Nonsteroidal Antiasthma Agents

Indications for Nonsteroidal Antiasthma Agents

  • Prophylactic management of mild persistent asthma.
  • Alternatives to ICS in step 2 care.
  • Useful in combination with ICS to reduce steroid dose.

Subgroups of Agents

  • Cromolyn-like drugs (mast cell stabilizers).
  • Antileukotrienes.
  • Monoclonal antibodies.

Identification of Agents

  • Cromolyn-Like Agents:
    • Cromolyn (generic only)
  • Antileukotrienes:
    • Zafirlukast (Accolate)
    • Montelukast (Singulair)
    • Zileuton (Zyflo, Zyflo CR)
  • Monoclonal Antibodies:
    • Omalizumab (Xolair)
    • Benralizumab (Faserna)
    • Mepolizumab (Nucala)
    • Reslizumab (Cinqair)

Mechanisms of Inflammation in Asthma

  • Asthma: inflammatory disorder of airways.
  • Extrinsic asthma: depends on allergy, atopy.
  • Intrinsic asthma: no evidence of sensitization.

Clinical Results of Asthma

  • Chronic airway inflammation with acute episodes.
    • Bronchoconstriction.
    • Mucosal swelling.
    • Mucus secretion.
  • Primarily an allergic response.

Immunologic Response

  • Involves mast cells and IgE.
  • Allergy is a mistaken immune response.

Mast Cell Release

  • Leukotrienes, prostaglandins, proteases, histamines, PAF, cytokines.

Cell-Mediated Immune Mechanism

  • T lymphocytes mediate immune response:
    • Helper/T4 (CD4+) cells (Th1 and Th2 cells).
    • Suppressor/T8 (CD8+) cells.
    • Cytotoxic T cells.
    • Natural killer cells.

Antibody-Mediated Immune Mechanism

  • B lymphocytes.
  • Classes of antibody: IgE, IgG, IgA, IgM, IgD.

Immune Response Generation

  • T lymphocytes interact with antigen.
  • IgE binds to mast cells.
  • Mast cells release mediators of inflammation.

Cascade of Mediators

  • Inflammatory response:
    • Vascular leakage, bronchoconstriction, mucus secretion, mucosal swelling.
  • Eosinophil activation leads to airway damage.

Cromolyn (Mast Cell Stabilizer)

  • Prophylactic agent.
  • Dosage: SVN 20 mg/ampule or 20mg/2mL (1%).
  • Mechanism: Prevents mast cell degranulation.
  • Side effects: Cough, nasal congestion, wheezing.

Leukotrienes and Inflammation

  • Potent bronchoconstrictors causing:
    • Airway edema.
    • Mucus secretion.
    • Ciliary beat inhibition.
    • Inflammatory cell recruitment.

Antileukotriene Agents

  • 5-LO inhibitor: Zileuton.
  • Leukotriene receptor antagonists: Zafirlukast, Montelukast.
  • Monoclonal antibodies: Omalizumab, Benralizumab, Mepolizumab, Reslizumab.

Zileuton

  • Dosage: Oral, 600 mg tablets qid.
  • Mechanism: Inhibits 5-LO enzyme.
  • Side effects: Headache, abdominal pain; monitor liver function; interacts with theophylline and warfarin.

Zafirlukast

  • Dosage: Oral, 10 mg bid (5-11 years), 20 mg bid (12+ years).
  • Mechanism: Leukotriene receptor antagonist.
  • Side effects: Headache, infection, nausea.

Montelukast

  • Dosage: Oral, 4 mg, 5 mg (chewable), 10 mg.
  • Mechanism: Binds to CysLT1 receptor.
  • Side effects: Diarrhea, laryngitis, pharyngitis, nausea.

Role of Antileukotrienes in Asthma Management

  • Protection against asthma triggers.
  • Chronic persistent asthma.
  • Use in relation to corticosteroids.
  • Churg-Strauss syndrome.

Clinical Use Summary of Antileukotrienes

  • Prophylactic controller drugs.
  • Alternative to inhaled corticosteroids or cromolyn.
  • Not optimal as monotherapy.
  • May reduce ICS dose.
  • Safe and effective for wide range of asthma severity.

Advantages of Antileukotrienes

  • Oral administration, possible once-daily dosing.
  • Safe, few side effects.
  • Effective in aspirin sensitivity and exercise-induced asthma.
  • Systemic distribution.
  • Additive effect with inhaled steroids.
  • Pediatric formulation (montelukast).

Disadvantages of Antileukotrienes

  • Limited anti-inflammatory action.
  • Unknown long-term toxicity.
  • Variable response (50-70%).
  • No response predictor.
  • Systemic drug exposure.
  • Not useful as monotherapy.

Monoclonal Antibodies

  • Treat severe asthma, require injection/infusion.
  • Omalizumab: Blocks IgE attachment to mast cells.
  • Benralizumab, mepolizumab, reslizumab: Block IL-5 in eosinophilic asthma.

Monoclonal Antibodies

  • Dosage: Parenteral administration.
  • Mechanism:
    • Omalizumab: Binds to IgE.
    • Benralizumab, mepolizumab, reslizumab: Blocks IL-5.
  • Side effects: Anaphylaxis, injection site reactions, fever, headache.

Clinical Use Summary of Monoclonal Antibodies

  • Prophylactic for severe persistent asthma.
  • Not for acute relief.
  • Not a replacement for ICS.
  • Not optimal as monotherapy.
  • May reduce ICS dose.
  • May reduce rescue agents.

Respiratory Care Assessment

  • Evaluate delivery formulation.
  • Appropriate device use.
  • Controller, not rescue.
  • Use peak flow meter.
  • Long term:
    • Severity of symptoms, exacerbations, ER visits, PFT.
    • Assess for side effects.