Tiotropium

1. Drug Name

• Generic Name: Tiotropium

• Brand Names: Spiriva, Spiriva Respimat, Spiriva HandiHaler

2. Drug Classification

• Class: Anticholinergic bronchodilator

• Subclass: Muscarinic receptor antagonist, Long-acting muscarinic antagonist (LAMA)

3. Mechanism of Action

• Tiotropium is a long-acting muscarinic antagonist (LAMA) that works by blocking acetylcholine from binding to muscarinic receptors (specifically M1 and M3 receptors) in the smooth muscle of the airways.

• Bronchodilation: By inhibiting the parasympathetic nervous system’s effects on the airway, tiotropium prevents bronchoconstriction and promotes bronchodilation. This leads to a reduction in airway resistance and improvement in airflow.

• Duration of Action: Unlike short-acting muscarinic antagonists (SAMAs) like ipratropium, tiotropium has a much longer duration of action (24 hours), allowing for once-daily dosing.

• Mucus Secretion: Tiotropium also inhibits the secretion of mucus from airway glands, helping reduce airway obstruction due to excessive mucus.

4. Pharmacokinetics

• Absorption:

  • Bioavailability: Tiotropium has a low systemic bioavailability (approximately 19% after inhalation) due to poor absorption into the bloodstream.

  • Tmax (Time to Peak Plasma Concentration): Peak plasma concentrations occur approximately 5 to 7 minutes after inhalation.

• Distribution:

  • Volume of Distribution (Vd): Tiotropium has a relatively high volume of distribution, reflecting its limited systemic exposure and primary activity within the lungs.

  • Protein Binding: Tiotropium is highly protein-bound in the plasma (approximately 72%).

• Metabolism:

  • Tiotropium undergoes minimal metabolism in the liver. It is primarily excreted unchanged via the kidneys.

  • It is not significantly metabolized by cytochrome P450 enzymes, reducing the likelihood of drug interactions.

• Excretion:

  • Half-life (t½): The half-life of tiotropium is approximately 5–6 days, which is why it only requires once-daily dosing.

  • Excretion: The majority of the drug (approximately 50%) is excreted unchanged in the urine. Renal impairment can lead to accumulation, but dose adjustments are not routinely required unless there is severe renal dysfunction.

• Special Considerations: In patients with renal impairment, there may be a need to monitor for potential accumulation, although no major adjustments are typically necessary for mild-to-moderate renal dysfunction.

5. Indications

• Primary Indications:

  • Chronic Obstructive Pulmonary Disease (COPD): Tiotropium is approved for the maintenance treatment of bronchospasm associated with COPD. It helps improve lung function and reduce exacerbations, improving the quality of life.

  • Asthma: It is also indicated for asthma in adults and children aged 6 years and older when added to maintenance therapy to improve control of asthma symptoms.

• Off-Label Uses:

  • Cystic Fibrosis: Occasionally used in patients with cystic fibrosis to help manage bronchoconstriction.

• Special Populations:

  • Pediatrics: Approved for asthma in children ≥6 years old, especially for those with inadequate control using short-acting bronchodilators.

  • Geriatrics: Elderly patients may require monitoring for anticholinergic side effects, such as dry mouth and urinary retention.

6. Dosage and Administration

• Adult Dosing:

  • COPD: Tiotropium is administered via inhalation of 18 mcg once daily using the HandiHaler device or Respimat inhaler.

  • Asthma: 2.5 mcg (2 inhalations of 1.25 mcg) once daily using the Respimat inhaler.

• Pediatric Dosing:

  • Asthma (ages 6–11): 2.5 mcg once daily (1.25 mcg per inhalation) using the Respimat inhaler.

• Dose Adjustments:

  • Renal Impairment: In patients with severe renal impairment (eGFR <30 mL/min/1.73 m²), the dose should be administered with caution, and monitoring for side effects may be necessary. However, routine dose reduction is not recommended for mild-to-moderate renal dysfunction.

• Missed Dose: If a dose is missed, the patient should take it as soon as they remember, but if it’s almost time for the next dose, skip the missed dose and resume the regular dosing schedule. Do not take two doses at once.

7. Contraindications

• Absolute Contraindications:

  • Hypersensitivity to tiotropium, atropine, or any of the excipients in the formulation.

• Relative Contraindications:

  • Glaucoma: Tiotropium, as an anticholinergic, may increase intraocular pressure. It should be used with caution in patients with glaucoma or those at risk for narrow-angle glaucoma.

  • Prostatic Hypertrophy or Urinary Retention: As with other anticholinergic agents, tiotropium can worsen symptoms of urinary retention, especially in older adults with BPH.

8. Warnings and Precautions

• Anticholinergic Effects: Common side effects of anticholinergics like dry mouth, blurred vision, and urinary retention should be monitored. These effects are especially concerning in elderly patients.

• Acute Narrow-Angle Glaucoma: Tiotropium should be used with caution in patients with a history of or predisposition to glaucoma due to the potential for increased intraocular pressure.

• Paradoxical Bronchospasm: As with all bronchodilators, tiotropium may cause paradoxical bronchospasm, which requires immediate discontinuation of the drug and medical intervention.

• Inhalation Instructions: Proper inhalation technique is critical. Misuse of the inhaler can lead to inadequate drug delivery and poor therapeutic outcomes.

9. Adverse Effects

• Common Adverse Effects:

  • CNS: Dry mouth, headache, and dizziness.

  • Respiratory: Cough, throat irritation.

• Less Common but Clinically Significant:

  • Cardiovascular: Tachycardia, palpitations, arrhythmias (rare).

  • GI: Constipation, dyspepsia.

  • Anticholinergic: Urinary retention, blurred vision, and difficulty swallowing.

• Rare/Serious:

  • Hypersensitivity: Anaphylaxis, rash, urticaria, swelling of the lips, tongue, or throat.

  • Paradoxical Bronchospasm: Sudden worsening of bronchospasm that may require medical intervention.

10. Drug Interactions

• Other Anticholinergics: Use with other anticholinergic medications (e.g., atropine, ipratropium) may increase the risk of systemic anticholinergic side effects, such as dry mouth and urinary retention.

• Beta-Agonists: Combined use of tiotropium with beta-agonists (e.g., salbutamol) may provide complementary bronchodilation, but caution should be taken to avoid excessive doses.

• CYP450 Interactions: Tiotropium has minimal interactions with the cytochrome P450 enzyme system, making it less likely to interact with other medications metabolized by these enzymes.

11. Clinical Pharmacology

• Pharmacodynamics: Tiotropium provides long-lasting bronchodilation through its antagonism of muscarinic receptors in the lungs, and its effects persist for 24 hours. This results in improved airflow and reduced bronchoconstriction in conditions like COPD and asthma.

• Additional Effects: By inhibiting mucus secretion and reducing bronchoconstriction, tiotropium also helps reduce symptoms like wheezing and breathlessness.

12. Special Populations

• Pregnancy: FDA Category C. Tiotropium should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.

• Lactation: It is not known whether tiotropium is excreted in human breast milk. It should be used during breastfeeding only if the benefit outweighs the potential risk.

• Geriatrics: In elderly patients, the incidence of anticholinergic side effects such as dry mouth and urinary retention may be higher, requiring monitoring and dose adjustments.

13. Therapeutic Uses

• COPD: Tiotropium is considered a first-line treatment for maintenance therapy in patients with COPD to reduce exacerbations and improve lung function.

• Asthma: Used as a maintenance medication in asthma, especially for patients who do not achieve adequate control with inhaled corticosteroids and short-acting bronchodilators.

• Clinical Trials: Studies show that tiotropium improves pulmonary function, reduces exacerbations, and decreases hospitalizations in patients with COPD.

14. Monitoring and Follow-Up

• Pulmonary Function Tests: Regular monitoring of lung function (e.g., spirometry) to assess the effectiveness of therapy.

• Intraocular Pressure: Regular eye exams for patients with a history of glaucoma.

• Anticholinergic Side Effects: Monitor for signs of anticholinergic toxicity, especially in older adults.

15. Overdose Management

• Symptoms of Overdose: Symptoms may include dry mouth, blurred vision, urinary retention, constipation, tachycardia, and confusion.

• Management: Overdose requires supportive care. In the case of oral overdose, activated charcoal may be considered if ingestion occurred within an hour.

16. Patient Counseling Information

• Proper Use: Instruct patients on how to correctly use the inhaler (HandiHaler or Respimat), including priming the device if needed and the importance of proper inhalation technique.

• Side Effects: Warn patients about potential anticholinergic side effects such as dry mouth and urinary retention. Advise on methods to alleviate dry mouth, such as sipping water or using sugar-free gum.

• Seek Immediate Medical Attention: Patients should be advised to seek immediate medical help if they experience signs of severe allergic reactions (e.g., swelling of the face, lips, or tongue) or worsening respiratory symptoms.