Antiviral agents

Dr.Anant Khot

Introduction

RNA viruses

Antiviral agents

Nucleosides, needs phosphorylation

intracellularly to become active except

foscarnet, cidofovir & trifluridine

Virustatic- Active only against replicating

viruses & do not affect latent viruses

Narrow margin safety

Mechanism of action

Acyclovir

PK- Bioavailability-PO ~15-20%, IV, Topical

CSF concentration s are ~ 20-50% of serum

values

Cleared primarily by glomerular filtration &

tubular secretion

Plasma t1/2 is 2-3 hrs

PO- Genital herpes- First episode or

recurrent disease

Suppression of recurrent genital herpes

Oral-labial HSV infections

Herpetic whitlow

HSV proctitis

Varicella treatment ≥2 yrs

Uses

IV-Severe HSV treatment

Mucocutaneous HSV infections in immuno -

suppressed patients

HSV encephalitis

Visceral HSV infections

Varicella in immunosuppressed host

patients

Neonatal HSV infection

Adverse Effects

Topical: Stinging and burning sensation after each

application. Punctate epithelial keratopathy

Systemic: Nausea, diarrhea, headache

IV infusion-reversible renal toxicity (E.g:

Crystalline nephropathy or interstitial nephritis)

or neurologic effects (E.g: Tremors, delirium,

seizures)

Adequate hydration & slow infusion

High doses → Chromosomal damage & testicular atrophy in rats

• No E/o teratogenicity, ↓ sperm production

or cytogenetic alterations in peripheral

blood lymphocytes

Valacyclovir

L- valyl ester of acyclovir (Bioavailability ~3-5

times > oral acyclovir)

Used for treatment of herpes zoster

ophthalmicus

Dose: 1 g three times daily for 7-10 days.

It is as effective as acyclovir in acute disease

& is more effective in reducing late neuralgia

Higher doses ~2 g QID- For prevention of

CMV disease after organ transplantation &

VZV reactivation after hematopoietic stem

cell transplantation

High dose- Confusion, hallucination &

seizure

AIDS (>8 g/d)- GI intolerance, TTP/HUS

Famciclovir

Diacetyl ester prodrug of 6-deoxypenciclovir

Active in vitro against HSV-1, HSV-2, VZV, EBV

& HBV

Bioavailability –PO ~70%

M.O.A: Penciclovir does not cause chain

termination Shortens the duration of zoster associated pain

↑ incidence of mammary adenocarcinoma in female rats receiving Famciclovir for 2yrs

Topical agents

Idoxuridine (0.1%) - superficial dendritic keratitis

Trifluridine (1% ) solution- keratoconjunctivitis &

recurrent epithelial keratitis due to HSV-1 & 2

Penciclovir (1% ) cream-recurrent herpes labialis

Docosanol (10% ) cream- inhibits fusion between

the host cell plasma membrane & HSV envelope

Ganciclovir

It has in vitro activity against CMV, HSV, VZV,

EBV, HHV-6 & HHV-8

Initial phosphorylation is catalyzed by

phosphotransferase (UL97) in CMV-infected cells

IV ganciclovir- CMV colitis, esophagitis &

pneumonitis in immunocompromised patients

IV→PO-↓ risk of CMV infection in transplant

recipients

Intravitreal injections- Rx of CMV retinitis

Ganciclovir gel is available for the treatment of

acute herpetic keratitis.

A/E- M.C.myelosuppression- reversible, dose

limiting

Others- fever, insomnia & peripheral neuropathy

Intravitreal inj-vitreous hemorrhage & retinal

detachment.

• CNS & hepatotoxicity

rarely reported

Mutagenic in mammalian cells & carcinogenic &

embryotoxic in animals at high doses

D/I- Ganciclovir + probenecid or trimethoprim

Valganciclovir

L-valyl ester prodrug of ganciclovir , mixture of

two diastereomers

Drug should be taken with food, BA ~ 60% .

The AUC0–24h of 900 mg of Valganciclovir~1.65

times that of oral ganciclovir

Use – Rx of CMV retinitis & prevention of CMV

disease in high-risk solid organ & BM

transplant recipients

Foscarnet

It is an inorganic pyrophosphate analog that

inhibits herpesvirus DNA polymerase, RNA

polymerase & HIV reverse transcriptase

It has in vitro activity against HSV, VZV,

CMV, EBV, HHV-6, HHV-8, HIV-1, and HIV-2.

Use: Treatment of end-organ CMV disease

including ganciclovir-resistant disease.

Acyclovir-resistant mucocutaneous HSV

infections

A/E-Nephrotoxicity with azotemia, proteinuria &

sometimes ATN-dose-limiting side effect

It is a potent chelator of divalent cations- hypo-

or hypercalcemia, hypo- or hyperphosphatemia,

hypokalemia, & hypomagnesemia

Genital ulcerations- high levels of ionized drug in

the urine

Cidofovir Cytosine nucleotide analog with in vitro

activity against CMV, HSV-1 & 2, VZV, EBV,

HHV-6, HHV-8, adenovirus, poxviruses,

polyomaviruses & HPV

M.O.A: Phosphorylation to the active

diphosphate is independent of viral enzymes

Use- IV- in the Rx of CMV retinitis

ADVERSE EFFECTSDose-dependent proximal tubular

nephrotoxicity

Proteinuria, azotemia, metabolic acidosis &

Fanconi’s syndrome may occur.

Other A/E- uveitis, ocular hypotony, &

neutropenia (15–24%)

Mutagenic, gonadotoxic & embryotoxic in

animals

IV cidofovir must be

administered with

high dose

probenecid 2g at 3

hrs before the

infusion & 1 gm at 2

& 8 hrs after