Nonsteroidal Antiasthma Agents

• Nonsteroidal antiasthma agents have an anti-inflammatory effect through mechanisms different from corticosteroids. These drugs are controllers, not rescue medications.

Three Subgroups of Agents

• Cromolyn-like drugs (mast cell stabilizers) are used prophylactically to treat the inflammatory response in asthma.
• Antileukotrienes (anti-LTs) block the inflammatory response in asthma.
• Monoclonal antibodies are DNA-derived humanized IgG antibodies.

Clinical Indications for Nonsteroidal Antiasthma Agents

• These agents are for prophylactic management of mild, persistent asthma.
• Cromolyn and anti-LTs serve as alternatives to inhaled corticosteroids (ICS) in asthma requiring step 2 care.
• Cromolyn is often used with infants and young children as alternatives to ICS in asthma requiring step 2 care because of safety profiles of ICS
• Anti-LTs can be useful in combination with ICS to reduce the steroid dose.

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.
• The release of IgE antibody leads to inflammation and asthma symptoms.
• Airway reactivity can also be triggered by nonspecific stimuli.

Two Forms of Asthma

• Extrinsic asthma is dependent on allergy, such as pollen or dust.
• Intrinsic asthma shows no evidence of sensitization to common inhaled allergens, caused by factors such as stress, cold or dry air, smoke anxiety, infections.

Clinical Results of Asthma

• Chronic persistent airway inflammation and occasional acute episodes of wheezing and airway obstruction occur.
• This includes 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, interaction of T lymphocytes with an antigen initiate the process. The antigen is presented by macrophages or B lymphocytes.
• IgE binds to effector cells like mast cells.
• When activated by subsequent exposure to an antigen or allergen, mast cells release physiologically active mediators of inflammation.

Immunological (Allergic) Response

• This response 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 factors lead to obstruction of airflow in the bronchioles.
• Accumulation and activation of eosinophils lead to damage of the airway.

Cromolyn (Mast Cell-Stabilizing) Agents

• This is an inhaled prophylactic aerosol drug, preventing the inflammatory response in asthma.
• Cromolyn sodium is also known as disodium cromoglycate.

Cromolyn Dosage and Administration

• Administered via small volume nebulizer (SVN) at 20 mg/ampule or 20mg/2mL (1%).

Cromolyn Mechanism of Action

• Prevents mast cell degranulation.

Cromolyn Side Effects

• Side effects include cough, nasal congestion, wheezing, nasal itching, epistaxis, and nose burning.

Cromolyn Clinical Efficacy

• Suppresses coughs associated with angiotensin-converting enzyme (ACE) inhibitors.
• It has anti-sickle cell effects and reduces 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 are potent bronchoconstrictors and stimulate other cells, causing airway edema, mucus secretion, ciliary beat inhibition, and recruitment of other inflammatory cells.
• Leukotrienes are synthesized after a mechanical, chemical, or physical stimulus activates the 5-lipoxygenase (5-LO) pathway.

Leukotriene Production

• Cysteinyl leukotriene (CysLT) receptors and effects of leukotrienes

Antileukotriene Types

• 5-LO inhibitor: Zileuton (Zyflo, Zyflo CR)
• Leukotriene receptor antagonists: Zafirlukast (Accolate) and Montelukast (Singulair)
• Monoclonal antibodies: Omalizumab (Xolair)

Zileuton

• Inhibits the 5-LO enzyme.
• Oral administration of 600 mg tablets four times daily.
• Side effects include headache, abdominal pain, loss of strength, and dyspepsia.
• Monitor liver function due to potential interactions with theophylline and warfarin.

Zafirlukast

• Leukotriene receptor antagonist administered orally.
• Dosage of 10 mg twice daily for children 5-11 years old, and 20 mg twice daily for those 12 years and older.
• Side effects include headache, infection, nausea, diarrhea, generalized and abdominal pain.

Montelukast

• Is a leukotriene receptor antagonists
• Binds with high affinity and selectivity to CysLT1 receptor subtype
• Oral administration with 4 mg and 10 mg tablets, and 5 mg chewable tablets.
• Side effects include diarrhea, laryngitis, pharyngitis, nausea, otitis, sinusitis, and viral infection.

Management in Asthma

• Role of antileukotriene agents includes protection against specific asthma triggers and managing chronic persistent asthma.
• Consider antileukotrienes in relation to corticosteroids.
• Note possible association with Churg-Strauss syndrome and efficacy against respiratory syncytial virus (RSV).

Antileukotriene Agents: Advantages

• Oral administration, with possible once-daily dosing.
• Safe, with few side effects.
• Effective in aspirin sensitivity and often in exercise-induced asthma.
• Systemic distribution reaches entire lung through the circulation.
• Additive effect with inhaled steroids, potentially reducing steroid dose.
• Formulation approved for pediatric dosing (montelukast).

Antileukotriene Agents: Disadvantages

• Antiinflammatory action is limited to one mediator pathway.
• Long-term toxicity is unknown.
• Variable response; effective in about 50% to 70% of patients.
• No predictor of patients who will respond.
• Systemic drug exposure, not limited to the lung.

Omalizumab

• It's a monoclonal antibody.
• Administered parenterally at 150/1.2 mL every 2 to 4 weeks.
• Hazards and rare side effects include anaphylaxis and malignancies but also injection site reactions, viral infections, URI, and pharyngitis.
• Used in uncontrolled moderate to severe asthma.
• It's a prophylactic and does not replace ICS, and is not optimal as monotherapy.

Respiratory Care Assessment of Nonsteroidal Antiasthma Agents

• Evaluate the patient for appropriate delivery formulation and correct use of the delivery device.
• This is a controller medication, not a rescue agent.
• Use a peak flow meter.
• Assess long-term severity of symptoms, exacerbations, ER visits, missed work/school, and pulmonary function tests (PFT).
• Assess for side effects, with the understanding that these agents are generally not useful as monotherapy.