Bronchial Asthma and its Treatment

Asthma

Bronchial asthma is a condition characterized by bronchial hyperreactivity and inflammation. The activation of IgE bound to mast cells by the antigen leads to the degranulation of mast cells, resulting in the release of various mediators, such as leukotrienes, prostaglandins, platelet-activating factor, histamine, and protease enzymes. These mediators can cause bronchoconstriction and inflammation, leading to hyperreactivity. Treatment options for bronchial asthma include bronchodilators, drugs inhibiting IgE, stabilizing mast cells, decreasing mediator production, and inhibiting mediators’ actions.

Bronchodilators:

Bronchodilators are the only drugs effective in terminating an acute attack of bronchial asthma. There are three groups of bronchodilators:

Sympathomimetics:

Adrenergic drugs, also known as β2 agonists, act by stimulating GPCRs, resulting in the activation of adenylyl cyclase, which increases cAMP and causes smooth muscle relaxation (bronchodilation). They also decrease mediator release from mast cells and increase mucociliary transport by increasing ciliary activity. β2 agonists delivered via inhalation are the fastest acting. Adrenaline and isoprenaline produce bronchodilation quickly, whereas ephedrine has a slower onset of action. Short-acting β2 agonists, such as Salbutamol, Levalbuterol, pirbuterol, terbutaline, isoetharine, bitolterol, fenoterol, and procaterol, are used to abort an attack of acute asthma due to their fast action by inhalation. Long-acting β2 agonists, such as salmeterol, formoterol, arformoterol, carmoterol, olodaterol, and indacterol, are preferred for prophylaxis due to their delayed or long-lasting action. Muscle tremors and tachycardia are the major side effects of β2 agonists. Salbutamol can cause intracellular movement of potassium from the blood, leading to hypokalemia.

GPCR: G Protein Coupled Receptor; 
PDE: Phosphodiesterase; 
AC: Adenylyl Cyclase; 
PKA: Protein Kinase (activated); 
MLCK: Myosin Light Chain Kinase.

Anticholinergics:

• These drugs mainly dilate large airways and are slower-acting bronchodilators compared to sympathomimetics.
• They are more effective for COPD than bronchial asthma.
• Ipratropium, tiotropium, and umeclidinium are anticholinergic drugs that can only be used through inhalation.
• Tiotropium and umeclidinium are longer-acting than ipratropium.
• Tiotropium is used for long-term prophylaxis of bronchial asthma in combination with corticosteroids, while umeclidinium is used for maintenance treatment of airflow obstruction in COPD.
• These drugs are the preferred bronchodilators in patients with bronchial asthma on β-blocker therapy.

Methylxanthines:

• This group includes caffeine, theophylline, and theobromine.
• Methylxanthines block adenosine receptors and inhibit enzyme phosphodiesterase.
• At high doses, they can cause the release of Ca++ from the sarcoplasmic reticulum in skeletal and cardiac muscles.
• These drugs are CNS stimulants and can cause tremors, delirium, and convulsions at toxic doses.
• Theophylline is a potent vasodilator and can cause hypotension, leading to reflex tachycardia.
• Caffeine can cause vasoconstriction of cranial vessels and dilation of other blood vessels.
• Methylxanthines cause slow but sustained bronchodilation, making them effective in bronchial asthma.
• Theophylline is given orally, and aminophylline is administered by slow i.v. Infusion.
• Theophylline has a narrow therapeutic index and toxic symptoms are related to GIT, CNS, and CVS.
• Smoking and enzyme inducers decrease plasma levels of theophylline, while enzyme inhibitors predispose to toxicity.
• Clearance of theophylline is slower in elderly, premature infants, and neonates, while children are more liable to develop CNS toxicity.

Interactions of Theophylline:

• Dose reduction is required in the elderly, patients with CHF, pneumonia, and hepatic insufficiency, and with enzyme inhibitors like ciprofloxacin, cimetidine, and erythromycin.
• Dose should be increased in smokers and children and with enzyme inducers like rifampicin and phenobarbitone.
• Theophylline can also be used to reduce the frequency of episodes of apnea in premature infants.
• PDE-4 inhibitors like roflumilast, cilomilast, and tofimilast are being tried for bronchial asthma.

Drug Inhibiting IgE Action: Omalizumab

Omalizumab is a monoclonal antibody that targets circulating IgE and is used to prevent bronchial asthma attacks in patients who do not respond to a combination of long-acting β2 agonists and high-dose inhaled steroids. It is administered subcutaneously.

Mast Cell Stabilizers:

Sodium Cromoglycate, Nedocromil, and Ketotifen Sodium cromoglycate and nedocromil prevent the degranulation of mast cells by trigger stimuli and are used only for prophylaxis of bronchial asthma. They are administered via inhalation. Ketotifen has antihistaminic action in addition to its mast cell stabilizing property and is specifically indicated for patients with multiple disorders such as atopic dermatitis, perennial rhinitis, and conjunctivitis.

Drugs Decreasing the Action of LTs:

Corticosteroids, Lipoxygenase Inhibitors, and LT Receptor Antagonists Corticosteroids are potent anti-inflammatory drugs that decrease bronchial hyperreactivity and mucosal oedema. They interfere with the generation of LTs by inhibiting the enzyme phospholipase A2. Inhaled steroids such as beclomethasone, budesonide, mometasone, fluticasone, flunisolide, and triamcinolone have little systemic activity after inhalation but may cause hoarseness of voice and oropharyngeal candidiasis. Lipooxygenase inhibitors such as zileuton inhibit the synthesis of LTB4 and LTD4. LT receptor antagonists such as montelukast and zafirlukast inhibit the bronchoconstrictor action of LTs at the cys LT1 receptor.

Monoclonal Antibodies Against IL-5:

Mepolizumab and Reslizumab Mepolizumab and reslizumab are monoclonal antibodies that inhibit the recruitment of eosinophils by targeting IL-5.

Special Types of Asthma

Exercise-induced asthma typically begins after exercise and recovers spontaneously within 30 minutes. Treatment is usually not required but can be done with Short-acting beta-agonists (SABA). Regular treatment with inhaled corticosteroids can prevent exercise-induced asthma. Anti-leukotrienes, mast cell stabilizers, and β2 agonists can also be used for this function.

Aspirin-induced asthma (AIA) is triggered by aspirin and is caused by the conversion of arachidonic acid to 15-Hydroxyeicosatetraenoic acid (15-HETE). Treatment should include combination therapy with inhaled corticosteroids, beta(2)-adrenoceptor agonists and LT modifiers. Furthermore, recently developed inhibitors of COX-2 may be safer in patients with AIA.

Brittle Asthma is a very severe form of asthma resistant to inhalational beta 2 agonists. Subcutaneous terbutaline is the DOC for Type 1 brittle asthma, and subcutaneous adrenaline is the DOC for Type 2 brittle asthma.

Aerosol Delivery of Drugs: Administration of Anti-Asthma Drugs via Inhalation Route

Four Classes of Anti-Asthma Drugs

Four classes of anti-asthma drugs, namely β2 agonists, anticholinergics, sodium cromoglycate, and steroids, can be administered by the inhalational route. The objective of this route is to decrease systemic side effects of these drugs.

Aerosols Using Drug in Solution

Two types of aerosols can be used to administer anti-asthma drugs in solution form, namely metered dose inhaler (MDI) and nebulizers.

Metered Dose Inhaler (MDI)

MDIs use chlorofluorocarbons or hydrofluoroalkane propellants to deliver the drug in spray form. However, chlorofluorocarbons are less preferred due to their effect on the ozone layer. The disadvantage of MDIs is that they require proper coordination between deep inspiration and inhaler activation, which many patients (especially children and the elderly) are unable to do. The use of a spacer decreases the requirement for this coordination.

Nebulizer

Nebulizers produce a mist of drug solution generated by pressurized air. They do not require hand-inspiration coordination and are therefore preferred in children, the elderly, and very severe episodes of asthma.

Aerosols Using Drugs as Dry Powder

Aerosols using drugs as dry powder include spinhaler and rotahaler. The disadvantage of these devices is that they require high-velocity inspiration, making them unsuitable for children, the elderly, and very sick patients. Additionally, they can cause irritation of the air passage, leading to cough and bronchoconstriction.

Disclaimer: This article is for informational purposes only and should not be taken as medical advice. Always consult with a healthcare professional before making any decisions related to medication or treatment.