Continuing Education Activity

Tiotropium maintenance therapy has well-established benefits for treating chronic obstructive lung disease. Mortality in chronic obstructive lung disease is often due to complications, including hyperinflation, decreased exercise tolerance, pulmonary infections, and chronic obstructive lung disease exacerbations. Tiotropium has been extensively studied in clinical trials and proven to prevent the progression of obstructive lung disease and these complications. This activity reviews the indications and contraindications, adverse effects, and monitoring of tiotropium. This activity also highlights the role of the interprofessional team in collaborating to manage patients who are using tiotropium.

Objectives:

• Identify the mechanism of action of tiotropium.

• Determine contraindications to tiotropium use.

• Evaluate tiotropium toxicity.

• Communicate working relationships among interprofessional healthcare providers to promote the safe use of tiotropium and promote medication adherence.

Indications

Tiotropium is a long-acting muscarinic antagonist medication that provides promising therapeutic benefits for chronic obstructive pulmonary disease (COPD) patients.

FDA-Approved Indications

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

A Non-FDA-Approved Use

• The use of tiotropium as an add-on therapy to inhaled corticosteroids and other maintenance therapies for pediatric patients from 6 to 11 years old.[1]

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  

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 3 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.[2]

Further studies of the use of tiotropium in patients with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage 1 (mild COPD with an FEV1 80% or more of normal) and GOLD stage 2 (moderate COPD with an 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.[3][4] 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, decrease COPD-related hospitalizations, reduce air trapping and exertional dyspnea (both of which are complications of obstructive lung disease).[4][5][6][7] A combined tiotropium and olodaterol (long-acting beta-agonist or LABA) therapy is also 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).[8][9]

Tiotropium has also shown promising therapeutic benefits for pediatric to adolescent 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 corticosteroid maintenance therapy for adolescent patients with moderate asthma, the results were significant (p less than 0.001 for 5 mcg of tiotropium; p less than 0.01 for 2.5 mcg of tiotropium) for improved peak FEV1 at 24 weeks on spirometry.[10] 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 two or more controller medications, respectively, the study results were significant (p less than 0.001 for 5 mcg of tiotropium) for improvements in peak and trough FEV1 on spirometry.[1] Both studies showed that tiotropium has an overall improvement in lung function in symptomatic pediatric asthma.

Mechanism of Action

Tiotropium is a second-generation and 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 inhibits Gq alpha-protein stimulation of the phospholipase C pathway, preventing intracellular calcium influx from inducing a cellular response in the respiratory airways.[11] The overall effect of tiotropium's anticholinergic effect on the respiratory airway is bronchodilation, decreased mucous gland secretions, decreased ciliary beat frequency, inhibition of fibroblast proliferation, and it exhibits 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 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 3 mAChRs, tiotropium has equal binding capabilities to the lungs' M1, M2, and M3 mAChRs. Still, it has been observed to have a 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 an inhalation spray or inhalation powder administered by an inhaler. Before using tiotropium inhalers, the inhaler device requires assembly and loading of the medication cartilage into the inhaler device, followed by priming. Proper priming of the tiotropium inhaler allows adequate medication delivery for oral inhalation. 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 on the side of the device estimates the remaining puffs in the medication cartilage available for use.

Available Tiotropium Preparations 

Inhalation spray

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

Inhalation powder

• 18 mcg of tiotropium bromide powder capsules are used with the inhaler device as maintenance therapy for COPD and to reduce 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.

Tiotropium Inhaler

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

1. First, remove the cap from the 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 inhaler's mouthpiece in 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 inhale air slowly into the lung, as tolerable. 
5. Remove the inhaler's mouthpiece from the mouth upon reaching the tolerable maximum volume of air inhalation.
6. Hold the breath for 10 seconds, followed by exhaling and breathing normally. 
7. Repeat this process as prescribed by your healthcare provider.
8. Close the cap on the inhaler device when completed.

Adult Dosing

Asthma 

• Tiotropium oral mist inhaler (1.25 mcg/actuation) 2 inhalations once daily.

COPD

• Dry powder oral inhaler (18 mcg/capsule) inhale the contents of 1 capsule once daily using a HandiHaler device. The contents of each capsule dose should be inhaled twice to ensure complete delivery of dosage.
• Tiotropium mist inhaler (2.5 mcg/actuation) 2 inhalations once daily. 

Specific patient population

• No dose adjustment is required for geriatric patients, patients with hepatic impairment, and/or patients with renal impairment. However, patients with moderate to severe renal impairment might experience anticholinergic adverse effects and should be closely monitored for potential toxicity.

Drug interactions

• Tiotropium has anticholinergic effects, and significant drug interactions are reported, so tiotropium dose or frequency might need adjustment based on concomitant medicine usage.[14]

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 include 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 should be used cautiously in patients with prostatic hyperplasia and bladder-neck obstruction, as it can worsen urinary retention. 

Tiotropium Bromide and Olodaterol Combination Therapy 

The most common adverse effects of tiotropium bromide and olodaterol combination therapy include nasopharyngitis, cough, and back pain. Less common side effects of tiotropium bromide and olodaterol combination therapy include dehydration, dizziness, insomnia, glaucoma, elevated intraocular pressure, blurred vision, 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.[15]

Contraindications

Tiotropium bromide and combination therapy of tiotropium bromide and olodaterol are not indicated for treatment and relief of acute bronchospasm.[14] Following are the contraindications as per the manufacturer's label.

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 due to maternal or fetal complications. The results of animal studies on tiotropium use during the pregnancy of rats and rabbits resulted in no anatomical abnormalities in offspring. It should not be used as a rescue medicine for an acute attack. Tiotropium should be discontinued if a paradoxical bronchospasm occurs.

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 its use in animal reproductive studies, so it currently classifies as pregnancy risk category C.

Monitoring

Patients prescribed tiotropium for COPD treatment should follow up regularly with their prescribing provider to monitor adverse effects and obstructive lung disease progression. Although tiotropium demonstrates poor absorption across the pulmonary capillaries for systemic circulation, the development of urinary retention and narrow-angle glaucoma have occurred as adverse effects resulting 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 follow-ups in the clinic. Monitoring for obstructive lung disease progression may involve inquiring about a patient's history of COPD exacerbations and pulmonary function testing by measuring FEV1 and peak flow lung volumes by spirometry.

Toxicity

Tiotropium demonstrates poor absorption across the respiratory alveolar capillaries and gastrointestinal tract; therefore, the risk of systemic medication toxicity is unlikely. Although high doses of tiotropium correlate with anticholinergic side effects, a literature review 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.[16] This case report concluded that the patient had a resolution of tachycardia after 5 days of treatment. Secondly, no systemic anticholinergic adverse effects were observed in a volunteered trial of inhalation of 282 mcg of tiotropium among 6 individuals.[13] If an 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 a 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 teach patients the difference between maintenance and rescue inhaler therapies. As tiotropium is a maintenance therapy for COPD and asthma, patients must understand that tiotropium offers no rescue benefits in an acute exacerbation of COPD or bronchospasm. Physicians, pharmacists, nursing staff, and other providers should correctly demonstrate the assembling and priming of a tiotropium inhaler to patients, as this may be challenging for patients who have never used an inhaler device. A provider's ability to teach and demonstrate to a patient the proper use of the inhaler device plays a critical role in medication efficacy.

While smoking remains among the leading causes of COPD in the United States, the healthcare team should assess for cigarette smoking during the treatment of COPD. Healthcare providers should encourage smoking cessation, which may decrease the mortality and risk of complications in patients with COPD. Tiotropium therapy is not described as having interactions with cigarette smoking, although it is well-established that smoking may alter the metabolism of medications in the liver.[17] The popularity of hookah, vapor THC, flavored nicotine vapor products, and electronic cigarettes continues to increase. The development of COPD and the effects of chronic use of these products remain research areas that require further investigation.

When the clinician decides to use tiotropium, they should consult with a pharmacist regarding dosing, potential drug interactions, and possible alternatives. The clinicians must also follow up with the patient and check for treatment efficacy and adverse reactions. Respiratory therapists may also be on the case and report their findings to the rest of the team as treatment progresses. As described above, tiotropium therapy requires a collaborative interprofessional effort between the healthcare team to ensure patient compliance and optimal therapeutic outcomes.