Term
| What is a limitation to current anti-viral therapy? |
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Definition
Current antiviral drugs do not eliminate latent/ non-dividing viruses.
This means that full recovery from infection relies heavily on the host's immune response! |
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Term
| What are the herpes viruses? |
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Definition
| The herpes viruses include the herpes simplex viruses, varicellovirus, and cytomegalovirus. |
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Term
| What are effective drugs against the herpes simplex virus? |
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Definition
Any drug with the ending "ovir" is effective against herpesviridae, and almost all of these "ovir"s are guanine nucleoside analogs.
Specifically against Herpes Simplex:
Acyclovir (and its prodrug valacyclovir), Penciclovir (and its prodrug famciclovir), and trifluridine are effective against HSV.
Always add valacyclovir in any gouping with acyclovir. It is simply a prodrug form of acyclovir that has better oral bioavailability. Of course, if giving medication by IV, there is no need to use the prodrug form and acyclovir is preferred... (the same is true for penciclovir and famciclovir) |
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Term
| How is penciclovir administered? |
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Definition
| Penciclovir, a drug against Herpes Simplex Virus, is administered topically. It's prodrug form, famciclovir, can be administered orally. |
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Term
| Which drug ending in "ovir" is effective against cytomegalovirus? |
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Definition
Recall: all drugs ending in "ovir" are good against viruses of the family herpesviridae. This family includes HSV, CMV, and varicellovirus.
Ganciclovir is the guanine nucleoside analoge (ovir) that is most effective against CMV. Its prodrug form, valganciclovir can be administered orally. |
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Term
| How do the guanine nucleoside analogs work? |
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Definition
| The guanine nucleoside analogs are the drugs ending in "ovir". For example: Acyclovir, Penciclovir, Ganciclovir and their prodrug forms. They must all be phosphorylated by viral thymidine kinase as the first step. This means that they only target cells that are infected by viruses. Non-infected cells will not express viral thymidine kinase! Once phosphorylated by viral thymidine kinase, host cell kinases phosphorylate them to a triphosphorylated form. In this triphosphorylated form, they are incorporated into viral DNA synthesis and both block continued DNA elongation and cause suicide inhibition of viral DNA-pol! Elongation is prevented because the analogs (drugs) do not have a 3' OH group, which is necessary for addition of the next nucleotide! |
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Term
| What spectrum of viruses is acyclovir active against? |
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Definition
| Acyclovir is active against all herpesviridae except cytomegalovirus. It is also effective against EBV. |
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Term
| What spectrum of viruses is ganciclovir effective against? |
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Definition
| Ganciclovir is effective against all herpesviridae and EBV. It is the drug of choice for CMV, whereas acyclovir is the drug of choice for all others (HSV, VZV, EBV) |
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Term
| How is resistance to acyclovir attained? |
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Definition
| Remember, acyclovir and the other "ovir"s require viral thymidine kinase as the first step in their activation. By altering the thymidine kinase, viruses can gain resistance to the drugs. |
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Term
| What are adverse effects of acyclovir? |
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Definition
| Acyclovir is used for HSV, VZV, and EBV ... it causes nausea and vomiting. At high doses, it also has nephrotoxicity (crystalluria, hematuria, and renal insufficiency) and can be neurotoxic. |
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Term
| What are adverse effects of ganciclovir? |
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Definition
| Remember ganciclovir is the DOC for CMV. It has dose-limiting myelosuppression and causes neutropenia and thrombocytopenia! |
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Term
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Definition
Trifluridine is a topical antiviral agent applied directly to HSV lesions. It is a pyramidine nucleoside analog.
The reason it can't be used systemically is that all of its phosphorylations are carried out by the host cells. This means it is not specific for infected cells and is therefore much more toxic. Recall that acyclovir, ganciclovir, penciclovir were all first phosphorylated by the viral thymidine kinase, targeting their effects to infected cells! |
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Term
| When would you use trifluridine? |
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Definition
| Trifluridine is a topical antiviral pyramidine analog. It is used in keratoconjunctivitis (ocular HSV infections) |
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Term
| What antivirals are used against CMV? |
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Definition
Ganciclovir (and its prodrug valganciclovir) are used for CMV infections. Cidofovir, Foscarnet, and Fomivirsen are also anti-CMV drugs.
Ganciclovir is a guanine nucleotide analog
Cidofovir is a cytosine analog
Foscarnet is an inorganic pyrophosphate analog
Fomivirsen is an antisense RNA to CMV mRNA |
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Term
| How can you protect against cidofovir's nephrotoxicity? |
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Definition
| cidofovir is a cytosine analog used in the treatment of CMV. It is toxic when it builds up to high concentrations in the kidney tubules. You can administer IV saline solution to help dilute it or you can give probenecid, which prevents its secretion into the tubules. By decreasing its concentration in the tubules, tubular cells are spared from its toxic effects |
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Term
| What is the MoA for foscarnet? |
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Definition
Foscarnet directly inhibits viral DNA polymerase and Reverse-transcriptase.
Sounds like "fast car net"... think about the polymerase and RT as cars on a track (the DNA/RNA), which are stopped by this "fast car net" (foscarnet) |
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Term
| When would you use foscarnet? |
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Definition
| Foscarnet, which directly inhibits viral DNA-pol and viral Reverse-Transcriptase, can be used in HSV resistant to acyclovir and CMV resistant to ganciclovir. |
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Term
| What drugs for respiratory viral infections inhibit viral uncoating? |
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Definition
Amantadine and rimantadine inhibit viral uncoating. Specifically, this is achieved by inhibiting the viral M2 ion channel. This causes a rise in the pH of the endosome. Recall that many viruses use the acidic environment of the endosome to their advantage, and it helps them uncoat. By blocking this, uncoating is inhibited.
These two drugs are active against influenza type A but not influenza type B. |
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Term
| What drugs can target influenza type A? |
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Definition
| Amantadine, Rimantadine, Oseltamivir, and Zanamivir can all target influenza type A |
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Term
| What drugs can target influenza type B? |
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Definition
Oseltamivir and Zanamivir are capable of targeting influenza type B (as well as type A)
recall, amantadine and rimantadine only work against type A! |
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Term
| How do Oseltamivir and Zanamivir work? |
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Definition
Oseltamivir and Zanamivir are neuraminidase inhibitors. They prevent the release of virions from infected cells, thereby hindering the spread of infection from one cell to the next. They are effective against influenza type A and type B
Oseltamivir is administered orally
Zanamivir is administered by inhalation and is therefore associated with the adverse effect of bronchospasm... |
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Term
| What is RSV and how is it treated? |
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Definition
RSV is the resporatory syncytial virus. It is treated with Ribavirin or palivizumab. Ribavirin inhibits RNA polymerase and is administed by oral inhalation in cases of RSV.
Palivizumab is a monoclonal antibody against the F glycoprotein on the surface of RSV |
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Term
| What are adverse effects of ribavirin? |
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Definition
Ribavirin is a drug used to treat respiratory syncytial virus. It is teratogenic and should ve AVOIDED DURING PREGNANCY.
It can also cause anemia and jaundice. |
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Term
| What is the importance of pegylated IFNs? |
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Definition
| Pegylated interferons are interferons joined to polyethylene glycol. This slows absorption and increases half life, allowing them to be given as weekly injections! Recall, interferons are useful endogenous antiviral proteins. |
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Term
| What are the protease inhibitor drugs? |
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Definition
| All of the protease inhibitor drugs, which are used in HIV anti-retroviral therapy end in "navir" and include indinavir, atazanavir, and ritonavir. |
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Term
| What are the nucleoside reverse transcriptase inhibitors (NRTIs)? |
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Definition
NRTIs are effective against HIV-1 and HIV-2. They are activated intracellularly by kinases. They 1) competetively inhibit reverse transcriptase and 2) cause DNA chain termination.
Zidovudine and Staviduine are Thymidine analogs
Lamivudine and Emtricitabine are cytosine analogs. Didanosine is and adenosine analog. Abacavir is a guanosine analog. (A bat cave has guano)
Don't combine two of the same analogs in therapy. For example, don't use both zidovudine and stavudine in the same regimen, they are both Thymidine analogs. |
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Term
| What drug is administered to help prevent vertical transmission of AIDS from mother to newborn? |
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Definition
| Zidovudine (AZT) is administered in pregnancy to prevent vertical transmission of AIDS. |
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Term
| What nucleoside analog used in anti-retroviral (HIV) therapy has a high risk of hypersensitivity reactions? |
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Definition
| Abacavir is the antiretroviral guanosine nucleoside analog that produces hypersensitivity in 8% of patients. Do not try to use the drug again (rechallenge) if the patient already experienced a reaction! |
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Term
| What are the non-nucleoside reverse transcriptase inhibitors (NNRTIs)? |
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Definition
NNRTIs include Nevirapine, Delavirdine, and Efavirenz.
They are non-competetive inhibitors of Reverse Transcriptase and are metabolized by the CYP450 system. |
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Term
| Which NNRTIs are inducers of the CYP450 system, and therefore decrease levels of other drugs, potetnially causing therapeutic failure? |
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Definition
| Nevirapine and Efavirenz both induce the CYP450 system. This means that other durgs must be increased to maintain their effect. For example, if coadministering Efavirenz and a protease inhibitor, you must increase the levels of the protease inhibitor. |
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Term
| Which NNRTIs inhibit the CYP450 system, therefore increasing the plasma levels of other drugs, potentially causing toxicity? |
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Definition
| Delavirdine inhibits the CYP450 system. SO decrease the level of protease inhibitor coadministered because using delavirdine will augment it! |
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Term
| What NNRTI should be avoided during pregnancy? |
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Definition
| The NNRTIs are delavirdine, Efavirenz and Nevrapine. Efavirenz is a category D drug and should be avoided in pregnancy. |
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Term
| Where do protease inhibitors act? |
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Definition
| Protease inhibitors block the action of viral proteases. These enzymes are active in post-translational processing of precursor proteins. This processing generally occurs in the maturation phase of viral development, after the virus has budded off from the infected cell. |
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Term
| How are protease inhibitors cleared? |
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Definition
| Protease inhibitors are metabolized by the CYP450 system. This is why coadministration of NNRTIs will alter the levels of protease inhibitor. Delavirdine will increase protease inhibitor levels. Efavirenz and Nevirapine will decrease the levels. A combination of PIs and NNRTIs is often used because the viral reverse transcriptase is error-prone and combination therapy is a means of preventing resistance development. |
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Term
| Which PI is not associated with carbohydrate and lipid metabolism impairment? |
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Definition
| Atazanavir is not associated with metabolic impairment. All the other Protease inhibitors can cause hyperglycemia, hypertiglyceridemia, buffalo hump (fat redistribution) and peripheral waisting. |
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Term
| What is the integrase inhibitor for HIV therapy? |
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Definition
Raltegravir is the drug that inhibits integrase.
It prevents the infection of new cells, but cannot do anything about cells that have already been infected. |
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Term
| What drug prevents fusion of the HIV virus with the cell membrane? |
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Definition
Enfuvirtide is a drug that targets the HIV gp41 protein. It prevents the conformational change in gp41 that draws the viral membrane and host cell membrane into intimate contact. It therefore prevents fusion of the membranes.
* enfuvertide prevents fusion |
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