV.
- Herpes simplex encephalitis.
- Neonatal HSV infection.
- Serious HSV or HZV infections.
- I/v acyclovir reduces incidence of cutaneous and visceral dissemination in immunocompromised patients with zoster.
- Well tolerated, minimum adverse effects.
- GIT -Nausea, diarrhoea, headache (orally)
- I/V infusion – reversible renal dysfunction, due to crystalline nephropathy and neurological toxicity (tremors, delirium, seizures).
Resistance: Due to thymidine kinase alteration
- L valyl ester of Acyclovir.
- Oral bioavailability > 3-5 times
- Potency> acyclovir
- Cytomegalovirus infections after organ transplantation
- In AIDS pts taking high doses, increased incidence of GIT upset, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.
- At high doses confusion, hallucinations and seizures.
- Acyclic Guanosine analogue
- Converted to penciclovir.
Mechanism of Action
- Activation by phosphorylation catalyzed by viral thymidine kinase
- Penciclovir triphosphate causes competitive inhibition of viral DNA polymerase to block DNA synthesis.
- Does not cause chain termination.
- First episode of genital herpes
- Recurrent genital herpes
- Chronic genital herpes suppression
- Acute herpes zoster (shingles)
- Well tolerated with no significant side effects.
Agents to Treat Cytomegalovirus Infections
Acyclic guanosine analog.
Mechanism of Action:
- Activation by triphosphorylation.
- Initial phosphorylation by virus specified protein kinase phosphotransferase UL97 in CMV – infected cells.
- Active drug competitively inhibits viral DNA polymerase thus causing termination of viral DNA elongation.
- Oral, I/V or intraocular implant.
- t ½ = 2-4 hours, may be increased to 6 hours or more.
- Bioavailability is poor 6-9 %
- CSF concentration 50%.
- Elimination by kidneys.
Spectrum of Activity
- CMV, HSV, VZV, EBV, HHV-6 & 8
- Potency > acyclovir for CMV
I/V administration use
- To delay progression of CMV retinitis (Foscarnet) in AIDS patients.
- CMV colitis and esophagitis.
- To reduce risk of CMV infection in transplant patients (Acyclovir).
- To treat CMV pneumonitis in immunocompromised patients, alongwith CMV immunoglobulin (more chances of resistance if used alone)
- Risk of Kaposi sarcoma is reduced in AIDS patients treated by Ganiciclovir.
Oral Administration, used in
- Prevention of end organ CMV in AIDS patient.
- As maintenance therapy for CMV retinitis
- To treat CMV retinitis. Intraocular implant remains for 6-8 weeks. Sometimes have to remove implant surgically.
- Myelosuppression particularly Neutropenia –most common
- CNS toxicity – headache, insomnia, seizures, peripheral neuropathy, (rare).
- Fever, rash, nausea, diarrhea, abnormal liver function.
- Vitreous hemorrhage and retinal detachment.
Spectrum of activity:
- CMV, HSV-1,HSV-2, VZV, EBV, HHV-6 HHV-8
- For Acyclovir resistant HSV,VZV infections
Only Intravenous route of administration
Only 40-65% reaches CSF
30% deposited in Bones
Mechanism of action:
- Inhibits directly viral DNA polymerase
- RNA Polymerase & HIV Reverse transcriptase –effective agent for HIV related infections.
Besides resistant cases of herpes simplex, varicella zoster virus and those resistant to Acyclovir:
- CMV retinitis
- CMV colitis
- CMV esophagitis
- Decreased incidence of Kaposi sarcoma
- Renal toxicity,
- electrolyte imbalance, and
- CNS toxicity.