Antiviral drugs Flashcards
Broad steps of managing viral infections
1) vaccination (most effective method if possible)
2) pharmacotherapeutic treatment via antiviral drugs
- narrow spectrum drugs and specific for one virus
- also includes palliative care
3) immune response stimulation (very controversial)
General consideration for antiviral drugs
Most viral infections resolve spontaneously unless immunosuppressive
Therapy primary aim is to minimize symptoms and infectivity
Drugs act by arresting the viral replication cycle
- do not kill
Almost impossible to not harm host cells due to viruses being obligate intracellular parasites
24-48 hrs after symptom onset is the best time to administer antivirals
Viral load must be monitored during treatment if symptoms are still present
5 Stages of the viral life cycle
Attachment and penetration of virus to host cell
Unloading of viral genome
Synthesis of viral components within the host cell
Assembly of viral particles
Release of virus from host cells
Antivirals against herpes
Target inhibition of DNA replication since they are DsDNA
- Analogs are phosphorylated to mimic nucleotides
- nucleotides are then incorporated into replicating DNA virus strand and inhibits DNA poly.
- results in truncated viral DNA that has little/no effect on host cells
Includes nucleoside analogs, DNA/RNA polymerase inhibitors
All strands are affected by all drugs but to varying efficacies
Types of herpes strands
HSV-1 = oral, skin,bran, lungs
HSV-2 = genitalia, rectum, meninges
HSV-3 = VZV, chicken pox, shingles
HSV-4 = Epstein Barr, infectious mono
HSV-5 = Cytomegalovirus (CMV)
Why do herpes viral drugs work more towards viral thymine kinase vs host thymine kinase to be phosphorylated?
Viral thymine kinase affinity for the “clovir” drugs is roughly 200-300x high than host cell thymine kinases
Acyclovir and valacyclovir
Acyclovir (IV, topical)
- is the ONLY herpes antiviral that can be IV administered
Valacyclovir (PO)
- more common since it can be taken PO
- is a prodrug of acyclovir (will be cleaved into acyclovir
Both of these work as guanosine analogs
Good vs HSV-1:4
Acyclovir (t1/2 =. 2.5-3 hrs) renal excretion
How does herpes viruses gain resistance to acyclovir?
Alter their thymine kinases or the DNA polymerases
Acyclovir ADRs
Nephrotoxicity: usually only in high doses without infusion
- High chance if on diuretics
Nausea, diarrhea, vomiting
Neurotoxicity: very rare
TTP occurs in patients that are HIV+
probencid and cimetidine decrease acyclovir clearance
Penciclovir and famciclovir
Penciclovir (topical) famciclovir (PO)
- similar MOA as acyclovir except does not cause DNA chain termination
- used for HSV-1/2 and VZV
Famciclovir is a prodrug of penciclovir so super high PO bioavailability
No major ADRs
Ganciclovir and valganciclovir
Ganciclovir = IV drug that is an analog of acyclovir
- same MOA and distribution as acyclovir
VERY potent against cytomegalovirus (CMV) and helps immunocompromised patients and a prophlayxis for transplant patients as well.
Renally excreted with t1/2 = 4 hrs
valganciclovir is the prodrug of ganciclovir
Ganciclovir and valganciclovir ADRs
Myelosuppression (major issues)
- can cause neutropenia and thrombocytopenia as well
Neurotoxicity
Teratogen since it is not as selective for viral DNA polymerases and thymine kinases
Foscarnet
IV drug that is apyrophosphate derivative that directly binds to DNA polymerase, skipping thymine kinase since it is already phosphorylated.
- prevents cleavage of pyrophosphate to triphosphates used to build viral DNA
Used for HSV infections that are resistant to acyclovir/ganciclovir
- also CMV in immunocompromised hosts
Renally excreted and t1/2 = 3-7 hrs
super broad so resistance is occurring, use sparingly
Foscarnet ADRs
Nephrotoxicity
Electrolyte imbalances (hypocalcemia, hypomagnesemia, hypokelmia)
Don’t co-administer with cidofivir
produces synergistic effect when given with ganciclovir
Cidofovir
IV durg that is A cytosine nucleotide analogy that is already phosphorylated
- Targets viral DNA polymerases and is used primarily for ganciclovir resistant CMV
- super potent for CMV in patients with AIDS*
Renally excreted and t1/2 = 2.6 hrs
Cidofovir ADRs
Nephrotoxicity: so bad that renal impaired patients cant take this drug
- administered with IV saline to reduce concentration of cidofovir in renal tubules to try and combat nephrotoxicity
Neutropenia
Embryotoxicty/gonadotoxicity (contraindicated in pregnancy)
Influenza and RSV infections with 4 types of drugs
Different from herpes since it uses RNA cycle to replicate
4 types: amantadine antivirals Neuraminidase inhibitors Viral replication inhibition RNA translation inhibition
Amantadine and rimantadine
PO drugs that Prevent and treat only influenza A types
- (70-90% effective, but 0% effective against influenza B or RSV)
MOA = prevent virus from uncoating and releasing genetic material
- specifically block M2 channels which are used to trigger dissociation of the virus capsid once it has been endocytosis via host cells.
- if M2 channels are open, then RNP proteins are released and initiate transcription
- Amantadine is also used against Parkinson’s disease but is the primary agent*
- is not recommended all the time since resistance develops very quickly*
Amantadine and rimantadine Pharmacokinetics and ADRs
Amantadine = renally cleared with half life of 12-18 hrs
Rimantadine = hepatically metabolized with renal clearance and a half life of 24-36 hrs.
- doses for both must be adjusted in renal impaired function patients
minor ADRs nothing serious
- do NOT take with antihistamines, psychotropics or anticholinergic drugs since it increases neurotoxicity*
Contraindicated in patients with seizure and/or psychiatric symptom history
Neuraminidase
viral enzyme with 3 \main functions
1) cleaves Salic acid form host cell receptors which allows for controlling of viral adhesion to host cells
2) promotes fusion of viral envelope with host cell membrane
3) aids in releasing of newly formed virus particles form infected cells
- again cleaving Sialic acid prevents aggregation of the virus on the host cell membrane
- primary job is to cleave sialic acid from host cells so hemagglutinin cant bind to host cells and prevent both entrance and exit of viral particles*
Neuraminidase inhibitors
Oseltamivir (PO), zanamivir (inhalation), peramivir (IV)
Bind to neuroaminidase and inhibit all actions
Treats influenza A/B and RSV types
- also is a prophylaxis for patients that cant take normal flu vaccine
Must be used within 24-48 hrs otherwise does not work anymore
ADRs are not severe, however must be careful with asthma or COPD patients especially if using zanamivir (can cause bronchospasms)
resistance is very common since it is such a broad agent
Ribavirin
Broad spectrum antiviral agent that is used only to kill RSV infections
- guanosine nucleoside analogue but mechanisms is not well known, does kill viral replication though.
- is hypothesized to inhibit viral RNA polymerase and deplete GTP as well as increase host immune system*
Resistance already exists for this drug so you have to test for it (primarily in influenza A/B though)
Ribavirin pharmacokinetics and ADRs
Ribavirin can be both PO and inhalation
- PO only for Hep C virus treatment though
- inhalation used for RSV infections
Renally cleared
ADR:
- hemolytic anemia that is dose dependent
- elevated bilirubin
- teratogen
Palivizumab
IM drug that acts on the RSV fusion protein and inhibits it at the A antigenic site
- prevents adhesion and entrance into host cells
ONLY use in high-risk pediatric patients
- must take monthly for a year and is also super expensive
ADRs = hypersensitivity, thrombocytopenia fever and rash
Metabolized through liver
Are antivirals cidal or static
Static (don’t kill just prevent load)
