Mechanism of Action

Ipratropium bromide is an anticholinergic (parasympatholytic) agent which, based on animal studies, appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released at neuromuscular junctions in the lung. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) which are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.

Pharmacodynamic Properties

Controlled clinical studies have demonstrated that Atrovent® (ipratropium bromide ) Inhalation Aerosol CFC does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions.

Pharmacokinetics and Metabolism

Most of an administered dose is swallowed as shown by fecal excretion studies. Ipratropium bromide is a quaternary amine. It is not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract as confirmed by blood level and renal excretion studies.

Autoradiographic studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier. The half-life of elimination is about 2 hours after inhalation or intravenous administration. Ipratropium bromide is minimally bound (0 to 9% in vitro) to plasma albumin and a1-acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half of the dose is excreted unchanged in the urine.

A pharmacokinetic study with 29 chronic obstructive pulmonary disease (COPD) patients (48-79 years of age) demonstrated that mean peak plasma ipratropium concentrations of 59±20 pg/mL were obtained following a single administration of 4 inhalations of ATROVENT HFA Inhalation Aerosol (84 mcg). Plasma ipratropium concentrations rapidly declined to 24±15 pg/mL by six hours. When these patients were administered 4 inhalations QID (16 inhalations/day=336 mcg) for one week, the mean peak plasma ipratropium concentration increased to 82±39 pg/mL with a trough (6 hour) concentration of 28±12 pg/mL at steady state.

Special Populations

Geriatric Patients

In the pharmacokinetic study with 29 COPD patients, a subset of 14 patients were > 65 years of age. Mean peak plasma ipratropium concentrations of 56±24 pg/mL were obtained following a single administration of 4 inhalations (21 mcg/puff) of Atrovent® HFA (ipratropium bromide HFA) Inhalation Aerosol (84 mcg). When these 14 patients were administered 4 inhalations QID (16 inhalations/day) for one week, the mean peak plasma ipratropium concentration only increased to 84±50 pg/mL indicating that the pharmacokinetic behavior of ipratropium bromide in the geriatric population is consistent with younger patients.

Renally Impaired Patients

The pharmacokinetics of ATROVENT HFA Inhalation Aerosol have not been studied in patients with renal insufficiency.

Hepatically Impaired Patients

The pharmacokinetics of ATROVENT HFA Inhalation Aerosol have not been studied in patients with hepatic insufficiency.

Clinical Studies

Conclusions regarding the efficacy of ATROVENT HFA Inhalation Aerosol were derived from two randomized, double-blind, controlled clinical studies. These studies enrolled males and females ages 40 years and older, with a history of COPD, a smoking history of > 10 pack- years, an FEV₁ < 65% and an FEV₁/FVC < 70%.

One of the studies was a 12-week randomized, double-blind active and placebo controlled study in which 505 of the 507 randomized COPD patients were evaluated for the safety and efficacy of 42 mcg (n=124) and 84 mcg (n=126) ATROVENT HFA Inhalation Aerosol in comparison to 42 mcg (n=127) Atrovent® (ipratropium bromide) Inhalation Aerosol CFC and their respective placebos (HFA n=62, CFC n=66). Data for both placebo HFA and placebo CFC were combined in the evaluation.

Serial FEV₁ (shown in Figure 1, below, as means adjusted for center and baseline effects on test day 1 and test day 85 (primary endpoint)) demonstrated that 1 dose (2 inhalations/21 mcg each) of ATROVENT HFA Inhalation Aerosol produced significantly greater improvement in pulmonary function than placebo. During the six hours immediately post-dose on day 1, the average hourly improvement in adjusted mean FEV₁ was 0.148 liters for ATROVENT HFA Inhalation Aerosol (42 mcg) and 0.013 liters for placebo. The mean peak improvement in FEV₁, relative to baseline, was 0.295 liters, compared to 0.138 liters for placebo. During the six hours immediately post-dose on day 85, the average hourly improvement in adjusted mean FEV₁ was 0.141 liters for ATROVENT HFA Inhalation Aerosol (42 mcg) and 0.014 liters for placebo. The mean peak improvement in FEV₁, relative to baseline, was 0.295 liters, compared to 0.140 liters for placebo.

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