ANTI VIRAL DRUGS Flashcards
Name 5 drugs used to treat herpes
acyclovir, famciclovir, ganciclovir, cidofovir, foscarnet
acyclovir: MOA and type
type: guanine nucleoside analog
MOA: 3 sequential phosphorylation events for activation
1. converted to the monophosphate by a viral thymidine kinase
TK encoded by herpes simplex and varicella zoster viruses
then converted to active drug (acyclovir triphosphate, by host cell kinases.
2. inhibits utilization of dGTP by HSV and VZV DNA pol.
3. acyclovir incorportated into viral DNA and acts as a chain terminator bc of lack of 3/ hydroxyl group.v Selectivity because higher affinity for viral DNA pol.
acyclovir: MOR. administration
mutations in viral thymidine kinase that dec. viral TK activity or that alter the affinity of TK ofr acyclovir
or, muts in viral DNA pol
oral and IV forms- but oral absorption is poor.
Use, administration, and sides of acyclovir. related prodrugs?
use:
Oral: oral/genaital HSV, VZV/shingles in adults
IV: HSV encephalitis, VZV in immunocompromised, VZV pneumonia
few sides, though can cause kidney damage if patient is not hydrated. may be neurotoxic at high doses.
valacyclovir is an oral prodrug
famiciclovir and penciclovir. use? prodrug?
famiciclovir is an oral prodrug of penciclovir
related to acyclovir in structure, MOA, MOR.
penicilovir used topically for recurrent mucocutaneous HSV infections (cold sores)
ganciclovir MOA and MOR
MOA: quanosine derivative similar to acyclovir
activation via initial phosphorylation step by a viral enzyme followed by 2 additional phosphorylation events by host kinases.
efficiently converted to monophosphate by CMV (acytomegalovirus) phosphotransferase. Could also work for HSV, VZV, epstein-barr, but we usually just give for CMV because we have good drugs with fewer side effects for HSV and VZV.
competitively inhibits viral DNA pol and is incorportated into growing DNA chain –> formation of an unstable complex. NOT a chain terminator.
it is a nucleoside analog
MOR as with aciclovir (TK or DNA pol mutations
Availabe IV and PO
Ganiciclovir sides and use
sides: frequent and severe- myelosuppression (neurtopenia and thrombocytopenia), CNS toxicity
use for CMV infections in immune-compromised pts like CMV retinitis and CMV pneumonia, and transplant prophylaxisis
What does foscarnet do? MOA, MOR, uses.
phosphate analog that reversibly blocks deoxynucleotidyl triphosphates (ie. prevents DNA pol from working). Doesn’t require phosphorylation steps.
MOR: rare, but can happen with DNA pol mutations
good for CMV, HSV, VZV, EBV, HHV-8.
may be used for CMV and HSV that is resistant to acyclovir.
Toxicity: renal, some rare hypokalemia.
only IV. good tissue penetration.
amantadine and rimantadine MOA and MOR
anti-influenza virus agents
tricyclic amines that inhibit uncoating of the viral RNA of influenza A within infected cells. interfere with ion channel function of the viral M2 protein (only present in influenza A). durgs accumulate in the endsomes where they prevent acid mediated dissociation of the viral ribonucleoprotein complex
MOR: point mutations in the TM domain of the M2 protein. prevalent.iuo
amantadine and rimantadine: side effects and clinical use
sides: GI disturbances and CNS complaints (fewer with rimantadine)
use as prophylaxis against influenza A virus infection in high risk ppl or within first 48 hrs of symptoms.
Zanamivir MOA
sialic acid analog that inhibits flu virus neuraminidase activity, which is needed for viral release of flu A and flu B
Zanamavir: uses and sides/contraindications
how is it administered?
uncomplicated influenza virus infections caused by influenza A or B, given within 48 hrs of symptoms onset. can shorten the duration of the flu. serious risks for people with asthma (causes bronchospasm)
administered in an inhaled form.
less resistance to zanamavir than to oseltamivir because zanamavir is smaller and can fit in NA pocket even after steric changes. only for ppl over 7
oseltamivir/Tamiflu: MOA, uses, and administration
oral drug that prevents release of influenza A and influenza B virus particles from infected cells, much like zanamivir. can cause GI upset. given within 48 hrs of symptoms. LOTS of resistance. Only for ppl over 1 yo.
AZT (zidovudine): MOA and MOR
thymidine nucleoside analog
phosphorylated by host cell thymidine kinase after diffuses into cells.
triphosphate form inhibits reverse transcriptase by competing with dTTP; incorporation causes DNA chain termination.
also may partially inhibit dTTP and dCTP levels- contributes to side effects.
resistance due to mutations in reverse transcriptase that reduce affinity for AZT
AZT/zidovudine side effects
bone marrow suppression –> neutropenia and anemia. Macrocytosis is the hallmark of adherence. inhibit some mitochondrial DNA pol, leading to fat redistribution and lactic acidosis (esp. the thymidine analogs) nausea, insomnia, headache, drug interactions
5 drugs that act a little like AZT (reverse transcriptase inhibitors). (not important for DPT)
- didanosine/ ddI
- zalcitabine (ddC)
- lamivudine (3TC)
- stavudine (d4T)
- abacavir (ABC)
didanosine- MOA and type. side effects?
analog of deoxyadenosine (purine) that is activated by phosphorylation. used to treat HIV. acts as a chain terminator. Sides of all NRTIs, but also pancreatitis.
zalcitabine, lamivudine, stavudine
pyrimidine nucleoside analogs. reverse transcriptase inhibitor. activated by phosphorylation. used to treat HIV. chain terminator.
abacavir: MOA and type. Side effects?
dGTP analog. acts as a chain terminator. activated by phosphorylation. reverse transcriptase inhibitor (HIV infection). Can cause fatal hypersensitivity in some people- check HLA type before prescribing this drug.
What are the side effects of zalcitabine, stavudine, and didanosine, lamivudine, and abacavir
all are less myelosuppressive than AZT.zalcitabine and stavudine can cause peripheral neuropathy
didanosine can cuase pancreatitis
nevirapine, delavirdine, efavirenz, etravirine
MOA, uses, sides
non-nucleoside analog inhibitor of HIV reverse transcriptase.
don’t need to be phosphorylated: they are non-competitive inhibitors that block RT action.
can be used to treat HIV in combo with other drugs or as a monotherapy in prevention of perinatal HIV (these uses less important for this class)
nevirapine can cause a life-threatening rash (not for this class)
Efavirenz is NOT for pregnant women- causes birth defects.
drug-drug interactions
HIV protease inhibitors (5)
ritonavir, indinavir, saquinavir, nelfinavir, amprenavir
How doe protease inhibitors work? MOR?
mimc peptide substrates of HIV protease and act as transition state analogs to compettively inhibit the protease. they bind more tightly than the native substrates.
resistance via mutations in the protease
side effects of indinavir and ritonavir? Of PIs in general?
inhibitors of cytochrome P450- beware of drug interactions! In fact, ritonavir is such a potent P450 analog that we use it in very small doses to prevent breakdown of other HIV drugs. this decreases frequency of dosing and necessary does and keeps other drug levels more consant.
PIs can cause GI probs, dyslipidemias, insulin resistance and fat redistribution.
Raltegravir- MOA, MOR, uses, sides
targets HIV integrase to prevent insertion of linear HIV DNA into host cell genome. that way, the provirus can’t form. This is a well tolerated drug, though there is occasionally nausea and vomiting. orally available.
resistance possible but rare- requires several mutations. no cross-resistance. should be part of initial therapy cocktail.
Maraviroc: use, sides, MOA, etc.
blocks CCR5 receptor and prevents HIV entry into macrophages and T cells. orally available and well tolerated. doesn’t work well once the virus switches to using CXCR receptors for entry.
Enfuvirtide: MOA, uses, sides, etc.
binds gp41 transmembrane glycoprotein of HIV and prevents fusion of viral envelope with host cell membrane. given as a subcutaneous injection. cuases a rxn at the injection site. may also cause allergy, CNS effects, and GI upset. respsitance seen from gp41 mutations. No cross-resistance with other anti-retrovirals.
Ribavirin uses (NOT FOR DPT)
resp viral infections in kids due to RSV
hemorrhagic fever due to Hanta virus
in combo with interferon alpha to treat hep C`
Interferon Alpha (NOT FOR DPT)
endogenous proteins
virus non-specific activites
altering cellular metabolic processes important for DNA and protein synthesis
cytokines
interferons induce cellular proteins that inhibit protein synthesis and lead to RNA cleavage.
inteferon-alpha uses and side effects (NOT FOR DPT)
hep B and hep C infections, esp. when combined with ribavirin. effects hard to predict because they cause such long-lasting changes
sides: flu-like symptoms and GI disturbances. bone marrow suppression and CNS toxicity, drug interactions (P450)
ribavirin MOA (NOT FOR DPT)
purine nucleoside analog
underoges phosphyrlation by host cell kinases
competitively inhibits GTP syntehsis, caping of viral mRNAs, and viral RNA0dependent RNA pol of some viruses
wide spectrum of activy, esp. against RSV, hemorrhagic fever, and hep C
