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Pharmacology and Therapeutics of Bronchodilators 1521-0081/12/6403-450–504$25.00 PHARMACOLOGICAL REVIEWS Vol. 64, No. 3 Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics 4580/3762238 Pharmacol Rev 64:450–504, 2012 ASSOCIATE EDITOR: DAVID R. SIBLEY Pharmacology and Therapeutics of Bronchodilators Mario Cazzola, Clive P. Page, Luigino Calzetta, and M. Gabriella Matera Department of Internal Medicine, Unit of Respiratory Clinical Pharmacology, University of Rome ‘Tor Vergata,’ Rome, Italy (M.C., L.C.); Department of Pulmonary Rehabilitation, San Raffaele Pisana Hospital, Istituto di Ricovero e Cura a Carattere Scientifico, Rome, Italy (M.C., L.C.); Sackler Institute of Pulmonary Pharmacology, Institute of Pharmaceutical Science, King’s College London, London, UK (C.P.P., L.C.); and Department of Experimental Medicine, Unit of Pharmacology, Second University of Naples, Naples, Italy (M.G.M.) Abstract............................................................................... 451 I. Introduction: the physiological rationale for using bronchodilators .......................... 452 II. ␤-Adrenergic receptor agonists .......................................................... 455 A. A history of the development of ␤-adrenergic receptor agonists: from nonselective ␤ Downloaded from adrenergic receptor agonists to 2-adrenergic receptor-selective drugs.................... 455 ␤ B. Short-acting 2-adrenergic receptor agonists........................................... 457 1. Albuterol........................................................................ 457 2. Fenoterol........................................................................ 457 3. Terbutaline ..................................................................... 458 ␤ pharmrev.aspetjournals.org C. Long-acting 2-adrenergic receptor agonists ........................................... 458 1. Formoterol ...................................................................... 459 2. Salmeterol ...................................................................... 460 ␤ D. Ultra-long-acting 2-adrenergic receptor agonists ...................................... 461 1. Indacaterol ...................................................................... 461 2. Olodaterol....................................................................... 462 3. Vilanterol ....................................................................... 463 4. Carmoterol ...................................................................... 464 5. LAS100977...................................................................... 464 by guest on April 28, 2016 6. PF-610355 ...................................................................... 465 7. AZD3199........................................................................ 465 ␤ E. Intravenous 2-adrenergic receptor agonists ........................................... 465 ␤ F. Side effects of 2-adrenergic receptor agonists ......................................... 466 III. Muscarinic acetylcholine receptor antagonists............................................. 467 A. Brief history of development ......................................................... 467 B. Short-acting muscarinic acetylcholine receptor antagonists.............................. 467 1. Atropine methonitrate............................................................ 467 2. Ipratropium bromide ............................................................. 467 3. Oxitropium bromide.............................................................. 468 C. Long-acting muscarinic acetylcholine receptor antagonists .............................. 468 1. Tiotropium bromide .............................................................. 468 D. Novel long-acting muscarinic acetylcholine receptor antagonists ......................... 469 1. Glycopyrronium bromide.......................................................... 469 2. Aclidinium bromide .............................................................. 469 3. Other muscarinic acetylcholine receptor antagonists under development............... 470 E. Side effects of muscarinic acetylcholine receptor antagonists ............................ 470 IV. Xanthines ............................................................................. 471 A. History of development .............................................................. 471 B. Theophylline ....................................................................... 471 C. Aminophylline...................................................................... 472 Address correspondence to: Mario Cazzola, Universita`di Roma ‘Tor Vergata,’ Dipartimento di Medicina Interna, Via Montpellier 1, 00133 Roma, Italy. E-mail: [email protected] This article is available online at http://pharmrev.aspetjournals.org. http://dx.doi.org/10.1124/pr.111.004580. 450 PHARMACOLOGY AND THERAPEUTICS OF BRONCHODILATORS 451 E. Novel xanthine drugs ............................................................... 472 F. Side effects of xanthines............................................................. 473 V. Novel classes of bronchodilators ......................................................... 474 A. Selective phosphodiesterase inhibitors ................................................ 474 B. Kϩ channel openers ................................................................. 475 C. Vasoactive intestinal peptide analogs ................................................. 475 D. Rho kinase inhibitors ............................................................... 476 E. Brain natriuretic peptide and analogs ................................................ 476 F. Nitrix oxide donors ................................................................. 477 G. E-prostanoid receptor 4 agonists ..................................................... 477 H. Bitter taste receptor agonists ........................................................ 478 VI. Combination therapy ................................................................... 478 A. Pharmacologic rationale for combination therapy ...................................... 478 ␤ 1. Combining 2-adrenergic receptor agonists and muscarinic acetylcholine receptor antagonists...................................................................... 478 ␤ 2. Combining 2-adrenergic receptor agonists and inhaled corticosteroids ................ 478 3. Combining muscarinic acetylcholine receptor antagonists and inhaled corticosteroids ................................................................... 479 ␤ B. Combination therapy of 2-adrenergic receptor agonists with muscarinic acetylcholine receptor antagonists ................................................................ 479 ␤ ␤ C. Novel long-acting 2-adrenergic receptor agonists (Ultra-long-acting 2-adrenergic receptor agonists) and long-acting antimuscarinic agent combinations under development ....................................................................... 479 ␤ D. Bifunctional muscarinic acetylcholine receptor antagonists and 2-adrenergic receptor agonists ........................................................................... 480 ␤ E. 2-Adrenergic receptor agonist or long-acting antimuscarinic agent/phosphodiesterase inhibitor combinations .............................................................. 481 ␤ F. Combination therapy of 2-adrenergic receptor agonists with inhaled corticosteroids ...... 481 ␤ 1. Novel combinations of long-acting 2-adrenergic receptor agonists and inhaled corticosteroids under development ................................................. 482 G. Combination therapy of long-acting muscarinic agonists with inhaled corticosteroids ...... 482 H. Other possible combination therapies ................................................. 483 I. Triple combination therapies......................................................... 483 VII. Controversies surrounding bronchodilators ............................................... 484 ␤ A. 2-Adrenergic receptor agonists ...................................................... 484 1. Tachyphylaxis and tolerance ...................................................... 484 2. Morbidity and mortality .......................................................... 484 B. Muscarinic acetylcholine receptor antagonists ......................................... 485 VIII. The role of bronchodilators in the management of asthma and chronic obstructive pulmonary disease ..................................................................... 485 IX. The use of bronchodilators in special populations.......................................... 487 A. Older people ....................................................................... 487 B. Pediatric populations................................................................ 487 C. Patients with heart failure .......................................................... 488 D. Polypharmacy ...................................................................... 489 E. Use of bronchodilation in athletes and the abuse of bronchodilators...................... 490 F. Pregnancy ......................................................................... 491 X. Pharmacogenetics of airway obstruction and the future .................................... 492 References ............................................................................ 494 Abstract——Bronchodilators are central in the chodilators work through their direct relaxation ef- treatment of of airways disorders. They are the main- fect on airway smooth muscle cells. at present, three
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