Antivirals Flashcards
What are one of the biggest challenges with treating viruses?
Most drugs work best when the virus is replicating, however most symptoms don’t appear until the virus load has already peaked in the blood.
- viral latency integrated into genome, can’t target
- virus uses host cellular machinery, limited targets
What are the most important keys in using antivirals?
- unable to target latent infections
- all drugs are viralstatic, requires competent immune system
What are two drugs that are used to prevent Influenza A and B adsorption/penetration of cells?
- Amantadine
- Oseltamivir
What drug is used to prevent and treat Influenza A?
Amantadine - blocks uncoating by inhibiting M2 protein from lowering the pH in the vesicle.
(Becoming more resistant every year)
What is the key in administering Amantadine and Oseltamivir?
- Must be started within 48 hours of the illness to effectively reducing fever and duration of the illness by several days.
What antiviral can be used to prevent infection of Influenza A and B?
Oseltamivir - Prodrug
–used as prevention in children under the age of 1–
What are the common side effects of Amantadine and Oseltamivir?
Amantadine - CNS Effects - slurred speech, anxiety, confusion
Oseltamivir - n/v/d, bronchitis
What antiviral can be used to treat occular herpes simplex 1 and 2?
Trifluridine - Thymidine Analog, inhibits virus DNA synthesis
–OPHTHALMIC only. Too toxic for systemic.
What are unique enzymes encoded by herpes virus family?
- *- Thymidine Synthase -**
- DNA Polymerase
- Ribonucleotide Reductase
How does Acyclovir selectively target infected cells?
Herpes Virus encodes Thymidine Synthase, which phosphorylates Acyclovir activating it.
- Targets Viral DNA Polymerase, preventing chain elongation by becoming incorporated into DNA
What are the uses for different modes of administering Acyclovir?
IV use - systemic herpes simplex, HSV encepholitis
Oral use - primary genital herpes, recurrent HSV1
topical - primary genital herpes
–Overall, well tolerated with n/v/ and HA
How is Famciclovir different from Acyclovir?
Famciclovir has similar mechanism of activation and targeting DNA Polymerase, but has a higher bioavailability. Tolerated Well.
What is used for treating acute herpes zoster?
Famciclovir.
Also used for treatment and suppression of recurrent genital herpes.
What antiviral is used topically to prevent recurrent oral herpes simplex?
Penciclovir, same mechanism as Acyclovir
What kind of people should be concerned with CMV infection?
- HIV - 80% of the time = Retinitis
- Organ transplant patients
- Most common infection in both patient populations, depends on CD4+ count.
What drug is used to treat CMV retinitis in AIDs patient and prevention of CMV in transplant patients?
Ganciclovir
How does Ganciclovir work and what are the adverse effects?
Activated my CMV Kinase, works like Acyclovir
Adverse Effects: Bone Marrow Suppression - enhances suppression of Zidovudine
What drug would be used if a herpes virus is resistant to Acyclovir?
Foscarnet - mimics pyrophosphate binding CMV DNA Polymerase
Also used for CMV Retinitis
What is the most concerning adverse side effect of Foscarnet?
Renal Damange and electrolyte imbalances. (30-50% of pts)
What is the best CMV Retinitis treatment?
HIV Treatment to elevate CD4+ counts, Foscarnet and Ganciclovir only slow progression of the retinitis causing many side effects.
What drugs are approved for treating Hepatitis B?
Lamivudine - nucleoside analog - inhibits HBV Reverse transcriptase
Tenofovir - AMP analog, inhibiting HBV Reverse Transcriptase
What drug is phosphorylated in vivo to treat RSV and Hep C?
Ribavirin -
- interferes with viral mRNA synthesis
- inhibits GTP Synthesis
- Inhibits GTP-capping of mRNA
How is Ribavirin used to treat Hepatitis C?
Ribavirin is used in combination with interferon-alpha and Boceprevir
What is the risk associated with Ribavirin?
- aerosol can clog airways and tubings while treating RSV
- IV/PO versions can cause Bone Marrow Suppression
How does Alpha-Interferons work and what are they used for?
- Interferon-alpha is used to induce the host immune system to elicit a great response against viral infections
- -Used improving disease course of Hep B and C
- -Genital Warts
What is the major drawback of using interferons as therapy?
Constant Flu-like symptoms (fatigue/body aches)
Bone Marrow suppression
Myalgias
What antiviral blocks NS3 protease of Hepatitis C?
Boceprevir - prevents the cleaving of the propeptide, inhibiting formation of virions
What are the major side effects of using Boceprevir?
- Bone Marrow Suppression
- Neutrapenia
- Induces CYP3A - many drug interactions
What is the recommended cocktail for treating Hep C?
Boceprevir + Interferon-alpha + Ribavirin
What are the most common Nucleoside Reverse Transcriptase Inhibitors used in HIV Therapy?
- Zidovudine
- Tenofovir
- Lamivudine
- Emtricitabine
- Abacavir
What NRTI drug is a thymidine nucleoside analog?
Zidovudine - binds RT, prevents elongation
What is a common side effect of Zidovudine?
Bone Marrow Suppression
Myopathy
–other drugs that reduce glucoronidation cause increased toxicity of Zidovudine
What are the common mechanisms of inhibiting Nucleoside Reverse Transcriptase?
- Nucleoside Analogs
- competitive inhibitors
- DNA chain termination after incorporation
What is the antiviral that is used for HIV treatment that is a prodrug and also treats Hep B?
Tenofovir - nucleoside prodrug
–Well Tolerated– Preferred Choice of HIV
Why is it a good idea to use Lamivudine and Zidovudine together?
They are both nucleoside analogs RT inhibitors, but if the HIV strain becomes resistant to one drug they are always susceptible to the other and vice versa. Synergistic
What is another drug that has the same profile as Lamivudine, but is apart of the preferred drug cocktail for HIV?
Emtricitabine (analog of Lamivudine)
- longer half life, minimal side effects
“Preferred Choice”
What NRTI requires genetic testing prior to starting due to possibly fetal hypersensativity?
Abacavir
What are common side effects of many NRTIs?
- Lactic Acidosis
- Hepatic Steatosis
- *Commonality for most NRTI side effects is Mitocondrial gamma-DNA Polymerase**
What is a non-nucleoside reverse transcriptase inhibitor used for HIV treatment?
Efavirenz - allosteric inhibitor of RT disrupting active site
What are the common side effects of Efavirenz?
Overall well tolerated very commonly used
–CNS effects, psychiatric symptoms, nightmares/vivid dreams
What are two commonly used protease inhibitors for HIV treatment?
- Lopinavir
- Ritonavir
What is the unique use of Ritonavir in treatment?
Ritonavir is used with other protease inhibitors, in order to boost their effectiveness due to Ritonavir being a potent inhibitor of CYP3A - preventing the metabolism of other proteases.
What is the common mechanism of action for Protease inhibitors?
Prevents viral protease from cleaving the Gag-pol polypeptide, competitive inhibitor
What are common toxicities of protease inhibitors?
- Can cause or worsen DM
- changes lipid distribution and increases CV risks
- changes fat distribution to build up in the gut, thinning of the face/legs
- inhibit CYP3A many drug interactions
What is a common fusion inhibitor for HIV?
Enfuvirtide - binds g41 subunit preventing the ‘snap back’ mechanism
When would a fusion inhibitor be used for HIV treatment?
Enfuvirtide - Last Resort ONLY. When patients have failed other therapies.
No cross reactivity or resistance
Administered SubQ Only (Some local reactions)
What is a CCR5 inhibitor and how does it work?
Maraviroc, binds CCR5 on host cells preventing HIV from using it as a co-receptor and entering the cells. T-cells and Macrophages.
Adverse: CV events and hepatotoxicty
What is an integrase inhibitor of HIV? When is it used?
Raltegravir, used when patients have failed previous treatment.
-well tolerated-
What are common reason why treatment for HIV fails?
- failure to maintain regimens / compliance
- resistant strains emerge
- side effects cause patients to stop drugs
- missing doses = allowing mutated viruses to replicate
What are the ideal combination of antiviral drugs for HIV treatment?
Three or more drugs
Commonly 2x NRTI and 1x NNRTI or PI or Integrase inhibitor
