Nonsteroidal Anti-asthma Agents

Nonsteroidal Anti-asthma Agents

• These drugs possess anti-inflammatory effects through mechanisms distinct from corticosteroids.
• The drugs described in this chapter act as controllers.

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

• Used for prophylactic management (control) of mild persistent asthma.
• They serve as alternatives to ICS in asthma requiring step 2 care.
• Cromolyn is often used for infants and young children as alternatives to ICS due to safety profiles.
• Anti-LTs can be used in combination with ICS to reduce the steroid dose.

Mechanisms of Inflammation in Asthma

• Asthma is an inflammatory disorder of the airways.
• Allergic stimuli can trigger IgE-mediated mast cell release of mediators of inflammation.
• Release of IgE antibody leads to inflammation and asthma symptoms.
• Airway reactivity can be triggered by nonspecific stimuli.
• Asthma is divided into extrinsic asthma (dependent on allergy like pollen or dust) and intrinsic asthma (caused by factors like stress, cold air, or smoke).

Key Point

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

Three Components of Asthma

• Acute asthma attacks resolve spontaneously or with treatment.
• Hyperresponsiveness of airways to various stimuli is present.
• Persistent inflammation gets worse over time.

Clinical Results of Asthma

• Includes chronic persistent airway inflammation and occasional acute episodes of wheezing and airway obstruction.
• Bronchoconstriction, mucosal swelling, and mucus secretion contribute to airway obstruction.
• Most instances of asthma are primarily an allergic response.

Generation of the Immune Response in Allergic Asthma

• It 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/allergen, mast cells release physiologically active mediators of inflammation.

Immunological (Allergic) 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.
• Accumulation and activation of eosinophils lead to damage of the airway.
• All the above lead to obstruction of airflow in the bronchioles.

Cromolyn (Mast Cell-Stabilizing Agent)

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

Clinical Efficacy of Cromolyn Sodium

• Used in suppressing a cough associated with an angiotensin-converting enzyme (ACE) inhibitor.
• An anti-sickle cell effect may be due to blocking of calcium-activated potassium channels.
• Clinical application is for prophylactic use only, with improvement potentially taking 2-4 weeks.

Antileukotriene Agents: Leukotrienes and Inflammation

• Leukotrienes are potent bronchoconstrictors and stimulate other cells to cause airway edema, mucus secretion, ciliary beat inhibition, and recruitment of other inflammatory cells.
• Biochemical pathways include the 5-lipoxygenase (5-LO) pathway.
• Action involves cysteinyl leukotriene (CysLT) receptors and effects of leukotrienes.

Antileukotriene Agents

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

Zileuton (Zyflo, Zyflo CR)

• Administered orally as 600 mg tablets four times daily.
• It inhibits the 5-LO enzyme.
• Hazards and side effects include headache, abdominal pain, loss of strength, and dyspepsia.
• Liver function should be monitored.
• Interacts with theophylline and warfarin.

Zafirlukast (Accolate)

• Dosage varies: Oral administration; 10 mg BID for children 5-11 years old and 20 mg BID for individuals 12 years old and older.
• It is a leukotriene receptor antagonist.
• Hazards/side effects include headache, infection, nausea, diarrhea, generalized/abdominal pain.

Montelukast (Singulair)

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

Antileukotriene Agents: Mechanism of Action

• Zileuton inhibits the 5-lipoxygenase (5-LO) enzyme to prevent leukotriene production
• Zafirlukast and montelukast antagonize the action of the cysteinyl leukotrienes (CysLTs) at the leukotriene receptor, CysLT1.

Management in Asthma

• Antileukotriene agents have a role in asthma management.
• Agents are used for protection against specific asthma triggers, chronic persistent asthma, and can be used in relation to corticosteroids.

Antileukotriene Agents: Advantages

• They can be administered orally, potentially once daily.
• They are safe, with few side effects to date.
• They are effective in aspirin sensitivity and often in exercise-induced asthma.
• Systemic distribution reaches the entire lung through the circulation.
• They have an additive effect with inhaled steroids.
• May reduce steroid dose or prevent an increase in steroid dose.
• Formulation approved for pediatric dosing (montelukast).

Antileukotriene Agents: Disadvantages

• Anti-inflammatory action limited to one mediator pathway.
• Unknown long-term toxicity.
• 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.
• Generally not useful as monotherapy.

Omalizumab (Xolair)

• Dosage is parenteral, 150/1.2 mL every 2 to 4 weeks.
• Acts as monoclonal antibodies.
• Hazards and side effects can include anaphylaxis and malignancies (rare), injection site reactions, viral infections, URI, and pharyngitis.
• Used for uncontrolled moderate to severe asthma.
• Acts as a prophylactic but does not replace ICS, not optimal as monotherapy.

Respiratory Care Assessment of Nonsteroidal Anti-asthma Agents

• Evaluate the patient for appropriate delivery formulation.
• Ensure there is appropriate use of the delivery device.
• Remember that the agent is a controller, not a rescue agent.
• Use of peak flow meter.
• Long term:
  • Severity of symptoms.
  • Exacerbations, ER visits, missed work/school, PFT.
  • Assess for side effects.