Ipratropium and Tiotropium Bromide

Mechanism

Mechanism of Action

Synthetic inhaled anticholinergic drugs with a highly ionized quaternary ammonium chemical structure. Due to their low lipophilicity, they do not cross the bronchial mucosa into the systemic circulation to an appreciable extent and lack passage through the blood-brain barrier. When inhaled, they competitively block postsynaptic muscarinic receptors of bronchial smooth muscle, inhibiting basal tonic vagal tone of the airway. Blockade of M₃ receptors prevents the activation of the G_q protein, the formation of inositol triphosphate and the release of intracellular calcium induced by acetylcholine, producing potent relaxation and bronchodilation of the local airway. Likewise, they significantly reduce local bronchial mucous secretion.

Ipratropium bromide (SAMA)

• Action: Short duration of bronchodilator action.
• Selectivity: Non-selective between M₁, M₂ and M₃ receptors. By blocking presynaptic M₂ it can transiently enhance the release of acetylcholine.
• Duration: 6 to 8 hours.
• Clinical use: Severe asthma attack or exacerbated COPD.

Tiotropium Bromide (LAMA)

• Action: Prolonged duration of bronchodilator action.
• Selectivity: Functional selectivity for M₁ and M₃ receptors, dissociating extremely slowly, with rapid dissociation of the M₂ receptor.
• Duration: More than 24 hours.
• Clinical use: Daily maintenance of COPD and bronchial asthma that is difficult to control.

Pharmacokinetics

Key Pharmacokinetics

• Routes: Pressurized metered aerosol inhalation (MDI), dry powder inhaler (DPI), liquid nebulization.
• Systemic absorption: Extremely low (systemic bioavailability less than 1-5% of the inhaled dose). The passively swallowed drug is eliminated unchanged in the feces due to its poor intestinal absorption.
• Metabolism: Partially hepatic due to minor inactive hydrolysis enzymatic reactions.
• Elimination half-life: Tiotropium has a plasma terminal elimination half-life of 24-44 hours secondary to its binding to receptors.
• Excretion: Renal and fecal.

Indicators and dose

Approved and Off-label Indications

Approved: Maintenance management and symptomatic relief of bronchospasm in chronic obstructive pulmonary disease (COPD), including chronic bronchitis and pulmonary emphysema; joint treatment of severe acute asthmatic attack in the emergency department (ipratropium associated with a β₂ agonist such as salbutamol).

Off-label: Perennial allergic rhinitis or excessive rhinorrhea (use of ipratropium by topical nasal spray).

Dosage and Adjustments

COPD maintenance (Ipratropium): 20-40 µ g (1 to 2 inhalations) three to four times a day in a scheduled manner.

COPD Maintenance (Tiotropium): Inhalation of 18 µ g (1 capsule for dry powder device) once a day at the same time.

Renal adjustment: No initial dose modification is required in patients with renal failure. In the case of tiotropium in severe renal failure (eGFR < 30 mL/min), close monitoring is advised due to possible mild systemic plasma accumulation.

Security

Contraindications

Absolute: History of demonstrated hypersensitivity to ipratropium, tiotropium, atropine or to soy/peanut proteins (in some formulations that use soy lecithin as a propellant).

Relative: Decompensated narrow-angle glaucoma (accidental direct ocular aerosol deposition due to leakage of the face mask can cause a closed-angle crisis), symptomatic prostatic urinary retention.

Adverse Effects (ADR)

Common: Localized xerostomia of the oral cavity, pharyngeal irritation, mild reflex cough, dysgeusia (unusual metallic taste post-dose), tension headache.

Serious: Acute paradoxical bronchospasm, exacerbation of urinary retention, sudden elevation of intraocular pressure with blurred vision if the eye is directly exposed to aerosol particles.

Interactions

Other anticholinergic drugs by inhalation or systemic route: Synergy in systemic adverse effects (constipation, xerostomia); coadministration is not recommended.

Pregnancy and Breastfeeding

FDA Classification: Category B (Ipratropium) / Category C (Tiotropium). Experimental studies in animal models do not reveal specific harms of ipratropium. There are no conclusive data on its presence in breast milk; They are considered safe given their low systemic bioavailability.