Tiotropium bromide: Difference between revisions

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{{Short description|Long-acting bronchodilator in the maintenance of COPD and asthma}}
{{drugbox |
{{Use dmy dates|date=December 2019}}
| image = Tiotropium.png
{{Drugbox
| width = 150
| Watchedfields = changed
| image2 = Tiotropium-3D-balls.png
| verifiedrevid = 401634790
|IUPAC_name = (1&alpha;,2&beta;,4&beta;,7&beta;)-<br />7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-<br />3-oxa-9-azoniatricyclo[3.3.1.0<sup>2,4</sup>]nonane
| image = Tiotropium bromide.svg
| InChI = 1/C19H22NO4S2/c1-20(2)12-9-11(10-13(20)17-16(12)24-17)23-18(21)19(22,14-5-3-7-25-14)15-6-4-8-26-15/h3-8,11-13,16-17,22H,9-10H2,1-2H3/q+1/t11?,12-,13+,16-,17-/m0/s1
| width = 150
| InChIKey = LERNTVKEWCAPOY-MCGYIYAPBV
| alt =
| StdInChI = 1S/C19H22NO4S2/c1-20(2)12-9-11(10-13(20)17-16(12)24-17)23-18(21)19(22,14-5-3-7-25-14)15-6-4-8-26-15/h3-8,11-13,16-17,22H,9-10H2,1-2H3/q+1/t11?,12-,13+,16-,17-/m0/s1
| image2 = Tiotropium-3D-balls.png
| StdInChIKey = LERNTVKEWCAPOY-MCGYIYAPSA-N
| width2 =
| CAS_number = 186691-13-4
| alt2 =
| ChemSpiderID=21106396
| caption =
| ATC_prefix = R03
| ATC_suffix = BB04
| PubChem = 131950
| DrugBank = DB01409
| C=19 | H=22 | N=1 | O=4 | S=2 |charge=+
| molecular_weight = 472.42
| smiles = O=C(OC1C[C@H]2[N+](C)(C)[C@@H](C1)[C@@H]3O[C@@H]23)C(O)(c4cccs4)c5cccs5
| bioavailability = 19.5% (inhalation)
| metabolism = [[hepatic]] 25%<br />([[CYP2D6]], [[CYP3A4]])
| elimination_half-life = 5–6 days
| excretion = [[renal]]
| pregnancy_AU = B1
| pregnancy_US =
| pregnancy_category =
| legal_AU = S4
| legal_CA =
| legal_UK = POM
| legal_US = Rx-only
| legal_status =
| routes_of_administration = inhalation (oral)
}}


<!-- Clinical data -->
'''Tiotropium''' ('''Spiriva''') is a long-acting, 24 hour, [[anticholinergic]] [[bronchodilator]] used in the management of [[chronic obstructive pulmonary disease]] (COPD). Tiotropium bromide ([[International Nonproprietary Name|INN]]) capsules for inhalation are co-promoted by [[Boehringer-Ingelheim]] and [[Pfizer Inc.|Pfizer]] under the trade name '''Spiriva'''.
| pronounce =
| tradename = Spiriva, others
| Drugs.com = {{drugs.com|monograph|tiotropium-bromide}}
| MedlinePlus = a604018
| DailyMedID = Tiotropium bromide
| pregnancy_AU = B1
| pregnancy_AU_comment = <ref name=Preg2019 /><ref name="AusPAR: Tiotropium bromide" />
| pregnancy_category =
| routes_of_administration = [[Oral administration|By mouth]], [[Route of administration#Mouth inhalation|inhalation by mouth]]
| class =
| ATC_prefix = R03
| ATC_suffix = BB04
| ATC_supplemental =


<!-- Legal status -->
== Mode of delivery ==
| legal_AU = S4
The patient removes one tiotropium capsule from the blister pack, places it into the piercing chamber of the inhalation device and closes the mouthpiece.
| legal_AU_comment = <ref>https://www.ebs.tga.gov.au/servlet/xmlmillr6?dbid=ebs/PublicHTML/pdfStore.nsf&docid=E07D6674E971FA91CA258752004228AF&agid=(PrintDetailsPublic)&actionid=1 {{Dead link|date=February 2022}}</ref><ref>{{cite web | title=Tiotropium bromide | website=Therapeutic Goods Administration (TGA) | url=https://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=356952 | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201030/https://search.tga.gov.au/s/search.html?collection=tga-artg&profile=record&meta_i=356952 | url-status=live }}</ref><ref name="AusPAR: Tiotropium bromide">{{cite web | title=AusPAR: Tiotropium bromide | website=Therapeutic Goods Administration (TGA) | date=29 November 2016 | url=https://www.tga.gov.au/auspar/auspar-tiotropium-bromide | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201033/https://www.tga.gov.au/auspar/auspar-tiotropium-bromide | url-status=live }}</ref>
| legal_BR = <!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F-->
| legal_BR_comment =
| legal_CA = <!-- OTC, Rx-only, Schedule I, II, III, IV, V, VI, VII, VIII -->
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled-->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment = <ref>{{cite web | title=Spiriva 18 microgram inhalation powder, hard capsule - Summary of Product Characteristics (SmPC) | website=(emc) | date=15 January 2019 | url=https://www.medicines.org.uk/emc/product/1693/smpc | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201031/https://www.medicines.org.uk/emc/product/1693/smpc | url-status=live }}</ref><ref>{{cite web | title=Spiriva Respimat 2.5 microgram, inhalation solution - Summary of Product Characteristics (SmPC) | website=(emc) | date=14 January 2021 | url=https://www.medicines.org.uk/emc/product/407/smpc | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201024/https://www.medicines.org.uk/emc/product/407/smpc | url-status=live }}</ref><ref>{{cite web | title=Tiogiva 18 microgram, inhalation powder, hard capsule - Summary of Product Characteristics (SmPC) | website=(emc) | date=2 June 2021 | url=https://www.medicines.org.uk/emc/product/12556/smpc | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201029/https://www.medicines.org.uk/emc/product/12556/smpc | url-status=live }}</ref>
| legal_US = Rx-only
| legal_US_comment = <ref>{{cite web | title=Spiriva Handihaler- tiotropium bromide capsule | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=820839ef-e53d-47e8-a3b9-d911ff92e6a9 | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201030/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=820839ef-e53d-47e8-a3b9-d911ff92e6a9 | url-status=live }}</ref><ref>{{cite web | title=Spiriva Respimat- tiotropium bromide inhalation spray spray, metered | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b656b14-fcaa-2741-f6f0-e0be48971c02 | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201028/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=7b656b14-fcaa-2741-f6f0-e0be48971c02 | url-status=live }}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV-->
| legal_UN_comment =
| legal_status = <!--For countries not listed above-->


<!-- Pharmacokinetic data -->
The capsule is manually pierced, and the medication is inhaled through the mouthpiece. It is recommended that inhalations are repeated 2 to 3 times to ensure all medication is drawn from the capsule. When properly done, the capsule will make a distinctive flutter or rattle, audible to the patient.
| bioavailability = 19.5% (inhalation)
| protein_bound =
| metabolism = [[Liver]] 25%<br />([[CYP2D6]], [[CYP3A4]])
| metabolites =
| onset =
| elimination_half-life = 5–6 days
| duration_of_action =
| excretion = [[Kidney]]


<!-- Identifiers -->
Once the powder capsules are removed from the blister pack, it should be taken immediately via the inhalation device. If a capsule is exposed to the air, it will rapidly degrade to the point the dose will become ineffective. Any previously exposed capsules should be discarded.
| CAS_number_Ref = {{cascite|correct|CAS}}
| CAS_number2_Ref = {{cascite|correct|CAS}}
| CAS_number = 136310-93-5
| CAS_supplemental = <br />{{CAS|186691-13-4}} ([[cation]])
| PubChem = 5487426
| PubChem2 = 5487427
| PubChemSubstance =
| IUPHAR_ligand = 367
| DrugBank = DBSALT000348
| DrugBank2 = DB01409
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 10482095
| UNII_Ref = {{fdacite|correct|FDA}}
| UNII = XX112XZP0J
| UNII2_Ref = {{fdacite|correct|FDA}}
| UNII2 = 0EB439235F
| KEGG = D01929
| ChEBI = 90959
| ChEBI2 = 90960
| ChEMBL = 3545181
| ChEMBL2 = 1900528
| NIAID_ChemDB =
| PDB_ligand = 0HK
| synonyms =


<!-- Chemical and physical data -->
The capsules cannot be taken orally - they will not be effective as respiratory medication if absorbed through the gastrointestinal tract and may have side effects if absorbed via this route.
| IUPAC_name = (1α,2β,4β,7β)-<br />7-[(hydroxidi-2-thienylacetyl)oxy]-9,9-dimethyl-<br />3-oxa-9-azoniatricyclo[3.3.1.0<sup>2,4</sup>]nonane bromide
| C = 19 | H = 22 | Br = 1 | N = 1 | O = 4 | S = 2
| SMILES = C[N+]1(C2CC(CC1C3C2O3)OC(=O)C(C4=CC=CS4)(C5=CC=CS5)O)C.[Br-]
| SMILES2 = C[N+]1(C2CC(CC1C3C2O3)OC(=O)C(C4=CC=CS4)(C5=CC=CS5)O)C
| StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C19H22NO4S2.BrH/c1-20(2)12-9-11(10-13(20)17-16(12)24-17)23-18(21)19(22,14-5-3-7-25-14)15-6-4-8-26-15;/h3-8,11-13,16-17,22H,9-10H2,1-2H3;1H/q+1;/p-1/t11?,12-,13+,16-,17+;
| StdInChI2_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI2 = 1S/C19H22NO4S2/c1-20(2)12-9-11(10-13(20)17-16(12)24-17)23-18(21)19(22,14-5-3-7-25-14)15-6-4-8-26-15/h3-8,11-13,16-17,22H,9-10H2,1-2H3/q+1/t11?,12-,13+,16-,17-/m0/s1
| StdInChI_comment =
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = DQHNAVOVODVIMG-RGECMCKFSA-M
| StdInChIKey2_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey2 = LERNTVKEWCAPOY-FPISHFTHSA-N
| density =
| density_notes =
| melting_point =
| melting_high =
| melting_notes =
| boiling_point =
| boiling_notes =
| solubility =
| sol_units =
| specific_rotation =
}}


<!-- Definition and medical uses -->
== Mode of action ==
'''Tiotropium bromide''', sold under the brand name '''Spiriva''' among others, is a long-acting [[bronchodilator]] (LAMA: long acting muscarinic antagonist) used in the management of [[chronic obstructive pulmonary disease]] (COPD) and [[asthma]].<ref name=ASHF2019/><ref name=BNF76>{{cite book|title=British national formulary : BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=247–248|edition=76th}}</ref> Specifically it is used during periods of breathing difficulty to prevent them from getting worse, rather than to prevent them from happening.<ref name=ASHF2019/> It is used by inhalation through the mouth.<ref name=ASHF2019/> Onset typically begins within half an hour and lasts for 24 hours.<ref name=ASHF2019/>


<!-- Side effects and mechanism -->
Tiotropium is a [[muscarinic receptor]] [[receptor antagonist|antagonist]], often referred to as an antimuscarinic or [[anticholinergic]] agent. Although it does not display selectivity for specific muscarinic receptors, on topical application it acts mainly on M<sub>3</sub> muscarinic receptors<ref name="pmid17127817">{{cite journal |author=Kato M, Komamura K, Kitakaze M |title=Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure |journal=Circ. J. |volume=70 |issue=12 |pages=1658–60 |year=2006 |month=December |pmid=17127817 |doi= 10.1253/circj.70.1658|url=http://joi.jlc.jst.go.jp/JST.JSTAGE/circj/70.1658?from=PubMed |format={{Dead link|date=May 2010}}}}</ref> located on smooth muscle cells and submucosal glands not to produce [[smooth muscle]] contraction and mucus secretion, thus producing a [[bronchodilator]]y effect.
Common side effects include a dry mouth, runny nose, upper respiratory tract infection, shortness of breath and headache.<ref name=ASHF2019>{{cite web |title=Tiotropium Bromide Monograph for Professionals |url=https://www.drugs.com/monograph/tiotropium-bromide.html |website=Drugs.com |publisher=American Society of Health-System Pharmacists |access-date=31 January 2019 |archive-date=14 October 2018 |archive-url=https://web.archive.org/web/20181014165156/https://www.drugs.com/monograph/tiotropium-bromide.html |url-status=live }}</ref> Severe side effects may include [[angioedema]], worsening [[bronchospasm]], and [[QT prolongation]].<ref name=ASHF2019/> Tentative evidence has not found harm during [[pregnancy]], however, such use has not been well studied.<ref name=Preg2019>{{cite web |title=Tiotropium Use During Pregnancy |url=https://www.drugs.com/pregnancy/tiotropium.html |website=Drugs.com |access-date=31 January 2019 |archive-date=31 January 2019 |archive-url=https://web.archive.org/web/20190131145317/https://www.drugs.com/pregnancy/tiotropium.html |url-status=live }}</ref> It is an [[anticholinergic]] medication and works by blocking [[acetylcholine]] action on [[smooth muscle]].<ref name=ASHF2019/>


<!-- History and culture -->
== Clinical use ==
Tiotropium was patented in 1989, and approved for medical use in 2002.<ref>{{cite book | vauthors = Fischer J, Ganellin CR |title=Analogue-based Drug Discovery |date=2006 |publisher=John Wiley & Sons |isbn=9783527607495 |page=447 |url=https://books.google.com/books?id=FjKfqkaKkAAC&pg=PA447 }}</ref> It is on the [[WHO Model List of Essential Medicines|World Health Organization's List of Essential Medicines]].<ref name="WHO21st">{{cite book | vauthors = ((World Health Organization)) | title = World Health Organization model list of essential medicines: 21st list 2019 | year = 2019 | hdl = 10665/325771 | author-link = World Health Organization | publisher = World Health Organization | location = Geneva | id = WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO | hdl-access=free }}</ref> In 2021, it was the 134th most commonly prescribed medication in the United States, with more than 4{{nbsp}}million prescriptions.<ref>{{cite web | title=The Top 300 of 2021 | url=https://clincalc.com/DrugStats/Top300Drugs.aspx | website=ClinCalc | access-date=14 January 2024 | archive-date=15 January 2024 | archive-url=https://web.archive.org/web/20240115223848/https://clincalc.com/DrugStats/Top300Drugs.aspx | url-status=live }}</ref><ref>{{cite web | title = Tiotropium - Drug Usage Statistics | website = ClinCalc | url = https://clincalc.com/DrugStats/Drugs/Tiotropium | access-date = 14 January 2024}}</ref>
=== Indications ===


== Medical uses ==
Tiotropium is indicated as a daily, 24 hour, maintenance treatment of [[chronic obstructive pulmonary disease]] (COPD).
Tiotropium is used as maintenance treatment of [[chronic obstructive pulmonary disease]] (COPD).<ref name=pmid18836213>{{cite journal | vauthors = Tashkin DP, Celli B, Senn S, Burkhart D, Kesten S, Menjoge S, Decramer M | title = A 4-year trial of tiotropium in chronic obstructive pulmonary disease | journal = The New England Journal of Medicine | volume = 359 | issue = 15 | pages = 1543–1554 | date = October 2008 | pmid = 18836213 | doi = 10.1056/nejmoa0805800 | hdl-access = free | hdl = 2437/111564 }}</ref><ref>Pocket Guide to COPD Diagnosis, Management and Prevention [Internet] Fontana, WI The [[Global Initiative for Chronic Obstructive Lung Disease]] (GOLD) 2020 [Cited 12 April 2020] Available from: https://goldcopd.org/wp-content/uploads/2020/03/GOLD-2020-POCKET-GUIDE-ver1.0_FINAL-WMV.pdf {{Webarchive|url=https://web.archive.org/web/20200712065545/https://goldcopd.org/wp-content/uploads/2020/03/GOLD-2020-POCKET-GUIDE-ver1.0_FINAL-WMV.pdf |date=12 July 2020 }}</ref> It may also be used as an add-on therapy in people with moderate-to-severe asthma on medium to high dose inhaled corticosteroids (ICS).<ref>{{cite journal | vauthors = Rodrigo GJ, Castro-Rodríguez JA | title = What is the role of tiotropium in asthma?: a systematic review with meta-analysis | journal = Chest | volume = 147 | issue = 2 | pages = 388–396 | date = February 2015 | pmid = 25322075 | doi = 10.1378/chest.14-1698 }}</ref><ref>{{cite book |title=Global Strategy for Asthma Management and Prevention (2020 update) |date=2020 |publisher=GOLD |url=https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-final-_wms.pdf |access-date=10 May 2020 |archive-date=19 May 2020 |archive-url=https://web.archive.org/web/20200519202726/https://ginasthma.org/wp-content/uploads/2020/04/GINA-2020-full-report_-final-_wms.pdf |url-status=live }}</ref> It is not however approved for [[Acute exacerbation of chronic obstructive pulmonary disease|acute exacerbations of COPD]] or acute worsening of asthma.<ref name=ASHF2019/>


Tiotropium is also used in a combination inhaler with [[olodaterol]], a [[Long-acting beta agonist|long-acting beta-agonist]], for the treatment of COPD, under the brand names ''Stiolto'' and ''Spiolto'' among others.<ref>{{cite web | title=Spiolto Respimat 2.5 microgram/2.5 microgram, inhalation solution - Summary of Product Characteristics (SmPC) | website=(emc) | date=14 January 2021 | url=https://www.medicines.org.uk/emc/product/6902/smpc | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201028/https://www.medicines.org.uk/emc/product/6902/smpc | url-status=live }}</ref><ref>{{cite web | title=Yanimo Respimat 2.5 microgram/2.5 microgram, inhalation solution - Summary of Product Characteristics (SmPC) | website=(emc) | date=14 January 2021 | url=https://www.medicines.org.uk/emc/product/10728/smpc | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201026/https://www.medicines.org.uk/emc/product/10728/smpc | url-status=live }}</ref><ref>{{cite web | title=Stiolto Respimat- tiotropium bromide and olodaterol spray, metered | website=DailyMed | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=01e15aee-40e0-23f3-537f-c96dd63e2cb1 | access-date=30 September 2021 | archive-date=1 October 2021 | archive-url=https://web.archive.org/web/20211001201023/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=01e15aee-40e0-23f3-537f-c96dd63e2cb1 | url-status=live }}</ref>
=== Adverse effects ===


== Adverse effects ==
Adverse effects are mainly related to its antimuscarinic effects. Common [[adverse drug reaction]]s (≥1% of patients) associated with tiotropium therapy include: dry mouth and/or throat irritation. Rarely (<0.1% of patients) treatment is associated with: [[urinary retention]], constipation, acute [[angle closure glaucoma]], palpitations (notably [[supraventricular tachycardia]] and [[atrial fibrillation]]) and/or allergy (rash, [[angioedema]], [[anaphylaxis]]).<ref>Rossi S, editor. [[Australian Medicines Handbook]] 2006. Adelaide: Australian Medicines Handbook; 2006</ref>


Adverse effects are mainly related to its [[antimuscarinic]] effects. Common [[adverse drug reaction]]s (≥1% of people) include: dry mouth and/or throat irritation. Rarely (<0.1% of patients) treatment is associated with: [[urinary retention]], constipation, acute [[angle closure glaucoma]], palpitations (notably [[supraventricular tachycardia]] and [[atrial fibrillation]]) and allergy (rash, [[angioedema]], [[anaphylaxis]]).<ref>{{cite book | veditors = Rossi S |title=Australian Medicines Handbook |location=Adelaide |year=2006 |title-link=Australian Medicines Handbook }}</ref> A 2006 review found the increase in bronchospasm was small and did not reach statistical significance.<ref>{{cite journal | vauthors = Kesten S, Jara M, Wentworth C, Lanes S | title = Pooled clinical trial analysis of tiotropium safety | journal = Chest | volume = 130 | issue = 6 | pages = 1695–1703 | date = December 2006 | pmid = 17166984 | doi = 10.1378/chest.130.6.1695 }}</ref>
A study of more than 15,000 patients published in the Journal of the American Medical Association in 2008 linked tiotropium and another member of its class ipratropium to increased risk of heart attacks, stroke and cardiovascular death.<ref>Singh S, Loke YK, Furberg CD. Inhaled anticholinergics and the risk of major adverse cardiovascular events. JAMA 2008;300(12)1439-1450.</ref>


Data regarding some serious side effects is mixed as of 2020.<ref name=ASHF2019/> In September 2008 a review found that tiotropium and another member of its class [[ipratropium]] may be linked to increased risk of heart attacks, stroke and cardiovascular death.<ref>{{cite journal | vauthors = Singh S, Loke YK, Furberg CD | title = Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis | journal = JAMA | volume = 300 | issue = 12 | pages = 1439–1450 | date = September 2008 | pmid = 18812535 | doi = 10.1001/jama.300.12.1439 }}</ref> The US FDA reviewed the concern and concluded in 2010 that this association was not supported.<ref name=pmid18836213/><ref>{{cite web | title=Follow-Up to the October 2008 Updated Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler) | website=U.S. [[Food and Drug Administration]] (FDA) | date=14 January 2010 | url=https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm197429.htm | archive-url=https://web.archive.org/web/20171102214206/https://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm197429.htm | archive-date=2 November 2017 | url-status=dead | access-date=20 December 2019}}</ref> A 2011 review of the tiotropium mist inhaler ([[Respimat]]); however, still found an associated with an increase in all cause mortality in people with COPD.<ref>{{cite journal | vauthors = Singh S, Loke YK, Enright PL, Furberg CD | title = Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials | journal = BMJ | volume = 342 | pages = d3215 | date = June 2011 | pmid = 21672999 | pmc = 3114950 | doi = 10.1136/bmj.d3215 }}</ref>
In 2010 the FDA announced it had completed its analysis of the Understanding the Potential Long-Term Impacts on Function with Tiotropium (UPLIFT) trial. UPLIFT was a large, 4-year clinical trial that compared Spiriva HandiHaler to placebo in 5,992 patients.


== Mechanism of action ==
In the UPLIFT trial, there was no significant increase in the risk of stroke, heart attack, or cardiovascular death between Spiriva HandiHaler and placebo.


Tiotropium is a [[muscarinic receptor]] [[receptor antagonist|antagonist]], often referred to as an antimuscarinic or [[anticholinergic]] agent. Although it does not display selectivity for specific muscarinic receptors, when topically applied it acts mainly on [[Muscarinic acetylcholine receptor M3|M<sub>3</sub>]] muscarinic receptors<ref name="pmid17127817">{{cite journal | vauthors = Kato M, Komamura K, Kitakaze M | title = Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure | journal = Circulation Journal | volume = 70 | issue = 12 | pages = 1658–1660 | date = December 2006 | pmid = 17127817 | doi = 10.1253/circj.70.1658 | doi-access = free }}</ref> located on smooth muscle cells and submucosal glands. This leads to a reduction in [[smooth muscle]] contraction and mucus secretion and thus produces a [[bronchodilator]]y effect.{{cn|date=February 2022}}
In November 2009, the FDA Pulmonary - Allergy Drugs Advisory Committee also reviewed data from the UPLIFT trial and voted that the UPLIFT findings adequately resolve the safety concerns for stroke, heart attack and cardiovascular death.<ref>FDA. Follow-Up to the October 2008 Updated Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler). FDA 2010</ref>


==Society and culture==
== Image collection ==
Tiotroprium is available in two inhaler formats: a soft mist inhaler (''Respimat'') and a dry powder inhaler (''HandiHaler'').<ref name=Dah2016/> The safety and efficacy profiles of both devices are comparable and people's preference should play a role in determining inhaler choice.<ref name=Dah2016>{{cite journal | vauthors = Dahl R, Kaplan A | title = A systematic review of comparative studies of tiotropium Respimat® and tiotropium HandiHaler® in patients with chronic obstructive pulmonary disease: does inhaler choice matter? | journal = BMC Pulmonary Medicine | volume = 16 | issue = 1 | pages = 135 | date = October 2016 | pmid = 27724909 | pmc = 5057252 | doi = 10.1186/s12890-016-0291-4 | doi-access = free }}</ref> There is no significant difference in all-cause [[Mortality rate|mortality]] between tiotropium soft mist inhalers compared to dry powder inhalers, however caution needs to be taken in people with severe heart or kidney problems.<ref>{{cite journal | vauthors = Wise RA, Anzueto A, Cotton D, Dahl R, Devins T, Disse B, Dusser D, Joseph E, Kattenbeck S, Koenen-Bergmann M, Pledger G, Calverley P | display-authors = 6 | title = Tiotropium Respimat inhaler and the risk of death in COPD | journal = The New England Journal of Medicine | volume = 369 | issue = 16 | pages = 1491–1501 | date = October 2013 | pmid = 23992515 | doi = 10.1056/NEJMoa1303342 | doi-access = free }}</ref>

<gallery>
{| border="0" cellpadding="0" cellspacing="0"
|[[Image:Spiriva3.png|thumb|Front view]]
Image:Spiriva3.png
Image:"Spiriva HandiHaler"-brand dry powder inhaler (open).png
|[[Image:Tiocap.png|thumb|160px|A previously pierced Spiriva capsule]]
</gallery>
|[[Image:SP2.png|thumb|Open (cleaning) view]]
|}

== See also ==
* [[Chronic obstructive pulmonary disease]] (COPD)


== References ==
== References ==
{{Reflist|2}}
{{Reflist}}


{{Asthma and copd rx}}
== External links ==
{{Muscarinic acetylcholine receptor modulators}}
* [http://spiriva.com/ Official SPIRIVA Site]
{{Portal bar | Medicine}}
* [http://www.centerwatch.com/patient/drugs/dru848.html Thomson CenterWatch]

{{Asthma_and_copd_rx}}
{{Cholinergics}}


[[Category:Drugs developed by Boehringer Ingelheim]]
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