The debate on S-enantiomers of β-agonists: Tempest in a teapot or gathering storm?☆☆☆★
1998; Elsevier BV; Volume: 102; Issue: 6 Linguagem: Inglês
10.1016/s0091-6749(98)70324-0
ISSN1097-6825
Autores Tópico(s)Pharmacological Effects and Assays
ResumoA certain drama is unfolding in the nearly 30-year attempt to clarify any serious adverse effects of β-agonists. Could the d-(S-) enantiomer in the racemic d/l (rac-, S/R) mixtures of these synthesized drugs be the culprit behind the purported increased morbidity and mortality envisioned by some?1Sears MR Taylor DR Print CG et al.Regular inhaled beta-agonist treatment in bronchial asthma.Lancet. 1990; 336: 1391-1396Abstract PubMed Scopus (842) Google Scholar Nearly inactive as β-agonists, the S-enantiomers have their own unique actions in complex systems and their own individual pharmacokinetic properties. Similar concerns are being voiced with other drug families possessing stereoisomers, including the β-antagonists.2Stoschitzky K Klein W Lindner W. Time to reassess chiral aspects of β-adrenoceptor antagonists.Trends Pharmacol Sci. 1997; 18: 306-307Abstract Full Text PDF PubMed Google Scholar Some of them are detailed in an editorial similar to this one.3Ind PW. Salbutamol enantiomers. Early clinical evidence in humans.Thorax. 1997; 52: 839-840Crossref PubMed Scopus (12) Google Scholar These concerns are not frivolous. The study presented in this issue (Nelson et al. J Allergy Clin Immunol 1998;102:943-52) is the first large-scale effort in asthmatic subjects to evaluate the long-term effects of these compounds by comparing thrice daily nebulized doses of the d/l-racemate of albuterol to the pure R (levo)-enantiomer administered over 4 weeks. At the very least, and in contrast to a single-dose study by another group,4Cockcroft DW Swystun VA. Effect of single doses of S-salbutamol, R-salbutamol, racemic salbutamol and placebo on the airway response to methacholine.Thorax. 1997; 52: 845-848Crossref PubMed Scopus (70) Google Scholar the study demonstrates greater potency of R-albuterol given alone than an equivalent amount given in the racemate, implying some interfering effect of the S-albuterol. If this were all, we could compensate with a larger dose of the racemate, but there are more insidious questions in the study. Over 4 weeks, the baseline FEV1 rose slightly but insignificantly (approximately 0.1 L) in the placebo group and the 2 levalbuterol groups but not in the 2 racemate groups. These differences were greater and significant if confined to patients not receiving inhaled corticosteroids. Are these differences spurious or meaningful, arising perhaps from a deleterious effect of the S-albuterol? When referred to the placebo response over 8 hours, all drug groups also show a trend of declining area under the curve at the 4-week interval. Is this tachyphylaxis or rather a consequence of the rising placebo baseline curve? We are not given the absolute FEV1 values to assist in making this judgement. Studies in the guinea pig have given us leads and helped define the issues. Like human airways, the smooth muscle of guinea pig airways contains β2 -adrenoreceptors, and prejunctional autoinhibitory M2 -muscarinic receptors exist at cholinergic terminals. Dysfunction of these M2 -receptors can be produced by viral infection5Fryer AD Jacoby DB. Parainfluenza virus infection damages inhibitory M2 -muscarinic receptors on pulmonary parasympathetic nerves in the guinea pig.Br J Pharmacol. 1991; 102: 267-271Crossref PubMed Scopus (163) Google Scholar and allergic reactions6Fryer AD Wills-Karp M. Dysfunction of M2 -muscarinic receptors in pulmonary parasympathetic nerves after allergen challenge.J Appl Physiol. 1991; 71: 2255-2261PubMed Google Scholar with resulting bronchospasm. M2 -receptors are also believed to be dysfunctional in asthma.7Ayala LE Ahmed T. Is there loss of a protective mechanism in asthma.Chest. 1989; 96: 1285-1291Crossref PubMed Scopus (92) Google Scholar, 8Minette PAH Lammers J-WJ Dixon CMS McKusker MT Barnes PJ. A muscarinic agent inhibits reflex bronchoconstriction in normal but not in asthmatic subjects.J Appl Physiol. 1989; 67: 2461-2465Crossref PubMed Scopus (170) Google Scholar However, there are differences. The guinea pig has a prominent sympathetic innervation to its airway smooth muscle, whereas in humans such innervation is scarce or absent. As assessed by functional means, β2 -adrenoceptors have been presumed to be inhibitory to acetylcholine output in airway smooth muscle of several species, including humans.9Minette PA Barnes PJ. Prejunctional inhibitory muscarinic receptors on cholinergic nerves in human and guinea pig airways.J Appl Physiol. 1988; 64: 2532-2537PubMed Google Scholar, 10Rhoden KJ Meldrum LA Barnes PJ. Inhibition of cholinergic neurotransmission in human airways by β2 -adrenoceptors.J Appl Physiol. 1988; 65: 700-705PubMed Google Scholar Yet when acetylcholine production is measured directly, β-agonists paradoxically are stimulatory in the guinea pig airway but have no discernible effect in the human airway.11Belvissi MG Patel HJ Takahashi T Barnes PJ Giembycz MA. Paradoxical facilitation of acetylcholine release from parasympathetic nerves innervating guinea-pig trachea by isoprenaline.Br J Pharmacol. 1996; 117: 1413-1420Crossref PubMed Scopus (42) Google Scholar By using data from studies of the guinea pig, one can model and develop ideas but can only speculate on their human application until many facets of human work converge on a consensus. We are not at that point with the S-enantiomers of β-agonists. A case in point is tachyphylaxis. In 1971, Conolly et al12Conolly ME Davies DS Dollery CT George CF. Resistance to β2 -adrenoceptor stimulants (a possible explanation for the rise in asthma deaths).Br J Pharmacol. 1971; 43: 389-402PubMed Google Scholar proposed that the preceding epidemic of asthma deaths was due to airway receptor tachyphylaxis produced by the very large doses of isoproterenol then marketed in the metered-dose inhaler (MDI). This conclusion was based on findings that the protective action of isoproterenol against histamine in guinea pigs was lost after 48 hours of its intraperitoneal injections. Tachyphylaxis has been subsequently produced and studied in intact animals, airway smooth muscle, and smooth muscle cultures, as well as at the molecular level. Yet it has been difficult to reach agreement until recently concerning its existence in the stable asthmatic subject receiving treatment, and virtually no data exist in the acutely ill patient. Among the most important findings emerging are that (1) the airway β2 -adrenoceptors of asthmatic subjects in a fatal attack are distinctly impaired compared with those from nonasthmatic subjects, although with a greater response to contractile agents13Bai TR Prasad FW. Abnormalities in airway smooth muscle in fatal asthma.Am Rev Respir Dis. 1990; 141: 552-557Crossref PubMed Scopus (151) Google Scholar ; (2) full agonists (isoproterenol, fenoterol, formoterol) produce tachyphylaxis more readily than partial agonists (albuterol terbutaline, salmeterol) both in vitro14January B Seibold A Whaley B et al.β2 -Adrenergic receptor desensitization, internalization, and phosphorylation in response to full and partial agonists.J Biol Chem. 1997; 272: 23871-23879Crossref PubMed Scopus (132) Google Scholar and in vivo15Ellul-Micallef R Fenech FF. Effects of intravenous prednisolone in asthmatics with diminished adrenergic responsiveness.Lancet. 1975; 2: 1269-1271Abstract PubMed Scopus (114) Google Scholar ; (3) systemic corticosteroids rapidly reverse acutely produced tachyphylaxis,15Ellul-Micallef R Fenech FF. Effects of intravenous prednisolone in asthmatics with diminished adrenergic responsiveness.Lancet. 1975; 2: 1269-1271Abstract PubMed Scopus (114) Google Scholar, 16Stephan WC Chick TW Avner BP Jenne JW. Tachyphylaxis to inhaled isoprotenerol and the effect of methylprednisolone in dogs.J Allergy Clin Immunol. 1980; 65: 105-109Abstract Full Text PDF PubMed Scopus (32) Google Scholar, 17Tan KS Grove A McLean E Gnosspelius Y Hall IP Lipworth BJ. Systemic corticosteroid rapidly reverses bronchodilator subsensitivity induced by formoterol in asthmatic patients.Am J Respir Crit Care Med. 1997; 156: 28-35Crossref PubMed Scopus (133) Google Scholar but inhaled corticosteroids in large doses do not prevent it18Yates DH Kharitonov SA Barnes PJ. An inhaled glucocorticoid does not prevent tolerance to the bronchoeffective effect of a long-acting inhaled β2 -agonist.Am Rev Respir Crit Care Med. 1996; 154: 1603-1607Crossref PubMed Scopus (114) Google Scholar ; (4) provocational challenge techniques with methacholine or histamine can quantitate tachyphylaxis from as little as 200 μg albuterol per day,19Bhagat R Swystun VA Cockroft DW. Salbutamol-induced increased airway responsiveness to allergen and reduced protection versus methacholine: dose response.J Allergy Clin Immunol. 1996; 97: 47-52Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar or salmeterol20Cheung D Timmers MC Zwinderman AH Bel EH Dijkman JH Sterk PJ. Long-term effects of a long-acting β2 -adrenoreceptor agonist, salmeterol, on airway hyperresponsiveness in patients with mild asthma.N Engl J Med. 1992; 327: 1120-1198Crossref Scopus (394) Google Scholar (even from a single dose21Verbene AAPH Hop WCJ Creyghton FBM et al.Airway hyperresponsiveness after a single dose of salmeterol and during four months of treatment in children with asthma.J Allergy Clin Immunol. 1996; 97: 938-946Abstract Full Text PDF PubMed Scopus (41) Google Scholar ) and can detect a 2-fold difference in delivered drug22Simons RER Soni NR Watson WTA Bechner AB. Bronchodilator and bronchoprotective effects of salmeterol in young patients with asthma.J Allergy Clin Immunol. 1992; 90: 840-846Abstract Full Text PDF PubMed Scopus (48) Google Scholar ; and (5) protection against complex airway challenges (eg, exercise,23Ramage L Lipworth BJ Ingram CG Cree JA Dhillon DP. Reduced protection against exercise induced bronchoconstriction after chronic dosing with salmeterol.Respir Med. 1994; 88: 363-368Abstract Full Text PDF PubMed Scopus (244) Google Scholar allergen,24Cockroft DW Swystun VA Bhagat R. Interaction of inhaled β2 -agonist and inhaled corticosteroid on airway responsiveness to allergen and methacholine.Am J Respir Crit Care Med. 1995; 152: 1485-1489Crossref PubMed Scopus (87) Google Scholar and adenosine monophosphate25O’Connor BJ Aikman SL Barnes PJ. Tolerance to the non-bronchodilator effects of inhaled β2 -agonists in asthma.N Engl J Med. 1992; 327: 1204-1208Crossref PubMed Scopus (295) Google Scholar ) may even more readily show tachyphylaxis, perhaps because additional, more susceptible β2 -adrenoceptors are involved.25O’Connor BJ Aikman SL Barnes PJ. Tolerance to the non-bronchodilator effects of inhaled β2 -agonists in asthma.N Engl J Med. 1992; 327: 1204-1208Crossref PubMed Scopus (295) Google Scholar Although the practical importance of such tachyphylaxis may be negligible when recommended treatment guidelines are followed, scenarios can certainly be visualized in which it could make a difference. The peak bronchodilator response is poorly suited to detect tachyphylaxis because, as stressed by Ahrens et al26Ahrens RC. On comparing inhaled beta adrenergic agonists.Ann Allergy. 1991; 67: 296-298PubMed Google Scholar, 27Ahrens RC Bonham AC Annis L Ries R. Use of bronchial provocation with histamine to compare the pharmacodynamics of inhaled albuterol and metaproterenol in asthmatic patients.J Allergy Clin Immunol. 1987; 79: 876-882Abstract Full Text PDF PubMed Scopus (49) Google Scholar and the Food and Drug Administration Proceedings,28Proceedings of the FDA Joint Advisory Committee on Pharmacokinetics/Pharmacodynamics of Beta Agonists. Food and Drug Administration, Gaithersburg (MD)Aug 16, 1996Google Scholar even a single puff from the MDI in the subjects with mild-to-moderate asthma studied quickly increases airway caliber to the insensitive plateau range of its dose-response curve. Differences may then only appear in the area under the curve and duration of response. It is yet to be shown, however, that protection from challenge and bronchodilation are mechanistically any different as far as smooth muscle relaxation is concerned. Guinea pig studies now lead to the cholinergic system, and sensitization to ovalbumin is usually required. Functional antagonism to isoproterenol or prostaglandin E2 by carbacholine is enhanced 10-fold by ovalbumin sensitization, although not by histamine.29Wills-Karp M Gilmour MI. Increased cholinergic antagonism underlies impaired β2 -adrenergic response in ovalbumin-sensitized guinea pigs.J Appl Physiol. 1993; 74: 2729-2735PubMed Google Scholar Fenoterol instilled intratracheally for 6 weeks, repeated ovalbumin injection, or both enhance responses to acetylcholine both in vitro and in vivo, whereas the response to fenoterol is unaffected as tested 72 hours later.30Wang Z Bramby AM McNamera A. Chronic fenoterol exposure increases in vivo and in vitro airway responses in guinea pigs.Am J Respir Crit Care. 1994; 149: 960-965Crossref PubMed Scopus (52) Google Scholar After rechallenge with ovalbumin, the sensitized guinea pig shows an increased cholinergic contractile response despite a normal response to β-agonists, probably because of events distal to the M3 -receptor.31Whicker SD Compton MR Seale JP Black JL. The effect of sensitization and aerosol antigen challenge in guinea pigs—studies of airway receptor function and characteristics.Pulm Pharmacol. 1990; 3: 129-136Crossref PubMed Scopus (7) Google Scholar Such challenge releases mediators, which evidently act synergistically with the cholinergic response.32Udem BJ Adams III., GK An analysis of the functional interactions of selected contractile agonists in the guinea pig isolated trachea.J Pharmacol Exp Ther. 1988; 246: 47-53PubMed Google Scholar For more than a decade, Morley and coworkers33Morley J. Anomalous effects of albuterol and other sympathomimetics in the guinea pig.Clin Rev Allergy Immunol. 1996; 14: 65-89Crossref PubMed Scopus (24) Google Scholar, 34Handley DA McCullough JR Crowther SD Morley J. Sympathomimetic enantiomers and asthma.Chirality. 1998; 10: 262-272Crossref PubMed Scopus (37) Google Scholar have pursued the role of β-agonists in producing airway hyperresponsiveness in the guinea pig, and they are now focusing on S-enantiomers. In ovalbumin-sensitized animals, infusion of rac-albuterol for less than an hour totally suppresses bronchial obstruction produced by inhaled antigen, but when continued for 48 hours, the animals succumb to challenge.35Mazzoni L Naef R Chapman ID Morley J. Hyperresponsiveness of airways following exposure of guinea pigs to racemic mixtures and diastomers of β2 -selective sympathomimetics.Pulm Pharmacol. 1994; 7: 367-376Crossref PubMed Scopus (79) Google Scholar These researchers discount tachyphylaxis of β2 -adrenoceptors as the explanation, preferring to incriminate S-albuterol because inhaled isoproterenol or rac-albuterol is still protective, although tachyphylaxis is clearly only relative to the dose used and could have been overridden by larger effective doses. Infusion of S-albuterol over 1 hour enhances responsiveness to inhaled histamine, as does tracheal deposition of particulates containing S-albuterol, S-terbutaline, or S-isoproterenol. In all cases hyperresponsiveness requires an intact vagus nerve. Tissue studies also point to the cholinergic system, but now direct measurement of acetylcholine after electric field stimulation avoids the uncertainties involved in previous functional studies (eg, from interfering NaNc neuropeptide release). In the purely β2 action of cAMP production, the receptor affinity of the S-enantiomer of albuterol is several orders of magnitude less than that of the R-enantiomer,36Penn RB Frielle T McCullough JR Aberg G Benovic JL. Comparisons of R-, S-, and RS-albuterol interaction with human β2 - and β2 -adrenergic receptors.Clin Rev Allergy Immunol. 1996; 14: 37-45Crossref PubMed Scopus (97) Google Scholar and stimulation of acetylcholine release in equine respiratory smooth muscle is correspondingly much weaker.37Zhang X-Y Zhu F-X Olszewski MA Robinson NE. Effects of enantiomers of β2 -agonists on ACh release and smooth muscle contraction in the trachea.Am J Physiol. 1998; 274: L32-L38PubMed Google Scholar However, when used in roughly equal concentration (as in the racemate), S-albuterol paradoxically seems to counteract the calcium-lowering effect of R-albuterol in uncontracted bovine trachea, actually increasing measured Ca++ in smooth muscle cells and by itself causing cell shortening.38Mitra S Ugur M Ugur O Goodman HM McCullough JR Yamaguchi H. (S)-Albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle.Mol Pharmacol. 1998; 53: 347-354PubMed Google Scholar Earlier workers39Takuwa Y Takuwa N Rasmussen H. The effect of isoproterenol on intracellular calcium concentration.J Biol Chem. 1998; 263: 762-768Google Scholar also found a paradoxical rise in Ca++ with addition of either isoproterenol or forskolin to uncontracted bovine trachea cells. But when contracted by methacholine or histamine, bovine tracheal smooth muscle cells are relaxed by isoproterenol, forskolin, and 8-Br-cAMP, and this correlates with calcium lowering.39Takuwa Y Takuwa N Rasmussen H. The effect of isoproterenol on intracellular calcium concentration.J Biol Chem. 1998; 263: 762-768Google Scholar, 40Hoiting BH Meurs H Schuiling M Kuipers R Elzinga CRS Zaagsma J. Modulation of agonist-induced phospoinositide metabolism, Ca++ signalling and contraction of airway smooth muscle by cyclic AMP-dependent mechanisms.Br J Pharmacol. 1996; 117: 419-426Crossref PubMed Scopus (44) Google Scholar S-albuterol is found to have the characteristics of a contractile agonist operating through the phospholipase C pathways, reacting or cross-reacting at the M3 -muscarinic receptor.38Mitra S Ugur M Ugur O Goodman HM McCullough JR Yamaguchi H. (S)-Albuterol increases intracellular free calcium by muscarinic receptor activation and a phospholipase C-dependent mechanism in airway smooth muscle.Mol Pharmacol. 1998; 53: 347-354PubMed Google Scholar If S-albuterol levels sufficiently exceed R-albuterol on cumulative dosing,34Handley DA McCullough JR Crowther SD Morley J. Sympathomimetic enantiomers and asthma.Chirality. 1998; 10: 262-272Crossref PubMed Scopus (37) Google Scholar, 41Eaton EA Walle UK Wilson HM Aberg G Walle T. Stereoselective sulfate conjugation of salbutamol by human lung and bronchial epithelial cells.Br J Clin Pharmacol. 1996; 41: 201-206Crossref PubMed Scopus (49) Google Scholar it is conceivable that relaxation would be seriously impaired. Returning to the article by Nelson et al in this issue, it is difficult to make any sense of the baseline variations at 4 and 5 weeks. The authors quite reasonably suggest that the relative failure of the 2 rac-albuterol baselines to rise with the others was due to the presence of S-albuterol. But should we uncritically accept the rising baselines in the placebo and levalbuterol groups? By history, all groups used their MDI rac-albuterol to a modest and similar degree (about 4 puffs/day), including the preliminary wash-out week. Were all patients previously on a larger intake, with the S-albuterol now subsiding to a lower level in the non-rac subjects? Or were rising baselines due to some extraneous factor, such as drop outs, seasonal effects, training, or holdover of drug from the last nebulized dose 8 or more hours previously? Examination of the 8-hour bronchodilation responses, particularly to 1.25 mg levalbuterol, raises this possibility. And why should inhaled corticosteroids mitigate these changes to the point of insignificance (P = .41)? The study will undoubtedly be repeated in some form, perhaps with fewer dose groups, particularly to restudy the baseline changes and the effects of corticosteroids, which were both key to the study. Comparison of the 2 preparations on inherent responsiveness to methacholine challenge and other constrictants is crucial to the hyperresponsiveness issue. Examination of other β2 -agonists such as terbutaline, the S-enantiomer of which does not accumulate and which also produces some tachyphylaxis,42Weber RW Smith JA Nelson HS. Aerosolized terbutaline in asthmatics: development of subsensitivity with long-term administration.J Allergy Clin Immunol. 1982; 70: 417-422Abstract Full Text PDF PubMed Scopus (74) Google Scholar will be necessary. Certainly the idea of an adversely acting S-enantiomer, with all its implications for treatment, particularly of the acute attack, is novel and powerful, but it deserves thorough study before passing judgement on the racemic preparations we now use so widely and satisfactorily.
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