Chemotherapy of Ocular Viral Infections Flashcards
What are the stages for the multiplication cycle of a virus?
Adsorption Penetration Uncoating Biosynthesis Maturation Release
Is it normal for a virus to have both DNA and RNA?
Not normally, but some viruses (DNA based) keep extra RNA to help speed up the replication
How is adsorption of a virus into the host done?
Usually by electrostatic attraction; some viral particles can bind to outer membrane receptor sites
How is penetration of a virus into a host cell done?
Usually acomplished by fusion of viral envelop or coat with the host cell
Or pinocytosis
When does uncoating occur?
During fusion or once the virus enters the cytoplasm, DNA/RNA passing into cell nucleus
Describe the biosynthesis stage of the viral multiplication cycle
Replicating more DNA/RNA via transcription to make viral progeny using the host cells’ apparatus. (Viral enzymes and proteins produced by the host)
Describe the maturation stage of the viral replication cycle
Assembly phase
Combining of parts to mak ethe viable viral progeny
Some of this occurs in the nucleus
Describe the release stage of the viral replication cycle
Generally occurs with lysis and death of the host
Some of this is done via exocytosis
Talk about the principles of antiviral agents
To be effective must act on intracellular level (serious problem with selectivity between virus and host)
Enzymes used by viruses are not native and can direct antiviral action against the viral enzymes.
Can also block viral fusion or by preventing the uncoating/assembly
Virally infected cells have a higher metabolism and take up more of the antiviral for example than normal cells.
Describe how resistance to antivirals can form
Can occur with antiviral use
Anticipate increased resistance
Develop and use newer drugs on more viral conditions
Use of multiple drugs has prevented some resistance
One mechanism of resistance is decreased phosphorylation of antivirals, thus inhibiting their ability to kill viral infections
Another mechanism is accumulation of mutations to develop resistance
Describe the general toxicities seen with antiviral use
Any rapidly dividing cell will also be affected by the antivirals
Stomatitis (inflammation of mucous membrane of mouth), anorexia, nausea, vomiting and weight loss
Occasionally see alopecia (baldness), blood dyscarsias (abnormal material present in blood), bone marrow depression, kidney/liver impairment and convulsions
Rarely get neurological disorders - insomnia, depression and dizziness
Describe the MOA, class, spectrum and toxicities for Idoxuridine
Deoxy-thymidine(Nucleotide) Analog; First and Prototypical Agent
0.1% solution (not available in the US anymore)
Spectrum - Herpes Simplex
Mimicks substrate that is phosphorylated by thymidine kinase to become an active cytotoxic metabolite.
Toxicity - Highly significant ocular toxicity, directly blocking DNA synthesis in normal cells.
Acute ocular toxicities - pain, photophobia, mild edema of the lids, punctate epithelial keratopathy, limbal follicles, follicular conjunctival response, ptosis, allergic reactions and permanent punctal stenosis
Describe the MOA, class, spectrum and toxicities for Trigluridien (Viroptic)
Nucleotide Analog; 1.0% Solution
Spectrum - In vivo and in vitro; HSV I and II and vaccina
Good ocular penetration and more effective than idoxuridine
Metabolized to triphosphate derivative and inhibits thymidine kinase very effectively like IDU
Toxicities less severe or frequent when compared to IDU or vidarabine
Transient stinging/burning, lid edema, conjunctival hyperemia, chemosis, keratitis, corneal edema and slower healing,
Steroids are contraindicated in which viral condition?
Any herpetic lesion involving the epithelial layer of the cornea, can cause multiplication of the HSV keratitis
Except in the case of deep stromal disease without any epithelial involvement. But start with a low dose and taper ASAP.
Rule of thumb is if there is active epithelial damage, no steroid unless there is underlying cause (scarring/white cell concretions in cornea) then use it; but keep in mind you have the HSV infection must be controlled first as the steroids speed the viral replication!
HSV develops resistance to the nucleotide analogs by what suspected mechanism?
Altered binding to enzyme/substrate to decrease the phosphorylation of the antiviral.
Readily seen in vitro (in test tube)
Why can nucleotide analog antivirals not be taken orally?
Very rapidly inactivated by GI enzyme nucleotidase
Describe the MOA, class, spectrum and toxicities for Acyclovir (Zovirax)
Oral, topical, IV not topical; Acyclic Deoxy-guanosine derivative (Nucleotide derivative)
Affects herpes-zoster, epstein-barr, CMV (lesser) and doesn’t effect vaccina, adeno virus or RNA viruses
Highly selective action; preferential phosphorylation of acyclovir molecule by thymidine kianse into triphosphate acyclovir that is worked into the DNA. Very effective. (Especially in vitro)
Resistance to acyclovir seen in vaccina and some HSV I due to substrate specificity in thymidine kinase.
Topical toxicities - minimal, burning, stinging and some punctate keratitis
Systemic - NVD, headache, skin rash
No healing/immunosuppression.
Besides the listed viruses that acyclovir (zovirax) can treat, what other conditions has it been shown to be good in treating?
Herpes Zoster Ophthalmicus Keratoconjunctivitis - Shown to decrease the severity and duration of the outbreak/systemic conditions, and especially in reducing the incidence of neurotrophic pain post infection
When comparing Acyclovir (Zovirax) to Famiciclovir (Famvir) and Valacyclovir (Valtrex) how do the latter two differ from acyclovir?
Fewer doses per day
Describe the MOA, class, spectrum and toxicities for Ganciclovir (Cytovene)
Oral/Injectable; Nucleotide analog (requires phosphorylation)
Treats immunocompromised patients with CMV Retinitis/preventing CMV retinitis in transplant patients
Must be phosphorylated to be active, some more selectivity in CMV infected cells as well as being more sensitive to ganciclovir
Resistance possible and cross resistant with cidofovir
Toxicities - Retinal Detachment (not sure why), Bone marrow depression leading to agranulocytosis and thrombocytopenia
Describe the MOA, class, spectrum and toxicities for Cidofovir (Vistide)
Derivative of ganciclovir; acyclic deoxy-guanosine analog (nucleotide analog)
Injected/IV
A newer compound compared to ganciclovir
Resistance possible and cross resistance with ganciclovir
Toxicities
Dose Dependent Nephrotoxicity
Proteinuria
Increased serum creatnine
NVD, anorexia, abdominal pain, hair loss, rash, fever, anemias, amblyopia, conjunctivitis and hypotony
When is it indicated to use ganciclovir or cidofovir?
Sight/Life threatening infection that hasn’t responded to other treatments
Ganciclovir and cidofovir are toxic to normal cells.
Describe the MOA, class, spectrum and toxicities for Foscarnet (Foscavir)
Pyrophosphate derivative; powder only, meant for injections
Effective against all herpes group viruses, but used for CMV retinitis exclusively (and in the AIDs patients)
Doesn’t need to be phosphorylated to disrupt DNA polymerase and reverse transcriptase like nucleotide analogs
Taken up by viral rapidly dividing cells more than normal cells; relatively selective
Toxicities - Frequent decreased renal function
Bone marrow depression, fever, NVD, anemia, headache and seizures
Describe the MOA, class, spectrum and toxicities for Fomivirsen (Vitravene)
Antisense Agent; Used for intravitreal injections (but removed)
“Viralstatic” (not a cure)
Oligonucletide blocking expression of 2 specific viral proteins (inhibits translation of mRNA)
Does not interfere with other antivirals and a great combination drug
Toxicity - Less frequent/severe compared to other antivirals, mostly to intraocular structures - Iritis, increased IOP, vitritis and cataracts
