Asthma: Recent Advances in Management

Transcription

1 Harb A. Harfi, MD* *Allergy/Immunology, Department of Pediatrics, King Faisal Specialist Hospital and Research Centre HA Harfi, Asthma: Recent Advances in Management. 1981; 1(1): KEYWORDS Asthma Pharmacology, clinical Dyspnea Disodium cromoglycate Beclomethasone Theophylline Introduction Asthma is a chronic, complex disease. Factors which can trigger asthma include allergies, pollution, respiratory infections, exertion, cold air, dust, humidity, strong odors, emotions, and drugs. It is characterized by recurrent episodes of reversible airway obstruction and dyspnea. The number of people affected by asthma, the morbidity, and the social implications are tremendous. 1 Recently, a better understanding of the disease s mechanisms and pathophysiology has led to more specific drug use and better management of the asthmatic patient. 2 This article deals with the management of asthmatic patients according to the recent developments. Normally, the bronchi are dilated due to constant catecholamine stimulation of the beta-adrenergic receptors. Bronchial tree sensitivity in the asthmatic patient may be due to the pre-existing blockade of the beta-adrenergic receptors present in the smooth muscles. 3-5 Agents such as acetylcholine, histamine, serotonin, prostaglandin F 2 alpha, and methacholine, capable of constricting bronchial smooth muscles, will be unopposed in the presence of this blockade. Asthmatic patients are very sensitive to bronchial challenge with methacholine as demonstrated by R. G. Townley and others. 6-8 Following an allergic reaction, in extrinsic asthma, mast cells release potent chemical mediators such as the slow reacting substance of anaphylaxis (SRS- A), histamine, and eosinophil chemotactic factor of anaphylaxis (ECF-A). These mediators, in the presence of beta blockade, cause bronchocon-striction, excessive mucus production, inflammation, and edema of the mucous linings of the bronchial tubes. Cyclic nucleotides can modulate the mast cells, basophils, generation and release of these chemical mediators as well as their action on smooth muscles. 9,10 Thus, endogenous cyclic adenosine monophosphate (AMP) elevation will inhibit the formation and release of SRS-A while elevation of cyclic guanosine monophosphate (GMP) will enhance the formation and release of SRS-A leading to bronchospasm. Therefore, drugs which increase the level of intracellular cyclic AMP or decrease its inactivation cause bronchodilation. Drugs or agents that increase intracellular cyclic GMP or decrease the level of cyclic AMP cause bronchospasm. 11 Figure 1 summarizes the various receptors with their biochemical modulations and the mechanism of action of the various agents used in treatment of allergic disease. Asthma Treatment Methylxanthines Theophylline is a phosphodiesterase inhibitor, and therefore it increases intracellular cyclic AMP by preventing the degradation of cyclic AMP into its inactive form 5-AMP. Figure 1. Theophylline may be the only drug needed in cases of mild asthma. When given intravenously, it may reverse an asthmatic attack that failed to respond to sympathomimetic agents. 12 The clinical response and the improvement in pulmonary function correlates with the serum concentration of theophylline. 13 Patient requirements for and tolerance to theophylline vary greatly. This is especially true in children. However, serum concentration of 10 to 20µg/ml is considered optimal for most patients. Concentration above 20µg/ml is associated with a high risk of toxicity. 14,15 If the patient has not received theophylline preparation in the preceding six hours, optimal serum theophylline level is usually attained by a loading dose of five to sixmg/kg aminophylline given intravenously over 15 to 20 minutes, followed by a maintenance dose averaging 0.9 mg/kg/hr given as a continuous IV infusion. The loading dose should be omitted or adjusted when the patient has been taking theophylline preparations.

2 Figure 1. Diagramatic representation of the various receptors found on lung mast cell or bronchial smooth muscle cell. Adopted with modification from: Townley RG: Advances in asthma and allergy, vol 2: with kind permission of Fisons Corporation. The long-term management anhydrous theophylline dose for children is usually five mg/kg every six hours for short-acting preparations or eight to nine mg/kg every eight hours for slow-release preparations. For adults, 250 to 500 mg every eight hours is usually satisfactory. Using serum level as a guideline, these doses should be adjusted up or down according to the individual's tolerance and clinical response. Patients who smoke, have congestive heart failure, or liver disease require smaller dosages due to prolonged half-life of serum theophylline.16 Patients who suffer from nocturnal asthma are helped by using slow-release theophylline preparations. Beta-adrenergic stimulants Beta-adrenergic stimulants act by stimulating beta receptors in the smooth muscle cells of the bronchial tree. Thus, the level of cyclic AMP increases leading to bronchodilation and vasodilation. Beta-adrenergic stimulants act by activating the beta receptor adenylcyclase complex. 17 Cyclic 3',5'- AMP is produced in the presence of adenosine triphosphate (ATP). Figure 1. The basic structure of adrenergic agents is a catechol nucleus and a side chain. Figure 2. The pharmacologic activity of an adrenergic agent is related to its catecholamine structure. The nucleus is made of a benzene ring with two hydroxy groups on position three and four and an amine side chain. Changes in the basic structure, especially in the amine side chain, lead to changes in the relative activity of the sympathomimetric agent. For example, adrenaline stimulates alpha and beta receptors about the same degree. Figure 3. As more N-Alkyl groups are added, the agents become more a beta-adrenergic stimulator with less activation of alpha receptors, hence the decrease in cardiogenic side effects. Changes in the alpha position of the chain will lead to more selective activation of beta 2 -adrenergic receptors, mostly bronchial, and less stimulation of beta 1 -adrenergic receptors, mostly cardiac. 18

3 Figure 2. Cathecholamine structure of adrenergic drugs. Among the new sympathomimetric agents, sal-butamol is the best example of the more specific beta 2 -receptor stimulant which has been extensively and comparatively tested It is inhaled, 100 to 200 µg every six hours, given intravenously 500 µg, or orally in a two to four milligram dose three to four times daily. Children should be given a dose of 0.15mg/kg of body weight, every six hours. Ideally, salbutamol should be inhaled by older children and adults to avoid its minor side effects of tremors and cardiac stimulation. Other beta 2 stimulants, agonists, include isoetharine, terbutaline, salmefamol, and trimetoquinol. Disodium cromoglycate (DSCG) Disodium cromoglycate (cromolyn sodium) is probably one of the safest drugs used in the treatment of allergic diseases. It prevents the release of chemical mediators from mast cells due to antigen-antibody reactions. Its mechanism of action is related to its ability to prevent the influx of calcium ions, essential to activate microfilament contraction into the sensitized cells therefore stabilizing the cell membrane. It is also probable that it inhibits phosphodiesterase. 22,23 Figure 1. Cromolyn sodium is effective in Type I and Type III allergic reactions. It inhibits bronchospasm in allergic asthma, exercise-induced bronchospasm, or intrinsic asthma. When given before bronchial challenge with antigen or histamine, DSCG is able to block the bronchospasm.24 DSCG, when inhaled, is effective in over 60 percent of patients with severe asthma.25 Its value is preventative and it should not be given to a symptomatic patient. DSCG is indicated in several situations with patients on other therapies. For example, it can be given to some chronic steroid-dependent asthmatic patients, and the dosage of steroid can be decreased or even discontinued. Disodium cromoglycate should be given for a period of four to eight weeks, before resorting to steroid therapy for patients whose asthma cannot be controlled by around-the-clock therapy. The asthmatic patient whose condition is exacerbated by exercise or antigen exposure should receive DSCG in addition to the full therapeutic dosage of bronchodilators.

4 Figure 3. Adrenaline structure. When indicated. DSCG should be added to the bronchodilators being used. If there is a favorable response, other drugs such as steroids, can be reduced gradually. It the response is unsatisfactory after a reasonable trial period, DSCG should be discontinued and an inhaled steroid, such as beclo-methasone dipropionate, should be tried. The beclomethasone dipropionate should replace rather than be added to DSCG. It is most important to remember that during asthma flare-ups, disodium cromoglycate should be discontinued. Corticosteroids Although steroids have been used over a quarter of a century in the treatment of allergic diseases, neither their optimal dosage nor the exact mechanism of action is known. However, experimental studies indicate that steroids enter cellular cytoplasm to combine with a receptor which in turn binds to the DNA of the nucleus. A newly formed mrna directs the synthesis of a new protein through which steroids exert their specific actions. 26 This explains the slow effects of steroids, which takes more than four hours. Corticosteroids seem to facilitate adenylcyclase stimulation of beta-adrenergic drugs, inhibit endogenous histamine formation, and reduce lung cyclic GMP level. 27,28 Beclomethasone is a steroid administered as a topical inhalation. When given in the recommended dose of 100 µg four times daily, there is usually no pituitary-adrenal axis suppression. It is indicated for steroid-dependent patients and for patients who require frequent short courses of systemic steroids. Studies have indicated the benefit gained from beclomethasone After inhaling this medication, the patient should gargle or drink some water to prevent possible monilial growth in the pharynx. Occasionally, patients may have hoarseness or cough after using beclomethasone. Like DSCG, the use of beclomethasone should be discontinued temporarily when the patient is having an asthmatic attack. In this situation, a short course of systemic steroid should be given. Anticholinergic agents Patients with bronchial asthma have hyperirritable airways. This is apparent when bronchial challenge with actyl-methacholine results in bronchospasm and pulmonary function drop, or after stimulation of the tracheobronchial tree irritant receptors by cold air, dust, sulphur dioxide, and other pollutants. This leads to vagal reflex and bronchospasm. The effect can be abolished by inhaled atropine and atropine-like substances. A new synthetic anticholinergic drug, SCH-1000 (ipratropium), when inhaled at a 40 to 80 µg dose, relieved bronchospasm with minimal side effects. 32,33 The mechanism of action is probably through cholinergic receptor inhibition hence tissue cyclic GMP reduction and decreased mediator release. Figure 1. The main indications for ipratropium is for patients with exercise-induced asthma, and those who are very sensitive to cold air and other non-specific irritants. Other agents As our understanding of the mechanisms and pathophysiology of asthma improves, more therapeutic agents are introduced. Prostaglandins E 1 and E 2 are being evaluated both in animals and humans for their possible use as bronchodilators. Some patients have more autonomic imbalance with predominance of alpha-adrenergic stimulation. These patients respond to phentolamine and other alpha-adrenergic blockers. 34 However, these agents do not have

5 enough clinical use to recommend routine use for asthmatic patients. Summary and Recommendations Modern management of bronchial asthma has improved, especially in the past decade, due to better understanding of the mechanisms and physiology of asthma. This has led to the introduction of better and more specific therapy. It is very hard to make specific recommendations for the treatment of a particular patient without assessing the severity of his symptoms. In general, if the asthma is mild, the use of one drug, either theophylline or beta 2 agonist, is enough. If the symptoms are not relieved then a combination of theophylline and one of the selective beta 2 stimulants should be given. If there are occasional flare-ups, an inhaled beta 2 stimulant such as salbutamol has to be added. In case of moderate to severe asthma, a four to eight week course of cromolyn sodium should be tried, after the acute asthma is controlled with a short course of prednisone. In case the patient does not have sufficient symptomatic relief after using theophylline and beta2 stimulants around-the-clock and a good trial of cromolyn sodium is ineffective, try beclomethasone dipropionate inhalation after DSCG is discontinued and the symptoms are controlled with a short course of prednisone. In case of frequent asthmatic flare-up while the patient is taking beclomethasone, prednisone should be added in the smallest effective dosage given once in the morning. This dosage may be increased during acute episodes of asthma. REFERENCES 1. Asthma and the other allergic diseases. NIAID Task Force Report. NIH Publication No May van As A: Beta-adrenergic stimulant bronchodilators. In: Stein M, ed: New Directions in Asthma. Park Ridge, Illinois, The American College of Chest Physicians 1975 pp Townley RG, Trapani IL, Szentivanyi A: Sensitization to anaphylaxis and to some of its pharmacological mediators by blockade of the beta adrenergic receptors. J Allergy 39(3): Smith AP: Role of prostaglandins in the pathogenesis and treatment of asthma. In: Austen KF, Lichenstein LM, eds: Asthma: Physiology, lmmunopharmacology and Treatment. New York, Academic Press 1974 pp Szentivanyi A: The beta adrenergic theory of the atopic abnormality in bronchial asthma. J Allergy 42(4): Townley RG, Dennis M, Itkin IH: Comparative action of acetyl-beta-methylcholine, histamine, and pollen antigens in subjects with hay fever and patients with bronchial asthma. J Allergy 36(2): Alanko K, Poppius H: Anticholinergic blocking of prostaglandin-induced bronchoconstriction. Br Med J 1: Spector SL, Farr RS: Bronchial inhalation procedures in asthmatics. Med Clin North Am 58: Lewis RA, Wasserman SI, Goetzi EJ, Austen KF: Formation of slow-reacting substance of anaphylaxis in human lung tissue and cells before release. J Exp Med 140(5): Kaliner MA, Orange RP, Austen KF: Immunological release of histamine and slow reacting substance of anaphylaxis from human lung. J Exp Med 136: Middleton E Jr : The biochemical basis for the modulation of allergic reactions by drugs. Pediatr Clin North Am 22(1): Feldman NT, McFadden ER Jr: Asthma: therapy old and new. Med Clin North Am 61(6): Mitenko PA, Ogilvie RI: Rational intravenous doses of theophylline. New Engl J Med 289(12): Jacobs MH, et al.: Clinical experience with theophylline: relationships between dosage, serum concentration, and toxicity. JAMA 235(18): Jenne JW : Rationale for methylxanthines in asthma. In: Stein M, Ed: New Directions in Asthma. Park Ridge, Illinois, The American College of Chest Physicians 1975 pp Jusko WJ, et al. : Factors affecting theophylline clearances: age, tobacco, marijuana, cirrhosis, congestive heart failure, obseity, oral contraceptives, benzodiazepines, barbiturates, and ethanol. J Pharm Sci 68(11): Harper WJ, Simmonds AB, eds: Advances in Drug Research. London and New York, Academic Press 1979 vol Avner SE: Beta-adrenergic bronchodilators. Pediatr Clin North Am. 22(1): Hartley D, Jack D, Lunts LHC, Ritchie AC: New class of selective stimulants of ß-adrenergic receptors. Nature 219:861-62

6 Kennedy MCS, Simpson WT: Human pharmacological and clinical studies on salbutamol: a specific ß-adrenergic bronchodilator. Br J Dis Chest 63: Avner SE, et al.: A double-blind crossover study of aerosolized salbutamol, isoproterenol, and placebo in nine asthmatic children. J Allergy Clin Immunol 49(42): (Abstract) 22. Johnson HG, Bach MK: Prevention of calcium ionophore-induced release of histamine in rat mast cells by disodium cromoglycate. J Immunol 114: Lavin N, et al.: An action of disodium cromoglycate: inhibition of cyclic 3',5'-AMP phosphodiesterase. J Allergy Clin Immunol 57(1): Kolotkin BM, Lee CK, Townley RG: Duration and specificity of sodium cromolyn on allergen inhalation challenges in asthmatics. J Allergy Clin Immunol 53(5): Godfrey S, Balfour-Lynn L, König P: The place of cromolyn sodium in the long-term management of childhood asthma based on 3- to 5-year follow-up. J Pediatr 87(3): Baxter JD, Forsham PH : Tissue effects of glucocorticoids. Am J Med 53: Aviado DM, Carillo LR: Antiasthmatic action of corticosteroids: a review of the literature on their mechanism of action. J Clin Pharmacol 10: Goldberg N, O'Dea RF, Haddox MK: In: Greengard P and Robison GA, eds: Advances in Cyclic Nucleotide Research. New York, Raven Press 1973 p Godfrey S: The place of a new aerosol steroid, beclomethasone dipropionate, in the management of childhood asthma. Pediatr Clin North Am 22(1): Vandenberg R, Tovey E, Love I, et al.: Beclomethasone dipropionate. Trial of a new inhalational steroid preparation in the treatment of steroid-dependent chronic asthmatics. MedJAust 1(7): Champion P. et al.: Beclomethasone dipropionate in asthma. Can Med Assoc J 113(3): Gross NJ: Sch 1000: a new anticholinergic bronchodilator. Am Rev Respir Dis 112: Petrie GR, Palmer KN : Comparison of aerosol ipratropium bromide and salbutamol in chronic bronchitis and asthma. Br MedJ 1(5955): Kerr JW, Govindaraj M, Patel KR : Effect of alpha-receptor blocking drugs and disodium cromoglyate on histamine hypersensitivity in bronchial asthma. Br Med J 2(5702):