Antivirals for Influenza

Antiviral agents against influenza are important in preventing and treating influenza infection. Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza is often self-limited, but high-risk populations suffer significant morbidity and mortality from the illness. Different classes of drugs act on the influenza virus Influenza virus Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza. Neuraminidase inhibitors include oseltamivir (oral), zanamivir (inhalation) and peramivir (IV); these drugs act by inhibiting neuraminidase, the enzyme that cleaves off the new virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview particle. By blocking the enzymatic effect, further release of progeny virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview to nearby respiratory cells is reduced. Baloxavir, a selective inhibitor of influenza cap-dependent endonuclease, inhibits viral mRNA synthesis. Both neuraminidase inhibitors and baloxavir have activity against influenzas A and B. Adamantanes, or M2 inhibitors, include amantadine and rimantadine, which are active against influenza A but are not often used owing to resistance.

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Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

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Overview

Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza

  • Virus strains are classified by the core proteins (A, B, C).
  • Seasonal influenza is an illness caused by influenza A or B virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview.
  • Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza is often a self-limited infection, but those at risk for complications can have significant morbidity and mortality.
  • Antiviral drugs are available for prevention and treatment of influenza.

Mechanism of invasion

  • A viral particle attaches its hemagglutinin (HA) spikes to sialic acid–containing receptors on the surface of respiratory epithelial cells.
    • The viral particle is internalized via receptor-mediated endocytosis. 
    • The virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview uncoats via the action of M2 protein, allowing an influx of hydrogen particles. 
    • The viral RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure then moves into the nucleus of the cell → replication → messenger RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation into new viral proteins.
  • Viral particles are brought to the surface of the cell and assembled into virions. 
  • Hemagglutinin again binds to the sialic acid–containing receptors. 
  • Neuraminidase then cleaves the new viral particle off of the respiratory epithelial cell → infection of nearby cells.

Classes of antiinfluenza agents

  • Active against influenza A and B:
    • Neuraminidase inhibitors:
      • Oseltamivir
      • Peramivir
      • Zanamivir
    • Selective inhibitor of influenza cap-dependent endonuclease: baloxavir
  • Active against influenza A: adamantanes (amantadine, rimantadine)

Neuraminidase Inhibitors

Chemistry and pharmacodynamics

  • Analogues of sialic acid 
  • Mechanism of action: 
    • Inhibits influenza neuraminidase by causing a conformational change in the enzyme
    • Neuraminidase cleaves off the virion from the sialic acid–containing receptor: 
      • This act is important to release the virion from the infected cells.
      • Without the enzymatic step, viral aggregation occurs at the cell surface.
    • Inhibition of neuraminidase → ↓ viral spread in the respiratory tract
  • Mechanism of resistance:
    • Mutations in neuraminidase
    • Mutations in hemagglutinin

Pharmacokinetics

Table: Pharmacokinetics of neuraminidase inhibitors
Category Oseltamivir Peramivir Zanamivir
Absorption
  • Oral
  • Absorbed rapidly
  • Bioavailability not decreased by food
  • IV
  • Single 600-mg dose
Inhalation
Distribution
  • Low plasma protein binding
  • Half-life: 6–10 hours
  • 30% protein-bound
  • Half-life: 20 hours
  • On inhalation, drug reaches oropharynx and lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs
  • Half-life: 2–3 hours
Metabolism No significant metabolism
Excretion
  • Renal
  • Unchanged in urine
  • Requires dose adjustment in renal insufficiency
  • Renal
  • Unchanged in urine
  • Requires dose adjustment in renal insufficiency
Up to 15% absorbed and excreted in the urine

Indications

  • Prophylaxis against seasonal influenza: oseltamivir, zanamivir
  • Treatment of influenza (≤ 48 hours after symptom onset)

Adverse effects and contraindications

Table: Adverse effects and contraindications of neuraminidase inhibitors
Oseltamivir Peramivir Zanamivir
Adverse effects
  • Nausea, vomiting
  • Headache
  • Hallucination, delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium, confusion
  • Hypersensitivity reactions ( SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, EM)
  • Renal and hepatic function abnormalities
  • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
  • Hypersensitivity reactions ( SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome, EM)
  • Hallucinations, delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium
  • Sore throat
  • Cough, bronchospasm
Contraindications
  • Hypersensitivity to oseltamivir
  • Precaution with cardiovascular, hepatic and renal diseases
  • Hypersensitivity to peramivir
  • Precautions with renal disease
  • Hypersensitivity to zanamivir
  • Precautions with COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD) and asthma Asthma Asthma is a chronic inflammatory respiratory condition characterized by bronchial hyperresponsiveness and airflow obstruction. The disease is believed to result from the complex interaction of host and environmental factors that increase disease predisposition, with inflammation causing symptoms and structural changes. Patients typically present with wheezing, cough, and dyspnea. Asthma
COPD COPD Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD): chronic obstructive pulmonary disease Chronic obstructive pulmonary disease Chronic obstructive pulmonary disease (COPD) is a lung disease characterized by progressive, largely irreversible airflow obstruction. The condition usually presents in middle-aged or elderly persons with a history of cigarette smoking. Signs and symptoms include prolonged expiration, wheezing, diminished breath sounds, progressive dyspnea, and chronic cough. Chronic Obstructive Pulmonary Disease (COPD)
EM: erythema multiforme Erythema multiforme Erythema multiforme (EM) is an acute hypersensitivity reaction characterized by targetoid skin lesions with multiple rings and dusky centers. Lesions may be accompanied by systemic symptoms (e.g., fever) and mucosal lesions (e.g., bullae). Erythema Multiforme
SJS SJS Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome: Stevens-Johnson syndrome Stevens-Johnson syndrome Stevens-Johnson syndrome (SJS) is a cutaneous, immune-mediated hypersensitivity reaction that is commonly triggered by medications, including antiepileptics and antibiotics. The condition runs on a spectrum with toxic epidermal necrolysis (TEN) based on the amount of body surface area (BSA) involved. Stevens-Johnson Syndrome

Selective Inhibitor of Cap-Dependent Endonuclease

Chemistry and pharmacodynamics

  • Baloxavir marboxil (BXM): prodrug that undergoes hydrolysis to become baloxavir acid (BXA), the active form.
  • Mechanism of action: 
    • Activity against an earlier part of viral replication (compared to neuraminidase inhibitors)
    • Inhibits the enzyme, virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview cap-dependent endonuclease (CEN):
      • An enzyme in the influenza virus Influenza virus Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza polymerase, CEN facilitates the cap-snatching process during viral mRNA synthesis.
      • Inhibiting CEN → ↓ transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription
    • Hence, inhibits viral replication 

Pharmacokinetics

  • Absorption: 
    • Available in oral form 
    • Avoid intake with dairy products, calcium-fortified beverages, and antacids.
  • Distribution: 
    • Protein binding: 94%
    • Long half-life: 80 hours
  • Metabolism: metabolized by UGT1A3 and CYP3A4 
  • Excretion: biliary excretion

Indications

  • Acute uncomplicated influenza (≤ 48 hours after symptom onset)
  • Postexposure prophylaxis for influenza 

Adverse effects and contraindications

  • Adverse effects:
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Rash
    • Hypersensitivity reactions
    • Delirium, hallucination
  • Contraindications: hypersensitivity to baloxavir

Adamantanes

Chemistry and pharmacodynamics

  • Amantadine (1-aminoadamantane hydrochloride) and rimantadine (amantadine derivative): tricyclic amines
  • Mechanism of action (M2 inhibitor): 
    • Targets M2 ion channel protein, which allows for hydrogen ion influx, and facilitates viral uncoating
    • In effect, prevents viral replication
  • Mechanism of resistance: mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations involving RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure sequence that encodes for the M2 protein (transmembrane domain)

Pharmacokinetics

Table: Pharmacokinetics of adamantanes
Category Amantadine Rimantadine
Absorption Good oral bioavailability Good oral bioavailability
Distribution
  • Half-life: 12–18 hours
  • 67% protein-bound
  • Half-life: 24–36 hours
  • 40% protein-bound
Metabolism No significant metabolism Undergoes hepatic metabolism
Excretion Renal (excreted unchanged) Renal

Indications

  • Influenza Influenza Influenza viruses are members of the Orthomyxoviridae family and the causative organisms of influenza, a highly contagious febrile respiratory disease. There are 3 primary influenza viruses (A, B, and C) and various subtypes, which are classified based on their virulent surface antigens, hemagglutinin (HA) and neuraminidase (NA). Influenza typically presents with a fever, myalgia, headache, and symptoms of an upper respiratory infection. Influenza Viruses/Influenza A (but role limited owing to widespread resistance)
  • Drug-induced parkinsonism syndromes
  • Parkinson disease

Adverse effects and contraindications

  • Adverse effects:
    • Neuropsychiatric:
      • Anxiety
      • Insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia
      • Confusion
      • Hallucination
      • Seizure
    • Amantadine: anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs effect (dry mouth, mydriasis)
  • Contraindications:
    • Hypersensitivity to adamantanes
    • Amantadine is contraindicated in angle closure glaucoma Glaucoma Glaucoma is an optic neuropathy characterized by typical visual field defects and optic nerve atrophy seen as optic disc cupping on examination. The acute form of glaucoma is a medical emergency. Glaucoma is often, but not always, caused by increased intraocular pressure (IOP). Glaucoma ( anticholinergic Anticholinergic Anticholinergic drugs block the effect of the neurotransmitter acetylcholine at the muscarinic receptors in the central and peripheral nervous systems. Anticholinergic agents inhibit the parasympathetic nervous system, resulting in effects on the smooth muscle in the respiratory tract, vascular system, urinary tract, GI tract, and pupils of the eyes. Anticholinergic Drugs effect).
  • Precautions in psychosis, seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures, hepatic and renal impairment

Comparison of Antiviral Agents for Influenza

Table: Comparison of antiviral agents for influenza
Neuraminidase inhibitors Baloxavir Amantadine
Mechanism of action Inhibits neuraminidase, preventing spread to uninfected cells Endonuclease inhibitor, preventing mRNA synthesis Prevents M2 channel activity, inhibiting viral uncoating
Absorption
  • Oral
  • IV
  • Inhalation
Oral Oral
Elimination Renal Biliary excretion Renal
Indications Prevention and treatment of influenzas A and B Prevention and treatment of influenzas A and B Treatment and prophylaxis of influenza A (use limited owing to resistance)
Notable adverse effects
  • Oseltamivir: nausea, vomiting
  • Zanamivir: sore throat, cough
  • Peramivir: diarrhea
Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea CNS side effects

References

  1. Acosta, E.P. (2017). Antiviral agents (nonretroviral). Chapter 62 of Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172486085
  2. ​​Safrin, S. (2021). Antiviral agents. Chapter 49 of Katzung, B.G., & Vanderah, T.W. (Eds.), Basic & Clinical Pharmacology, 15th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2988&sectionid=250602382
  3. Zachary, K.C. (2020). Pharmacology of antiviral drugs for influenza. UpToDate. Retrieved September 1, 2021, from https://www.uptodate.com/contents/pharmacology-of-antiviral-drugs-for-influenza#H116594844 
  4. Zachary, K.C. (2021). Treatment of seasonal influenza. UpToDate. Retrieved September 1, 2021, from https://www.uptodate.com/contents/treatment-of-seasonal-influenza-in-adults

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