Discuss the pharmacology of drugs used in the treatment of bronchial asthma.

Outline:

·        Pathogenesis of asthma.

·        b₂-agonists.

·        Theophylline.

·        Mast cell stabilizers.

·        Antimuscarinics.

·        Corticosteroids.

·        Antihistamines.

·        Leukotriene antagonists.

Suggested Answer:

Asthma is a disease characterized by an increased responsiveness of the trachea and bronchi to various stimuli and characterized by widespread narrowing of airways that changes in severity either spontaneously or as a result of therapy. In Singapore, according to the latest statistics, 8% of the adults and 15% of the children have asthma.

The mechanism underlying the pathogenesis of asthma is multi-factorial, but is largely triggered by mast cell degranulation and the subsequent release of inflammatory mediators such as histamine, prostaglandins, leukotrienes and cytokines which mediate early asthma responses including bronchoconstriction, mucosal edema and mucus secretion and late asthmatic responses including cellular infiltration, epithelial damage and airway hyperreactivity.

Currently available anti-asthmatic drugs can be divided into 2 major classes. One is bronchodilator (relievers) including b₂-agonists, theophylline, and antimuscarinics. The other is anti-inflammatory agents (preventers) including mast cell stabilizers and corticosteroids. New pharmacological approaches of asthma therapy include more specific and potent receptor antagonists such as 2nd generation H₁-receptor antagonists and leukotriene antagonists.

b₂ agonists are the drug of choice for bronchodilator treatment. It is indicated in the prevention and reversal of bronchospasm. Constricted airway relaxes in response to increased cAMP level subsequent to b₂-receptor activation. b₂ agonists have also been shown to stabilize mast cells, decrease microvascular leakiness, increase mucociliary clearance and decrease acetylcholine release from the vagus.

b-adrenergic agonists with varying degree of b-selectivity are available for use in asthma treatment. Inhalation by nebulizer or metered-dose inhaler (MDI) is the preferred route of administration because it produces sufficiently high local concentration of drug in the airways and the least side effects. Oral b₂ agonists benefit patients with noctural asthma. Parenteral b₂ agonists are reserved for severe asthmatic attack. Epinephrine is the drug of choice for anaphylaxis treatment. Short-acting b₂ agonists with a half-life of 1 – 3 h are epinephrine, isoproterenol and isoetharine; medium-acting ones (3 – 6h) are salbutamol, fenoterol and terbutaline; long-acting ones (> 12h) are salmeterol and bambuterol.

Inhaled b₂ agonists are well tolerated with infrequent side effects such as skeletal muscle tremor, tachycardia, hyperglycaemia and hypokalaemia. Oral and parenteral treatment will increase the frequency and intensity of the side effects.

Theophylline is a bronchodilator of moderate potency. It is less effective than b₂ agonists in relaxing constricting airways. Together with its narrow therapeutic range and frequent side effects, the importance of theophylline in asthma therapy his waning. The solubility of theophylline base is low and is much enhanced by forming complexes with ethylenediamine salt, e.g. aminophylline. Sustained-release preparations are available to produce constant drug level for up to 12hrs.

Theophylline has been shown to inhibit phosphodiesterase activity resulting in increased level of cAMP in the airway smooth muscle. It may exert its effect by blocking the adenosine receptor. Theophylline has been shown to inhibit mast cell degranulation, decreased microvascular leakiness and increased mucociliary clearance.

Absorption of theophylline from the GI tract is usually rapid and complete. It is widely distributed and 90% metabolized by liver cytochrome P450 and the rate of metabolism is subject to wide variations. The half-life is 8h. Enzyme inhibition by allopurinol, cimetidine, ciprofloxacin, clarithromycin, enoxacin, erythromycin, propranolol and verapamil increases its plasma concentration while enzyme induction by carbamazepine, isoproterenol, phenobarbitone, phenytoin and rifampicin increases its clearance.

Theophylline is indicated as adjunct maintenance therapy for chronic asthmatics whose symptoms remain poorly controlled by a combination of b₂ agonists and anti-inflammatory agent. Sustained-released formulations of theophylline are also useful for noctural asthma. Theophylline has been shown to improve lung function of chronic obstructive pulmonary disease patient.

Side effects of theophylline are related to plasma concentration which include nervousness, tremor, anxiety, nausea, vomiting, anorexia, abdominal discomfort, cardiac arrhythmias and seizures.

Antimuscarinics produce bronchodilation by competitively blocking muscarinic receptors in the airway. Ipratropium bromide is a quaternary amine, which is poorly absorbed by the GI tract and does not cross blood-brain barrier. It produces a more variable bronchodilating response and is less effective than the b₂ agonists in asthma therapy. Ipratropium is more effective against psychogenic and vagally-induced bronchospasms and  in patients with chronic obstructive pulmonary disease. Side effects are an unpleasant taste and paradoxical bronchospasm.

Mast cell stabilizers such as sodium cromoglycate and nedocromil sodium are extremely insoluble salts and inhalation is the only route of administration for asthma therapy. They act by specifically preventing lung mast cell degranulation and the subsequent release of inflammatory mediators which further reduce activation of eosinophils, neutrophils and macrophages. Mast cell stabilizers are indicated for prophylactic control of mild to moderate asthma. They do not have direct bronchodilating effect and are therefore not used in terminating an existing asthma attack. They can reduce overall bronchial reactivity in 4 weeks but are less effective than inhaled steroid therapy. Common side effects are throat irritation, mouth dryness, and wheezing.

Inhaled steroid is the first line effective adjunctive therapy to b₂ agonists for moderate to severe asthma. They are beclomethasone, budesonide, triamcinolone, flunisolide and fluticasone. Inhaled steroid is the preferred route of administration to minimize systemic side effects. It is the drug of choice for nocturnal asthma. IV steroid is reserved for acute severe attack.

Corticosteroids act by binding to cytosolic steroid receptor leading to certain gene regulations. They increase synthesis of lipocortin, an inhibitor of phospholipase A₂ and to decrease various cytokines production. Steroid treatment also decreases the number of mast cells, macrophages, T lymphocytes and eosinophils in the airway. Inhaled steroid can reduce airway hyper-responsiveness in 2 – 4 weeks. Moreover, corticosteroid increases b₂ receptor density in airway smooth muscle.

Common side effects of inhaled steroids are oropharyngeal candidiasis and dysphonia which can be reduced through the use of aerosol spacer and good oropharyngeal hygiene. In patients who cannot stop taking oral steroid, the use of alternate day oral steroid is preferable to daily treatment.

Second generation of antihistamines are highly specific and potent H₁ receptor antagonists. They are ketotifen, terfenadine, astemizole, loratadine and azelastine. Ketotifen is now being used for prophylactic control of asthma, especially in children. Antihistamines act by competitively blocking the H₁ receptor to decrease airway smooth muscle contraction, vascular permeability and sensory fiber reflex release of neuropeptides. Their major action is to prevent mast cell and basophil degranulation and subsequent release of inflammatory mediators. Common aside effects are minor drowsiness, dry mouth and weight gain.

Zileuton is the first antileukotriene antagonist to become available for chronic treatment of asthmatics, who are not controlled by conventional therapy. The drug inhibits 5-lipoxygenase, thus preventing formation of all leukotrienes, including LTB4, LTC4, LTD4 and LTE4, which cause airway constriction, vasopermeability, mucous hypersecretion, mucosal edema and reduced mucociliary clearance.