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03 Deja Review-Micro Viral Drugs/Vaccines

Terms in this set (49)

What is the mechanism by which amantadine and rimantadine inhibit cell entry of influenza A?
Amantadine and rimantadine inhibit the ion channel function of the influenza A M2 protein. This prevents the pH-dependent step of viral uncoating during endocytosis.
Why is rimantadine used more widely than amantadine?
Amantadine has central nervous system (CNS) side effects. Rimantadine, as a deriv- ative of amantadine, acts via the same mechanism but with fewer side effects.
What is the mechanism of action of enfuvirtide which blocks fusion of human immunodeficiency virus (HIV)?
Blocks entry of HIV by inhibiting glycoprotein 41 (gp41)-mediated fusion with the CD4 cell membrane
What nucleoside inhibitor is widely used to treat herpesvirus infections?
Acyclovir is used to treat herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), varicella-zoster virus (VZV), and Epstein-Barr virus (EBV). However it has no effect on latent HSV and VZV.
What is the mechanism of action of acyclovir?
Acyclovir is a guanosine nucleoside analog that is phosphorylated by viral thymidine kinase. After phosphorylation, it competes with deoxyguanosine triphosphate (dGTP)
for binding to the viral DNA polymerase and thus prevents further elongation of the DNA.
How does acyclovir achieve its selectivity?
Acyclovir is highly selective because it must be phosphorylated by a virally encoded thymidine kinase to become activated. Activated acyclovir also preferentially inhibits viral DNA polymerase.
What is selective toxicity?
The extent to which a drug can inhibit viral replication without damaging the host cell
Does acyclovir affect recurrences of the herpesvirus after treatment?
No. While it reduces recurrences during treatment, it does not affect latency once treatment is stopped.
How does acyclovir differ from ganciclovir in terms of its clinical use?
Ganciclovir is similar to acyclovir as it is also a guanosine nucleoside analog, but it is more active against cytomegalovirus (CMV). It is activated by a phosphokinase
encoded by CMV. It is used to treat the retinitis caused by CMV in AIDS patients as well as other CMV infections.
What is the main nonnucleoside inhibitor of herpesvirus?
Foscarnet
What is the mechanism of action of foscarnet against herpesvirus?
It is a pyrophosphate analog. It binds at the pyrophosphate cleavage site of DNA polymerase and prevents removal of phosphate from the nucleoside triphosphate. This ultimately inhibits the extension of the DNA strand. Foscarnet also inhibits viral RNA polymerase.
Does foscarnet have to be activated by tyrosine kinase or other kinases?
No. Foscarnet is active in vitro and does not require activation by a kinase. It is used in acyclovir-resistant strains of HSV or ganciclovir-resistant strains of CMV. However, not all resistant HSV or CMV will be sensitive to foscarnet because resistance may have developed from mutations in the kinase or DNA polymerase. Mutations in DNA polymerase may also confer resistance to foscarnet.
What is highly active antiretroviral therapy (HAART)?
Regimen of three to four anti-HIV drugs that usually consists of two nucleoside reverse transcriptase inhibitors (NRTIs) plus one or two protease inhibitors (PIs) or a nonnucleoside reverse transcriptase inhibitor (NNRTI)
How effective is HAART?
Very effective in reducing mortality and morbidity in compliant patients. However, patients have a quick return to viremia if they stop treatment.
What is the prototype for nucleoside inhibitor of reverse transcriptase?
Zidovudine, also known as azidothymidine (AZT)
What is the mechanism of action of AZT?
It inhibits viral RNA-dependent DNA polymerase (reverse transcriptase) by incorporating into the DNA chain to from a phosphodiester bond with the incoming nucleotide and causes chain termination because it lacks a functional 3' hydroxyl group.
Unlike acyclovir, why does AZT have significant adverse side effects?
While acyclovir is phosphorylated by viral thymidine kinase exclusively, AZT is phosphorylated by normal host-cell kinases, so it is activated in all cells.
List some other NRTIs, their indications, and their side effects:
Didanosine (ddI, Videx): deoxyadenosine analog is usually prescribed in combination with other NRTIs; common side effects in- clude pancreatitis, peripheral neuropathy,
hyperuricemia, and rarely mitochondrial toxicity leading to lactic acidosis (associated with all NRTIs).
Zalcitabine (ddC, Hivid): cytosine analog is usually prescribed in combination; common side effects include peripheral neuropathy and oral ulcerations.
Stavudine (d4T, Zerit): thymidine analog that is not generally used with AZT because it may reduce phosphorylation of stavudine; main side effects are peripheral neuropathy and stomatitis.
Lamivudine (3TC, Epivir): cytosine analog that is very effective when used with AZT and can also be used for the treatment of chronic hepatitis B infections; well tolerated with minimal side effects such as headache and dizziness.
Abacavir (ABC, Ziagen): guanosine analog that is significantly more effective than other NRTIs; associated with fatal hypersensit- ivity reactions in 2% to 5% of patients, but
sensitivity can be reasonably predicted with genetic analysis (HLA B 5701).
Tenofovir (Viread): belongs to a newer class of nucleotide reverse transcriptase inhibitor (NtRTI); less side effects because it does not require conversion of nucleoside to nucle- otide, but most common side effects include nausea, diarrhea, vomiting, and flatulence.
What is the mode of action of NNRTIs?
They inhibit the reverse transcriptase by binding near its active site and inducing a conformational change. They are noncompetitive inhibitors of reverse transcriptase.
What three NNRTI drugs are available in the United States?
1. Nevirapine
2. Delavirdine
3. Efavirenz
What are the main considerations to use NNRTI as treatment?
They should be used in combination and never as monotherapy. Resistance occurs rapidly, and resistance to one nonnucleoside analog usually implies resistance to all non-nucleoside analogs.
What is the mode of action of viral protease inhibitors (PI)? Should they be used as monotherapy?
They bind to the active site of HIV protease via specific peptide bonds. The protease therefore cannot cleave the viral precursor. Protease inhibitors should not be used as monotherapy. They leave the proviral DNA unaffected, which means that they cannot suppress the virus on their own.
What are some Pis available in the United States?
Saquinavir, ritonavir, indinavir, nelfinavir, and amprenavir, fosamprenavir, lopinavir, atazanavir, tipranavir, darunavir. Often re- gimens are "boosted" by including small
doses of ritonavir, which inhibits the metabolism of the other drugs.
What are the side effects of Pis?
Nausea, diarrhea, disfiguring fat accumulation in the back of the neck, insulin resistance, hepatotoxicity, and hyperlipidemia. Indinavir has also been associated with nephrolithiasis and indirect hyperbilirubinemia.
What are two antiviral drugs that are used against influenza A and B to inhibit cell-to- cell transmission? What is their mode of action?
1. Zanamivir (Relenza)
2. Oseltamivir (Tamiflu)
They inhibit neuraminidase on the surface of the virus and decrease the ability of the influenza virus to be released from infected cells.
What is the antiviral drug that is used against respiratory syncytial virus (RSV) and what is its mechanism of action?
Ribavirin. It is a guanosine analog that must be phosphorylated to have antiviral activity. It is thought to interfere with guanosine triphosphate (GTP) synthesis, inhibit capping of viral mRNA, and inhibit viral RNA poly- merase. It is active against a wide range of viruses, including influenza A, hepatitis C virus (HCV), RSV, and parainfluenza virus.
What is an important side effect of ribavirin?
Hemolytic anemia in 10% of patients
What drugs are used to prevent HIV infection in a neonate?
AZT and nevirapine
What drugs are used after an HIV needlestick injury?
AZT, lamivudine, and indinavir or nelfinavir or tenofovir. The regimen is individualized depending on the source patient's history of antiretroviral exposure and resistance.
What is the risk of HIV infection from a hollow-bore needlestick injury from an infected patient?
1/300
What types of viral vaccines induce active immunity?
Live-attenuated and killed (inactivated) virus vaccines
What are subunit vaccines?
Subunit vaccines consist of purified protein viral components. They are similar to killed vaccines in that they do not induce a cytotoxic T-cell response.
Name the live-attenuated viral vaccines:
Sabin polio (oral polio vaccine [OPV]), influenza (intranasal), VZV, measles-mumps-rubella (MMR vaccine), yellow fever, smallpox
Mnemonic: Some Feeble Viruses May Yet Strike (Sabin polio, Flu, VZV, MMR, Yel- low fever, Smallpox)
Name the killed inactivated viral vaccines:
Salk polio (inactivated polio vaccine [IPV]), hepatitis A virus (HAV), influenza (IM), rabies
Mnemonic: Salk Has Influenced Rx (pre- scriptions) (Salk polio, HAV, Influenza, Rabies)
Name some subunit vaccines:
Hepatitis B and influenza A
What are the advantages of live viral vaccines?
1. Since the virus multiplies in the host, it pro- duces a CD8 cytotoxic T-cell response.
2. Vaccines given by the natural route of infec- tion induce an immunoglobulin G (IgG) and immunoglobulin A (IgA) response.
3. Live viral vaccines are contagious and may spread immunity to people who were never vaccinated.
4. Live viral vaccines produce a response that is stronger and longer and often confer lifelong protection.
What are the disadvantages of live viral vaccines?
1. Live viral vaccines can revert to virulence and cause the very disease they are meant to prevent.
2. Live viral vaccines that do not revert can still cause disease in immunocompromised patients and are relative contraindications.
3. The virus from live viral vaccines can spread to other people and hence cause disease if the vaccine reverts to virulence or if the patient is immunocompromised.
4. Other viruses can contaminate live viral vaccines (eg, in the 1960s, live polio vaccine was contaminated with SV40, but no side effects have been detected in humans from SV40 ex- posure).
What is the only live viral vaccine that has reverted to virulence in the past?
Live polio vaccine (Sabin polio vaccine)
What are the advantages of killed viral vaccines?
1. Contamination less likely since the same process that kills the virus in the vaccine would also kill any contaminants.
2. Do not revert to virulence.
3. Vaccines are heat stable so they can be used
in hot climates (important for worldwide vaccine programs targeting the underdeveloped world).
What are the disadvantages of killed viral vaccines?
1. Inactivation process may create a vaccine that generates an inadequate immune response.
2. Since the virus does not multiply, there is no CD8 T-cell response.
3. No IgA response.
4. Shorter duration of immunity, resulting in the
need for repeated vaccination or booster.
When are most vaccines given, pre- or postexposure to disease-causing agent?
Preexposure
How is passive immunity conferred?
Administering preformed immune globulins
What is passive-active immunity?
Administering both preformed immune globulins to provide protection in the short term and a viral vaccine to provide protection in the long term
Give two common examples of passive-active immunity:
Patients infected with rabies or
hepatitis B
virus are given both:
1. Immune globulins
2. Vaccine postexposure
What types of viral vaccines are in the research pipeline?
1. Purified viral antigen produced from recom- binant yeast and bacteria
2. DNA vaccines containing purified DNA cod- ing for viral proteins
3. Currently used live viral vaccines with patho- genic virus, such as HIV, spliced into genome
Which vaccines should not be given to patients with a history of anaphylactic reactions to eggs? Why?
Influenza, measles, mumps, and yellow fever vaccines as these are grown in chick embryos
When is varicella-zoster immunoglobulin used?
In patients who may have been exposed to VZV, are not immune, and are immunocompromised or pregnant
What is the concept of herd immunity?
Collective immunity for a group of people. It is attained when a critical percentage of the population has been vaccinated so that unimmunized individuals are also protected.
What trait must a vaccine absolutely confer to attain herd immunity?
Vaccine must both prevent transmission of the disease and prevent the disease itself.
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