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Drug Reference

tiotropium

Long-acting muscarinic antagonist (LAMA)· Brands: Spiriva, Spiriva Respimat, Braltus, TiovaINH

Mechanism of action
Tiotropium is a quaternary ammonium antimuscarinic that is poorly absorbed and largely confined to the airway after inhalation. It binds all muscarinic receptor subtypes, but dissociates very slowly from M3 receptors on airway smooth muscle and from M1 receptors on parasympathetic ganglia, while dissociating quickly from presynaptic M2 autoreceptors. This kinetic selectivity gives prolonged blockade of acetylcholine-mediated bronchoconstriction, so bronchodilation lasts beyond 24 hours and once-daily dosing is possible. Loss of cholinergic tone also reduces mucus hypersecretion. The block is competitive and reversible, so it can be overcome by high local concentrations of cholinergic agonist.
Pharmacokinetics
Tiotropium is given by oral inhalation, either as a dry powder from capsules in a purpose-built device or as a soft mist inhaler. Systemic bioavailability is low, roughly 20 per cent for the dry powder and about 33 per cent for the soft mist, because most of the swallowed fraction is not absorbed. Peak plasma concentrations occur within about 5 to 7 minutes of inhalation. Plasma protein binding is about 72 per cent. Metabolism is minimal, with a small fraction handled by CYP2D6 and CYP3A4, and most of a systemically available dose is excreted unchanged in the urine. Terminal elimination half-life at steady state in COPD is around 5 to 6 days. Clearance falls with increasing age and with renal impairment, but dose adjustment is not usually needed in mild to moderate impairment.
Indications & dosing

Maintenance bronchodilator therapy in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema

Teaching example using the dry powder inhaler. The Respimat soft mist inhaler delivers 5 micrograms once daily (two puffs of 2.5 micrograms), giving equivalent bronchodilation. Not for acute relief of breathlessness; ensure a short-acting reliever is available.

  • adult · INH: 18 microgram once daily · Teaching example using the dry powder inhaler. The Respimat soft mist inhaler delivers 5 micrograms once daily (two puffs of 2.5 micrograms), giving equivalent bronchodilation. Not for acute relief of breathlessness; ensure a short-acting reliever is available.

Add-on maintenance therapy in severe asthma inadequately controlled on inhaled corticosteroid plus a long-acting beta-2 agonist

Teaching example via Respimat (two puffs of 2.5 micrograms). Licensed as add-on in some regions but not others; check the local formulary. Continue the inhaled corticosteroid and do not use as a rescue inhaler.

  • adult · INH: 5 microgram once daily · Teaching example via Respimat (two puffs of 2.5 micrograms). Licensed as add-on in some regions but not others; check the local formulary. Continue the inhaled corticosteroid and do not use as a rescue inhaler.

Add-on maintenance therapy in severe asthma in children and adolescents aged 6 years and older

Teaching example via Respimat (two puffs of 1.25 micrograms). Not licensed for children under 6 years. Add-on to an inhaled corticosteroid with or without a long-acting beta-2 agonist; monitor for antimuscarinic effects.

  • pediatric · INH: 2.5 microgram once daily · Teaching example via Respimat (two puffs of 1.25 micrograms). Not licensed for children under 6 years. Add-on to an inhaled corticosteroid with or without a long-acting beta-2 agonist; monitor for antimuscarinic effects.
Contraindications & precautions
  • Known hypersensitivity to tiotropium, atropine or related antimuscarinic agents such as ipratropium · Risk of anaphylaxis, angioedema and other severe hypersensitivity reactions.
  • Hypersensitivity to lactose, milk protein or other excipients of the specific inhaler formulation · Dry powder capsules commonly contain lactose monohydrate, which may carry trace milk protein. Check the individual product.
  • Narrow-angle glaucoma · Absorbed antimuscarinic activity can raise intraocular pressure. Use only if the benefit justifies the risk, and monitor.
  • Urinary retention, bladder neck obstruction or symptomatic benign prostatic hyperplasia · Antimuscarinic action can precipitate or worsen retention. Ask about voiding difficulty at review.
  • Myasthenia gravis · Antimuscarinic agents can worsen muscle weakness.
  • Severe renal impairment, for example creatinine clearance below 30 mL/min · Tiotropium is mainly excreted unchanged by the kidneys, so exposure may rise. Monitor if used.
  • Tiotropium is a maintenance bronchodilator and must not be used to relieve acute breathlessness or an acute attack. Patients should keep a short-acting reliever inhaler available.
  • Explain that the dry powder capsule is inhaled through the device and must never be swallowed.
  • Advise patients to report eye pain, blurred vision, coloured halos or red eyes, and any difficulty passing urine, as these may be antimuscarinic effects needing review.
  • For the soft mist inhaler, avoid spraying into the eyes, as the mist can precipitate acute narrow-angle glaucoma.
  • Review the total antimuscarinic burden before adding tiotropium, since combining it with another long-acting muscarinic antagonist or with ipratropium duplicates therapy.
  • Use with caution in patients with cardiac arrhythmia, recent myocardial infarction or severe renal impairment, and reassess if new palpitations or worsening breathlessness occur.
Adverse effects
  • Dry mouth
  • Pharyngitis
  • Constipation
  • Cough
  • Dizziness
  • Paradoxical bronchospasmserious
  • Urinary retentionserious
  • Acute narrow-angle glaucoma with eye pain, blurred vision or coloured halosserious
  • Atrial fibrillationserious
  • Anaphylaxis, angioedema and urticariaserious
Monitoring, pregnancy & toxicity
  • COPD or asthma symptom control and frequency of exacerbations · At each clinical review
  • Anticholinergic adverse effects (dry mouth, constipation, blurred vision, urinary retention, tachycardia) · At each review and if symptoms occur
  • Renal function (eGFR or creatinine clearance) in patients with moderate to severe renal impairment · Baseline and periodically as clinically indicated
  • Ocular symptoms or intraocular pressure in patients with narrow-angle glaucoma risk · Baseline and if eye pain or visual change occurs
  • Urinary symptoms in patients with benign prostatic hyperplasia or retention risk · Baseline and periodically
  • Paradoxical bronchospasm after inhalation · Observe after first dose and at each dose escalation
  • Pregnancy: Use only if clearly needed. There are no adequate human data on tiotropium in pregnancy. Animal studies do not show direct teratogenic effects at clinically relevant exposures. For asthma or COPD in pregnancy, prefer inhaled therapies with more established safety data, such as short-acting beta-2 agonists and inhaled corticosteroids, and involve the respiratory or obstetric team. Do not stop effective treatment without medical advice.
  • Toxicity: Anticholinergic effects such as dry mouth, constipation, blurred vision, urinary retention, tachycardia, and reduced sweating. · Stop the drug. Provide supportive care. Treat specific effects: catheterise for urinary retention, use cooling measures for hyperthermia, and consider specialist advice for severe tachycardia. There is no specific antidote.
  • Toxicity: Acute narrow-angle glaucoma with eye pain, redness, headache, nausea, and decreased vision. · Stop tiotropium immediately and refer for urgent ophthalmology assessment. Treatment typically includes topical beta-blockers, alpha-2 agonists, carbonic anhydrase inhibitors, and pilocarpine as advised by ophthalmology.
  • Toxicity: Paradoxical bronchospasm after inhalation, with wheeze, cough, or dyspnoea. · Stop the drug and give a short-acting beta-2 agonist. Consider an alternative long-acting bronchodilator once the patient has stabilised.
  • Toxicity: Hypersensitivity reactions including angioedema, urticaria, rash, and anaphylaxis. · Stop the drug. Treat angioedema or urticaria with antihistamines and corticosteroids as needed. For anaphylaxis, give intramuscular adrenaline and follow anaphylaxis protocols.
Clinical notes
Tiotropium is maintenance bronchodilator therapy, usually once daily, for COPD, and in some regions as add-on maintenance in asthma not controlled by inhaled corticosteroid plus a long-acting beta-2 agonist. It is not a rescue medicine and must not be used for acute breathlessness or an acute exacerbation; patients still need a short-acting reliever. Inhaled capsules are for inhalation only and must never be swallowed. Common adverse effects are dry mouth, constipation, cough and pharyngitis; less common but important effects include urinary retention, acute narrow-angle glaucoma and paradoxical bronchospasm. Use with caution in prostatic hyperplasia, bladder outlet obstruction, narrow-angle glaucoma and moderate to severe renal impairment, and take care to avoid eye contact with the soft mist. Device types, strengths and the licensed asthma indication vary between countries, so check the local formulary.

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BNF; local formulary; manufacturer's summary of product characteristics