Combivent pharmacokinetics and molecular data

Pharmacokinetics
Overview Mechanism of action Pharmacokinetics/metabolism Special populations Drug-drug interactions Pharmacodynamics
 * Mechanism of action (ipratropium)
 * Mechanism of action (albuterol)
 * Mechanism of action (combivent)
 * Pharmacokinetics/metabolism (ipratropium)
 * Pharmacokinetics/metabolism(albuterol)
 * Pharmacokinetics/metabolism (combivent)

Overview
Combivent Inhalation Aerosol is a combination of the anticholinergic bronchodilator, ipratropium bromide, and the beta2-adrenergic bronchodilator, albuterol sulfate. Return to top

Mechanism of action (ipratropium)
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 the 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 receptors on bronchial smooth muscle. Return to top

Mechanism of action (albuterol)
In vitro studies and in vivo pharmacologic studies have demonstrated that albuterol has a preferential effect on beta2-adrenergic receptors compared with isoproterenol. While it is recognized that beta2-adrenergic receptors are the predominant receptors on bronchial smooth muscle, recent data indicate that there is a population of beta2-receptors in the human heart which comprise between 10% and 50% of cardiac beta-adrenergic receptors. The precise function of these receptors, however, is not yet established. Activation of beta2-adrenergic receptors on airway smooth muscle leads to the activation of adenylyl cyclase and to an increase in the intracellular concentration of cyclic- 3',5'- adenosine monophosphate (cyclic AMP). This increase of cyclic AMP leads to the activation of protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular ionic calcium concentrations, resulting in relaxation. Albuterol relaxes the smooth muscles of all airways, from the trachea to the terminal bronchioles. Albuterol acts as a functional antagonist to relax the airway irrespective of the spasmogen involved, thus protecting against all bronchoconstrictor challenges. Increased cyclic AMP concentrations are also associated with the inhibition of release of mediators from mast cells in the airway. Albuterol has been shown in most clinical trials to have more bronchial smooth muscle relaxation effect than isoproterenol at comparable doses while producing fewer cardiovascular effects. However, all beta-adrenergic drugs, including albuterol sulfate, can produce a significant cardiovascular effect in some patients. Return to top

Mechanism of action (combivent)
Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol is expected to maximize the response to treatment in patients with chronic obstructive pulmonary disease (COPD) by reducing bronchospasm through two distinctly different mechanisms, anticholinergic (parasympatholytic) and sympathomimetic. Simultaneous administration of both an anticholinergic (ipratropium bromide) and a beta2-sympathomimetic (albuterol sulfate) is designed to benefit the patient by producing a greater bronchodilator effect than when either drug is utilized alone at its recommended dosage. Return to top

Pharmacokinetics/metabolism (ipratropium)
Much 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. Plasma levels of ipratropium bromide were below the assay sensitivity limit of 100 pg/mL.

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 α1-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. Autoradiographic studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier. Return to top

Pharmacokinetics/metabolism (albuterol)
Albuterol is longer acting than isoproterenol in most patients because it is not a substrate for the cellular uptake processes for catecholamines nor for metabolism by catechol-O-methyl transferase. Instead, the drug is conjugatively metabolized to albuterol 4'-O-sulfate. In a pharmacokinetic study in 12 healthy male volunteers of two inhalations of albuterol sulfate, 103 mcg dose/inhalation through the mouthpiece, peak plasma albuterol concentrations ranging from 419 to 802 pg/mL (mean 599±122 pg/mL) were obtained within three hours post-administration. Following this single-dose administration, 30.8±10.2% of the estimated mouthpiece dose was excreted unchanged in the 24-hour urine. Since albuterol sulfate is rapidly and completely absorbed, this study could not distinguish between pulmonary and gastrointestinal absorption. Intravenous pharmacokinetics of albuterol were studied in a comparable group of 16 healthy male volunteers; the mean terminal half-life following a 30-minute infusion of 1.5 mg was 3.9 hours with a mean clearance of 439 mL/min/1.73 m2. Intravenous albuterol studies in rats demonstrated that albuterol crossed the blood-brain barrier and reached brain concentrations amounting to about 5% of the plasma concentrations. In structures outside the blood-brain barrier (pineal and pituitary glands), the drug achieved concentrations more than 100 times those in whole brain. Studies in pregnant rats with tritiated albuterol demonstrated that approximately 10% of the circulating maternal drug was transferred to the fetus. Disposition in fetal lungs was comparable to maternal lungs, but fetal liver disposition was 1% of maternal liver levels. Studies in laboratory animals (minipigs, rodents, and dogs) have demonstrated the occurrence of cardiac arrhythmias and sudden death (with histologic evidence of myocardial necrosis) when beta-agonists and methylxanthines were administered concurrently. The significance of these findings when applied to humans is unknown. Return to top

Pharmacokinetics/metabolism (combivent)
In a crossover pharmacokinetic study in 12 healthy male volunteers comparing the pattern of absorption and excretion of two inhalations of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol to the two active components individually, the co-administration of ipratropium bromide and albuterol sulfate from a single canister did not significantly alter the systemic absorption of either component. Ipratropium bromide levels remained below detectable limits (<100 pg/mL). Peak albuterol level obtained within 3 hours post-administration was 492±132 pg/mL. Following this single administration, 27.1 ±5.7% of the estimated mouthpiece dose was excreted unchanged in the 24-hour urine. From a pharmacokinetic perspective, the synergistic efficacy of Combivent Inhalation Aerosol is likely to be due to a local effect on the muscarinic and beta2-adrenergic receptors in the lung. Return to top

Special populations
The pharmacokinetics of Combivent® (ipratropium bromide and albuterol sulfate) Inhalation Aerosol or ipratropium bromide have not been studied in patients with hepatic or renal insufficiency or in the elderly. Return to top

Drug-drug interactions
No specific pharmacokinetic studies were conducted to evaluate potential drug-drug interactions. Return to top

Pharmacodynamics
The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one. Controlled clinical studies have demonstrated that ipratropium bromide does not alter either mucociliary clearance or the volume or viscosity of respiratory secretions. In studies without a positive control, ipratropium bromide did not alter pupil size, accommodation or visual acuity (see ADVERSE REACTIONS). Ventilation/perfusion studies have shown no clinically significant effects on pulmonary gas exchange or arterial oxygen tension. At recommended doses, ipratropium bromide does not produce clinically significant changes in pulse rate or blood pressure. Return to top