Antivirals: Flu and Hepatitis Flashcards
The current available antiviral drugs target three main groups of viruses, what are they?
Influenza
Hepatitis
Herpes
First lets start with the antiviral drugs for influenza. First up are the Neuraminidase inhibitors (Oseltamivir and Zanamivir). What are the general features?
Neuraminidase is a essential enzyme in the replication of influenza A and B viruses
- -cleaves sialic acid residues from viral proteins and surface proteins of infected cells, functioning to promote virion release and to prevent clumping of newly released virions.
- -by giving these drugs there is interference with these actions, thus impede viral release and viral spread
What are the pharmacokinetics for the Neuraminidase Inhibitors?
Oseltamivir: prodrug. activated in the gut and liver. orally taken and excreted renally
Zanamivir: intranasally and 4-20% is absorbed systemically (excreted in urine)
Neuraminidase inhibitors are approved for what use?
Oseltamivir: tx of children greater than 1 year and adults with A or B influenza.
Zanamivir: tx of children greater than 7 and adults with A or B influenza.
–tx needs to be started within 48h of disease onset
–reduce the febrile period during infection
What are the AE of Neuraminidase inhibitors?
Oseltamivir: n/v/d/abd pain/ neuropsychiatric
Zanamivir: acute bronchospasm
What is the resistance pattern for the Neuraminidase Inhibitors?
Oseltamivir resistant influenza A has been reported
Normally if resistance to oseltamivir occurs then zanamivir is also resistant
What is the recommendation of Neuraminidase Inhibitors and pregnancy?
Recommended for the tx or prophylaxis of influenza in pregnant women and women up to 2 weeks postpartum
–also should get the vaccine if prego
Next influenza drug are the M2 Inhibitors (Amantadine and Rimantadine). What are some features?
Inhibit replication of influenza A virus by impairing the function of the membrane protein M2
–M2 is an acid activated ion channel required for viral uncoating and nucleocapsid release
What are the pharmacokinetics for M2 inhibitors?
Amantadine: well absorbed after oral admin and is excreted by glomerular filtration
Rimantadine: well absorbed orally but undergoes hepatic metabolism
What are M2 inhibitors used for?
Susceptible Influenza A infection
- -need to be given within 48 hours of disease onset
- reduce duration of symptoms by 1 day
What has limited the use of M2 inhibitors in the clinical setting?
Resistance
- -Amantadine resistance: emerges within 2-4 day of tx
- -Rimantadine: M2 mutation confers cross resistance
- -no longer used due to resistance
What are the AE of M2 inhibitors?
Amantadine: well tolerated.
- -mild neurologic symptoms, esp in old ppl taking neuroaffective drugs
- -neuro symptoms are less severe and frequent with rimantadine
Can M2 inhibitors be used in pregnancy?
NOPE
Next antiviral drugs will focus on Hepatitis. What are the goals of antiviral tx?
Hep B: suppressive
Hep C: viral eradication
First antiviral used for Hepatitis is Interferons. What are some features?
Natural occurring proteins produced in response to viral infection.
–alpha, beta and gamma
Only available in parenteral formation, either SQ or IM
Administered daily or 3 times a week
Extensive renal metabolism
What is pegylation in terms of Interferon tx for Hepatitis?
Attachment of IFN to a large inert polyethylene glycol
- -reduces the rate of absorption and excretion of IFN and therefore increases plasma concentration
- -administered once a week
What is the MOA for interferon?
IFN initiate a cascade of events via Janus Kinases
- -leads to cellular responses (inhibition of virus replication, suppression of cell proliferation, enhancement of the phagocytic activity of macrophages, and augmentation of the specific cytotoxicity of lymphocytes)
- -antiviral action is due to activation of a host cell ribonuclease that degrades viral mRNA
- -IFNalpha promotes formation of NK cells that destroys infected liver cells
IFNa have been used in multiple viral infection and are most commonly used for chronic viral hepatitis alone or in combo with other drugs. When used in combo?
Combo with ribavirin
—acute HCV infection to chronic HCV is reduced
Pegylated + ribavirin
–superior to standard IFNalpha in chronic HCV
What are the AE of Interferon?
Neuropsychiatric disorders (screen for depression) (if depressed can give serotonin reuptake inhibitors) Neurological disturbances Myelosuppression Cardiovascular disorders Endocrine Disorders Pulmonary Disorders
The next drug used in the tx of Hepatitis is Ribavirin, what are some features?
MOA is diverse and not understood.
Oral (first pass metabolism so only 65% bioavailable), Aerosolized(Some absorbed systemically) and IV formulations
Ribavirin is used for what?
In combo with IFNalpha for HCV
Tx of RSV in kids (if RSV pneumonia then give via inhalation)
Off label for: HSV, Influenza, Severe acute resp syndrome, Coronavirus, Lassa Fever
What are the AE of Ribavirin?
Aerosolized: sudden deterioration of resp function and cardio effects. Hemolytic anemia. Depression and relapse of drug abuse
Do not use in patients with past psychiatric disorders
Teratogenic effects: do not give to pregos or their partners (use contraception during therapy and 6 months after)
The current tx of HCV is IFNalpha plus ribavirin. Recently two serine protease inhibitors have been approved. The first is Boceprevir. What are some features?
HCV protease inhibitor
Used in combo with interferon and ribavirin
Exerts anti-HCV properties by binding reversibly to the HCV nonstructural 3 protein inhibiting viral replication
Orally and metabolized in the liver
AE: Flu like illness and Anemia (can be severe)
The second protease inhibitor is Telaprevir, what are some features?
Same MOA as Boceprevir
Tx of naive HCV patients and those who do not benefit from tx with IFNalpha and ribavirin
AE: anemia, and rash (can be severe with eosinophilia)
In addition to IFN’s several nucelos(t)ide analogs are available for the tx of hepatitis. What is the mechanism of their anti-HBV property?
Competitive Inhibition of HBV DNA polymerase
Nucleos(t)ide analogs have what additional properties?
Additional anti-HIV properties
- -recommended that HBV patients considered for tx with these drugs be tested for HIV infection, and monotherapy with these drugs be avoided to reduce risk of HIV resistance.
- -hep B may also develop resistance therefore use of combo drugs is recommended
If discontinuation of Nucleos(t)ide analogs what happens?
Severe exacerbation of hepatitis
- -monitoring for hepatotoxicity should be performed after stopping tx.
- -lactic acidosis may occur and should be withdrawn if there is an increase in ALT levels
The first Nucleoside analog is Lamivudine, what are some features?
Nucleoside analog of cytosine
- -phosphorylated intracellularly into its active 5’triphosphate metabolite
- -active metabolite is incorporated into viral DNA by HBV polymerase
- -DNA chain termination
What are the AE of Lamivudine?
AE:
–mild
Clinical utility of lamivudine is limited by the rapid development of antiviral resistance
The second Nucleoside analog is Entecavir, what are some feature?
Nucleoside guanosine analog
–considered one of the most potent agents for the tx of patients with Hep B
MOA:
–inhibits 3 specific function of HBV polymerase: priming of the HBV DNA polymerase, reverse transcription of the negative strand from the pregenomic mRNA, and synthesis of positive strand HBV DNA
Resistance:
–high barrier to resistance and requires at least 3 mutations for resistance to occur
