Pharmacotherapeutic Group: Anticholinergics. ATC Code: R03BB01.
Pharmacology: ATROVENT (ipratropium bromide) is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In nonclinical studies, it appears to inhibit vagallymediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Anticholinergics prevent the increase in intracellular concentration of Ca++ which is caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle. Ca++ release is mediated by the second messenger system consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol).
The bronchodilation following inhalation of ATROVENT (ipratropium bromide) is primarily local and site specific to the lung and not systemic in nature.
Preclinical and clinical evidence suggest no deleterious effect of ATROVENT (ipratropium bromide) on airway mucous secretion, mucociliary clearance or gas exchange.
Clinical trials: In controlled 85 - 90 day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema) significant improvements in pulmonary function occurred within 15 minutes, reached a peak in 1-2 hours, and persisted up to 4 - 6 hours.
The bronchodilator effect of ATROVENT in the treatment of acute bronchospasm associated with asthma has been shown in studies in adults and children over 6 years of age. In most of these studies ATROVENT was administered in combination with an inhaled beta-agonist.
Although the data are limited, ATROVENT has been shown to have a therapeutic effect in the treatment of bronchospasm associated with viral bronchiolitis and bronchopulmonary dysplasia in infants and very small children.
Pharmacokinetics: Absorption: The therapeutic effect of ATROVENT is produced by a local action in the airways. Time courses of bronchodilation and systemic pharmacokinetics do not run in parallel.
Following inhalation 10 to 30% of a dose is generally deposited in the lungs, depending on the formulation and inhalation technique. The major part of the dose is swallowed and passes the gastro-intestinal tract.
The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes). Cumulative renal excretion (0-24 hrs) of the parent compound is approximated to 46% of an intravenously administered dose, below 1% of an oral dose and approximately 3 to 13% of an inhaled dose. Based on these data the total systemic bioavailability of oral and inhaled doses of ipratropium bromide is estimated at 2% and 7 to 28% respectively.
Taking this into account, swallowed dose portions of ipratropium bromide do not relevantly contribute to systemic exposure.
Distribution: The drug is minimally (less than 20%) bound to plasma proteins. Nonclinical data indicate that quaternary amine ipratropium does not cross the placental or the blood-brain barrier. The known metabolites show very little or no affinity for the muscarinic receptor and have to be regarded as ineffective.
Biotransformation: After intravenous administration approximately 60% of a dose is metabolised, mainly by conjugation (40%), whereas after inhalation about 70% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%).
The known metabolites, are formed by hydrolysis, dehydration or elimination of the hydroxy-methyl group in the tropic acid moiety.
Elimination: Ipratropium has a total clearance of 2.3 L/min and a renal clearance of 0.9 L/min.
In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was 6.3% following intravenous application, 88.5% following oral dosing and 69.4% after inhalation. Regarding the excretion of drug-related radioactivity after intravenous administration, the main excretion occurs via the kidneys. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.6 hours.