Antiviral & Antifungal Drugs
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Transcript of Antiviral & Antifungal Drugs
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