Tiotropium

Usage

Tiotropium is prescribed for the long-term maintenance treatment of bronchospasm and dyspnea associated with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema. It is also used as add-on maintenance therapy for moderate to severe asthma in patients aged 6 years and older, and for the prevention of COPD exacerbations. It is not for the relief of acute bronchospasm.

Pharmacological classification: Tiotropium is classified as a long-acting muscarinic antagonist (LAMA) and an anticholinergic bronchodilator.

Mechanism of action: Tiotropium blocks the action of acetylcholine at M3 muscarinic receptors in the bronchial smooth muscle, leading to bronchodilation and improved airflow to the lungs.

Alternate Names

Tiotropium bromide (INN), Tiotrópio (Spanish), Tiotropium (Latin)

Brand names: Spiriva®, Spiriva® HandiHaler®, Spiriva® Respimat®, Braltus®, Stiolto® Respimat® (in combination with olodaterol)

How It Works

Pharmacodynamics: Tiotropium’s primary action is bronchodilation through competitive and reversible antagonism of M3 muscarinic receptors in the lungs. It exhibits selectivity for M3 over M2 receptors, potentially minimizing cardiac side effects. The drug’s long duration of action is attributed to its slow dissociation from M3 receptors.

Pharmacokinetics: After inhalation, tiotropium exhibits low systemic absorption (~20%). Peak plasma levels are reached within 5-7 minutes. It has a large volume of distribution and is moderately protein-bound (72%). Tiotropium undergoes minimal metabolism, primarily non-enzymatic hydrolysis. Elimination is primarily through renal excretion (74% unchanged) with a long elimination half-life of approximately 27-38 hours.

Mode of action: Tiotropium binds competitively and reversibly to M3 muscarinic receptors on bronchial smooth muscle cells. This prevents acetylcholine from binding and activating these receptors, thereby inhibiting bronchoconstriction and promoting bronchodilation.

Receptor binding, enzyme inhibition, or neurotransmitter modulation: As an anticholinergic, tiotropium competitively inhibits the binding of acetylcholine to M3 muscarinic receptors. It does not directly affect enzymes or neurotransmitters other than through its action on these receptors.

Elimination pathways: Tiotropium is primarily excreted unchanged in the urine (74%), with minor non-enzymatic hydrolysis and minimal CYP450 metabolism.

Dosage

Standard Dosage

Adults:

• COPD:
  • Spiriva® HandiHaler®: Inhalation of the contents of one 18 mcg capsule once daily.
  • Spiriva® Respimat®: Two puffs (5 mcg) once daily.
  • Stiolto® Respimat®: Two puffs (2.5 mcg tiotropium/2.5 mcg olodaterol) once daily.
  • Braltus®: Inhalation of the contents of one 10 mcg capsule once daily.
• Asthma (age 12 years and older):
  • Spiriva® Respimat®: Two puffs (2.5 mcg) once daily.

Children (age 6-17 years):

• Asthma: Spiriva® Respimat®: Two puffs (2.5 mcg) once daily.

Special Cases:

• Elderly Patients: No dose adjustment is necessary.
• Patients with Renal Impairment: No dose adjustment is necessary for mild to moderate impairment. Monitor for anticholinergic adverse effects in moderate to severe renal impairment (creatinine clearance ≤50 mL/min).
• Patients with Hepatic Dysfunction: No dose adjustment is necessary.
• Patients with Comorbid Conditions: Close monitoring is recommended, particularly for patients with narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction, as tiotropium can exacerbate these conditions.

Clinical Use Cases

Tiotropium is not indicated for the following clinical situations as it is not a rescue medication for acute events:

• Intubation
• Surgical Procedures
• Mechanical Ventilation
• Intensive Care Unit (ICU) Use
• Emergency Situations (e.g., status epilepticus, cardiac arrest)

Dosage Adjustments

Dose adjustments may be necessary for patients with moderate to severe renal impairment. Close monitoring for anticholinergic side effects is recommended in these cases.

Side Effects

Common Side Effects:

Dry mouth, constipation, headache, nausea, sore throat, cough, upper respiratory tract infection, sinusitis, pharyngitis, rhinitis, urinary tract infection, dyspepsia, blurred vision.

Rare but Serious Side Effects:

Acute angle-closure glaucoma, urinary retention, angioedema, anaphylaxis, paradoxical bronchospasm, allergic reactions (urticaria, pruritus, rash).

Long-Term Effects:

While long-term side effects are generally minimal, some patients may experience chronic dry mouth or constipation.

Adverse Drug Reactions (ADR):

Angioedema, anaphylaxis, paradoxical bronchospasm, acute angle-closure glaucoma, urinary retention, severe allergic reactions.

Contraindications

• Hypersensitivity to tiotropium, ipratropium, atropine, or any component of the formulation.
• Severe hypersensitivity to milk proteins (for formulations containing lactose).
• Narrow-angle glaucoma.

Drug Interactions

Tiotropium may interact with other anticholinergic medications, potentially increasing the risk of anticholinergic side effects. Concomitant use with other drugs that prolong the QT interval may increase the risk of arrhythmias (although this is less of a concern with inhaled tiotropium).

• Commonly prescribed medications: Anticholinergic agents (e.g., antihistamines, tricyclic antidepressants), medications that prolong the QT interval.
• Over-the-Counter (OTC) drugs and supplements: Antihistamines, decongestants containing anticholinergic agents.
• Food and lifestyle factors: No specific food or lifestyle interactions are known.

Pregnancy and Breastfeeding

• Pregnancy Safety Category: B1 (Australia), Not Assigned (US FDA). Limited data are available. Use only if the benefit outweighs the risk.
• Fetal risks: Animal studies do not show increased risk of major birth defects; some studies show decreased fetal weights.
• Breastfeeding: Small amounts of tiotropium are excreted in breast milk. Use with caution. Monitor infant for potential anticholinergic effects.

Drug Profile Summary

• Mechanism of Action: Muscarinic antagonist (anticholinergic) causing bronchodilation.
• Side Effects: Dry mouth, constipation, headache, upper respiratory tract infections, urinary tract infections. Serious: acute angle-closure glaucoma, urinary retention, angioedema, anaphylaxis.
• Contraindications: Hypersensitivity, narrow-angle glaucoma, milk protein allergy.
• Drug Interactions: Other anticholinergics, QT prolonging agents.
• Pregnancy & Breastfeeding: Limited data; use with caution.
• Dosage: Adults (COPD/Asthma): 2 puffs (2.5 or 5 mcg depending on inhaler type) once daily. Children (Asthma, 6-17 yrs): 2 puffs (2.5 mcg) once daily.
• Monitoring Parameters: Respiratory function (FEV1, peak flow), cardiovascular parameters, intraocular pressure (if at risk for glaucoma), urinary function.

Popular Combinations

• Tiotropium/olodaterol (Stiolto® Respimat®): Combines a LAMA with a long-acting beta2-agonist (LABA) for synergistic bronchodilation.

Precautions

• General Precautions: Assess for history of hypersensitivity, narrow-angle glaucoma, prostatic hyperplasia, or bladder neck obstruction.
• Pregnant Women: Use only if potential benefit outweighs the risk.
• Breastfeeding Mothers: Use with caution, monitor infant.
• Children & Elderly: Generally well tolerated, use standard dosage unless renally impaired.
• Lifestyle Considerations: No specific lifestyle restrictions are typically necessary.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Tiotropium?

A: The recommended dosage for adults with COPD is 5 mcg (2 puffs from Respimat® or 1 capsule from HandiHaler®) once daily, while for asthma, it is 2.5 mcg (2 puffs from Respimat®) once daily. For children aged 6-17 with asthma, it is 2.5 mcg (2 puffs from Respimat®) once daily.

Q2: How does Tiotropium differ from short-acting bronchodilators?

A: Tiotropium is a long-acting bronchodilator providing 24-hour bronchodilation, while short-acting bronchodilators like albuterol provide rapid but shorter-term relief (4-6 hours). Tiotropium is for maintenance therapy and not for acute bronchospasm.

Q3: What are the most common side effects of Tiotropium?

A: Dry mouth, constipation, and upper respiratory tract infections are among the most common side effects.

Q4: Can Tiotropium be used in patients with narrow-angle glaucoma?

A: Tiotropium is contraindicated in patients with narrow-angle glaucoma, as it can precipitate or worsen the condition.

Q5: Are there any drug interactions I should be aware of with Tiotropium?

A: Concomitant use of tiotropium with other anticholinergic medications should be approached with caution, as it may increase the risk of anticholinergic effects.

Q6: Can Tiotropium be used during pregnancy?

A: Tiotropium should be used during pregnancy only if the potential benefit outweighs the potential risk to the fetus. Consult a specialist.

Q7: Is Tiotropium safe for use in elderly patients?

A: Tiotropium is generally safe for use in elderly patients at the standard recommended dosage, unless there is renal impairment.

Q8: What should I do if a patient experiences paradoxical bronchospasm after using Tiotropium?

A: Discontinue Tiotropium immediately and switch to an alternative bronchodilator. Paradoxical bronchospasm is a rare but serious side effect.

Q9: Can Tiotropium be used with inhaled corticosteroids?

A: Yes, Tiotropium can be used in combination with inhaled corticosteroids (ICS) in the management of both COPD and asthma. In fact, for patients with moderate to severe asthma, tiotropium is often added on to a combination of ICS and a LABA.