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DuoNeb (ipratropium bromide and albuterol sulfate) Inhalation Solution is a combination of the β2-adrenergic bronchodilator, albuterol sulfate, and the anticholinergic bronchodilator, ipratropium bromide.

Albuterol Sulfate

Mechanism of Action

The prime action of β-adrenergic drugs is to stimulate adenyl cyclase, the enzyme that catalyzes the formation of cyclic-3',5'-adenosine monophosphate (cAMP) from adenosine triphosphate (ATP). The cAMP thus formed mediates the cellular responses. In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on β2-adrenergic receptors compared with isoproterenol. While it is recognized that β2-adrenergic receptors are the predominant receptors in bronchial smooth muscle, recent data indicated that 10% to 50% of the βreceptors in the human heart may be β2-receptors. The precise function of these receptors, however, is not yet established. Albuterol has been shown in most controlled clinical trials to have more effect on the respiratory tract, in the form of bronchial smooth muscle relaxation, than isoproterenol at comparable doses while producing fewer cardiovascular effects. Controlled clinical studies and other clinical experience have shown that inhaled albuterol, like other β-adrenergic agonist drugs, can produce a significant cardiovascular effect in some patients.

Pharmacokinetics

Albuterol sulfate is longer acting than isoproterenol in most patients by any route of administration, because it is not a substrate for the cellular uptake processes for catecholamine nor for the metabolism of catechol-O-methyl transferase. Instead the drug is conjugatively metabolized to albuterol 4'-O-sulfate.

Animal Pharmacology/Toxicology

Intravenous studies in rats with albuterol sulfate have demonstrated that albuterol crosses the blood-brain barrier and reaches brain concentrations amounting to approximately 5% of plasma concentrations. In structures outside of the blood-brain barrier (pineal and pituitary glands), albuterol concentrations were found to be 100 times those found in whole brain.

Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrythmias and sudden death (with histological evidence of myocardial necrosis) when beta-agonists and methyl-xanthines are administered concurrently. The clinical significance of these findings is unknown.

Ipratropium Bromide

Mechanism of Action

Ipratropium bromide is an anticholinergic (parasympatholytic) agent, which blocks the muscarinic receptors of acetylcholine, and, based on animal studies, appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cGMP), resulting from the interaction of acetylcholine with the muscarinic receptors of bronchial smooth muscle.

Pharmacokinetics

The bronchodilation following inhalation of ipratropium is primarily a local, site-specific effect, not a systemic one. Much of an inhaled dose is swallowed as shown by fecal excretion studies. Following nebulization of a 1-mg dose to healthy volunteers, a mean of 4% of the dose was excreted unchanged in the urine.

Ipratropium bromide is minimally (0% to 9% in vitro ) bound to plasma albumin and α1acid glycoproteins. It is partially metabolized to inactive ester hydrolysis products. Following intravenous administration, approximately one-half is excreted unchanged in the urine. The half-life of elimination is about 1.6 hours after intravenous administration. Ipratropium bromide that reaches the systemic circulation is reportedly removed by the kidneys rapidly at a rate that exceeds the glomerular filtration rate. The pharmacokinetics of DuoNeb (ipratropium bromide and albuterol sulfate) Inhalation Solution or ipratropium bromide have not been studied in the elderly and in patients with hepatic or renal insufficiency (see PRECAUTIONS).

Animal Pharmacology/Toxicology

Autoradiographic studies in rats have shown that ipratropium does not penetrate the blood-brain barrier.

DuoNeb® (ipratropium bromide and albuterol sulfate)

Mechanism of Action

DuoNeb (ipratropium bromide and albuterol sulfate) is expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms: sympathomimetic (albuterol sulfate) and anticholinergic/parasympatholytic (ipratropium bromide). Simultaneous administration of both an anticholinergic and a β2-sympathomimetic is designed to produce greater bronchodilation effects than when either drug is utilized alone at its recommended dosage.

Animal Pharmacology/Toxicology

In 30-day studies in Sprague-Dawley rats and Beagle dogs, subcutaneous doses of up to 205.5 mcg/kg of ipratropium administered with up to 1000 mcg/kg albuterol in rats and 3.16 mcg/kg ipratropium and 15 mcg/kg albuterol in dogs (less than the maximum recommended daily inhalation dose for adults on a mg/m² basis) did not cause death or potentiation of the cardiotoxicity induced by albuterol administered alone.

Pharmacokinetics

In a double blind, double period, crossover study, 15 male and female subjects were administered single doses of DuoNeb (ipratropium bromide and albuterol sulfate) or albuterol sulfate inhalation solution at two times the recommended single doses as two inhalations separated by 15 minutes. The total nebulized dose of albuterol sulfate from both treatments was 6.0 mg and the total dose of ipratropium bromide from DuoNeb (ipratropium bromide and albuterol sulfate) was 1.0 mg. Peak albuterol plasma concentrations occurred at 0.8 hours after dosing for both treatments. The mean peak albuterol concentration following administration of albuterol sulfate alone was 4.86 (± 2.65) mg/mL and it was 4.65 (± 2.92) mg/mL for DuoNeb (ipratropium bromide and albuterol sulfate) . Mean AUC values for the two treatments were 26.6 (± 15.2) ng·hr/mL (albuterol sulfate alone) versus 24.2 (± 14.5) ng·hr/mL (DuoNeb (ipratropium bromide and albuterol sulfate) ). The mean t½ values were 7.2 (± 1.3) hours (albuterol sulfate alone) and 6.7 (± 1.7) hours (DuoNeb (ipratropium bromide and albuterol sulfate) ). A mean of 8.4 (± 8.9)% of the albuterol dose was excreted unchanged in urine following administration of two vials of DuoNeb (ipratropium bromide and albuterol sulfate) which is similar to 8.8 (± 7.3)% that was obtained from albuterol sulfate inhalation solution. There were no statistically significant differences in the pharmacokinetics of albuterol between the two treatments. For ipratropium, a mean of 3.9 (± 5.1)% of the ipratropium bromide dose was excreted unchanged in urine following two vials of DuoNeb (ipratropium bromide and albuterol sulfate) Inhalation Solution, which is comparable with previously reported data.

Clinical Trials

In a 12 week, randomized, double-blind, positive-control, crossover study of albuterol sulfate, ipratropium bromide, and DuoNeb (ipratropium bromide and albuterol sulfate) , 863 COPD patients were evaluated for bronchodilator efficacy comparing DuoNeb (ipratropium bromide and albuterol sulfate) with albuterol sulfate and ipratropium bromide alone.

DuoNeb (ipratropium bromide and albuterol sulfate) demonstrated significantly better changes in FEV₁, as measured from baseline to peak response, when compared with either albuterol sulfate or ipratropium bromide. DuoNeb (ipratropium bromide and albuterol sulfate) was also shown to have the rapid onset associated with albuterol sulfate, with a mean time to peak FEV₁ of 1.5 hours, and the extended duration associated with ipratropium bromide with a duration of 15% response in FEV₁ of 4.3 hours.

Figure 3: 1-3: Mean Change in FEV ₁ - Measured on Day 14

This study demonstrated that each component of DuoNeb (ipratropium bromide and albuterol sulfate) contributed to the improvement in pulmonary function, especially during the first 4 to 5 hours after dosing, and that DuoNeb (ipratropium bromide and albuterol sulfate) was significantly more effective than albuterol sulfate or ipratropium bromide alone.

Last reviewed on RxList: 4/22/2011
This monograph has been modified to include the generic and brand name in many instances.