Antiviral agents Flashcards
(26 cards)
What is a virus?
- contains 1 or more strands of DNA or RNA, often with an outer protein or lipoprotein coat
- intracellular parasites, so hard to develop drugs that kill viruses without harming the host
- drugs prevent entry of cituses into cells, block replication of cirus in the cell
3 approaches used for tx & prevention of viral dz
- immunological control (vaccination)
- stimulation of natural resistance mechanisms in the host
- chemotherapy
5 stages of viral replication
- ATTACHMENT & PENETRATION
- UNCOATING: protein coat of virus dissolved, liberates viral RNA or DNA
- SYNTHESIS OF VIRAL COMPENENTS: virus takes over host cell nucleus and replicates its DNA or RNA, then makes proteins
- PACKAGING AND ASSEMBLY OF VIRUS PARTICLE: viral genome maybe encapsulated by viral protein, multiple membranes or no protein
- RELEASE OF VIRUS: some are released rapidly, others slowly
HSV causes what?
a variety of lesions, including herpetic gingivostamatitis, herpes labialis, herpes zoster and eczema herpeticum
Which 2 drugs are most frequently used to tx herpes
oral acyclovir or valcyclovir
IV tx may be needed if herpes infection is severe or life threatening
Acyclovir (Zovirax) & Valcyclovir (Valtrex): what are they? effective against? toxicity?
synthetic guanosine derivative
very effective against HSV1 & HSV2
low toxicity
Very low toxicity
-cyclovirs : how do they work
CYCLOVIRS must be phosphorylated by VIRAL THYMIDINE KINASE to monophosphate compound which can be taken up by cell
PHOSPHORYLATION MORE RAPIE (30-300x) in HERPES INFECTED CELLS than non-HSV infected cells
phosphorylation to triphosphate by host enzymes allows for COMPETITION WITH deoxyGTP
INHIBITS VIRAL DNA POLYMERASE; cases chain termination, which stops DNA replication
acyclovir toxicity and resistance
b/c acyclovir is very CONCENTRATED in infected cells, it is virtually NON-TOXIC to normal cells at therapeutic doses
RESISTANCE can develop; viruses may decrease their level of thymidine kinase or alter the DNA polymerase
Acyclovir, Valcyclovir: route of admin/availability
active, orally, topically or IV, but oral bioavailability of acyclovir is low
Valcyclovir (Valtrex): a pro-drug with high bioavailability which is given orally & converted to acyclovir->higher serum levels, higher effectiveness
Uses of Acyclovir, Valcyclovir
topically: herpes keratitis
orally & applied topically for GENITAL HERPES, increases healing of lesions by 3-5d, decreases duration of pain, new lesions
used chronically to tx recurrent herpes
IV ADMINISTRATION for herpes simplex encephalitis or neonatal herpes
tx of varicella zoster infections (shingles, post-herpetic neuralgia)
prophylaxis in immunocompromised pts post-organ transplant
tx of herpetic gingivostamatitis & recurrent intraoral herpes simplex
longterm suppressive tx recommended for tx of eczema herpeticum
Acyclovir, Valcyclovir side effects
MINIMAL w/ORAL use: naseua, diarrhea, headache (rarely)
-high IV dose may case renal tubular obstruction; this is avoided by HYDRATION & slow infusion
SAFE IN PREGNANCY
Tifluridine (Viroptic):
what is it?
used for?
main toxicity?
fluorinated thymidine analogue which inhibits viral DNA synthesis
used TOPICALLY for HERPES infections RESISTANT TO ACYCLOVIR
main toxicity: visual haze & discomfort
Famciclovir (Famvir): use mechanism/conversion excreted by? (C) side effects
- converted in vitro to PENCICLOVIR (Denavir)
- used for management of acute HERPES ZOSTER (SHINGLES) or recurrent genital herpes
- phosphorylated by VIRAL THYMIDINE KINASE like acyclovir
- excreted by kidney, renal fxn important
- nausea, HA & diarrhea common
Docosanol (Abreva):
how does it work?
use?
SEs?
- inhibits fusion btwn host cell plasma membrane & herpes simplex virus (HSV) envelope; prevents entry of virus into the cell
- used TOPICALLY for COLD SORES
- available OTC
- may irritate skin or cause HA
Ganciclovir Sodium (Cytovene); Valganciclovir (Valcyte)
synthetic analogues of guanosine, similar to acyclovir, but slightly more toxic
active against CMV & herpes
PHOSPHORYLATED by thymidine kinase in cells infected w/HERPES
& by VIRAL PROTEIN KINASE PHOSPHOTRANSTERASE IN CMV INFECTED CELLS
once phosphorylated, inhibits DNA polymerase, suppresses DNA chain elongation & inhibits CMV replication
VALGANCICLOVIR: prodrug w/much higher oral absorption than ganciclovir
Uses of valganciclovir, ganciclovir
VALGANCICLOVIR used ORALLY for prophylaxis & therapy of CMV infections
used prophylactically in organ transplant pts to reduce risk of developing CMV, herpes
IV to tx life or sight threatening CMV infections
OCULAR IMPLANT which lasts 5-8mos is available for tx of CMV retinitis
Valganciclovir, ganciclovir toxicity
NEUTROPENIA: mainly when given IV, esp. when COMBINED WITH ZIDOVUDINE
other adverse effects: fever, rash, phlebitis, confusion, HA, coma, seizures and abnormal LFTs
Cidofovir (Vistide) used to tx (2) structure/mechanism unique feature side effects
used for CMV RETINITIS & HERPES infections
cytosine analogue, inhibits viral DNA polymerase
doesn’t need intracellular activation=USEFUL AGAINST STRAINS RESISTNAT TO GANCICLOVIR
may cause renal tubular necrosis (prevented w/hydration & probenicid)
SEs: oclar hypotonia, uveitis & probenacid-related hypersensitivity
Foscarnet (Foscavir)
directly inhibits HSV DNA POLYMERASE & HIV reverse trascriptase
USED TO TX ACYCLOVIR-RESISTANT HERPES infections & CMV RETINITIS (often in aids)
only IV, sometime w/ganciclovir
eliminated by kidney so toxicity includes RENAL INSUFFICIENCY
hypo or hypercalcemai when combined w/pentamidine
malaise, N/V, fatigue, HA, CNS disturbances, seizures, hallucinations, genital ulcers may occur from high levels in urine, esp men
Fomivirsen (Vitravene): how does it work, indication, SEs
-ANTISENSE COMPOUND complementary to a mRNA sequence in CMV; inhibits protein synthesis & viral replication
admin by INTRAVITREAL injection
-used for tx of CMV retinitis in AIDS pts who failed other therapy
-can be used w/either foscarnet of ganciclovir
SEs: OCULAR INFLAMMATION & VISUAL IMPAIRMENT
Oseltamivir (Tamiflu): type of med, action, administration, activation, excretion
NEURAMINIDASE INHIBITOR active against both influenza A & B
INHIBIT RELEASE OF VIRUS FROM INFECTED CELLS
oral admin
activated in gut & liver, excreted by the kidney; also used for tx of bird flu
some forms seasonal H1N1 have become resistant
Zanamivir (Relenza): type of med, action, administration, activation, excretion
- NEUROAMINIDASE INHIBITORS active against influenza A & B
- INHIBIT RELEASE OF VIRUS FROM INFECTED CELLS
- give INTRANASALLY or by ORAL INHALER b/c it is not absorbed orally
- tx is initiated 35-48h after onset of symptoms, & lasts for 5 days
adverse effects of Zanamivir (3)
may WORSEN RESPIRATORY FXN in patients with chronic obstructive pulmonary dz
or
cause BRONCHOSPASM in asthmatics
causes nasal & throat discomfort
adverse effects of Oseltamivir (2)
NAUSEA & VOMITING, reduced if taken with food
