Asthmatic State – an overview | ScienceDirect Topics

Beta-2 adrenergic receptor agonistsBeta-2 adrenergic receptor agonists activate adenylate cyclase and convert ATP into cyclic AMP. In airway smooth muscle cells an elevation in cyclic AMP causes relaxation. Therefore, these drugs are bronchodilators. A bronchodilatory response may be produced during the early and late phases of an acute exacerbation. Beta-2 adrenergic receptor agonists also inhibit the release of mast cell mediators, but this effect does not inhibit the development of the late phase response. These drugs do not generally produce an anti-inflammatory effect, even though elevations in cyclic AMP generally inhibit the release of pro-inflammatory mediators. Beta-2 adrenergic receptor agonists are inhaled for symptomatic relief of bronchospasm, as reliever agents, for severe bronchospasm such as that which occurs during status asthmaticus, and for prophylaxis of obstruction that occurs during exercise. While nonselective beta-agonists, such as isoproterenol and metaproterenol are efficacious bronchodilators, they also stimulate cardiac beta-1 receptors, causing tachycardia and, potentially, cardiac arrhythmias. Beta-2 selective agonists are, therefore, preferred as they are selective for the airway smooth muscle. Beta-2 adrenergic receptor agonists useful for treating asthma include the short-acting beta-2 agonists (‘SABA’) terbutaline, albuterol (racemic; also known as salbutamol), levo-albuterol, pirbuterol, and bitolterol. Some of these agents may be administered orally, subcutaneously, or by inhalation. Salmeterol and formoterol are long-acting beta-2 adrenergic receptor selective agonists (‘LABA’). Their onset of action is slower than other beta-2 selective agonists, and they are used for prophylaxis rather than for treatment of bronchospasm in an acute attack. LABA are administered in combination with glucocorticoids, not alone (there is a ‘black box warning’ for LABA), as their use as monotherapy is associated with increased severity of asthma attacks and death; they are contraindicated in status asthmaticus. Some beta-2 adrenergic receptor-selective agonists induce muscle tremors.EpinephrineEpinephrine, a catecholamine, is a non-selective agonist at both alpha-1 and -2 and beta-1 and -2 adrenergic receptors. It is used for the treatment of severe bronchospasm and status asthmaticus.Methyl xanthinesThe methyl xanthines, theophylline and aminophylline (the ethylenediamine salt of theophylline), are airway smooth muscle relaxants with unclear mechanisms of action. Relaxation may result from inhibition of cyclic nucleotide phosphodiesterases. Theophylline also inhibits adenosine receptors, which may block stimulation of mast cell mediator release by adenosine. Lastly, by preventing mediator release from and trafficking of inflammatory cells, theophylline may exert an anti-inflammatory effect. Histone acetyltransferase activity is increased in biopsies of asthmatic airways and is associated with enhanced inflammatory gene expression. Theophylline is thought to inhibit gene transcription of inflammatory cytokines by enhancing histone deacetylase activity, which allows winding of DNA around histone. Once a prominent drug in asthma therapy, the use of theophylline has diminished with the advent of beta-2 adrenergic receptor-selective agonists for achieving bronchodilation and the realization that glucocorticoids are superior anti-inflammatory agents. Generally, in low doses it is useful as a reliever medication, and it is also employed in the management of status asthmaticus and in those severe asthmatics who have not responded to front-line therapies. This is because of its side effects which include nausea, headache, arrhythmias, and seizures. In addition, plasma levels of theophylline are unpredictable from dose, and are affected by hepatic, cardiac, and viral diseases. Theophylline plays a more prominent role in the treatment of chronic obstructive pulmonary disease, and may one day be replaced with more selective phosphodiesterase 4 inhibitors.AnticholinergicsThe release of acetylcholine from parasympathetic postganglionic neurons stimulates contraction of airway smooth muscle through M3-muscarinic receptors and secretion of mucus via M1-muscarinic receptors. In asthma, reflex pathways are thought to be activated, which increase vagal outflow that leads to cholinergically-mediated bronchoconstriction. Ipratropium (off label in the US for asthma treatment) is a non-selective muscarinic receptor antagonist and quaternary amine (i.e., positively-charged) derivative of atropine. Ipratropium causes fewer systemic side effects than atropine because it is not as readily absorbed. By blocking muscarinic receptors, ipratropium inhibits vagal activation of smooth muscle and glandular secretion in the airways. Ipratropium is administered by inhalation, and may cause dry mouth. Its effects are slow in onset (hour) but relatively long-lived (6   hours). It is much less effective in causing bronchodilation than beta-2 adrenergic receptor-selective agonists. It has no anti-inflammatory effect, and is not effective in every patient, but may provide relief in asthmatics suffering from psychogenic asthma.GlucocorticoidsThe powerful anti-inflammatory effect of glucocorticoids prevents and reverses many of the pathophysiological changes that occur in the airway wall of the asthmatic patient, but the drugs do not relax airway smooth muscle. An anti-inflammatory effect is accomplished with a group of drugs that are administered by inhalation and a group that is taken systemically. The inhalation agents include fluticasone, budesonide, flunisolide, mometasone, and beclomethasone, and triamcinolone, whereas the systemic agents include hydrocortisone, prednisone, prednisolone, and methylprednisolone. The inhalation agents are used for prophylaxis in milder forms of asthma, whereas the systemic agents are indicated for management of severe asthma and status asthmaticus. The glucocorticoids inhibit gene transcription of inflammatory cytokines by enhancing histone deacetylase activity. Glucocorticoids may also prevent down-regulation of beta adrenergic receptors, which has been reported to occur in the smooth muscle of asthmatic airways. Hours are required for the onset of the anti-inflammatory response to glucocorticoids. Their administration at the beginning of the early phase of an asthma attack is targeted at ameliorating the magnitude of the inflammatory response and bronchoconstriction that occurs during the late phase response. When the drugs are used chronically, both the early and the late phase responses are inhibited. In intermediate stages of asthma the inhaled glucocorticoids are often combined with LABA. Little inhaled glucocorticoid is absorbed into the systemic circulation, and the drugs are relatively free of side effects when administered by this route. Some slight, transient growth retardation may occur in children, and oral candidiasis may occur. Systemic delivery of glucocorticoids gives rise to their side effects, which include osteoporosis, weight gain, hypertension, diabetes, myopathy, psychiatric disturbances, skin fragility, and cataracts.CromonesThe cromones, sodium cromoglycate and nedocromil, produce anti-inflammatory effects in some (60-70%) asthmatic patients. They do not relax airway smooth muscle. While the precise mechanism of action of these agents is not defined, they are thought to decrease inflammatory mediator release from mast cells, macrophages, and eosinophils. These drugs can block chloride channels, which could interfere with C-fiber sensory nerve reflexes in the airway wall. The cromones are administered chronically by inhalation only, and prevent the early and late asthmatic responses in mild to moderate asthma. These drugs are not as potent as anti-inflammatory agents as are the inhaled glucocorticoids. Side effects associated with cromones are rare, and the drugs alleviate steroid-induced side effects when they are administered to children. The cromones are less effective in older patients than in children.Leukotriene receptor antagonistsLeukotriene receptor antagonists (‘LTRA’) are used for treating mild to moderate asthma and for preventing exercise-induced obstruction (off label in the US). This class of drugs includes zafirlukast, montelukast, and pranlukast (not in the US). These drugs inhibit stimulation of the CysLT1 receptor by the pro-inflammatory cysteinyl leukotrienes LTC3, LTD4 and, to a lesser extent, LTE4, formed by inflammatory cells. Leukotrienes are potent airway smooth muscle contractile agonists, and blockade of the leukotriene receptors attenuates bronchoconstriction mediated by them. The leukotriene receptor antagonists are an alternative to inhaled steroids for asthma prophylaxis. Effective orally on a chronic basis, they are not used to treat acute exacerbations. When LTRA are used to reduce patient dependence on steroids, symptoms suppressed by the steroids may reappear. One such disease is Churg-Strauss syndrome, which consists of skin rash, pulmonary inflammation, eosinophilia, and heart failure.5′-Lipoxygenase inhibitors5′-Lipoxygenase is the enzyme that converts arachidonic acid, through intermediates, to leukotriene A4 (LTA4). LTA4 is converted spontaneously to LTB4, a chemotactic mediator or to LTC4 through the action of LTC4 synthase, and LTD4 and LTE4 are derived sequentially from LTC4 through the actions of peptidases. The orally-active anti-inflammatory drug, zileuton, is a selective inhibitor of the enzyme, 5′-lipoxygenase. Inhibition of LTB4 results in an anti-inflammatory effect, and inhibition of the formation of LTC4 and LTD4 abrogates their bronchoconstrictor and pro-inflammatory effects. Zileuton is administered chronically for asthma management and for exercise-induced obstruction (off label), and is not indicated for treatment of acute asthma attacks. When oral zileuton is used to reduce patient dependence on steroids, Churg-Strauss syndrome may appear.OmalizumabOmalizumab, also known as rhuMAB-E25 is a monoclonal antibody directed against IgE that was is approved for use in moderate to severe allergic asthma who are not controlled adequately with inhaled glucocorticoids and are atopic. It binds to the high-affinity Fc receptor of circulating IgE in the blood, and inhibits the binding of IgE to mast cells. Thus, the release of mast cell and other mediators is inhibited. It also binds to low-affinity Fc receptors on antigen-processing cells and decreases the release of pro-inflammatory mediators. The drug causes a substantial decrease in circulating IgE levels. Omalizumab must be given by injection and is very expensive.

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