Atrovent Mechanism of Action

Pharmacotherapeutic group: Anticholinergics. ATC Code: R03BB01.
Pharmacology: Mode of action: Atrovent (ipratropium bromide) is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In non-clinical studies, it appears to inhibit vagally mediated 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.
Non-clinical and clinical evidence suggests 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.
Nebuliser solution: 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.
Inhalation solution: The bronchodilator effect of ATROVENT in the treatment of acute bronchospasm associated with asthma has been shown in studies in adults. In most of these studies ATROVENT was administered in combination with an inhaled beta-agonist.
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).
Nebuliser solution: 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.
Inhalation solution: Cumulative renal excretion (0-24 hrs) of the parent compound is 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: Kinetic parameters describing the disposition of ipratropium were calculated from plasma concentrations after i.v. administration. A rapid biphasic in plasma concentrations is observed. The apparent volume of distribution at steady-state (Vdss) is approximately 176 L (≈ 2.4 L/kg). 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.
Nebuliser solution: 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.
Inhalation solution: The half-life of the terminal elimination phase is approximately 1.6 hours.
In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for, 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was, 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.
Toxicology: Preclinical safety data: Nebuliser solution: Local and systemic tolerability of ipratropium bromide has been comprehensively investigated in several animal species using various administration routes.
Single-dose toxicity: Acute inhalational, oral and intravenous toxicity has been assessed in several rodent and non-rodent species.
When administered by inhalation, the minimum lethal dose in male guinea pigs was 199 mg/kg. In rats, no mortality was observed up to the highest technically feasible doses (0.05 mg/kg after 4 hours of administration or 160 puffs of ipratropium bromide at a dose of 0.02 mg/puff).
The oral LD50 values for mice, rats and rabbits were 1585, 1925 and 1920 mg/kg respectively. The intravenous LD50 values for mice, rats and dogs were 13.6, 15.8 and approx. 18.2 mg/kg respectively. Clinical symptoms included mydriasis, dry oral mucosa, dyspnoea, tremor, spasms and/or tachycardia.
Repeated-dose toxicity: Repeated-dose toxicity studies have been performed in rats, rabbits, dogs and rhesus monkeys. In inhalation studies up to 6 months in rats, dogs and rhesus monkeys, the no observed adverse effect levels (NOAELs) were 0.38 mg/kg/day, 0.18 mg/kg/day and 0.8 mg/kg/day respectively. Dryness of the oral mucosa and tachycardia were noted in dogs. No histopathological lesions related to ipratropium bromide were observed in the bronchopulmonary system or in any other organs. In rats, the NOAEL after 18 months of oral administration was 0.5 mg/kg/day.
Repeated-dose inhalation toxicity studies in rats for up to 6 months and in dogs for up to 3 months with other formulations (intranasal formulation, alternative propellant HFA 134a and lactose powder formulations) revealed no additional information on the general toxicity profile of ipratropium bromide.
Intranasal administration for up to 6 months revealed a no effect level (NOEL) of >0.20 mg/kg/day in dogs and confirmed the results of earlier studies with intranasal administration for up to 13 weeks. Repeated-dose toxicity studies of ipratropium bromide have shown the toxicological profiles of the HFA formulation and the conventional CFC formulation to be similar.
Local tolerability: An aqueous solution of ipratropium bromide (0.05 mg/kg) was locally well tolerated when administered to rats by inhalation (single administration over 4 hours). In the repeated-dose toxicity study, ipratropium bromide was locally well tolerated.
Immunogenicity: Neither active anaphylaxis nor passive cutaneous anaphylactic reactions occurred in guinea pigs.
Genotoxicity and carcinogenicity: There was no evidence of genotoxicity in vitro (Ames test) or in vivo (micronucleus test, dominant lethal test in mice, cytogenetic assay in Chinese hamster bone marrow cells).
No tumorigenic or carcinogenic effects were demonstrated in long-term studies in mice and rats.
Reproductive and developmental toxicity: Studies to investigate the possible influence of ipratropium bromide on fertility, embryo-/foetotoxicity and peri-/postnatal development have been performed in mice, rats and rabbits.
High oral doses (1000 mg/kg/day in rats and 125 mg/kg/day in rabbits) were maternotoxic for both species and embryo-/foetotoxic in rats and resulted in lower foetal weight. Malformations related to ipratropium bromide were not observed. The highest technically feasible doses for inhalation of the metered-dose aerosol (1.5 mg/kg/day in rats and 1.8 mg/kg/day in rabbits) had no adverse effects on reproduction. Inhalation solution: Not applicable.