PTN - Antivirals (Mehta) Flashcards
If the triphosphate version of acyclovir (ACV) and zidovudine (AZT) are the actual pharmacological inhibitors, why are the drugs not administered as the triphosphate?
A. Not stable in circulation
B. No mechanism to enter cell
C. Too expensive to synthesize
D. All of the above
D. All of the above
What are the 3 mechanisms that lead to acyclovir resistance?
- Impaired production of viral thymidine kinase (most common)
- Altered thymidine kinase substrate specificity
- Altered viral DNA polymerase (rare)
How do the cyclovir drugs (acyclovir, famcyclovir, etc.) exhibit selective toxicity to virally-infected cells over human cells?
Human thymidine kinase will not phosphorylate the drug, and human DNA polymerase is not inhibited by the triphosphate.
What drug is used to treat cytomegalovirus?
Gancyclovir
One of the main side effects of treating with the drug gancyclovir is that it causes myelosuppression (neutropenia and thrombocytopenia). What drug can be co-administered to prevent this from happening?
A G-CSF analog (Filgrastim) will increae production of neutrophils
What is the drug acyclovir used to treat?
Herpesvirus infections
Specifically, HSV-1 and 2 and VZV
High concentrations can be used to treat VZV and CMV, but gancyclovir works best for CMV
What is the mechanism of action of foscarnet?
Non-competitive inhibition of viral DNA polymerase
Foscarnet reversibly blocks the pyrophosphate binding site of viral polymerase to inhibit cleavage of pyrophosphate from dNTPs
What are the two major dose-limiting toxicities of foscarnet?
- Nephrotoxicity
- Hypocalcemia
What are the 5 classes of current anti-retrovirals?
- Nucleoside/Nucleotide reverse transcriptase inhibitors (NRTIs)
- Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
- Protease inhibitors (PIs)
- Integrase Strand Transfer Inhibitors (INSTIs)
- Early inhibitors
How does drug resistance to anti-retroviral therapy occur in HIV patients who faithfully take their medications?
HAART suppresses viral load to undetectable levels, but often there is a latent viral reservoir that is not affected by HAART.
This reservoir replenishes during resistance or interruption of drug therapy.
How does highly-active antiretroviral therapy (HAART) help to limit the emergence of resistant virus?
HAART is a combination therapy and uses multiple types of antiretroviral drugs to try to inhibit as many types of HIV virus and to prevent resistance to individual drug therapies.
True or False: Single agent drug resistance to HIV therapy is present in every individual infected with HIV.
True
This is the reason that HAART is more effective than a single drug at diminishing the effects of HIV.
Patient’s HIV genotypes are also determined to provide the therapy that each patient will best respond to.
What are the 2 toxicities specific to all nucleoside reverse transcriptase inhibitors (NRTIs)?
- Lactic acidosis
- Hepatic steatosis
What prototype drug is considered to be a nucleoside reverse transcriptase inhibitor (NRTI)?
Zidovudine (AZT)
What is the clinical manifestation of Stevens-Johnson Syndrome?
A. Polyp-like skin lesions
B. Erectile dysfunction
C. Dermis separates form epidermis
D. A henway
C. Dermis separates from epidermis
Stevens-Johnson Syndrome is a consequence of non-nucleoside reverse transcriptase inhibitors (NNRTIs). It begins as a fever and rash that spreads to the mucous membranes and other parts of the skin. Eventually, the epidermis separates from the dermis, leading to blistering and sloughing off of the epidermal layer of skin.
Which class of antiretroviral drug causes significant gastrointestinal side effects, dyslipidemia, and lipodystrophy?
HIV Protease Inhibitors (PI)
Protease inhibitors (ritonavir, atazanavir, lopinavir) inhibit cytochrome P450 enzymes.
Lipodystrophy - inability to produce fat
Dyslipidemia and lipodystrophy lead to increased levels of glucose in the blood, which overwhelms insulin receptors, leading to insulin resistance and diabetes.
What drug is given with other protease inhibitors to boost antiretroviral activity in HIV patients?
Ritonavir
More potent activity against resistant viruses without the risk of developing resistance.
What are the distinct side effects of atazanavir that differentiates it from other protease inhibitors?
Increased bilirubin levels and nephrolithiasis
Like other protease inhibitors, it also causes hyperglycemia and GI intolerance
What are the specific side effects of Ritonavir, a protease inhibitor
- GI intolerance
- Hyperlipidemia and hyperglycemia
- Taste perversion - metallic taste to mouth
- Perioral parasthesia
- Hepatitis
What step of HIV pathogenesis does an integrase strant transfer inhibitor (INSTI) inhibit?
INSTIs inhibit the viral enzyme integrase, which is responsible for integrating viral DNA into host genome.
Without this integration, the virus cannot hijack host DNA transcription mechanisms. This prevents formation of viral capsid proteins and RNA, preventing new virions from being released.
What is a potential disadvantage to using an integrase inhibitor?
Myopathy and elevated creatine phosphokinase (CPK)
Integrase inhibitors can lead to degradation of heart and skeletal muscle.
Which HIV drug class currently has the least severe side effects?
A. Protease inhibitors
B. Integrase inhibitors
C. Reverse transcriptase inhibitors
D. Non-nucleoside RT inhibitors
C. Reverse transcriptase inhibitors
Because reverse transcriptase is not normally present in human cells, it leads to the least amount of side effects.
What are interferons used to treat?
Hepatitis B, Hepatitis C, and HPV
Interferon activates 2’5’-oligoadenylate synthetase, an enzyme that activates RNAseL. What is the function of RNAseL?
RNAseL is a proteolytic enzyme that cleaves viral RNA to prevent replication and formation of virions.
What does protein kinase P1 do and how does it limit viral transmission and replication of hepatitis B virus?
P1 binds eIF-2a and inactivates it, preventing initiation of viral mRNA translation
What does ribavirin treat on its own? What about in conjunction with interferon and viral nucleosides or protease inhibitors?
Ribavirin (aerosol) is mainly used to treat viral pneumonia and bronchiologis caused by respiratory syncytial virus (RSV).
When used with interferon and viral nucleosides/protease inhibitors (entecavir, boceprevir), it treats hepatitis B and C
Which 2 antiviral drugs are considered to be teratogenic, and should not be prescribed to pregnant women?
Gancyclovir and ribovirin
What type of drug is sofosbuvir and what virus is it used to treat?
Sofosbuvir is an RNA polymerase inhibitor.
It is used to treat Hepatitis C
Which antiviral drug is used as a hepatitis B nucleoside inhibitor?
Entecavir
What 2 prototype drugs are used to treat hepatitis C?
- Boceprevir (hep C protease inhibitor)
- Sofosbuvir (hep C RNA polymerase inhibitor)
What are some of the limitations to current hepatitis C virus therapies?
- Cost
- Does not prevent reinfection
- Drug-resistance likely to emerge
- Does not repair already damaged liver - can lead to cirrhosis and risk of liver cancer
What are the two surface antigens that are used to categorize types of influena viruses?
Hemagglutinin (H1-H16) and neuraminidase (N1-N9)
Hemagglutinin binds to cell surface and docks, allowing for endocytosis of virus.
Neuraminidase anchors viral progeny on cell surface as they bud off of host cell. This anchor is cleaved, which allows the virion to infect other cells.
How does oseltamavir (tamiflu) limit viral infection of influenza A virus?
Oseltamavir preents the release of viral progeny by blocking detachment of neuraminidase.
Viral progeny bud off the side of the infected cell, but remain attached to surface neuraminidase. Once this neuraminidase is cleaved, the viral progeny are released to infect other host cells.
