Beta receptor agonists

When an asthmatic attack has been triggered by histamine at H1 receptors, the objective is to redilate the bronchi with a E2 receptor agonist in the upper and mid airways. These cause relaxation of bronchial smooth muscle and thus allows the airway to dilate. These materials are mainstays of the treatment of asthma, as well as a variety of other pulmonary diseases in which it is desired to decrease airway resistance. They provide rapid symptomatic relief where the predominant cause of reduced airway calibre is bronchial smooth muscle contraction, or they may be used as regular maintenance therapy to avert symptoms. Their preventative effect is particularly seen in the suppression of exercise-induced asthma41. Beta receptor agonists also increase the rate of mucociliary clearance, known to be abnormally slow in patients with obstructive airways disease. Inhaled E2 receptor agonists are less effective if airway inflammation is a major factor in the disease. The oldest member of the class is salbutamol (called albuterol in the U.S.), and a range of other materials are available, including metaproterenol, fenoterol and terbutaline.

Adrenocorticosteroids

Adrenocorticosteroids (generally simply termed 'steroids') inhibit the inflammatory process by mechanisms which are poorly understood. It is possible that they may include interference with prostanoid formation and the inhibition of the cellular signaling between cells involved in the immune response. They prevent not only the early inflammatory phenomena such as oedema and increased blood flow, but also later effects such as phagocyte activity and capillary proliferation. The drugs used, e.g. beclomethasone dipropionate, betamethasone and budesonide, exert a topical effect in the lungs but are generally inactivated when swallowed. The doses required are low (400-800 pg daily), resulting in low plasma concentrations thereby minimizing systemic side effects. Modern treatment of asthma in childhood favours the use of small doses of steroid to keep inflammatory processes suppressed.

Leukotriene inhibitors

The cysteinyl leukotrienes (LTC4, LTD4, LTE4) are products of arachidonic acid metabolism and are released from various cells, including mast cells and eosinophils. These eicosanoids bind to cysteinyl leukotriene receptors (CysLT) found in the human airway. Cysteinyl leukotrienes and leukotriene receptor occupation have been correlated with the pathophysiology of asthma, including airway edema, smooth muscle contraction, and altered cellular activity associated with the inflammatory process, which contribute to the signs and symptoms of asthma. Singulair (Montelukast sodium) is an orally active compound that binds with high affinity and selectivity to the CysLTj receptor (in preference to other pharmacologically important airway receptors, such as the prostanoid, cholinergic, or E-adrenergic receptor). Montelukast sodium inhibits physiologic actions of LTD4 at the CysLTj receptor without any agonist activity.

Other bronchodilating agents

Other bronchodilators include anticholinergic drugs which act by blocking the muscarinic action of acetylcholine, and thus preventing bronchial muscles from being constricted via innervation. Since reflex bronchoconstriction may be mediated through the stimulation of pulmonary sensory fibres, there is much interest in inhibition of this pathway as a method of controlling asthma. A quaternary derivative of atropine, ipratropium bromide, is commonly delivered by nebulizer and has been successful in the control of acute asthma. Methyl-xanthines (for example theophylline and aminophylline) have been used for many years in the USA as a first line treatment for asthma, but theophylline cannot be inhaled and must be injected, as it is an irritant to the lung. Methyl-xanthines are however less effective than E2-receptor agonists administered by aerosol41.

Mucolytics

Various pharmacological agents alter the rheological function of mucus, which has been exploited particularly to thin mucus to aid in its clearance from the bronchi. Water, saline and mucolytic aerosols are important as aids in the removal of the bronchial secretions which accumulate in chronic bronchitis, bronchiectasis, cystic fibrosis and asthma. Inorganic and organic iodides act directly on mucus and are used therapeutically. Addition of potassium iodide reduces the apparent viscosity, presumably due to an effect of the halide on the configuration of the glycoprotein42.

Traditionally aerosols have been used in an attempt to liquefy secretions and induce sputum clearance, either by mucociliary action or coughing. Inhalation of aerosolized water does liquefy and clear secretions43. It can however be an irritant and cause broncho-constriction in asthmatics44. Saline aerosol is bland and may well improve mucociliary clearance, particularly in a hypertonic concentration where it facilitates expectoration41. It may liquefy sputum by enhancing chloride (and water) flux across the bronchial mucosa45. Mucolytic aerosols are also widely used; N-acetyl-cysteine (Airbron) being best known in Britain, and 2 mercapto-ethane ethane sulphonate (Mistabron) in Europe. Mistabron appears to enhance mucociliary clearance in patients with chronic bronchitis46. Other molecules such as DL-penicillamine and dithiothreitol act on the sulphhydryl bonds in mucus causing thinning, though nebulization of dithiothreitol causes intense irritation and is therefore unsuitable for clinical exploitation47.

On rare occasions antihistamines and antibiotics may by given as aerosols. Antibiotics are given because in asthmatics the mucus thickens and "plugs" the bronchiole. This plug may then become a focus for infection. Some antibiotics, notably the tetracyclines48, interact with mucus glycoprotein causing thickening. The exudates formed during inflammation and disease probably cause a mucus thickening by physical entrapment of mucus with biopolymers such as albumin, IgG, or IgA leading to changes in mucus viscoelasticity.

Systemically-absorbed drugs

As has been mentioned, the pulmonary route has been used to achieve systemic delivery. A product containing ergotamine tartrate is available as an aerosolized dosage inhaler (360 pg per dose) and has the advantage of avoiding the delay in drug absorption due to gastric stasis associated with migraine. In vaccine delivery, aerosol administration of para-influenza Type 2 vaccine has been found to be more effective than subcutaneous injection49). Penicillin reaches the bloodstream in therapeutic quantities after pulmonary delivery, but kanamycin is poorly absorbed from the lung so can only be used for local drug delivery.

The deep lung has been investigated as a site for delivering large molecule proteins and peptides as it is believed that the morphology of the alveolar epithelium predisposes it to absorb large molecule compounds. The pulmonary route has been explored for the delivery of insulin and human growth hormone, and absorption was found to be greatest in those subjects with the highest penetration index, implying that deep central deposition is a prerequisite for absorption50 51. The pharmacokinetics of these materials, which have extremely short intravenous half-lives of 3 and 40 minutes respectively, were dominated by the slower limiting pulmonary absorption rate.

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