Physiological Pharmaceutics

244 Physiological PharmaceuticsAdrenocorticosteroidsAdrenocorticosteroids (generally simply termed ‘steroids’) inhibit the inflammatory processby mechanisms which are poorly understood. It is possible that they may includeinterference with prostanoid formation and the inhibition of the cellular signaling betweencells involved in the immune response. They prevent not only the early inflammatoryphenomena such as oedema and increased blood flow, but also later effects such asphagocyte activity and capillary proliferation. The drugs used, e.g. beclomethasonedipropionate, betamethasone and budesonide, exert a topical effect in the lungs but aregenerally inactivated when swallowed. The doses required are low (400–800 µg daily),resulting in low plasma concentrations thereby minimizing systemic side effects. Moderntreatment of asthma in childhood favours the use of small doses of steroid to keepinflammatory processes suppressed.Leukotriene inhibitorsThe cysteinyl leukotrienes (LTC 4, LTD 4, LTE 4) are products of arachidonic acid metabolismand are released from various cells, including mast cells and eosinophils. These eicosanoidsbind to cysteinyl leukotriene receptors (CysLT) found in the human airway. Cysteinylleukotrienes and leukotriene receptor occupation have been correlated with thepathophysiology of asthma, including airway edema, smooth muscle contraction, andaltered cellular activity associated with the inflammatory process, which contribute to thesigns and symptoms of asthma. Singulair (Montelukast sodium) is an orally activecompound that binds with high affinity and selectivity to the CysLT 1receptor (in preferenceto other pharmacologically important airway receptors, such as the prostanoid, cholinergic,or ß-adrenergic receptor). Montelukast sodium inhibits physiologic actions of LTD 4at theCysLT 1receptor without any agonist activity.Other bronchodilating agentsOther bronchodilators include anticholinergic drugs which act by blocking the muscarinicaction of acetylcholine, and thus preventing bronchial muscles from being constricted viainnervation. Since reflex bronchoconstriction may be mediated through the stimulation ofpulmonary sensory fibres, there is much interest in inhibition of this pathway as a methodof controlling asthma. A quaternary derivative of atropine, ipratropium bromide, iscommonly delivered by nebulizer and has been successful in the control of acute asthma.Methyl-xanthines (for example theophylline and aminophylline) have been used for manyyears in the USA as a first line treatment for asthma, but theophylline cannot be inhaled andmust be injected, as it is an irritant to the lung. Methyl-xanthines are however less effectivethan ß 2-receptor agonists administered by aerosol 41 .MucolyticsVarious pharmacological agents alter the rheological function of mucus, which has beenexploited particularly to thin mucus to aid in its clearance from the bronchi. Water, salineand mucolytic aerosols are important as aids in the removal of the bronchial secretionswhich accumulate in chronic bronchitis, bronchiectasis, cystic fibrosis and asthma.Inorganic and organic iodides act directly on mucus and are used therapeutically. Additionof potassium iodide reduces the apparent viscosity, presumably due to an effect of the halideon the configuration of the glycoprotein 42 .Traditionally aerosols have been used in an attempt to liquefy secretions and inducesputum clearance, either by mucociliary action or coughing. Inhalation of aerosolized waterdoes liquefy and clear secretions 43 . It can however be an irritant and cause bronchoconstrictionin asthmatics 44 . Saline aerosol is bland and may well improve mucociliary