Tiotropium bromide

Tiotropium bromide, sold under the brandname Spiriva among others, is a long-acting bronchodilator used in the management of chronic obstructive pulmonary disease (COPD) and asthma.[4][1] Specifically it is used to try to prevent periods of worsening rather than for those periods themselves.[4] It is used by inhalation through the mouth.[4] Onset typically begins within half an hour and lasts for 24 hours.[4]

Tiotropium
Clinical data
Trade namesSpiriva, Braltus[1]
AHFS/Drugs.comMonograph
MedlinePlusa604018
License data
Pregnancy
category
    Routes of
    administration    		Inhalation by mouth
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • UK: POM (Prescription only) [3]
    • US: ℞-only
    Pharmacokinetic data
    Bioavailability19.5% (inhalation)
    MetabolismLiver 25%
    (CYP2D6, CYP3A4)
    Elimination half-life5–6 days
    ExcretionKidney
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    PDB ligand
    CompTox Dashboard (EPA)
    ECHA InfoCard100.234.575
    Chemical and physical data
    FormulaC19H22BrNO4S2
    Molar mass472.416 g/mol g·mol−1
    3D model (JSmol)
      (verify)

    Common side effects include a dry mouth, runny nose, upper respiratory tract infection, shortness of breath and headache.[4] Severe side effects may include angioedema, worsening bronchospasm, and QT prolongation.[4] Tentative evidence has not found harm during pregnancy, however, such use has not been well studied.[2] It is an anticholinergic medication and works by blocking acetylcholine action on smooth muscle.[4]

    Tiotropium was patented in 1989, and approved for medical use in 2002.[5] It is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[6] In the United States the wholesale cost was about US$13.75 per dose as of 2019.[7] In the United Kingdom a dose costs the NHS about 0.86 pounds as of 2019.[1] In 2017, it was the 82nd most commonly prescribed medication in the United States, with more than nine million prescriptions.[8][9] There is no generic version available in the United States as of 2019.[10]

    Medical uses

    Tiotropium is used for maintenance treatment of chronic obstructive pulmonary disease (COPD) which includes chronic bronchitis and emphysema.[11] It is not however used for acute exacerbations.[11]

    Adverse effects

    Adverse effects are mainly related to its antimuscarinic effects. Common adverse drug reactions (≥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).[12]

    Tiotropium and another member of its class ipratropium were linked to increased risk of heart attacks, stroke and cardiovascular death.[13] The U.S. Food and Drug Administration (FDA) requested further trials; these are now complete, and adequately resolve the previous safety concerns.[14]

    Tiotropium mist inhaler (Respimat) has been found to be associated with an increase of all cause mortality in people with COPD.[15]

    Mechanism of action

    Tiotropium is a muscarinic receptor 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 M3 muscarinic receptors[16] located on smooth muscle cells and submucosal glands. This leads to a reduction in smooth muscle contraction and mucus secretion and thus produces a bronchodilatory effect.

    References
    1. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 247–248. ISBN 9780857113382.
    2. "Tiotropium Use During Pregnancy". Drugs.com. Retrieved 31 January 2019.
    3. "Tiotropium (Braltus) 10mcg Inhalation Powder - Summary of Product Characteristics (SmPC)". (emc). 1 February 2019. Retrieved 14 April 2020.
    4. "Tiotropium Bromide Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 31 January 2019.
    5. Fischer, Jnos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 447. ISBN 9783527607495.
    6. World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl:10665/325771. WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
    7. "NADAC as of 2019-01-30". Centers for Medicare and Medicaid Services. Retrieved 31 January 2019.
    8. "The Top 300 of 2020". ClinCalc. Retrieved 11 April 2020.
    9. "Tiotropium - Drug Usage Statistics". ClinCalc. Retrieved 11 April 2020.
    10. "Generic Spiriva Availability". Drugs.com. Retrieved 31 January 2019.
    11. "Spiriva Handihaler". The American Society of Health-System Pharmacists. Retrieved 3 April 2011.
    12. Rossi S, ed. (2006). Australian Medicines Handbook. Adelaide.
    13. Singh S, Loke YK, Furberg CD (September 2008). "Inhaled anticholinergics and risk of major adverse cardiovascular events in patients with chronic obstructive pulmonary disease: a systematic review and meta-analysis". JAMA. 300 (12): 1439–50. doi:10.1001/jama.300.12.1439. PMID 18812535.
    14. "Follow-Up to the October 2008 Updated Early Communication about an Ongoing Safety Review of Tiotropium (marketed as Spiriva HandiHaler)". U.S. Food and Drug Administration (FDA). 14 January 2010. Archived from the original on 2 November 2017. Retrieved 20 December 2019.
    15. Singh, S; Loke, YK; Enright, PL; Furberg, CD (14 June 2011). "Mortality associated with tiotropium mist inhaler in patients with chronic obstructive pulmonary disease: systematic review and meta-analysis of randomised controlled trials". BMJ (Clinical Research Ed.). 342: d3215. doi:10.1136/bmj.d3215. PMC 3114950. PMID 21672999.
    16. Kato M, Komamura K, Kitakaze M (December 2006). "Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure". Circ. J. 70 (12): 1658–60. doi:10.1253/circj.70.1658. PMID 17127817.
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