Tiotropium


Article Author:
Benjamin Delgado


Article Editor:
Tushar Bajaj


Editors In Chief:
James Beauchamp
Mark Pellegrini
Nicole Hale-Crutch


Managing Editors:
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Frank Smeeks
Kristina Soman-Faulkner
Benjamin Eovaldi
Radia Jamil
Sobhan Daneshfar
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Steve Bhimji
John Shell
Matthew Varacallo
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Hajira Basit
Phillip Hynes
Kavin Sugumar


Updated:
4/29/2019 7:29:11 PM

Indications

Tiotropium is a long-acting muscarinic antagonist medication that has shown to provide promising therapeutic benefits for patients with chronic obstructive pulmonary disease (COPD). The "Understanding Potential Long-Term Impacts on Function with Tiotropium" study also known as UPLIFT, established that tiotropium use in patients with COPD resulted in three significant findings. First participants of the experimental group receiving tiotropium had a reduced risk of COPD exacerbations, second, when compared to the placebo group, the experimental group had an overall improved lung function and quality of life through the course of the 4-year trial, and thirdly the tiotropium reduced respiratory and cardiac morbidity in COPD patients.[1] 

Further studies of the use of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild COPD with a FEV1 80% or more of normal), and GOLD stage 2 (moderate COPD with a FEV1 between 50% to 80% of normal) resulted in a lower rate of disease progression as measured by postbronchodilator FEV1, suggesting that tiotropium use in early stages of COPD was beneficial for patients.[2][3] Additional studies conducted on the benefits of tiotropium use in COPD patients found the following: proven to increase walking endurance exercise, improve exercise tolerance when used in combination with pulmonary rehabilitation, decreased COPD related hospitalizations, reduce air trapping and exertional dyspnea (both of which are complications of obstructive lung disease).[4][5][3][6] There is also a combined tiotropium and olodaterol (long-acting beta-agonist or LABA) therapy available on the market. When dual bronchodilator therapy of tiotropium and olodaterol versus the use of tiotropium monotherapy was studied, there was improved quality of life and lung function among patients with GOLD stage 2 to GOLD stage 4 COPD (moderate to very severe COPD).[7][8]

Tiotropium has also shown to provide promising therapeutic benefits for pediatric to adolescent age patients with symptomatic moderate to severe asthma. In a 1-year randomized controlled trial that studied the use of tiotropium as add on therapy to inhaled corticosteroids maintenance therapy for adolescent patients with moderate asthma, the results were significant (p less than 0.001 for 5mcg of tiotropium; p less than 0.01 for 2.5mcg of tiotropium) for improved peak FEV1 at 24 weeks on spirometry.[9] When tiotropium was studied in a randomized controlled trial in pediatric patients with severe asthma as an add on therapy in addition to either medium dose inhaled corticosteroids or high-dose inhaled corticosteroids with either 1 or more controller medications or 2 or more controller medications respectively, the study results were significant (p less than 0.001 for 5mcg of tiotropium) for improvements in peak and trough FEV1 on spirometry.[10] Both studies showed that tiotropium has an overall improvement in lung function in symptomatic pediatric asthma.

 Clinically, the use of tiotropium includes the following FDA-approved indications and use:

  • Reduction of bronchospasm
  • Reduction of COPD exacerbations
  • Maintenance therapy of asthma in patients older than 6-years-old
  • Maintenance therapy for patients with chronic obstructive lung disease (COPD) 
  • Maintenance therapy for bronchitis
  • Maintenance therapy for emphysema  

A non-FDA approved use (or off label use) of tiotropium includes:

  • The use of tiotropium as add-on therapy to inhaled corticosteroids and other maintenance therapies for pediatric patients from over 6 years to 11 years old.[10]

The use of combination tiotropium and olodaterol therapy (LAMA/LABA dual bronchodilator therapy) includes the following FDA-approved indications:

  • Maintenance therapy for patients with chronic obstructive lung disease (COPD)
  • Maintenance therapy for bronchitis
  • Maintenance therapy for emphysema  

Mechanism of Action

Tiotropium is a second generation is a long-acting muscarinic receptor antagonist that exerts its primary therapeutic effect on the M1, M2, and M3 muscarinic acetylcholine receptors (mAChRs) in the lungs preventing acetylcholine binding. Once the patient inhales the medication as either an inhalation spray or inhalation powder, the quaternary ammonium compound reversibly binds to M1 mAChRs of the nerve ganglia of the lung, M2 mAChRs postganglionic nerve fibers of the lung, and M3 mAChRs of the smooth muscles and mucous glands of the lung. Specifically when tiotropium binds to the M1 and M3 mAChRs, this molecule ultimately inhibiting Gq alpha-protein stimulation of phospholipase C pathway preventing the influx of intracellular calcium from inducing a cellular response in the respiratory airways.[11] The overall effect of tiotropium anticholinergic effect on the respiratory airway is bronchodilation, decreased mucus gland secretions, decrease the ciliary beat frequency, inhibition of fibroblast proliferation, and exhibit a poorly understood anti-inflammatory effect in the lungs.[11][12] 

A unique chemical property of tiotropium is that it is a quaternary ammonium compound, this makes the medication readily highly specific to targeting the mAChRs of the respiratory pathway without the capability to be absorbed across the alveolar-capillary beds to enter the systemic circulation. Of the three mAChRs tiotropium has equal binding capabilities to the M1, M2, and M3 mAChRs in the lungs, but has been observed to have prolonged anticholinergic effect only on the M1 mAChRs and M3 mAChRs and rapid dissociation to the M2 mAChRs.[13][12]

Administration

Tiotropium may be prescribed as either an inhalation spray or inhalation powder administered by an inhaler device. Before using tiotropium inhalers, the inhaler device requires assembly and loading the medication cartilage into the inhaler device followed by priming. Proper priming of the tiotropium inhaler allows adequate medication dose delivery for oral inhalation use. The inhaler device designed to deliver tiotropium medication consists of a cap, mouthpiece, air vent, a dose indicator, and a dose release button. The dose indicator located on the side of the device estimates the remaining amount of puffs in the medication cartilage available for use.  

How to Use Tiotropium Inhaler

 The daily use of the inhaler consist of the following steps: 

  1. Remove the cap from inhaler device exposing the mouthpiece and the air vent.
  2. Exhale the maximum volume of air from the lungs without inhaling air back into the lungs. 
  3. Place the mouthpiece of the inhaler to the mouth, creating a tight seal with the lips around the mouthpiece without covering the air vents on the side of the inhaler device. The mouthpiece should be aimed at the back of the throat, avoiding the front of the teeth and tongue.
  4. While holding the inhaler to the mouth, slowly inhale air through the mouthpiece of the inhaler device while simultaneously pressing the dose release button and continuing to slowly inhale air into the lung as tolerable. 
  5. Once the tolerable maximum volume of air inhalation is reached, remove the mouthpiece of the inhaler from the mouth.
  6. Hold the breath for 10 seconds, followed by exhaling and breathing normally. 
  7. Repeat this process as prescribed by your health care provider.
  8. Close the cap on the inhaler device when completed.

Available Tiotropium Preparations 

Inhalation Spray

  • 2.5 mcg of tiotropium bromide for the treatment of COPD.
  • 1.25 mcg of tiotropium bromide for the treatment of asthma patients 6 years of age and older.  

Inhalation Powder

  • 18 mcg of tiotropium bromide powder capsules used with the inhaler device as maintenance therapy of COPD and reduction in associated COPD exacerbations and bronchospasms. 

Tiotropium Bromide and Olodaterol Inhalation Spray

  • Dual bronchodilator mixture of 3.124 mcg tiotropium bromide monohydrate and 2.736 mcg olodaterol hydrochloride for maintenance therapy of COPD.

Adverse Effects

Tiotropium Bromide

The most frequently encountered adverse effects of tiotropium include pharyngitis, bronchitis, sinusitis, dry mouth, cough, and headaches. Less common side effects of tiotropium includes insomnia, cataract, blurry vision, epistaxis, rhinitis, laryngitis, dysphagia, gingivitis, chest pain and palpitations, joint swelling, abdominal pain, gastroesophageal reflux disease,  paralytic ileus of the intestine, abnormal liver function test, dysuria, urinary retention, angioedema, dry skin, herpes zoster, and dehydration.[13]   

Tiotropium Bromide and Olodaterol Combination Therapy 

The most common adverse effects tiotropium bromide and olodaterol combination therapy include nasopharyngitis, cough, and back pain. Less common side effects of tiotropium bromide and olodaterol combination therapy includes dehydration, dizziness, insomnia, glaucoma, elevated intraocular pressure, vision blurred, epistaxis, dry mouth, pharyngitis, dysphonia, bronchospasm, laryngitis, sinusitis, atrial fibrillation, palpitations, supraventricular tachycardia, tachycardia, hypertension, oropharyngeal candidiasis, dysphagia, gastroesophageal reflux disease, gingivitis, glossitis, stomatitis, paralytic ileus of the intestine, hypokalemia, constipation, urinary retention, dysuria, rash, pruritus, dry skin, edema, arthralgia, joint swelling.[14] 

Contraindications

Tiotropium bromide and combination therapy of tiotropium bromide and olodaterol are not indicated for treatment and relief of acute bronchospasm. 

Tiotropium Bromide

Tiotropium bromide is contraindicated in patients with a hypersensitivity to tiotropium, ipratropium, and atropine (due to the risk of anaphylaxis) and narrow-angle glaucoma. Powder tiotropium capsules contain milk protein and are contraindicated for use in patients with allergies to milk. Tiotropium has links to increased risk of heart attacks, stroke, and cardiovascular death. The use of tiotropium in pregnancy has not yet been shown to pose any risk to maternal or fetal complications. The results of animal studies conducted on tiotropium use during the pregnancy of rats and rabbits resulted in no anatomical abnormalities in offspring.  

Tiotropium Bromide and Olodaterol Combination Therapy 

Tiotropium bromide and olodaterol combination therapy are contraindicated in patients with a hypersensitivity to tiotropium, Ipratropium, olodaterol, and atropine (due to the risk of anaphylaxis), and glaucoma. This medication is also contraindicated for the use of patients with asthma with a described US Boxed Warning for increasing the risk of asthma-related deaths. The literature lacks information on tiotropium bromide and olodaterol during human pregnancy and the use in animal reproductive studies; so it currently classifies as pregnancy risk category C.

Monitoring

Patients that are prescribed tiotropium for the treatment of COPD should follow up regularly with their prescribing provider for the monitoring of adverse effects and obstructive lung disease progression. Although tiotropium his poor absorption across the pulmonary capillaries for systemic circulation, the development of urinary retention and narrow-angle glaucoma has been described as adverse effects that can result in dysuria and permanent vision damage respectively.[13] Prescribing providers may want to monitor the patient for medication compliance, and obstructive lung disease progression by regular follows in the clinic. Monitoring for obstructive lung disease progression may consist of inquiring a patients history of COPD exacerbations and pulmonary function testing by measurement of FEV1 and peak flow lung volumes by spirometry.   

Toxicity

Tiotropium demonstrates poor absorption across both the respiratory alveolar capillaries and gastrointestinal tract; therefore the risk of systemic medication toxicity is unlikely. Although high doses of tiotropium correlates with anticholinergic side effects, a review of the literature describes two incidences of high dose tiotropium inhalation/ingestion with unique outcomes. First, a case report of a 74-year-old male with accidental ingestion of a total of 90 mcg of powered tiotropium capsules caused refractory tachycardia that was managed by physostigmine, metoprolol tartrate, and diltiazem.[15] This case report concluded that the patient had a resolution of tachycardia after five days of treatment. Secondly, in a volunteered trial of inhalation of 282 mcg of tiotropium among six individuals, there were no systemic anticholinergic adverse effects observed.[13] If accidental overdose of tiotropium occurs, appropriate treatment consists of discontinuation of the use of the medication.

Enhancing Healthcare Team Outcomes

COPD is a chronic disease that results in the loss of lung function and ultimately the development of life-threatening complications if left untreated. Tiotropium has numerous benefits as maintenance therapy in patients with COPD, and it is crucial that physicians and pharmacists carefully educate patients about their medication adherence and compliance with chronic therapy in addition to describing the adverse side effects of tiotropium. Patient education should include teaching patients the difference between maintenance inhaler therapy and rescue inhaler therapies. As tiotropium is a maintenance therapy for COPD and asthma, patients must understand that tiotropium offers no rescue benefits in the event of an acute exacerbation of COPD or bronchospasm. Physicians, pharmacists, nursing staff, and other providers should be able to properly demonstrate the assembling and priming of a tiotropium inhaler to patients as this may be challenging to patients who have never used an inhaler device before. A provider's ability to teach and demonstrate to a patient the proper technique of using the inhaler device plays a critical role in medication efficacy.

While smoking remains one of the leading causes of COPD in the United States, physicians, nurses, and pharmacists should assess for cigarette smoking during the treatment of COPD. Smoking cessation should always be encouraged by healthcare providers, as this may decrease the mortality and risk of complications in patients with COPD. Tiotropium therapy is not described to have interactions with cigarette smoking, although it is well established that smoking may alter the metabolism of medications in the liver.[16] The gaining popularity of hookah, vapor THC, flavored nicotine vapor products, and electronic cigarettes continues to increase, and the effects of the development of COPD and effects of chronic use of these products remains an area of research that requires further investigation.

As described above, tiotropium therapy requires a collaborative interprofessional effort between physicians, nurses, and pharmacists to ensure patient compliance and optimal therapeutic outcomes. [Level V]


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Tiotropium - Questions

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A 16-year-old male patient presents to the emergency room following accidentally self-administering 4 puffs of his grandmother's 2.5 mcg of tiotropium inhaler, receiving a total of 10 mcg of the medication. The adolescent claims to have been playing with the inhaler device and self administer the medication out of curiosity. On physical exam he is asymptomatic. Vital signs: blood pressure 100/20 mmHg, respiratory rate 8/minute, heart rate 70 bpm, temperature 36 F, and pulse oximetry on room air 99%. What characteristics of tiotropium allowed this patient to remain asymptomatic of systemic symptoms of tiotropium toxicity?



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An 80-year-old male presents with the following pulmonary function test results: increase residual lung volume, forced expiratory volume in one second (FEV1)/forced vital capacity (FVC) ratio less than 0.07, FEV1 between 50% to 80% of normal. Which medication is the recommended maintenance therapy based on this patient's spirometry results?



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A 74-year-old male was recently discharged from the hospital for what he describes an episode of cough attacks and shortness of breath. In the last 14 months, the patient has had two admissions to the hospital for related complaints in which he required treatment with inhaled corticosteroids and short-acting beta agonist. He has a social history significant for 55 pack-years of tobacco smoking and recently quit smoking three months ago. Which of the long-acting bronchodilators is first-line therapy in patients with persistent pulmonary disease symptoms?



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Tiotropium - References

References

Decramer M,Celli B,Kesten S,Lystig T,Mehra S,Tashkin DP, Effect of tiotropium on outcomes in patients with moderate chronic obstructive pulmonary disease (UPLIFT): a prespecified subgroup analysis of a randomised controlled trial. Lancet (London, England). 2009 Oct 3;     [PubMed]
Bédard ME,Brouillard C,Pepin V,Provencher S,Milot J,Lacasse Y,Leblanc P,Maltais F, Tiotropium improves walking endurance in COPD. The European respiratory journal. 2012 Feb;     [PubMed]
Casaburi R,Kukafka D,Cooper CB,Witek TJ Jr,Kesten S, Improvement in exercise tolerance with the combination of tiotropium and pulmonary rehabilitation in patients with COPD. Chest. 2005 Mar;     [PubMed]
Tashkin DP,Celli B,Senn S,Burkhart D,Kesten S,Menjoge S,Decramer M, A 4-year trial of tiotropium in chronic obstructive pulmonary disease. The New England journal of medicine. 2008 Oct 9;     [PubMed]
O'Donnell DE,Flüge T,Gerken F,Hamilton A,Webb K,Aguilaniu B,Make B,Magnussen H, Effects of tiotropium on lung hyperinflation, dyspnoea and exercise tolerance in COPD. The European respiratory journal. 2004 Jun;     [PubMed]
Zhou Y,Zhong NS,Li X,Chen S,Zheng J,Zhao D,Yao W,Zhi R,Wei L,He B,Zhang X,Yang C,Li Y,Li F,Du J,Gui J,Hu B,Bai C,Huang P,Chen G,Xu Y,Wang C,Liang B,Li Y,Hu G,Tan H,Ye X,Ma X,Chen Y,Hu X,Tian J,Zhu X,Shi Z,Du X,Li M,Liu S,Yu R,Zhao J,Ma Q,Xie C,Li X,Chen T,Lin Y,Zeng L,Ye C,Ye W,Luo X,Zeng L,Yu S,Guan WJ,Ran P, Tiotropium in Early-Stage Chronic Obstructive Pulmonary Disease. The New England journal of medicine. 2017 Sep 7;     [PubMed]
Han MK,Ray R,Foo J,Morel C,Hahn B, Systematic literature review and meta-analysis of US-approved LAMA/LABA therapies versus tiotropium in moderate-to-severe COPD. NPJ primary care respiratory medicine. 2018 Aug 27;     [PubMed]
Buhl R,Maltais F,Abrahams R,Bjermer L,Derom E,Ferguson G,Fležar M,Hébert J,McGarvey L,Pizzichini E,Reid J,Veale A,Grönke L,Hamilton A,Korducki L,Tetzlaff K,Waitere-Wijker S,Watz H,Bateman E, Tiotropium and olodaterol fixed-dose combination versus mono-components in COPD (GOLD 2-4). The European respiratory journal. 2015 Apr;     [PubMed]
Hamelmann E,Bateman ED,Vogelberg C,Szefler SJ,Vandewalker M,Moroni-Zentgraf P,Avis M,Unseld A,Engel M,Boner AL, Tiotropium add-on therapy in adolescents with moderate asthma: A 1-year randomized controlled trial. The Journal of allergy and clinical immunology. 2016 Aug;     [PubMed]
Szefler SJ,Murphy K,Harper T 3rd,Boner A,Laki I,Engel M,El Azzi G,Moroni-Zentgraf P,Finnigan H,Hamelmann E, A phase III randomized controlled trial of tiotropium add-on therapy in children with severe symptomatic asthma. The Journal of allergy and clinical immunology. 2017 Nov;     [PubMed]
Lubiński W, [Tiotropium as a controller of bronchoconstriction]. Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego. 2004 May;     [PubMed]
Belmonte KE, Cholinergic pathways in the lungs and anticholinergic therapy for chronic obstructive pulmonary disease. Proceedings of the American Thoracic Society. 2005;     [PubMed]
ZuWallack AR,ZuWallack RL, Tiotropium bromide, a new, once-daily inhaled anticholinergic bronchodilator for chronic-obstructive pulmonary disease. Expert opinion on pharmacotherapy. 2004 Aug;     [PubMed]
Dhillon S, Tiotropium/Olodaterol: A Review in COPD. Drugs. 2016 Jan;     [PubMed]
Gregory MD,Mersfelder TL,Jamieson T, Accidental overdose of tiotropium in a patient with atrial fibrillation. The Annals of pharmacotherapy. 2010 Feb;     [PubMed]
Kroon LA, Drug interactions and smoking: raising awareness for acute and critical care providers. Critical care nursing clinics of North America. 2006 Mar;     [PubMed]

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