Antivirals/ Antiretrovirals Flashcards
Why is host toxicity higher for antivirals than antibiotics?
difficult to interfere with viral protein synthesis w/o affecting host cell pathways
Antivirals are predominantly do what with viruses?
virustatic; do not eliminate non-replicating or latent virus
Influenza Viruses are classified how?
RNA; types A (96%) and B, Highly variable and undergo frequent mutations; subtypes of hemagglutinin and neuraminidase
What is the most effective approach to prevent flu?
vaccination; certain high-risk populations may require additional prophylaxis with drug therapy
What is used in cases where vaccination is contraindicated?
chemoprophylaxis
Patients with suspected influenza and high risk of developing complications may benefit from chemotherapy if started ?
within 48 hr after onset of symptoms
Amantadine MOA and resistance?
Blocks influenza A M2 ion channel protein and reduces influx of protons that ultimately interferes with viral uncoating
Does not bind to the influenza B M2 channel (different amino acid sequence)
Pharmacokinetic properties of Amantadine?
Orally available and well absorbed from the GI tract; Eliminated by renal excretion so dose must be reduced in renal insufficiency
Therapeutic uses for amantadine?
not recommended for routine use due to resistance
Prevention and treatment of influenza A; supplanted by neuraminidase inhibitors
Parkinson’s disease
Adverse effects of amantadines?
generally well-tolerated
CNS effects (tremors, nervousness, confusion, dizziness, ataxia) are common
Teratogenic in animals – contraindicated in pregnancy (category C)
Drug interactions – anticholinergic drugs
What is the category and MOA of oseltamivir?
competitive inhibitor of neuraminidase; interferes with replication and spread by preventing release from infected cells
What are the pharmacokinetics of oseltamivir?
orally available prodrug that is metabolized in the liver to the active carboxylate form; carboxylate is excreted by the kidneys
What are the therapeutic uses of oseltamivir?
Prevention and treatment of influenza A and B; Must be given within 48 hr of onset of symptoms to be effective; reduces duration and severity of symptoms (no clinical benefit after this time); For flu prevention in nursing home residents
What is the resistance and adverse reactions of oseltamivir?
variable in seasonal flu; some in isolates of H5N1 (avian flu); generally well-tolerated; some nausea/vomiting and headache
What are the PK of zanamivir?
Low oral bioavailability – administered as a dry powder for oral inhalation
What are the adverse effects of zanamivir?
Bronchospasm and deterioration of lung function (fatalities have occurred) in patients with asthma or COPD
What is the MOA of acyclovir?
Selectively converted to acyclo-GMP by viral thymidine kinase in the cytosol of infected cells (affinity is 200-fold greater than for mammalian TK); Host cell kinases convert acyclo-GMP to acyclo-GTP; Inserted into viral DNA by viral DNA polymerase and causes chain termination
What is the mechanism of resistance to acyclovir?
viral TK deficiency; important concern in immunocompromised patients who receive prolonged therapy
Acyclovir PK properties?
Orally effective but low bioavailability; widely distributed in the body and eliminated unchanged by the kidneys
How is valacyclovir different from acyclovir?
L-valyl ester prodrug that has 5-fold greater oral bioavailability; rapidly converted to acyclovir by hepatic first-pass metabolism
What are the therapeutic uses for acyclovir?
HSV – initial or recurrent infection;
Genital (oral, topical, IV)
Prim. herpetic gingivostomatitis
Prophylaxis/treatment in immnsupp, HSV encephalitis; ZVZ- infections in children and adults (oral, IV); Elderly with localized herpes zoster (oral)
Immunocompromised patients with herpes zoster
What are the adverse effects of acyclovir?
generally well-tolerated (top/orally); dose-limiting toxicities after IV use:
Reversible renal dysfunction from crystalline nephropathy
Neurotoxicity – alt. sensorium, tremor, myoclonus, seizures, extrapyramidal signs
What is the MOA of ganciclovir?
Selectively converted to the mono-PO4 by CMV UL97 kinase; further metabolized by host cell kinases to di- and tri-phosphates which inhibits viral DNA polymerase; DNA chain is not immediately terminated because of the 3’-like OH group
What are the PK properties of ganciclovir?
analogous to acyclovir/valacyclovir; valganciclovir (Valcyte) has a much higher oral bioavailability than ganciclovir
How is the selectivity of ganciclovir compared to acyclovir?
lower to CMV than A is to HSV; ther. index is much lower
What are the therapeutic uses of ganciclovir?
restricted due to toxicity; Treatment of CMV retinitis in immunocompromised patients (oral, IV, ocular insert); Prevention of CMV infection in transplant patients
What are the adverse effects of gancyclovir?
Myelosuppression is the major dose-limiting toxicity; need to perform CBC and can be treated with G-CSF (filgrastim); CNS effects – fever, headache, convulsions, behavioral changes
What is the MOA of cidofovir?
Not dependent on viral TK phosphorylation; converted to the active diphosphate by host cell kinases; Diphosphate competitively inhibits viral DNA polymerase (displaces dCTP)
What are the PK prop. of cidofovir?
Poor oral bioavailability; usually given IV: Prolonged intracellular t1/2 permits infrequent dosing regimens; Cleared by renal glomerular filtration and tubular secretion (90%); usually given with probenecid to block OAT1-mediated efflux
What are the therapeutic uses of cidofovir?
CMV retinitis in AIDS patients; alternative to ganciclovir, foscarnet
What are the adverse effects of cidofovir?
Nephrotoxicity – major dose-limiting toxicity; PCT dysfunction (proteinuria, azotemia, glycosuria); probenecid and saline pre-hydration reduce the risk; Neutropenia (monitor CBC); Possible human carcinogen and teratogen
What is the MOA of foscarnet?
Inhibits herpesvirus DNA polymerase; 100-fold higher inhibitory activity of viral vs. mammalian polymerase; Inhibits HIV reverse transcriptase; Not phosphorylated by viral or host cell kinases
What are the PK prop. of foscarnet?
Oral bioavailability is poor; usually give IV; Taken up slowly by cells and not metabolized; 80% eliminated unchanged in the urine
What are the therapeutic uses of foscarnet?
not as active as primary agents; used mostly for drug-resistant infections; Treatment of CMV retinitis (including ganciclovir-resistant) in AIDS patients; Acyclovir-resistant HSV and VZV infections
What are the adverse effects of foscarnet?
Nephrotoxicity; Pronounced electrolyte disturbances – symptomatic hypocalcemia (paresthesias, arrhythmias, tetany, seizures)
What are the properties of HCV infection?
RNA; does not integrate into human genome; curable; >70% of patients acute to chronic; significant morbidity and mortality
What are the general features of HCV treatment?
no vaccine; Left untreated it can result in progressive liver injury with fibrosis and eventual cirrhosis; major risk factor for HCC
What is the MOA of ribavirin?
multiple; Converted to mono-, di-, and tri-phosphates by host cell kinases
Inhibits IMP dehydrogenase, depletes GTP
Causes lethal mutations in RNA viruses
What are the PK prop. of ribavirin?
Given orally, IV and by aerosol inhalation; Avidly taken up by cells (high Vd); long plasma half-life (200-300 hr);
Eliminated by hepatic metabolism and renal excretion
What are the uses of ribavirin?
Oral ribavirin in combination with peg-interferons is the standard of care
Pediatric RSV bronchiolitis and pneumonia – given by inhalation to hospitalized children
What are the adverse reactions of ribavirin?
Hemolytic anemia (after oral or IV use) Contraindicated during pregnancy – category X
What are the Classification of human endogenous IFNs?
3 major classes – IFN-a, IFN-b, IFN-g; only IFN-a is used clinically
What are IFNs?
Host-derived polypeptide cytokines expressed in response to viral infection; Possess antiviral, immunomodulatory and antiproliferative activities
What is the MOA of IFN-a2a?
Binds to receptors on host cell membrane and activates JAK-STAT pathway (inhibits protein synthesis, maturation and release) Stimulates host immune system – up-regulates MHC class I and II
What are the formulations of IFN?
Conventional (IFN-a2a) – short-acting
Long-acting – pegylated IFN-a2a (Pegasys) – IFN attached to large inert PEG
What are the PK prop. of IFN?
Not absorbed orally; well absorbed after SC or IM
Pegylation provides superior efficacy and once-per-week dosing
What are the uses of IFN?
Chronic HCV and HCB in combo with other drugs
Condylomata acuminata from HPV; administered directly into the lesions
Some cancers
What are the adverse effects of IFN?
Flu-like syndrome in >50% of patients; occurs early on and diminishes with continued therapy
Neuropsychiatric – depression
Myelosuppression – granulocytopenia and thrombocytopenia
What are the properties of HBV?
DNA virus that integrates into host genome; HBV polymerase is functionally related to retroviral RT
What are the general features of treatment of HBV?
Vaccination is the most effective approach to prevent HBV infection; given to high risk adult groups and universally for infants
Why is prolonged therapy necessary for HBV?
required to produce a sustained response; Development of resistance
Relapse after therapy is discontinued
What are risks to carriers of HBV?
increased risk of hepatitis that can lead to fibrosis/cirrhosis and HCC; drug therapy is recommended for patients with persistently elevated ALT and HBV DNA
How is pegIFN-a2a dosed?
given SC 1/wk X 48 wks
What is the MOA of entecavir?
converted by host cell kinases to the triphosphate; inhibits HBV DNA polymerase and acts as a chain terminator; guanosine analog
What are the PK prop. of entecavir?
orally available and excreted in urine
What are the uses of entecavir?
1st line chronic HBV (evid. of viral rep and liver inflammation for 1 yr), Lower incidence of resistance with long-term therapy, Not as active against HIV
What are the adverse effects of entecavir?
Risk of lactic acidosis and severe hepato-megaly with steatosis; Acute exacerbations of HBV after discontinuation; monitor liver function
What are the treatment goals of antiretrovirals?
Maximal and durable suppression of plasma HIV RNA; Restoration and/or preservation of immune function; Limitation of drug adverse effects; Reduction in HIV-associated morbidity and mortality
What are the treatment guidelines of antiretrovirals?
recommend drug therapy: 1) in symptomatic patients; 2) when CD4 counts are ≤350 cells/µL; 2) in pregnancy; and 3) in HIV nephropathy or HBV regardless of CD4 count
What is the drug regimen for antiretroviral therapy?
A 3-drug regimen of HAART is the minimum standard of care; expected clinical outcome is undetectable viral load by 24 weeks
What is considered therapeutic failure of antiretroviral therapy?
an increase in viral load in a patient with previously undetectable virus despite continued treatment; usually requires initiation of a completely new regimen
Why does HIV mutate rapidly?
replicates constantly and because RT is error-prone;
Why is strict adherence to antiretroviral therapy?
crucial to maintain viral load below levels that are associated with development of drug resistance and disease progression; Probability of drug resistance is directly proportional to the viral load
What are the therapeutic consequences of Antiretroviral therapy?
lifelong and complex; non-adherence-> emergence of permanent drug resistance and disease progression; long term met. effects of therapy (10-40% HIV lipodystrophy syndrome, most associated with increased risk of MI
The complex PK drug interactions that apply to all protease inhibitors and NNRTIs results from?
inhibition/induction of CYPs
What is Immune reconstitution inflammatory syndrome?
reversal of immunodeficiency in patients with low CD4 counts; usually occurs during initial phase of treatment; due to accelerated inflammatory rxn to overt or subclinical opportunistic infection
What is the MOA of zidovudine (AZT)?
(NRTI), converted to active triphosphate by host cell kinases; insertion of ZTP into viral DNA by RT causes chain termination (no 3’-OH group);inhibits RT activity; competes with endogenous TTP for the nucleotide binding site
What is the selectivity of zidovudine (AZT)?
low affinity for mammalian DNA polymerase but is capable of inhibiting mitochondrial DNA polymerase
What is the method and properties of resistance of zidovudine (AZT)?
Accumulates gradually in RT when used as the sole agent; prolonged monotherapy promotes cross-resistance to other NRTIs
How is zidovudine usually given to reduce likelihood of resistance?
Usually combined with lamivudine (Combivir) to maintain low viral load
What are the PK prop. of zidovudine?
Orally available and widely distributed into tissues (CNS); short half-life
Eliminated by hepatic glucuronidation
What are the ther. uses of zidovudine?
combination with other antiretrovirals for HIV infection; usually combined with lamivudine
Prevention of HIV infected mother-to-child transmission as monotherapy
Post-exposure prophylaxis in healthcare workers
What are the adverse effects of zidovudine?
Myelosuppression – severe anemia and granulocytopenia; monitor CBC
Rare lactic acidosis with hepatic steatosis; risk factors include female sex, obesity and prolonged exposure to the drug
What are the unique characteristics of lamivudine?
much lower toxicity than AZT; also treats HBV
What are the unique characteristics of emtricitabine?
3TC analog that can be administered once per day
What are the unique characteristics of Tenofovir?
only nucleotide; also treats HBV
What are the MOA of efavirenz?
Non-competitive (allosteric) inhibition of HIV-1 RT
Does not require phosphorylation and is not inserted into the DNA strand
Does not inhibit host cell DNA polymerases
What is the mechanism of resistance of efavirenz?
Highly susceptible due to single amino acid changes in RT NNRTI-binding pocket; resistance emerges in only a few days if given as monotherapy
HIV-2 is intrinsically resistant
What are the PK prop. of efavirenz?
Orally effective and cleared by hepatic CYPs (2B6, 3A4)
Can be given in once-daily dosing
What are the uses of efavirenz?
HIV-1 infection; commonly used in a 1X per day fixed-dose combination with tenofovir and emtricitabine (Atripla)
Effective in patients who have failed previous antiretroviral therapy not containing an NNRTI
What are the adverse effects of efavirenz?
CNS symptoms (50% of patients) – dizziness, insomnia, drowsiness, vivid dreams; resolve with continued use
Rash – can be severe and life-threatening but usually resolves
Teratogen (pregnancy category D)
What are the unique features of Nevirapine from other NNRTIs?
boxed-warning for liver toxicity
What category of antiretroviral are lopinavir and ritonavir?
protease inhibitor
What is the MOA of lopinavir and ritonavir?
Competitive inhibition of HIV protease
Prevents cleavage of gag and pol precursor polyproteins; virus fails to mature and remains non-infective
Human aspartyl proteases are not inhibited by these drugs
What are the PK prop of lopinavir?
orally available and well-absorbed, active antiretroviral component; Extensively metabolized by hepatic CYP3A4; also a substrate for P-glycoprotein efflux transporter
What are the PK prop of ritonavir?
orally available and well absorbed; presence only “boosts” the activity of lopinavir by inhibiting its CYP-mediated clearance; Extensively metabolized by hepatic CYP3A4; also a substrate for P-glycoprotein efflux transporter
What are the adverse effects of ritonavir and lopinavir?
GI intolerance is the most common effect
Lipodystrophy syndrome with long-term use
What are the drug interactions of ritonavir and lopinavir?
Ritonavir is a potent inhibitor of CYP3A4; also induces 3A4; Other CYP inhibitors (antifungal agents, grapefruit juice, clarithromycin); reduce the dose; Other CYP inducers (rifampin, anticonvulsants, St. John’s wort); loss of efficacy; Prolongs effects of PDE5 inhibitors for ED
What are the unique features of atazanavir from other protease inhibitors?
less likely to cause lipodystrophy; FDA warning – do not use with proton pump inhibitors (PPIs - omeprazole) because they reduce efficacy
What is the MOA of enfuvirtide?
binds to HIV gp41 protein and prevents the HIV envelope from fusing with the CD4 T cell membrane
What are the PK prop. of enfuvirtide?
administered SC 2X/day; only antiretroviral that must be given parenterally
What are the uses of enfuvirtide?
added to existing regimens when there is evidence of HIV replication despite continued therapy
What are the adverse effects of enfuvirtide?
Injection-site reactions – common and persistent pain, erythema and cysts; Elevated risk of bacterial pneumonia
What is the MOA of maraviroc? Use?
blocks chemokine CCR5 co-receptor; prevents binding of viral gp120; only antiretroviral that targets a host protein
Used only in CCR5-tropic HIV infections (no activity against CXCR4 trope)
What is the MOA and selectivity of raltegravir?
Inhibits HIV integrase; prevents insertion of viral DNA into host genome
Selectivity – human DNA does not undergo excision and re-integration
What are the PK prop, uses and adverse effects of raltegravir?
orally avail, cleared by glucuronidartion; HIV infections in HAART; gen well tolerated
Direct acting antivirals for HCV that target specific nonstructural proteins of HCV?
NS3/4A – serine protease that cleaves viral polyproteins into mature forms (analogous to HIV protease); NS5B – RNA polymerase responsible for replicating viral RNA; NS5A – protein critical in viral replication and assembly
What is MOA of simeprevir? resistance?
inhibits viral NS3/4A protease; high if used alone
What are the PK prop of simeprevir?
orally 1X per day always in combination with ribavirin/IFN or sofosbuvir
What are the adverse reactions to simeprevir?
photosensitivity and rash; contraindicated during pregnancy (X); CYP3A4-related drug interactions
What is the MOA of sofosbuvir (Sovaldi)?
nucleotide prodrug metabolized to the active triphosphate; inhibits NS5B polymerase and acts as a chain terminator
What are the PK prop. of sofosbuvir (Sovaldi)?
efficacy across all HCV genotypes and a high barrier to resistance, orally 1X per day in combination with ribavirin/IFN
