Respiratory Anti-Virals

Influenza Virus

Hemagglutinin (16) and neuraminidase (9) are the target for the flu vaccine.

Neuraminidase promote viral spreading and infection:

• Enable release of virions

• Cleave sialic acid residues from mucus

M2 proton ion channel: allow the acidification of the interior of the virion in influenza A (NB in influenza B).

Neuraminidase Inhibitors - Drugs

• Oseltamivir (oral)

• Zanamivir (inhaled)

• Peramivir (IV)

Oseltamivir, Zanamivir, Peramivir - Mechanism of Action

• Inhibit the enzyme neuraminidase in influenza A and B virus.

• Blocks release of progeny virion.

Neuraminidase Inhibitors

Oseltamivir, Zanamivir, Peramivir - Therapeutic Use

Seasonal influenza who have been symptomatic for NO more than 48 hours.

For 2024-2025, the CDC recommends use of oseltamivir (oral), zanamivir (inhaled), peramivir (IV) or baloxavir (oral) for treatment of outpatients with acute uncomplicated influenza.

Neuraminidase Inhibitors

Oseltamivir, Zanamivir, Peramivir - Side Effects & Toxicity

• Oseltamivir: nausea, vomiting, and headache.

• Zanamivir: cough, bronchospasm.

• Peramivir: diarrhea, although serious rare skin or hypersensitivity reactions.

*All neuraminidase inhibitors increase the risk of hallucinations, delirium, and abnormal behavior.

Neuraminidase Inhibitors

Polymerase Acid Endonuclease Inhibitor - Drugs

Baloxavir marboxil (single pill oral)

Baloxavir marboxil - Mechanism of Action

Cap-Dependent Endonuclease (CEN) Inhibitor

Polymerase Acid Endonuclease Inhibitor

Baloxavir marboxil - Therapeutic Use

• Single dose oral treatment of acute uncomplicated flu

• Active against influenza A and B.

Polymerase Acid Endonuclease Inhibitor

Baloxavir marboxil - Side Effects & Toxicity

Well tolerated, none more common than placebo in clinical trials.

*Less side effects than oseltamivir.

Polymerase Acid Endonuclease Inhibitor

Synthetic Guanosine Analogue - Drugs

Ribavirin

Ribavirin - Mechanism of Action

Inhibits replication of RNA and DNA viruses by inhibiting the formation of guanosine triphosphate → blocks RNA-dependent RNA polymerase.

Synthetic Guanosine Analogue

Ribavirin - Therapeutic Use

• Treatment of infections with respiratory syncytial virus (RSV), hepatitis C, Lassa virus.

• Also used for the treatment of flu (not currently recommended by CDC).

Synthetic Guanosine Analogue

Ribavirin - Side Effects & Toxicity

Dose dependent transient anemia, elevated bilirubin.

Synthetic Guanosine Analogue

Adamantanes - Drugs

• Amantadine

• Rimantadine

Many strain of influenza are now resistant, and they are NOT recommended any more by the CDC. This could change in the future based on future re-emergence of susceptible virus.

Adamantanes

Amantadine, Rimantadine - Mechanism of Action

Block the M2 proton ion channel and block replication

active against influenza A ONLY (not influenza B, M2 is absent and replaced by NB).

Adamantanes

Amantadine, Rimantadine - Therapeutic Use

• Prevention and treatment of influenza.

• Amantadine: Parkinson disease (increase in dopamine release?)

Adamantanes

Amantadine, Rimantadine - Side Effects & Toxicity

• Gastrointestinal: nausea, anorexia

• Central nervous system: nervousness, difficulty in concentrating, insomnia, light-headedness

• Serious: marked behavioral changes

- Delirium, hallucinations, agitation, and seizures (alteration of dopamine?)

• Teratogenic

Adamantanes

C) within 48 hours after the onset of the fever

Several colleagues of a 26-year-old medical student living on campus have developed a flu. This student has become sick with fever and muscle ache. You advise this student that the best time to initiate a treatment including oseltamivir is:

A) 48 hours before the onset of the symptom

B) within 48 hours after he/she returns from break

C) within 48 hours after the onset of the fever

D) after a minimum of 48 hours of coughing and/or fever

E) useless if he/she has been vaccinated this year against the flu

F) immediately

COVID-19 – SARS-CoV-2

Protease Inhibitor - Drugs

Ritonavir-Boosted Nirmatrelvir (Paxlovid) (oral)

Ritonavir-Boosted Nirmatrelvir (Paxlovid) - Mechanism of Action

Nirmatrelvir

- 3C-like protease (3CLPRO) inhibitor → inhibit viral replication.

Ritonavir

- A potent inhibitor of cytochrome P450 CYP3A4.

Protease Inhibitor

Ritonavir-Boosted Nirmatrelvir (Paxlovid) - Therapeutic Use

Mild-to-moderate COVID-19 (>12yo) who are at risk of severe illness.

Protease Inhibitor

Ritonavir-Boosted Nirmatrelvir (Paxlovid) - Side Effects & Toxicity

• Dysgeusia (taste disorder that causes an altered sense of taste, where foods taste metallic, sour, bitter, or sweet)

• Diarrhea, hypertension, and myalgia.

• Anaphylaxis, hepatotoxicity

Protease Inhibitor

Ritonavir-Boosted Nirmatrelvir (Paxlovid) - Drug Interaction

Interaction with the CYP3A4 inhibition and metabolism.

- CYP3A4 inducers decrease efficacy of paxlovid.

- CYP3A4 inhibitors increase the risk of toxicity of paxlovid.

- Drugs dependent on CYP3A4 for clearance can accumulate and become toxic.

Protease Inhibitor

Adenosine Triphosphate Analog

Remdesivir (IV)

Remdesivir - Mechanism of Action

Inhibit of viral RNA-dependent RNA polymerase → termination of RNA transcription.

Adenosine Triphosphate Analog

Remdesivir - Therapeutic Use

• Remdesivir was originally investigated as a treatment for Ebola virus but has potential to treat a variety of RNA viruses including SARS-CoV-2.

• Should be started within 7 days of symptoms onset.

Adenosine Triphosphate Analog

Remdesivir - Side Effects & Toxicity

• Nausea, elevated transaminase

• Anaphylaxis

74% eliminated in the urine and 18% eliminated in the feces.

Adenosine Triphosphate Analog

Nucleotide Analogue - Drugs

Molnupiravir (oral)

Molnupiravir - Mechanism of Action

Prodrug hydrolyzed in N4-hydroxycytidine

→ phosphorylated in tissue to the active 5’-triphosphate form.

→ incorporated into the genome of new virions.

→ accumulation of inactivating mutations (viral error catastrophe).

Nucleotide Analogue

Molnupiravir - Therapeutic Use

• Activity against influenza, MERS-CoV, and SARS-CoV-2

• High-risk adults with mild to moderate COVID-19.

Nucleotide Analogue

Molnupiravir - Side Effects

• Diarrhea, nausea, dizziness

• Skin rash, anaphylaxis

Nucleotide Analogue

Monoclonal Antibody - Drugs

Bebtelovimab

(NOT IN USE ANYMORE)

Bebtelovimab - Mechanism of Action

Neutralizing human mAb that binds to the spike protein.

Monoclonal Antibody (NOT IN USE ANYMORE)

Bebtelovimab - Therapeutic Use

Mild to moderate COVID-19 in non-hospitalized adults and pediatric patients aged ≥12 years and weighing ≥40 kg who are at high risk of disease progression.

Monoclonal Antibody (NOT IN USE ANYMORE)

Bebtelovimab - Side Effects

Anaphylaxis

Monoclonal Antibody (NOT IN USE ANYMORE)