Chemical formula: C₂₀H₃₀BrNO₃ Molecular mass: 332.463 g/mol PubChem compound: 657308
Ipratropium is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties.
It is thought that its bronchodilator activity is also present in people receiving β-blockers. The drug may be useful when the use of xanthine derivatives or adrenergic stimuli is not indicated or tolerated by the patient. It is preferred in patients with chronic bronchitis or emphysema. The maximum bronchodilator effect is observed 30-90 minutes after inhalation.
In nonclinical studies, it appears to inhibit vagally mediated reflexes by antagonising 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 ipratropium is induced by local drug concentrations sufficient for anticholinergic efficacy at the bronchial smooth muscle and not by systemic drug concentrations.
In clinical trials using metered dose inhalers in patients with reversible bronchospasm associated with chronic obstructive pulmonary disease significant improvements in pulmonary function (FEV1 increases of 15% or more) occurred within 15 minutes, reached a peak in 1-2 hours, and persisted for approximately 4 hours.
Preclinical and clinical evidence suggest no deleterious effect of ipratropium on airway mucous secretion, mucociliary clearance or gas exchange.
The bronchodilator effect of ipratropium in the treatment of acute bronchospasm associated with asthma has been shown in studies in adults and children ≥6 years of age. In most of these studies ipratropium was administered in combination with an inhaled beta2-agonist.
The therapeutic effect of ipratropium 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, device and inhalation technique. The major part of the dose is swallowed and passes through 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 contribute significantly to systemic exposure.
The drug is minimally (less than 20%) bound to plasma proteins. Nonclinical data indicate that the quaternary amine ipratropium does not cross the placental or the blood-brain barrier.
After intravenous administration approximately 60% of the dose is metabolised, mainly by conjugation (40%), whereas after inhalation about 77% of the systemically available dose is metabolised by ester hydrolysis (41%) and conjugation (36%).
The known metabolites, which are formed by hydrolysis, dehydration or elimination of the hydroxy-methyl group in the tropic acid moiety, show very little or no affinity for the muscarinic receptor and have to be regarded as ineffective
Ipratropium has a mean 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 3.2 hours.
The toxicity of ipratropium bromide has been investigated extensively in the following types of studies: acute, subchronic and chronic toxicity, carcinogenicity, reproductive toxicity and mutagenicity via oral, intravenous, subcutaneous, intranasal and/or inhalation routes. Based on these toxicity studies, the probability of systemic anticholinergic side effects decreases in the following order:
intravenous > subcutaneous > oral > inhalation > intranasal.
Pre-clinically, ipratropium bromide was found to be well-tolerated. Two-year carcinogenicity studies in rats and mice have revealed no carcinogenic activity at doses up to approximately 1,200 times the maximum recommended human daily dose for intranasal ipratropium. Results of various mutagenicity tests were negative.
Studies to investigate the possible influence of ipratropium bromide on fertility, embryo-fetotoxicity, and peri-/postnatal development have been performed on mice, rats and rabbits. High oral levels, i.e. 1000 mg/kg/day in the rat and 125 mg/kg/day in the rabbit were maternotoxic for both species and embryo-/fetotoxic in the rat, where the fetal weight was reduced. Treatment-related malformations were not observed. The highest, technically feasible doses for inhalation of the pressurised inhalation, solution, 1.5 mg/kg/day (human equivalent dose of 0.24 mg/kg/day) in rats and 1.8 mg/kg/day (human equivalent dose of 0.576 mg/kg/day) in rabbits, showed no adverse effects on reproduction.
These doses are 6- and 14-fold the maximum recommended human daily dose (MRHDD) of 2 mg or 0.04 mg/kg (based on a body weight of 50 kg).
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