Antimicrobials Part 2 (Antivirals) Flashcards
Antiviral drugs are all ______-spectrum and relatively ______
Narrow, specific
Antivirals may also be used to treat symptoms in ______ care
Palliative
Antivirals work by inhibiting viral replication and, therefore, are ______.
Viristatic
Antiviral drugs are ______ ______ to produce compared to antibacterial drugs, because virii rely on ______ ______ and associated machinery to reproduce. It is difficult to suppress viral replication without also ______ host cells.
More difficult, host cells, harming
Some antivirals are most effective in shortening the illness if administered within ______ ______ of symptoms onset
24-48 hours
Preexisting ______ and ______ are important determinants of the outcome of viral infections
Immunity, immunocompetency
The 5 stages of the viral life cycle that can be targeted for therapy are:
- Attachment and penetration of the virus to host cell
- Uncoating of the viral genome within the host cell
- Synthesis of viral components within the host cell
- Assembly of viral particles
- Release of the virus to spread and invade other cells
Anti-Herpesvirus Agents
Nucleoside analogs, DNA/RNA polymerase inhibitors
Acyclovir, valacyclovir, famiciclovir, ganciclovir, valganciclovir, foscarnet, cidofovir
Anti-Herpesvirus Agents Spectrum of Activity
All agents have activity against the herpes virus
Clinical efficacy differs between specific HSV strains
Most anti-herpesvirus agents are ______ ______
Nucleoside analogs
Anti-Herpesvirus Agents (Nucleoside Analogs) MOA (4 steps)
- Must first be activated by viral phosphorylation via thymidine kinase
- Phosphorylated agents mimic endogenous nucleotides
- Phosphorylated drug is then incorporated into the replicating viral DNA strand and inhibits viral DNA polymerase
- Results in termination of viral DNA synthesis with little effect on host cell DNA replication
Acyclovir (Zovirax) and Valacyclovir (Valtrex) Route of Administration
Acyclovir (IV, PO, topical)
Valacyclovir (PO, greater bioavailability with PO access)
Valacyclovir is the prodrug of acyclovir
Acyclovir (Zovirax) and Valacyclovir (Valtrex) MOA
Guanosine analogs inhibit viral DNA synthesis by incorporation into the replicating viral DNA following phosphorylation by HSV-coded thymidine kinase. The false nucleotide competes with dGTP for viral DNA polymerase, causing early termination of viral DNA.
Acyclovir Viral Resistance Mechanisms
Altered or deficient thymidine kinase and viral DNA polymerase
Acyclovir Pharmokinetics
PO availability = 15-20%
Only anti-HSV agent approved for IV administration
Well distributed throughout the body, including CSF
t1/2 = 2.5-3 hours
Renally eliminated
Valacyclovir Pharmokinetics
Oral prodrug of acyclovir with improved absorption
PO availability = 54-70%
Similar distribution to acyclovir
Acyclovir/Valacyclovir ADRs (5)
- Nephrotoxicity
- GI upset: nausea, vomiting, diarrhea
- Neurotoxicity
- Hematologic toxicity: TTP reported in patients who are HIV+
- Local irritation from topical formulation
Acyclovir/Valacyclovir DDIs (2)
- Risk of nephrotoxicity is higher with diuretics or other nephrotoxins being co-administered
- Probenecid and cimetidine decrease drug clearance
Penciclovir (Denavir) and Famciclovir (generic only) Route of Administration
Penciclovir (topical)
Famciclovir (PO) - Prodrug of penciclovir with much better oral bioavailability
Penciclovir and Famciclovir MOA
Acyclic guanosine nucleoside derivatives.
MOA similar to acyclovir, but does NOT cause termination of the viral DNA chain.
Penciclovir and Famciclovir ADRs
- Diarrhea, nausea
- Headache
- Confusion
- Rash, hives
Resistance is not common, but includes thymidine kinase-deficient HSV
Ganciclovir and Valganciclovir Route of Administration
Ganciclovir (IV)
Valganciclovir (PO) - valyl ester of ganciclovir
Ganciclovir Pharmokinetics
MOA and drug distribution is the same as acyclovir
t1/2 = 4 hours
Renally eliminated
Accumulates in patients with renal failure or with agents that block renal excretion (probenecid)
Ganciclovir Clinical Uses
Much greater activity against HSV-5 (Cytomegalovirus, CMV) infection in immunocompromised patients and as prophylaxis in transplant patients
Valganciclovir Pharmokinetics
MOA the same as ganciclovir and acyclovir
The added valyl ester improves oral absorption
Prodrug of ganciclovir (becomes hydrolyzed to ganciclovir in the intestines and liver)
Ganciclovir and Valganciclovir ADRs
- Myelosuppression (bone marrow suppression) is the major dose-limiting adverse effect - severe neutropenia occurs in 15-40% of patients and is sometimes fatal; thrombocytopenia occurs in 5-20% of patients
- Neurotoxicity
- Carcinogenic and teratogenic; warning for use in pregnancy
- Less selective than acyclovir and penciclovir, greater risk of affecting host cell’s DNA
Foscarnet Spectrum of Activity
Pyrophosphate derivative
IV administration
Used for HSV infections resistant to acyclovir, ganciclovir, some cidofovir-resistant CMV infections, and CMV retinitis in immunocompromised hosts
Foscarnet MOA
Directly inhibits HSV DNA/RNA polymerase by binding to the pyrophosphate binding site.
Inhibits DNA chain elongation.
Prevents cleavage of pyrophosphate from deoxynucleotide triphosphates.
Does not require activation by thymidine kinase.
Foscarnet Pharmokinetics
t1/2 = 3-7 hours
Distributes well throughout the body, including CSF
Foscarnet ADRs
- Nephrotoxicity: requires extensive pre-hydration with normal saline
- Electrolyte imbalances: hypocalcemia, hypomagnesemia, hypokalemia, dysphosphatemia
Cidofovir (generic only) Spectrum of Activity
Cytosine nucleotide analog
Structure includes a phosphate group
IV administration
Used for ganciclovir-resistant CMV, CMV retinitis in patients with AIDS
Cidofovir-resistant isolates tend to be cross-resistant to ganciclovir
Cidofovir MOA
Does not require activation by viral or cellular enzymes.
Directly inhibits viral DNA polymerases.
Cidofovir Pharmokinetics
Parent drug t1/2 = 2.6 hours
Active metabolite t1/2 = 17-65 hours
Poor CSF distribution
Cidofovir ADRs
Nephrotoxicity: Renally eliminated and can produce significant renal toxicity - contraindicated in patients with renal impairment and in those taking nephrotoxic drugs; oral probenecid and IV saline are co-administered to reduce concentration secreted into renal tubules; serum levels can be reduced by 75% via hemodialysis
Agents Active Against Influenza and RSV (4 classes)
- Amantadine antivirals: Influenza A
- Neuraminidase inhibitors: Influenza A, B
- Inhibition of viral replication: RSV
- Inhibition of RNA translation
Amantadine and Rimantadine Spectrum of Activity
Amantadine (generic) and rimantadine are used for prevention and treatment of Influenza type A
70-90% protective against Influenza A, but not type B
Amantadine and Rimantadine MOA
Prevents virus from uncoating and releasing genetic material: viral ion channels (M2) allow H+ into the virus after endocytosis; triggers dissociation of virus capsid, then Influenza A ribonucleoprotein (RNP) is released into the host cell cytosol.
Amantadine and rimantadine block M2 channels.
Amantadine and Rimantadine Pharmacokinetics
Administered PO
Good bioavailability
Amantadine is renally cleared
Rimantadine is hepatically metabolized, then renally cleared
Dose adjustment required in patients with impaired renal function and over age 65
Amantadine and Rimantadine ADRs
Minor dose-related CNS and GI effects
Amantadine and Rimantadine DDIs
DDIs between amantadine and antihistamines, psychotropic, or anticholinergic drugs can increase neurotoxicity.
High amantadine levels are associated with delirium, hallucinosis, seizures, coma, and cardiac arrhythmias.
Exacerbations of preexisting seizure disorders and psychiatric symptoms.
What is neuraminidase?
A virus-specific, antigenic hydrolytic enzyme.
Multifunctional:
1. Controls viral adhesion to host cells (cleaves sialic acid residues on host cell receptors)
2. May promote fusion of the viral envelope with the host cell membrane
3. Aids release of newly formed virus particles from infected cells
Neuraminidase Inhibitors Drugs
Oseltamivir (PO, Tamiflu)
Zanamivir (inhaled, Relenza)
Peramivir (IV, Rapivab)
Neuraminidase Inhibitors MOA
- Prevents viral neuraminidase from releasing new virii from host cell
- Can prevent/treat influenza A, B, and RSV and used as prophylaxis in patients who cannot tolerate these vaccines
- If administered within 24-48 hours after onset of symptoms, modestly decreases the intensity and duration of symptoms
Neuraminidase Inhibitors Pharmokinetics
Oseltamivir is an active prodrug, hydrolyzed by the liver to its more active form.
Renally eliminated.
Neuraminidase Inihibitors ADRs
Transient GI discomfort and nausea.
Respiratory tract irritation.
Caution in individuals with asthma or COPD as bronchospasm may occur.
Baloxivir marboxil Spectrum of Activity, MOA, ADRs
- PO, single dose treatment of Influenza A and B
- Inhibits viral polymerase acidic protein (CAP) endonuclease and inhibits viral replication by preventing “cap-snatching” of host cells’ replication machinery
- May cause headache, diarrhea, increased serum ALT/AST
Ribavirin Spectrum of Activity
Broad spectrum antiviral agent.
Used primarily in RSV infections.
Ribavirin MOA
Guanosine nucleoside analog.
Exact mechanism of action is not well characterized, but viral replication is inhibited significantly.
Phosphorylated into active form, like acyclovir.
Some inhibition of viral RNA polymerase.
Ribavirin Pharmokinetics
Administered PO or inhaled.
Aerosol treatment used for RSV infections in immunocompromised infants and young children with severe infections.
Oral preparation is approved for treatment of Hep C as a component of combination therapy.
Renally eliminated.
Ribavirin ADRs
- Dose-dependent hemolytic anemia (can be severe), elevated bilirubin
- Contraindicated in pregnancy; teratogenic effects
Palivizumab (IM) Spectrum of Activity
Prophylaxis at start of RSV season.
Only indicated for high-risk pediatric patients.
Palivizumab MOA
Monoclonal antibody directed against the A antigenic site of the RSV F protein.
Prevents adhesion and entry into host cell.
Palivizumab Pharmokinetics and ADRs
- Metabolized through the CYP450 pathways.
2. ADRs include hypersensitivity (anaphylaxis), severe thrombocytopenia, fever, and rash.
