DNA Polymerase Inhibitors

Agents To Treat HSV & VZV Infections

Acyclovir (Zovirax)

• 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:

1. Virus thymidine kinase phosphorylate Acyclovir into monophosphate.
2. Host cell kinases convert monophosphate to diphosphate & triphosphate compounds.
3. Acyclovir triphosphate inhibits viral DNA synthesis by
4. Competitive inhibition of DNA Polymerase
5.  Incorporation into viral DNA strand, hence lengthening and elongation does not occur.

Pharmacokinetics

• 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.

Therapeutic Uses

Oral Acylovir

1. Primary genital herpes, recurrent genital herpes.
2. Long term chronic suppression of genital herpes.
3. Recurrent herpes labialis
4. Herpes proctitis
5. Mucocutaneous herpes in immunocompromised patients
6. Decreases total number of lesions and duration of varicella and cutaneous zoster infections.

   I/V Acyclovir

1. Prophylactically before organ transplantation, it prevents reactivation of HSV.
2. Herpes simplex encephalitis.
3. Neonatal HSV infection.
4. Serious HSV or HZV infections.
5. I/v acyclovir reduces incidence of cutaneous and visceral dissemination in immunocompromised patients with zoster.

Adverse Effects

• 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

Valacyclovir

• L valyl ester of  Acyclovir.
• Oral bioavailability  > 3-5 times
• Potency> acyclovir

Additional uses:

• Cytomegalovirus infections after organ transplantation

Adverse effects

1. Rash
2. GIT
3. In AIDS pts taking high doses, increased incidence of GIT upset, thrombotic thrombocytopenic purpura and hemolytic uremic syndrome.
4. At high doses confusion, hallucinations and seizures.

Famciclovir

• 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.

Therapeutic Uses

1. First episode of genital herpes
2. Recurrent genital herpes
3. Chronic genital herpes suppression
4. Acute herpes zoster (shingles)
5. Well tolerated with no significant side effects.

Agents to Treat Cytomegalovirus Infections

Ganciclovir

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.

Pharmacokinetics

• 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

Therapeutic uses

I/V administration use

1. To delay progression of CMV retinitis (Foscarnet) in AIDS patients.
2. CMV colitis and esophagitis.
3. To reduce risk of CMV infection in transplant patients (Acyclovir).
4. To treat CMV pneumonitis in immunocompromised patients, alongwith CMV immunoglobulin (more chances of resistance if used alone)
5. Risk of Kaposi sarcoma is reduced in AIDS patients treated by Ganiciclovir.

Oral Administration, used in

1. Prevention of end organ CMV in AIDS patient.
2. As maintenance therapy for CMV retinitis

Intraocular uses

• To treat CMV retinitis. Intraocular implant remains for 6-8 weeks. Sometimes have to remove implant surgically.

Adverse Effects

1. Myelosuppression particularly Neutropenia –most common
2. CNS toxicity – headache, insomnia, seizures,  peripheral neuropathy, (rare).
3. Fever, rash, nausea, diarrhea, abnormal liver function.
4. Vitreous hemorrhage and retinal detachment.

Foscarnet

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:

1. Inhibits directly viral DNA polymerase
2. RNA Polymerase &  HIV Reverse transcriptase –effective agent for HIV related infections.

Anti-retroviral agent.

Therapeutic uses:

Besides resistant cases of herpes simplex, varicella zoster virus and those resistant to Acyclovir:

1.  CMV retinitis
2.  CMV colitis
3.  CMV esophagitis
4.  Decreased incidence of Kaposi sarcoma

Adverse effects:

1. Renal toxicity,
2. electrolyte imbalance, and
3. CNS toxicity.

Continue Reading

Anti Viral Drugs

Anti Influenza Agents

Anti Retroviral Agents (HAART) -Highly Active Antiretroviral Therapy

Anti Hepatitis Drugs