Nonsteroidal Anti-Asthma Agents

Three Subgroups of Nonsteroidal Anti-Asthma Agents

• These drug groups have an anti-inflammatory effect through mechanisms different from corticosteroids
• Cromolyn-like drugs (mast cell stabilizers) are used prophylactically to treat the inflammatory response in asthma
• Antileukotrienes block the inflammatory response in asthma
• Monoclonal antibodies are DNA-derived humanized IgG antibodies

Clinical Indications for Nonsteroidal Anti-Asthma Agents

• Used for prophylactic management of mild persistent asthma
• Alternatives to ICS (inhaled corticosteroids) in asthma requiring step 2 care include Cromolyn and Anti-LTs
• As alternatives to ICS in asthma requiring step 2 care, Cromolyn is often used with infants and young children because of safety profiles
• Anti-LTs can be useful in combination with ICS to reduce the steroid dose
• All nonsteroidal anti-asthma drugs described are controllers

Drug Groups in Asthma Management

• Controllers include inhaled corticosteroids, oral corticosteroids, cromolyn sodium, long-acting inhaled and oral β agonists, leukotriene modifiers, sustained-release theophylline, and monoclonal antibodies (omalizumab)
• Relievers include short-acting inhaled β agonists, systemic corticosteroids, and inhaled anticholinergic bronchodilators

Identification of Nonsteroidal Anti-Asthma Agents

• Cromolyn sodium formulation: Small volume nebulizer (SVN) 20 mg/ampule or 20mg/2mL (1%) for adults and children ≥2 yr: 20 mg inhaled four times daily
• Cromolyn sodium formulation: Spray: 5.2 mg per actuation. Available over the counter (OTC) for adults and children ≥2 yr: 1 spray in each nostril, 3-6 times daily, every 4-6 hr
• Cromolyn sodium formulation: Oral concentrate: 100 mg/5 mL for adults and children ≥ 13 yr: 2 ampules four times daily, 30 min before meals and bedtime and children 2-12 yr: 1 ampule four times daily, 30 min before meals and bedtime
• Zafirlukast (Accolate) formulation: Tablets: 10 and 20 mg for adults and children ≥ 12 yr: 20 mg twice daily, without food and children 5-11 yr: 10 mg twice daily
• Montelukast (Singulair) formulation: Tablets: 10 mg and 4- and 5-mg cherry-flavored chewable for adults and children ≥ 15 yr: One 10-mg tablet daily, children 6-14 yr: One 5-mg chewable tablet daily, children 2-5 yr: One 4-mg chewable tablet or one 4-mg packet of granules daily and children 6-23 mo: One 4-mg packet of granules daily
• Zileuton (Zyflo; Zyflo CR) formulation: Tablets: 600 mg for adults and children ≥ 12 yr: One 600-mg tablet four times per day; CR, two tablets twice daily, within 1 hr of morning and evening meals
• Omalizumab (Xolair) formulation: Adults and children ≥ 12 yr: Subcutaneous injection every 4 wk; dose depends on weight and serum IgE level

Mechanisms of Inflammation in Asthma

• Asthma is an inflammatory disorder of the airways
• Allergic stimuli often trigger IgE-mediated mast cell release of mediators of inflammation
• Release of IgE antibody leads to inflammation and asthma symptoms
• Airway reactivity can also be triggered by nonspecific stimuli
• Asthma is divided into two forms: extrinsic and intrinsic
• Extrinsic Asthma: Dependent on allergy (ex: pollen or dust)
• Intrinsic Asthma: Shows no evidence of sensitization to common inhaled allergens and is caused by factors such as stress, cold or dry air, smoke anxiety, infections

Key Point

• The clinical result of asthma is chronic persistent airway inflammation and occasional acute episodes of wheezing and airway obstruction caused by bronchoconstriction, mucosal swelling, and mucus secretion

Three Components of Asthma

• Acute asthma attack: resolves spontaneously or with treatment
• Hyperresponsiveness of airways to various stimuli
• Persistent inflammation that becomes worse

Clinical Results of Asthma

• Chronic persistent airway inflammation and occasional acute episodes of wheezing and airway obstruction
• Asthma involves bronchoconstriction, mucosal swelling, and mucus secretion
• Most instances of asthma are primarily an allergic response

Generation of the Immune Response

• In an allergic asthmatic response
• The immune response is initiated by the interaction of T lymphocytes with an antigen presented by other cells (macrophages or B lymphocytes)
• IgE binds to effector cells such as mast cells
• When activated by subsequent exposure to an antigen or allergen, mast cells release physiologically active mediators of inflammation

Immunological (Allergic) Response

• Allergic response of asthma involves mast cells and IgE
• Mast cells release leukotrienes, prostaglandins, proteases, histamines, platelet-activating factor (PAF) and cytokines

Cascade of Mediators

• The inflammatory response manifests as vascular leakage, bronchoconstriction, mucus secretion, and mucosal swelling
• These symptoms all lead to obstruction of airflow in the bronchioles
• Accumulation and activation of eosinophils lead to damage of the airway

Cromolyn (Mast Cell-Stabilizing) Agent

• Inhaled prophylactic aerosol drug to prevent the inflammatory response in asthma
• Cromolyn sodium (disodium cromoglycate) is administered via SVN 20 mg/ampule or 20mg/2mL (1%)
• It mechanism of action prevents mast cell degranulation
• Side effects include cough, nasal congestion, wheezing, nasal itching, epistaxis, and nose burning

Clinical Efficacy

• Cromolyn is used in suppressing a cough associated with an angiotensin-converting enzyme (ACE) inhibitor
• Cromolyn has anti-sickle cell effects by reduction in sickling possibly due to blocking of calcium-activated potassium channels
• It is for prophylactic use only and may take 2-4 weeks for improvement in patient's symptoms

Antileukotriene Agents

• Leukotrienes and inflammation
• Leukotrienes are potent bronchoconstrictors that stimulate other cells to cause airway edema, mucus secretion, ciliary beat inhibition and recruitment of other inflammatory cells
• Cell sources of leukotrienes are not preformed and stored so they are synthesized after a mechanical, chemical, or physical stimulus activates
• Biochemical pathways is 5-lipoxygenase (5-LO) pathway
• Cysteinyl leukotriene (CysLT) receptors and effects of leukotrienes
• 5-LO inhibitor
  • Zileuton (Zyflo, Zyflo CR)
• Leukotriene receptor antagonists
  • Zafirlukast (Accolate)
  • Montelukast (Singulair)
• Monoclonal antibodies
  • Omalizumab (Xolair)

Zileuton

• Zileuton (Zyflo, Zyflo CR) dosage: oral administration of 600 mg tablets qid
• It mechanism of action inhibits 5-LO enzyme
• Hazards and side effects include headache, abdominal pain, loss of strength, dyspepsia, monitor liver function, and interacts with theophylline and warfarin

Zafirlukast

• Zafirlukast (Accolate) dosage: Oral administration of 10 mg bid for children 5-11 years old and 20 mg bid for 12 years old and older
• Its mechanism of action is to be a leukotriene receptor antagonists
• Hazards and side effects include headache, infection, nausea, diarrhea, generalized and abdominal pain

Montelukast

• Montelukast (Singulair) dosage: Oral administration in 4 mg and 10 mg as well as 5 mg chewables are available
• It mechanism of action is to be a leukotriene receptor antagonists that binds with high affinity and selectivity to CysLT₁ receptor subtype
• Hazards and side effects include diarrhea, laryngitis, pharyngitis, nausea, otits, sinusitis, and viral infection

Management in Asthma

• The role of antileukotriene agents in asthma management include protection against specific asthma triggers, chronic persistent asthma, use in relation to corticosteroids, Churg-Strauss syndrome, respiratory syncytial virus (RSV) ,and a summary of clinical use of antileukotriene therapy

Antileukotriene Agents: Advantages

• Offers oral administration, possible once-daily dosing
• Safe, with few side effects to date
• It is effective in aspirin sensitivity and often in exercise-induced asthma
• Systemic distribution reaches entire lung through the circulation
• Has an additive effect with inhaled steroids
• May reduce steroid dose or prevent an increase in steroid dose
• Approved formulation for pediatric dosing (montelukast)

Antileukotriene Agents: Disadvantages

• Has an antiinflammatory action limited to one mediator pathway
• Unknown long-term toxicity
• Has a variable response-effective in about 50% to 70% of patients
• No predictor of patients who will respond
• Systemic drug exposure, not limited to lung
• Generally not useful as monotherapy

Omalizumab

• Omalizumab (Xolair) dosage is parenteral administration of 150/1.2 mL every 2 to 4 weeks
• The mechanism of action is to block monoclonal antibodies
• Hazards and side effects include anaphylaxis and malignancies (rare), injection site reactions, viral infections, URI, and pharyngitis
• The role of Omalizumab in asthma management is for uncontrolled moderate to severe asthma
• The drug is a prophylactic that does not replace ICS, and is not optimal as monotherapy

Respiratory Care Assessment of Nonsteroidal Anti-Asthma Agents

• Evaluate the patient for appropriate delivery formulation
• Appropriate use of delivery device
• Controller is NOT a rescue agent
• Using a peak flow meter
• Assess for long term symptoms like severity of symptoms, exacerbations, ER visits, missed work/school, and PFT as well as any side effects