Early Protective Effects of Tiotropium Bromide in Patients with Airways Hyperres P O N S I V E N E S S
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European Review for Medical and Pharmacological Sciences 2004; 8: 259-264 Early protective effects of tiotropium bromide in patients with airways hyperres p o n s i v e n e s s C. TERZANO, A. PETROIANNI, A. RICCI, L. D’ANTONI, L. ALLEGRA* Department of Cardiovascular and Respiratory Sciences, Respiratory Diseases Unit, Fondazione E. Lorillard Spencer Cenci, “La Sapienza” University - Rome (Italy) *Institute of Respiratory Diseases, University of Milan, Ospedale Maggiore IRCCS – Milan (Italy) Abstract. – Tiotropium is an anticholiner- Introduction gic drug for Ch ronic Obstructive Pulmonary Di sease (COPD) patients, with a peak b ron- Ti o t rop ium is a qu atern a ry amm o niu m chodilator effect observed after 1.5 to 2 hours and a long duration of action. The aim of our co ngener of atropine. It has been developed study was to quantify the early protection of a as a lon g-acting an ticho linergic bro n c h o d i l a- single dose of inhaled tiotropium against metha- tor for inhalation by patients with chronic ob- choline-induced bronchoconstriction in asthmat- s t ructive pu lmon ary d isease (COPD). Dru g ic patients with airway hyperresponsiveness. p ro p e rties o f ant icho lin ergic agent s have Ten subjects (7M, 3F), with history of asthma been well-kno wn to man y cultures for many and a baseline FEV (Forced Expiratory Volume 1 1 1 c e n t u r i e s . In the 1920s the d iscovery o f the sec) >80% of pred icted, were enrolled in the s t u d y. Each subject perfo rmed three meth a- adrenergic agonists displaced these agents as choline challenge tests, with a time of 72 hours th e first-line treatmen t for obstru ctive dis- between each challenge: Test A (methacholine eases. Nevertheless in last decades there has challenge test), an d successively, at random, been a renewed interest in the use of anti- Test B (methacholine 30 minutes after inhaled cholinergic drugs, given the increase in preva- Tiotropium) and Test C (methacholine 30 minutes lence an d m orb idity of asth ma and COPD, after inhaled Placebo). PD20 (Provocative Dose and the better understanding of the choliner- causing a 20% decrease in basal FEV1 value) was reached to assess airways responsiveness. gic mechanisms that control airway calibre in All the subjects showed in Test A and Test C obstructive diseases. The newer anticholiner- a mild-moderate airway hyperresponsiveness. gic agents are water-soluble, quatern a ry am- In Test B no PD20 was reached at the inhaled mo n iu m co m p o u n d s th at are p o o rly ab - maximu m do se o f meth ach ol ine (1600 µg), sorbed, and via inhalatio n cause fewer sys- F E V before tiotropium was 88.6% ± 4.4, begin- 2,3 1 temic side effects . ning test FEV1 92.6% ± 4.3, end test FEV1 8 5 . 7 % ± 4.6. In patients with acute asthma the m ech a- Inhaled tiotropium bromide 18µg has shown nism s for broncho constriction and dilatatio n a pro tective effect ag ain st methacholin e-in- a re mediated by the autono mic nervo us sys- du ced bro nchoconstriction in asth matic p a- tem . The majo rity of au ton om ic nerves in tients, with mild-moderate airways h yp err e- hu man airways are b ran ch es of th e vagu s sponsiveness, already 30 minutes after its ad- n e rve; it s eff e ren t in nervat io n is d erived m i n i s t r a t i o n . f ro m th e p ostgan glionic fibres that en d in smoo th muscle of the airways, in submu cosal Key Words: glan d s an d in vascu lar st ru c t u re s 4. Met h ach o lin e, Airwa ys h yp erre s p o n s i v e n e s s , Ph ysio logically th e release of acetylcholine Tio t r op iu m, Muscarin ic rec e p t o r s . stimulates muscarinic receptors at these sites and resu lts in smo o th mu scle co ntract io n Abbreviations: an d th e release of secretions from su bm u- CO PD = C hronic Obstructive Pulmonary D isease; cosal gland s. MCh = Methacholine; ACh = Acetylcholine; F EV1 In humans there are 5 muscarinic receptor = Forced Expiratory Volume in 1 second; PD20 = subtypes (M1-M5) all encoded by individual Pr ovocative Dose causing a 20% decrease in basal genes and exhibit distinct pharmacology and 5,6 FE V 1 va l u e . tissue distribution . 259 C. Terzano, A. Petroianni, A. Ricci, L. D’antoni, L. Allegra The M1 receptors are lo cated in parasym- Th is m ay weak en th e effect o f th e p at hetic g ang lia and are resp o nsib le fo r postjunctional M3 muscarinic receptor block- c h o l i n e rgic neurotransm ission . They may fa- ade on airway smooth muscle and submucos- cilitate nicotinic transmission or be responsi- al glands. Otherwise antagonists that bind se- b le fo r m ain tain in g ch o lin ergic to n e. lectively t o M3 an d M1 recep to rs m ay be Inhibition would reduce cholinergic tone and m o re effective in inh ibitin g cholin ergic ef- thu s wou ld red uce bro nchoco nstriction. M1 fects in the airways. recep tors are also fo un d on alveo lar walls, Ti o t ropium brom id e is a recen tly devel- where their function is unknown, on the air- oped , lo ng-actin g, selective antimuscarin ic way ep ith elium , an d in vario u s exo crin e drug. It is structurally similar to ipratropium glands7. with the exception of the presence of th io- Prejunctional M2 receptors are located on phen e rin gs o n tiotropium , which resu lt in po stganglio nic nerves in the smoo th muscle g reater lipoph ilicity and faster systemic m e- fibres and submucosal glands and inhibit the tabolism12,13. release o f acetylch olin e. Released acetyl- Tiotropium is a competitive muscarinic re- cho line is hydro lysed by the cholinesterase, cepto r an tago nist th at disp lays a 6-20-fold an d th e cho line is tak en u p. M2 re c e p t o r s higher affinity for m uscarinic recepto rs than wo rk as auto recep tors, provid in g negative i p r a t ro p i u m8. Ti o t ro pium bind s with sim ilar feed b ack on th e release o f acetylcho lin e. a ffinity to all subtypes of m uscarinic re c e p- They are activated by th e release of acetyl- tors, but it dissociates rapidly from M2 recep- cho line, lim iting the degree o f b ro n c h o c o n- tors and very slowly from M1 and M3 recep- striction. Agents that block M2 receptors in- tors, resulting in a prolonged duration of ac- hib it the negative feedback an d result in in- tion in physiologic experiments6,14. c reased acetylcholine release and there f o re , In hu man b ron chi, tiotropium has an in- incr eased tone in the bronchial smooth mus- hibitory reported effect with a slow onset of c l e8. M2 receptors predom inate in the heart action, a peak bronchodilator effect observed and mediate the bradycardic effects of Ach 7. after 1.5 to 2 h, and a prolonged duration. M3 recep tors are located on th e airw a y Methach olin e (MC h) ch allen ge test is a smooth muscle. M3 receptors typically medi- method of assessing airways responsiveness. It ate the direct con tract ile effects o f ACh . may vary over time, often increasing during ex- Their activation leads to the con traction o f acerbations and d ecreasing d uring tre a t m e n t airway smooth muscle. M3 receptors also are with antin flamm atory medications1 5. Airw a y located on submucosal glands, where they are h y p e rrespo nsiveness can be d emon strated in likely to be involved in mucus secretion9,10. almost all patients with current sym pto matic Although M4 and M5 receptors have been asthma an d even subjects with normal h ista- identified, the physiological roles of receptors mine or MCh airway responsiveness can devel- remain unknown. op symptoms of asthma if exposed to specific It should be n oted that in hibiting M1 and stimuli to which they are sensitized, such as an M3 r eceptors results in a beneficial reduction inhaled allergen or toluene diisocyanate. in b ro nch oconstriction , wh ereas inh ib itin g M e a s u rements of airways re s p o n s i v e n e s s M2 receptors p ro duces th e opp osite eff e c t . to in h aled bro n ch o co n stricto r m ed iato rs T h e re f o re the id eal anticholinergic drug for (such as MCh) can be useful in making a di- airways bronchoconstriction would preferen- agn osis o f asth ma, particu larly in p atien ts tially antagonize M1 and M3 receptors or the with symptoms of asthma with no evidence of M 3 receptor alone, with little affinity for the airflow obstruction.