ID: uncoating inhibitors, neuraminidase inhibitors, nucleoside analogues, azoles
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uncoating inhibitors (antivirals) indications:
- Influenza A
- No longer used right now bc every year new drugs come that that is specific to the season. Could re use it in the future
- Parkinson's disease
uncoating inhibitors drugs
- Amantadine (Symmetrel)
- Rimantadine (Flumadine)
why is Amantadine used for Parkinson's disease?
- Amantadine may cause greater amounts of dopamine to be released in the brain.
- It may also block acetylcholine receptors.
- The correct balance between acetylcholine & dopamine is needed for normal motor control.
life cycle of the virus:
- Attach to the host cell
- Enter the cell
- Release their nucleic acid contents
uncoating inhibitors MOA:
- Virus uncoating occurs via a protein called the M2 protein. Alterations in M2 could lead to resistance to antivirals.
- The M2 protein is a proton channel that plays a role in the break-up of the RNA-protein structure. This dissociation is pH-dependent.
- Uncoating inhibitors are thought to prevent the influx of protons through the M2 channel, although the specific mechanism for how this occurs is uncertain.
- Uncoating inhibitors may also inhibit viruses at a later stage but the mechanism for this is also unclear
uncoating inhibitors SE:
- CNS (rimantadine is less lipophilic, so… may not have as much of these symptoms
- Dry mouth
uncoating inhibs kinetics:
- Dosing adjustments needed for renal impairment and elderly
- Half life 17 hours; 29 hours in people >60; 34-51 hours if CrCl <40
what has made this class of medicine less useful clinically?
widespread adamantane resistance among influenza A (H3N2) virus strains
The most effective strategy for preventing influenza is:
- annual vaccination and frequent handwashing
- Annual influ vacc is the best way to prevent influ bc vacc can be given well before influ vireus exposures occur, and can provide safe and effective immunity throughout the influenza season
- Don’t prophylax everyone bc it could increase resistance
who would be a good candidate for prophylaxis?
- a wife whose husband is sick with the flu
- Antiviral medication are 70-90% effective in preventing influ and are useful adjuncts to therapy
neuraminidase inhibitors drugs:
- Zanamivir (Relenza)
- Oseltamivir (Tamiflu)
2 surface glycoproteins of influenza virus:
neuraminidase inhibs MOA:
- Hemagglutinins are responsible for binding & uptake of virus. The hemagglutinins bind to sialic acid residues on the host cell.
- Neuraminidases cleave the sialic acid that are bound to the viral hemagglutinin. This results in release of new virus.
- Viruses can alter these two surface proteins which gives the virus the ability to evade the host immune defenses and results in the possibility of new diseases each year.
- Drift and shift
- Neuraminidase Inhibitors block the cleavage of sialic acid and prevent the release of new virus from infected cells
influenza replication peaks at _____ hrs
neuraminidase inhibs must be given ____ to be effective
When taken early for infections, these drugs may shorten the duration of infection by:
When taken as prophylaxis, rate of infection reduced btwn:
- 24-72 hours
- 1-4 days
neuraminidase inhibs kinetics:
- Tamiflu is given orally
- Relenza is inhaled
cautions of Relenza:
Pt must know how to use Relenza appropriately
what are imp factors in the control of influenza?
- antiviral medications with activity against influenza viruses
- influenza vaccine
- hand washing
Influenza antiviral prescription drugs can be used to:
treat influenza or to prevent influenza.
Two FDA-approved influenza antiviral medications are recommended for use in the United States during the 2012-2013 influenza season:
- oseltamivir (Tamiflu®) and zanamivir (Relenza®)
- Oseltamivir and zanamivir are chemically related antiviral medications known as neuraminidase inhibitors that have activity against both influenza A and B viruses.
- Antiviral resistance to oseltamivir and zanamivir among circulating influenza viruses is currently low, but this might change. Also, antiviral resistance can emerge during or after treatment in certain patients (e.g., immunosuppressed).
when do you need to start therapy as soon as possible?
- if pt is:
- is hospitalized;
- has severe, complicated, or progressive illness; or
- is at higher risk for influenza complications.
Why do you have to target prophylaxis with caution?
So many ppl develop tolerance
cautions of neuraminidase inhibitors:
- Causes respiratory symptoms- do not use if you already have resp probs
- Tamalue is drug of choice
SE of neuraminidase inhibitors:
- Unusual dreams
- Possible worsening of respiratory symptoms, including bronchospasm
neucleoside analogue drugs:
- Acyclovir (Zovirax), acyclovir available parenteral
- Valacyclovir (Valtrex)
- Peniclovir (Denavir) topical
- Famciclovir (Famvir)
- Ganciclovir (Cytovene) also in parenteral
- Ganciclovir (Zirgan) ophthalmic
- Valganciclovir (valcyte)
- Cidofovir (Vistide)
BBW for Ganciclovir (Cytovene):
- Hematologic tox, carcinogen/teratogen;
Valganciclovir (Valcyte) BBW:
- Hematologic tox, carcinogen/teratogen;
- appropriate IV use;
- appropriate oral use
- CI if breastfeeding
Cidofovir (Vistide) BBW:
- renal impairment;
- carcinogen, teratogen risk
nucleoside analogue MOA:
- Tricks the virus to incorporate some of the drug into its DNA
- They reduce DNA synthesis and virus replication.
- Viral & host enzymes convert the nucleoside analogues to active nucleoside triphosphates which then compete with viral DNA polymerase for
- incorporation into the viral DNA strand.
- The end result is that the viral DNA chain is not completed.
- The nucleoside analogues work because their affinity is greater for the viral enzymes.
activation and MOA of nucleoside analogues:
- In an infected cell, viral enzymes perform the initial phosphorylation step then cellular kinases attach the remaining phosphate residues.
- Acyclovir is incorporated into viral DNA.
- Acyclovir lacks the 3’-OH group of deoxyribose and thus additional nucleotides cannot be added and the DNA chain is terminated
indications: (which drug for each indication!)
- Herpes: Acyclovir, famciclovir; penciclovir and valacyclovir
- CMV in immunocompromised patients:
- Ganciclovir and valganciclovir
- CMV retinitis infections resistant to other drugs in AIDS patients: Cidofovir
what is most effective for cold sores?
- ORAL antivirals (acyclovir, famciclovir,valacyclovir)
- decreasing the duration of cold sores by up to 2days.
- TOPICAL antivirals alone (penciclovir,etc) or OTC docosanol (Abreva) are only modestly effective. Save these for people who can't take oral antivirals or have mild andinfrequent cold sores.
first combo antiviral/anti-inflammatory drug for cold sores, herpes simplex labialis:
- contains acyclovir 5% and hydrocortisone 1%.
nucleoside analogues SE:
- Common: N&V, diarrhea, malaise
- More serious: Nephrotoxicity*; Confusion, hallucinations, seizures & delirium (higher incidence in patients with renal impairment); anemia, thrombocytopenia
- Nephrotoxicity is a particular concern with cidofovir. It binds to a transporter & accumulates in the renal cortex. It is given with probenecid.
why are nucleoside analgues given with probenecid?
It’s a competitor & helps to decrease renal impairment
examples of fungal infections?
Candida*, Crytptococcus, Aspergillus, Histoplasmosis, Microsporum, Tricophyton
Azoles (antifungals) drugs:
- Fluconazole (Diflucan)
- Itraconazole (Sporonox)
- Clotrimazole (Mycelex) topical
- Clotrimazole (Gyne-Lotrimin) vaginal
- Clotrimazole – slowly dissolved in mouth
- Miconazole (Oravig)
- Miconazole –topical, vaginally
- Miconazole (Monistat)
- Terconazole (Terazol)
- Voriconazole (Vfend) $972
- Ergosterol is a fundamental constituent of the fungal cell membrane.
- Azoles block fungal wall synthesis by blocking ergosterol synthesis.
- 14-alpha demethylase converts lanosterol to ergosterol in fungi
- 14-alpha demethylase is a CYP450 enzyme.§ Azoles are direct CYP450 inhibitors.· Lots of drug interactions!!!
- (Blocking an enzyme required to make ergosterol)
indications for azoles:
- For Superficial topical infections: Oral, Vaginal and Esophageal Candida
- Superficial infections include tinea pedis (athlete’s foot); tinea cruris (jock itch); tinea corporis (ringworm); onchyomycosis (nail fungus) and
- Yeast infections such as those caused by Candida albicans
- For uncomplicated systemic infections in otherwise healthy patients
species of candida:
SE of the azoles:
- Hepatotoxicity (rare)
indications for Voriconazole (Vfend):
severe fungal infections
SE of Voriconazole (vfend):
- transient abnormal vision
- Serious: hepatitis, pancreatitis, renal failure, sepsis
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