W11 Antivirals

What are the 5 main targets of antiviral drugs?

1) Attachment to host cell and entry, 2) Viral uncoating, 3) Nucleic acid synthesis, 4) Viral protein synthesis, 5) Assembly and release of viral particles

What are the 5 classifications of antiviral drugs?

1) Inhibitors of cell penetration, 2) Inhibitors of viral uncoating, 3) Nucleic acid synthesis inhibitors, 4) Integrase strand transfer inhibitors, 5) Assembly and release inhibitors (protease inhibitors & neuraminidase inhibitors)

What are the 2 subcategories of nucleic acid synthesis inhibitors?

1) Inhibitors of viral DNA and RNA synthesis, 2) Reverse transcriptase inhibitors (Nucleoside RTIs and Non-nucleoside RTIs)

Which antiviral classes target Assembly and Release of Viral Particles?

Protease inhibitors (target HIV assembly) and Neuraminidase inhibitors (target Influenza release)

What drug class does Enfuvirtide (Fuzeon®) belong to?

Inhibitor of cell penetration — specifically a Fusion Inhibitor

What is the mechanism of action of Enfuvirtide (Fuzeon®)?

It binds to the gp41 subunit of the viral envelope glycoprotein, preventing the conformational change required for fusion with the host cell membrane, thus blocking HIV entry

What subunit does Enfuvirtide bind to in order to block HIV fusion?

gp41 subunit of the viral envelope glycoprotein

What is the molecular composition of Enfuvirtide?

36 amino acid protein

What is the route of administration of Enfuvirtide (Fuzeon®)?

Subcutaneous injection

What is the clinical indication for Enfuvirtide (Fuzeon®)?

Persistant HIV-1 infection - used as an antiretroviral agent, typically in treatment-experienced patients resistant to other regimens

What are the ADRs associated with Enfuvirtide?

Fatigue, insomnia, GI upset, injection site reactions, hypersensitivity

What are examples of inhibitors of viral uncoating?

Amantadine (Symmetrel®) and Rimantadine (Flumadine®)

What is the mechanism of action of inhibitors of viral uncoating (Amantadine/Rimantadine)?

Inhibit the viral uncoating of influenza A virus within the host cell. They interfere with the ion channel function of the viral membrane M2 protein, inhibiting late-stage uncoating of virions

Against which influenza type are Amantadine and Rimantadine effective, and why?

Only Influenza A — because Influenza B lacks the M2 protein that these drugs target

Why are Amantadine and Rimantadine considered narrow spectrum antivirals?

They are only active against Influenza A (not Influenza B or any other virus), making their coverage very limited

What are examples of Nucleic acid sysntehsis inhibitors: DNA synthesis inhibitors (anti-herpesvirus agents)?

Acyclovir*, Ganciclovir, Valacyclovir*, and Famciclovir

Which antiviral is an example of both a DNA AND RNA synthesis inhibitor?

Foscarnet

What is the mechanism of action of Acyclovir (Zovirax®)?

Acyclovir is a prodrug that is first converted into acyclovir monophosphate by the herpes virus enzyme thymidine kinase. It is then further phosphorylated by host cell enzymes into acyclovir triphosphate, its active form. This active form inhibits viral DNA polymerase and prevents viral DNA chain elongation, stopping viral replication.

Why does Acyclovir selectively harm viral-infected cells and not normal human cells?

Because the enzyme that converts Acyclovir to its active form (thymidine kinase) is a viral enzyme — it is absent in uninfected human cells, so Acyclovir is only activated inside virally infected cells so its only selevtively activated in cells infected with herpes viruses.

What does the incorporation of the acyclovir-TP do?

Incorporated into the primer strand during viral DNA replication leads to chain termination and formation of an inactive complex with the viral DNA polymerase

What type of nucleoside analog is Acyclovir?

A synthetic guanosine analog

Under which antiviral class is Acyclovir categorized?

Prootype of Anti-herpesvirus agents (inhibitors of viral DNA synthesis)

What is the distribution of Acyclovir?

Distributed in most tissues and fluid including CSF; routes - PO, IV, Topical

How is Acyclovir excreted?

Renally

What are the clinical indications for Acyclovir (Zovirax®)?

Varicella zoster virus (chickenpox); Herpes Zoster (shingles); Infection by HSV (cold sores)

What is the key drug interaction associated with Acyclovir (Zovirax®)?

Acyclovir may diminish the therapeutic effect of the Zoster Vaccine (Live) — a time interval should be given between the vaccination and Acyclovir prescription; acyclovir should be stopped atleast 24 hrs prior to and 14 days after receiving a live attenuated zoster vaccine.

What are the ADRs that can occur with Acyclovir use?

Malaise, headache, GIT disturbances - well tolerated though.

What are NRTIs (Nucleoside Reverse Transcriptase Inhibitors)?

Nucleoside analogs that act as competitive inhibitors of HIV reverse transcriptase; they require conversion in the host cytoplasm to their triphosphate form to become active (prodrugs)

What specific enzyme do NRTIs target?

Viral reverse transcriptase

Why are NRTIs relatively less toxic to host cells?

Because viral reverse transcriptases are more easily fooled by NRTIs compared to host cell polymerases

What is an example of an NRTI?

Zidovudine (also called Azidothymidine or AZT)

What antiretroviral class does Zidovudine (Retrovir®) belong to?

Antiretrovirals (NRTIs) deoxythymidine analog

What are the key pharmacological features of zidovudine (AZT)?

Zidovudine is a deoxythymidine analog and prototype NRTI that inhibits reverse transcriptase; it is well absorbed from the GIT, widely distributed to tissues including CSF, metabolized by hepatic glucuronidation, and excreted in urine.

What are the therapeutic effects of Zidovudine?

Slows disease progression and prolongs survival in HIV patients

When is Zidovudine specifically indicated as a prophylactic agent?

In cases of needle stick injury, unprotected sex (post-exposure prophylaxis), and to prevent mother-to-child transmission of HIV

What is a common adverse drug reaction (ADR) of Zidovudine?

Myelosuppression (bone marrow suppression); GIT and CNS effects usually resolve during therapy; avoid other myelosuppressants like ganciclovir, ribavirin

What are NNRTIs (Non-Nucleoside Reverse Transcriptase Inhibitors)?

Non-nucleoside compounds that do NOT need to be phosphorylated (unlike NRTIs) to be active

What is the mechanism of action of NNRTIs?

They bind to the HIV-1 reverse transcriptase (RT) enzyme at a site distant from the catalytic site, causing conformational changes that inhibit enzyme function (non comp inhibition basically)

Why can NRTIs and NNRTIs be used together in combination therapy?

Because they bind to different sites on HIV-1 reverse transcriptase, there is no cross-resistance between these two classes, making them complementary

What are 2 examples of NNRTIs?

Nevirapine (Viramune®) and Baloxavir marboxil (Xofluza®)

Which antiviral class does Nevirapine (Viramune®) belong to?

Antiretrovirals (NNRTI), active against HIV-1; indicated as a component of HIV combination therapy

What are some pharmacological characteristics of Nevirapine?

Causes confromational change to RT. Has excellent oral bioavailability; distributes to CSF

What are the common adverse drug reactions (ADRs) of Nevirapine (Viramune®)?

Abrupt onset of flu-like symptoms, abdominal pain, jaundice, fever with or without rash, and may progress to hepatic failure with encephalopathy. Skin rash is present in ~50% of cases; increase in cholesterol

What are the black box warnings for Nevirapine (Viramune®)?

Severe hepatotoxicity and severe life-threatening skin reactions

What is a key drug interaction of Nevirapine (Viramune®)?

Nevirapine is a strong inducer of CYP3A4, which decreases plasma levels of many co-administered drugs that are CYP3A4 substrates (carbamazepine, clozapine, dronedarone, ketoconazole, nifedipine, ranolazine, rivaroxaban etc; Cat X interaction)

Is Baloxavir marboxil (Xofluza®) a prodrug?

Yes, Baloxavir marboxil is a prodrug

What is the mechanism of action of Baloxavir marboxil (Xofluza®)?

Baloxavir marboxil is a prodrug → converted to baloxavir (mainly by UGT1A3) → inhibits PA endonuclease → blocks viral mRNA transcription → stops influenza virus replication.

What is the clinical indication for Baloxavir marboxil (Xofluza®)?

Acute uncomplicated influenza A and B in patients ≥12 years old who have been symptomatic for no more than 48 hours

What are some ADRs linked to Baloxavir marboxil?

Diarrhea, nasopharyngitis

What precautions need to be taken when administring Baloxavir marboxil?

Theyre not effective in bacterial infections; drug-drug, drug-food interactions. If a patient has an allergy to baloxavir (or its components) → DO NOT give the drug (hypersensitivty)

What are the common drug interactions of Baloxavir marboxil (Xofluza®)?

Metallic ions (Fe, Mg, Se, Ca, Zn) and fat-soluble vitamins (A, D, E, K) reduce the plasma concentration of Baloxavir marboxil, potentially decreasing its effectiveness.

How long before and after a live influenza vaccine should anti-influenza antivirals be avoided?

From 48 hours before to 2 weeks after administration of a live influenza virus vaccine, because antivirals may reduce the vaccine's effectiveness

What is the first integrase strand transfer inhibitor?

Raltegravir (Isentress®)

What is the mechanism of action of Raltegravir (Isentress®)?

Viral cDNA strand produced by reverse transcriptase is processed and inserted into the human genome by the enzyme HIV integrase. Raltegravir prevents integration of the proviral (HIV) gene into human DNA by inhibiting the catalytic activity of integrase enzyme

What are the indications for Raltegravir use?

Treatment of HIV-1 infection in combination with other antiretroviral agents

What is a common ADR of Raltegravir (Isentress®)?

Increased ALT (liver enzymes), insomnia, headache, increase in blood glucose. Cat C

What is a Category X drug interaction with Raltegravir (Isentress®)?

Antacids containing Aluminum hydroxide and Magnesium hydroxide reduce plasma levels of Raltegravir (Category X interaction — the interaction prevents the therapeutic effect)

What does Category X (Cat X) mean in the context of drug interactions?

The highest level of drug interaction severity, meaning the interaction prevents the therapeutic effect from occurring — these combinations should be avoided

Which antiviral class affects the assembly of virions?

Protease inhibitors (HIV)

Which antiviral class affects the release of virions?

Neuraminidase inhibitors (Influenza)

What is special about HIV-1 protease that makes it a good drug target?

HIV-1 protease is a dimeric aspartyl protease essential for viral proliferation, and it is encoded in the HIV genome — it is absent in uninfected CD4 cells, making it selectively targetable

What is the mechanism of action of HIV Protease Inhibitors?

HIV protease normally converts inactive precursor proteins into active viral proteins needed for viral maturation. Protease inhibitors reversibly bind to the HIV protease active site, blocking this cleavage and preventing proper viral assembly, resulting in immature, noninfectious virions.

What is an example of an HIV Protease Inhibitor?

Saquinavir (Fortovase®)

What is the specific mechanism of action of Saquinavir?

Sekectiveky toxic by potently inhibiting the HIV endcoded pretease but not host-encoded aspartyl proteases. It reversibly binds to the active site of HIV protease; virus particles are still produced in the presence of Saquinavir but are noninfectious (cannot infect new cells)

What are the indications for Saquinavir use?

Treatment of HIV, used in combination wih atleast 2 other antiretroviral agents.

What are the potential ADRs with Saquinavir use?

Nausea, chest pain, fatigue

When is Saquinavir contraindicated?

In patients with congenital or acquired QT prolongation, AV Block, or hepatic impairment

What is a key pharmacokinetic drug interaction of Saquinavir?

Saquinavir is a strong inhibitor of CYP3A4 and protease — this can significantly increase plasma levels of many CYP3A4-metabolized drugs Risk X interactio

Which formulation of Saquinavir provides the best bioavailability?

Soft gelatin capsule (NOT hard gelatin capsule)

Which viruses possess the neuraminidase (NA) enzyme?

Both Influenza A and Influenza B

What is the role of the neuraminidase (NA) enzyme in influenza?

NA is a viral glycoprotein that cleaves sialic acid residues that are linked to glycoproteins and glycolipids. It is essential for the release of newly formed virus particles from infected cells — without it, virions remain trapped and aggregate at the surface and cannot spread

How do neuraminidase inhibitors work?

They prevent the release of newly formed virions from infected cells, thereby limiting the spread of the influenza virus

What is an example of a neuraminidase inhibitor?

Oseltamivir (Tamiflu®)

Is Oseltamivir (Tamiflu®) a prodrug?

Yes, Oseltamivir is a prodrug

What is the route of administration of Oseltamivir (Tamiflu®)?

Oral (PO)

What is the clinical indication for Oseltamivir (Tamiflu®)?

Influenza A or B infection, and also used for influenza prophylaxis; (uncomplicated acute illness in children ≥2 weeks and adults who have been symptomatic for no more than 2 days; prophylaxis against influenza (A or B) infection in children ≥1 year of age and adults)

What drug interaction is associated with Oseltamivir (Tamiflu®)?

It may diminish the therapeutic effect of the live/attenuated Influenza Virus Vaccine — avoid concurrent use

What is the pregnancy category of Oseltamivir (Tamiflu®)?

Category C

How is Oseltamivir excreted?

Renally, probenecid increases plasma levels of oseltamivir

What ADRs might be seen with Oseltamivir use?

Nausea, abdominal discomfort

What DIs are associated with Oseltamivir?

May dimish the therapeutic effect of Influenza virus vaccine (Live/Attenuated). Avoid anti-influenza antivirals during the period beginning 48 hours prior to and ending 2 weeks after vaccine administration. Those receving oseltamivir within 2 weeks of the live intranasal spray vaccine should receive a repeat vaccine dose

What is HAART (Highly Active Antiretroviral Therapy)?

A combination ("cocktail") of several antiretroviral medicines used to slow the rate at which HIV makes copies of itself in the body. Three or more antiretroviral medicines usually combined, which is more effective than monotherapy to treat HIV

What classes of drugs are commonly used in HAART?

NRTIs (e.g., Zidovudine), NNRTIs (e.g., Nevirapine, Baloxavir marboxil), Protease inhibitors (e.g., Saquinavir), Fusion and entry inhibitors (e.g., Enfuvirtide), and Integrase inhibitors (e.g., Raltegravir)

Why is combination therapy (HAART) preferred for HIV over monotherapy?

Using multiple drugs with different mechanisms simultaneously reduces the chance of resistance developing and is more effective at suppressing viral replication

Why are Amantadine and Rimantadine not effective against Influenza B?

Influenza B lacks the M2 protein (ion channel) that these drugs target — without M2, the drugs have no viral target

What step in the HIV lifecycle does Raltegravir block?

Integration — it prevents the HIV proviral DNA from being inserted into the host cell's chromosomal DNA

What step in the HIV lifecycle do NRTIs (e.g., Zidovudine) block?

Reverse transcription — they inhibit HIV reverse transcriptase, preventing conversion of viral RNA into DNA

What step in the HIV lifecycle do NNRTIs (e.g., Nevirapine) block?

Reverse transcription — like NRTIs, but by binding a different (allosteric) site on HIV reverse transcriptase

What step in the HIV lifecycle do Protease Inhibitors (e.g., Saquinavir) block?

Assembly — they prevent proper cleavage of HIV polyproteins, so assembled virions are noninfectious

What step in the HIV lifecycle does Enfuvirtide block?

Cell entry/fusion — it prevents HIV from fusing with the host CD4+ T cell membrane

A patient on Raltegravir begins taking an OTC antacid for heartburn. What is the concern?

Antacids containing Aluminum hydroxide or Magnesium hydroxide cause a Category X drug interaction with Raltegravir — they reduce plasma levels of Raltegravir, potentially eliminating its therapeutic effect

A patient with HSV-1 oral infection is prescribed Acyclovir. They recently received a Zoster vaccine. What should the clinician consider?

Acyclovir may diminish the therapeutic effect of the Zoster Vaccine (Live) — a time interval should be given between vaccination and Acyclovir therapy. The vaccine should ideally be given before or well after Acyclovir

A patient with HIV takes Nevirapine and is started on a new medication metabolized by CYP3A4. What is the concern?

Nevirapine is a strong inducer of CYP3A4 — it increases metabolism of CYP3A4 substrates, potentially reducing their plasma levels and effectiveness

A patient taking Baloxavir marboxil (Xofluza®) also takes a daily multivitamin with Fe, Mg, Ca, Zn. What is the drug interaction?

Metallic ions (Fe, Mg, Se, Ca, Zn) reduce plasma concentration of Baloxavir marboxil, potentially decreasing its antiviral effectiveness — the supplement should be timed away from the drug dose

A patient with Influenza B infection is prescribed Amantadine. Is this appropriate?

No — Amantadine targets the M2 protein, which is only found in Influenza A, not Influenza B. It would be ineffective. Oseltamivir (Tamiflu®) would be the appropriate choice for Influenza B

A healthcare worker has a needlestick injury from an HIV-positive patient. Which drug is used for post-exposure prophylaxis?

Zidovudine (Retrovir®) — it is used as a prophylactic agent in post-exposure situations (needle stick, unprotected sex) and to prevent mother-to-child HIV transmission

A pregnant HIV-positive woman asks about preventing mother-to-child HIV transmission. Which drug is indicated?

Zidovudine (Retrovir®) is commonly used to prevent mother-to-child transmission of HIV

A patient with chronic HIV has increasing viral load. A drug that inhibits integration of viral DNA into host chromosomes is added. Which drug is this?

Raltegravir (Isentress®) — an integrase strand transfer inhibitor

A patient with HIV and suspected saquinavir therapy is found to have a prolonged QT interval on ECG. What should be done?

Saquinavir is contraindicated in patients with congenital or acquired QT prolongation — it should be discontinued and an alternative protease inhibitor considered

What is the difference in activation requirements between NRTIs and NNRTIs?

NRTIs are prodrugs that require phosphorylation (conversion to triphosphate form) in the host cytoplasm to become active. NNRTIs are non-nucleoside compounds that do NOT require phosphorylation — they are active as administered