Antivirals Flashcards
What’s mechanism of action of acyclovir?
Guanine analog requiring 3 phosphorylation steps for activation; 1st step occurs in infected cells by a viral thymidine kinase. 2nd/3rd steps by host cell kinases, accumulates only inside infected cells. It is a Competitive inhibitor viral DNA polymerase. Incorporated into viral DNA >chain termination
What are clinical indications of acyclovir?
Topical, cream-cold sores, ointment for initial genital herpes
Oral for primary/recurrent/suppressive genital herpes; acute VZ (chickenpox), HZ (shingles)
IV use: for severe infections: HSV / HSV encephalitis; VZ / HZ in immunocompromised patients
What are PK of Acyclovir?
PO bioavailability 10-30%, adm. 3-6X/day; CSF levels 50% of Cp
What are ADRs acyclovir?
PO ADRs: nausea / diarrhea, rash, headache, decreased renal function
IV-ADRs: phlebitis, nephrotoxicity/ (crystallization) usu. dose-limiting, CNS disturbances: tremor, delirium, seizures
Topical-ADRs: limited to local skin irritation
Valacyclovir– valine ester prodrug, increases acyclovir oral bioavailability 5X, adm. BID, same indications
What are PKs of famiciclovir?
Prodrug, converted 1st-pass metabolism to active metabolite>penciclovir; MA = acyclovir but no chain termination action
PO bioavailability 70-80%, adm BID
Indications of famciclovir
Use: genital herpes, acute HZ (shingles), recurrent HSV1 / HSV2 in AIDS patients
Penciclovir– topical cream for recurrent herpes labialis
ADRs famciclovir
ADRs: headache, nausea-diarrhea, rash, fatigue, pruritus (i.e., heptocellular dysfunction)
What’s mechanism of Trifluridine & vidarabine?
Trifluridine: Thymidine derivative activated by cellular phosphorylation to inhibit thymidylate synthetase\DNA polymerase
Vidarabine: Adenosine analog activated in viral-infected cells, inhibits DNA polymerase/causes chain termination
What are ADRs TRIFLURIDINE & VIDARABINE
Local burning\stinging, edema
Drug toxic to mammalian cell DNA synthesis, topical use only
burning, irritation, keratitis, uveitis, photophobia
What are indications of TRIFLURIDINE & VIDARABINE
Topical ophthalmic drops for HSV 1 & 2 keratoconjunctivitis and recurrent epithelial keratitis
What are different outcomes of CMV in normal person, seronegative mother, and AIDs?
In normal people - mononucleosis
Seronegative mother - CMV inclusion
AIDS - Multiple Sypmtomatic disease
What is the mechanism of ganciclovir?
Guanine analog, MA similar to acyclovir, triphosphorylation, inhibits viral DNA polymerase
What are indications and PK of ganciclovir?
CMV retinitis/GI-colitis/pneumonia
IV for acute infection; PO for maintenance & prophylaxis; intraocular implant sustained-release for 5-8 months
What are some ADRs of ganciclovir?
Dose-limiting toxicity - myelosuppression (anemia, neutropenia, thrombocytopenia)
ADRs: liver/renal dysfunction, fever, rash, mental changes, rare seizures, pancreatitis
What is mechanism of action , clinical indication, and ADRs of valganciclovir?
Valine ester prodrug of ganciclovir indicated for CMV in AIDS. Adm. PO, with food, increased PO bioavailability of Valcyte provides plasma levels = to IV ganciclovir. Rapidly converted > ganciclovir by intestinal/hepatic esterases. ADRs same as ganciclovir
What’s mechanism of action of cidofovir ?
inhibitor of viral DNA polymerases, cytosine nucleotide analog, broad activity > HSV 1&2, CMV, VZV
Doesn’t require viral enzymes for activation, still requires host cell phosphorylation conc = in infected and noninfected cells
Probenecid adm. to block uptake into renal PT to decrease nephrotoxicity
What are indications and ADRs of cidofovir?
Adm IV for ganciclovir-resistant CMV infection, initial once weekly then biweekly
ADRs – nephrotoxicity (esp. PT), neutropenia, metabolic acidosis, iritis, uveitis
What’s mechanism of action of foscarnet?
Inorganic pyrophosphate, doesn’t require phosphorylation activation
Blocks pyrophosphate binding site viral DNA / RNA polymerase & HIV reverse transcriptase
What are indications and ADRs of foscarnet?
Adm. IV CMV retinitis; ganciclovir/cidofovir -R; acyclovir-R HSV / VZ infections in AIDS
Nephrotoxicity dose-limiting: electrolyte disturbances- loss Mg/K, hypo- or hyperphosphatemia, hyper- or hypocalcemia (tetany, arrhythmias, seizures)
ADRs: headache, GI disturbances, tremors, seizures, genital ulcerations, anemia/BMS
What’s mechanism of action of Fomivirsen?
Antisense oligonucleotide, binds/inhibits mRNA protein synthesis & virus replication
What are indications and contraindications of Fomivirsen? (CMV)
Intravitreal injection in CMV retinitis in HIV-infected patients who can’t tolerate or have no response to other drugs
Initial injections for 2 weeks, maintenance for 4
Contraindicated in patients treated with cidofovir in previous 2-4 weeks, causes increased ocular toxicity
What are ADRs fomivirsen? (CMV)
ADRs - eye inflammation, iritis, vitreitis, inc intraocular pressure, vision changes
What are indication, ADRs, and contrindications of Amantadine? (influenza/rsv)
Prophylactic use in high risk patients for influenza A, provides ~ 70% protection.
ADRs: GI, CNS: confusion/ dizziness/ nervousness, releases dopamine, hypotension, anticholinergic effects
Contraindicated in pregn/ nursing mothers
RIMANTIDINE - 2-4 X more potent, less CNS, less ADRs, no longer in use due to high resistance
What is mechanism of action of amantadine?
Treatment: adm within 48 hr viral exposure
Blocks viral M2 protein/proton channel essential for viral entry/uncoating/release of viral genome into host’s cell. RIMANTIDINE - 2-4 X more potent, less CNS, less adrs
What is mechanism of action of neuramindinase inhibitors
Inhibit NA enzyme required for viral movement thru respiratory secretions to sites of infection and for release of progeny virons
orally inhaled BID for treatment influenza A or B, adm. within 30 hrs onset of symptoms, decs illness 1-3 days; ADRs: GI, nasal / throat discomfort, bronchospasm / breathing difficulties
Zanamivir
Prodrug, adm. orally, activated GI/liver, for prevention/treatment influenza A/B; adm. with food decreases abs. ADRs: nausea / vomiting / diarrhea, headache. Probenecid doubles the t1/2
Oseltamivir
What is mechanism of action, indication, and ADRs of Palivizumab?
monoclonal antibody, binds fusion protein of respiratory syncytial virus (RSV)
Used to prevent infection in neonates at risk for RSV infection, or those with bronchopulmonary dysplasia
Monthly IM injection 5-6 months during RSV season ; t1/2-18-20 days
Injection pain, allergy risk, elevation of serum aminotransferase levels
What does HAART stand for
Highly active antiretroviral therapy
Usually 3 drug combinations
Many different combinations
Skipping doses for even 1 day may allow drug resistance to develop
What is mechanism, indication, and ADR of ribavirin?
Purine nucleoside, broad antiviral activity, esp. RSV; activated by host enzymes, inhibits viral mRNA synthesis
Adm small-particle aerosol generator for 3-7 days to children with RSV
Decs pulm function, chest soreness, eye irritation, rash, GI, bone marrow suppression, teratogenic, mutagenic, embryolethal in all animal species
Ribavirin + IFNa combo, adm. PO for hepatitis C.
Can be used as part of HIV treatment
What is mechanism, indication, and ADR of IFNa?
IFNa is antiviral produced by all cells in response to viral infection; pegylated. degrades viral mRNA
Indicated for hepatitis B and C.
Combined with ribavirin for synergistic effect
t ½ , 5 vs. 80 hrs.; dec. dosing
Metabolized by liver and kidney enzymes; inhibits liver CYP 450 enzymes inc. t ½ of other drugs
ADRs – fever, chills, myelosuppression, headache, depression
What are 5 general mechanisms of HIV drugs?
Nucleoside reverse-transcriptase inhibitors (NRTIs); competitively inhibit RT, Group A (thymidine analogues), Group B (non -thymidine analogues ie. emtricitabine and tenofovir), drugs incorporated into viral DNA
Non-nucleoside reverse-transcriptase inhibitors (NNRTIs); bind RT directly, drugs not incorporated into viral DNA
Protease inhibitors (PIs)
Fusion Inhibitors – Enfuvirtide (Fuzeon), blocks fusion of viral and host membranes
Integrase Inhibitors - Raltegravir
What are common ADRs to nucleoside RT inhibitors?
Increased liver enzymes / hepatitis
Lactic acidosis/hepatomegaly with steatosis possible with NRTIs (not lamivudine, abacavir), when present requires drug discontinuation
Lipodystrophy syndrome - body fat changes (wasting/redistribution)
What’s MOA and PK of Zidovudine/AZT?
Enters cell, activated to triphosphate, inhibits HIV RT 100X»_space; mammalian DNA polymerase
Incorporated into viral DNA > chain termination
Good PO, effective CSF levels, rapid glucuronidation, t ½ - 1 hr
Dose-limiting bone marrow suppression/anemia /neutropenia, adm. Epogen and Neupogen/G-CSF
What are ADRs of zidovudine?
ADRS: GI, myalgia/myositis, CNS disturbances (anxiety, confusion)
Drug interactions: inc toxicity with drugs requiring glucuronidation, DMMS inhibitors, other myelosuppressants e.g. ganciclovir
What’s mechanism of action and indication of Stavudine?
Analog of thymidine, activated, same MA
Good PO , reaches effective CFS concentrations
Indicated for advanced HIV, active against most AZT- resistant strains. Not used with AZT, both compete for same enzyme required for phosphorylation
What are ADRs of Stavudine?
Peripheral neuropathy, pancreatitis, myalgia, GI, flu-like syndrome, CNS-mania/sleep disorders, rash
Claimed to cause lactic acidosis more frequently than other drugs
What’s MOA and indications of Lamivudine?
Used in combo with zidovudine in disease progression, similar mechanism, cytosine analog
Good PO (non food dependent), urinary excretion/ unchanged. Some reversal of AZT resistance/mutations when used with AZT
Combination prep with AZT (COMBIVIR)
Combivir indicated for HIV-PEP/needlestick
What are ADRs of lamivudine?
Minimal toxicity: headache, fatigue, fever, GI/abdominal pain , neuropathy, mild pancreatitis
high potency, good PO (non food dependent), effective CSF levels. ADRs: high incidence GI/n/v/d, rash, severe/fatal hypersensitivity rx, headache; no pancreatitis or neuropathy
abacavir
PREVEON): Adm with food (inc F), drug depletes L-carnitine, requires L-carnitine supplementation for muscle energy; GI/ liver disturbances, nephrotoxicity: proximal renal tubule dysfunction (Fanconi syndrome) / hypophosphatemia; causes disease exacerbation when discontinued; main use for hepatitis B
Adeofovir
What are ADRs of NRTIs?
Didanosine and Stavudine>mitochondrial DNA polymerase inhibition- cause peripheral neuropathy, pancreatitis, lipoatrophy
All NRTIs are associated with potentially fatal liver toxicity characterized by lactic acidosis and hepatomegaly with steatosis
NRTI treatment should be suspended in the event of rising aminotransferase levels, hepatomegaly, or metabolic acidosis of unknown cause
is associated with a hypersensitivity reactions characterized by: drug fever, rash, GI symptoms, malaise or respiratory distress. Sensitive individuals should never be rechallenged rapidly bc reactions can lead to death. DO HLA B5701 test
Abacavir = NRTI
What is mechanism of action of integrase inhibitor and some ADRs?
They work by inhibiting the insertion of proviral DNA into the host cell genome. Active site of the integrase enzyme includes two divalent metal cation serve as chelation targets for integrase inhibitors.
Raltegravir, elvitegravir, dolutegravir, bictegravir
Generally well-tolerated – nausea and diarrhea most common adverse effects
Chelation interactions with antacids significantly reduce bioavailability
Integrase inhibitors should be separated from antacids. Resistance occurs with single-point mutations within the integrase gene
low genetic barrier to resistance
Dosage adjustment is needed when used in combo with inducers/inhibitors of glucurondidation
Potential adverse effects: insomnia, headache, dizziness, diarrhea, nausea, fatigue, and muscle aches, increases in pancreatic amylase, serum aminotransferases, and creatine kinase (with rhabdomyolysis) Stevens-Johnson syndrome, hypersensitivity reaction, and toxic epidermal necrolysis
raltegravir = integrase inhibitor
The half-life of elvitegravir is 3 hours – but boosted to 9 hours with … – allowing for once-daily dosing
cobicistat
True or false: Elvitegravir does not need to be taken with food.
False; elvitegravir = integrase inhibitor
Cobicistat can inhibit …. contraindicated in patients with creatinine clearance < 70 mL/min, discontinue at creatinine clearance < 50 mL/min
renal tubular secretion of creatinine
Second-generation Integrase Inhibitor
Co-formulated with emtricitabine, and tenofovir alafenamide (teno-alaf)
Bicetegravir = integrase inhibitor
is a prodrug of tenofovir, analog of adenosine, which inhibits HIV reverse transciptase – cause chain termination.
Tenoalaf
is a prodrug of tenofovir
teno-disoproxil fumarate
Produce noncompetitive binding near catalytic site of RT, do not require activation nor are they incorporated into viral DNA. Good PO bioavailability.
Have lipid solubility and reach CNS. All undergo both renal/fecal excretion. Common ADRs: serious rash that may progress to Stevens-Johnson syndrome, GI/ liver disturbances/ hepatitis/liver toxicity, headache, fever
nonNucleoside Reverse Transcriptase Inhibitors
long t ½, penetrates CNS, DMMS inducer
ADRs: CNS mental disturbances dizziness, nightmares, delusions, contraindicated in pregnancy
Efavirenz = nonnucleoside reverse transcriptase
Inhibits HIV protease activity required for cleavage of viral polyprotein precursors. All inhibit P-450s (esp. CYP 3A4) (esp ritonavir)
Common ADRs: lipodystrophy/fat redistribution : buffalo hump, truncal obesity (protease paunch); insulin resistance-may cause hyperglycemia / diabetes; inc TGs/cholesterol
Generally low penetration of CNS except indinavir
protease inhibitors
Potent drug, esp. for advanced disease, higher adverse effects, worst tolerated protease inhibitor. Inhibitor CYP3A4, many drug interactions.
Plasma levels of saquinavir were inc (5X) in combination, good combination
Low doses used with other combo’s to inc Cp’s
GI disturbances, paresthesia, taste disturbances, inc liver enzymes/hepatitis, inc TGs
ritonavir = protease inhibitor
DMMS inducer
Decreases effectiveness of other drugs
Alternate to AZT prevention transmission during pregnancy
nevirapine = nonnucleoside reverse transcriptase inhibitor
DMMS inhibitor
Also may inhibit its own metabolism to 0 order
Delavirdine = Nonnucleoside Reverse Transcriptase
t 1/2 =14hrs, contraindicated with inducers of CYPs, can be administered with metformin. ADRs = insomnia, headache, and liver injury
dolutegravir = integrase inhibitor
What are the nucleoside Rt inhibitors?
zidovudine, stavudine, lamivudine, abacavir, adefovir
what are the herpes drugs?
acyclovir, famciclovir, trifluridine, vidarabine
What are the drugs for CMV virus
ganciclovir, valganciclovir, cidofovir, foscarnet, fomivirsen
What are the drugs for RSV?
amantadine, neuramindase inhibitor, palivizumab
