Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Other drugs for obstructive airway diseases, inhalants / Anticholinergics ATC code: R03BB01

Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In non-clinical studies, it inhibits 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 Aerovent (ipratropium) is primarily local and specific to the lung and is not systemic in nature.

Non-clinical and clinical evidence suggests that Aerovent (ipratropium) has no adverse effect on airway mucus secretion, mucociliary clearance or gas exchange.

Clinical trials
In controlled 85-day to 90-day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema), significant improvements in lung function occurred within 15 min. These improvements reached a peak in 1-2 hours and persisted for 4-6 hours.
The bronchodilator effect of Aerovent 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 Aerovent was administered in combination with an inhaled beta-agonist.

Pharmacokinetic Properties

5.2    Pharmacokinetic properties

Absorption
The therapeutic effect of Aerovent is produced by a local action in the airways. Time courses of bronchodilation and systemic pharmacokinetics do not run in parallel.

Following inhalation, 10 - 30% of a dose is generally deposited in the lungs, depending on the formulation and inhalation technique. The majority of the dose is swallowed and passes through the gastrointestinal tract.

The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes).
Aerovent                                                              Proposed prescribing information Boehringer Ingelheim                                                      January 2022- Minor Update Cumulative renal excretion (0 - 24 hours) of parent compound is below 1 % of an oral dose and approx. 3 - 13% of an inhaled dose. On the basis of these data, the total systemic bioavailability of oral and inhaled doses of ipratropium bromide is estimated at 2% and 7 - 28% respectively.
Taking this into account, swallowed portions of ipratropium bromide doses do not contribute significantly to systemic exposure.

Distribution
Kinetic parameters describing the disposition of ipratropium were calculated from plasma concentrations after intravenous administration. A rapid biphasic decline in plasma concentrations was observed. The apparent volume of distribution at steady state (Vdss) is approx. 176 l (equivalent to 2.4 l/kg). The drug is minimally (less than 20%) bound to plasma proteins. Non-clinical data indicate that the quaternary ammonium compound ipratropium does not cross the placenta or the blood-brain barrier.

The known metabolites show little or no affinity to the muscarinic receptor and must be regarded as ineffective.

Biotransformation
After intravenous administration, approx. 60% of the dose is metabolised, probably to a large extent by oxidation in the liver.

The known metabolites are formed by hydrolysis, dehydration or elimination of the hydroxymethyl group in the tropic acid moiety.

Elimination
The terminal elimination half-life is approx. 1.6 hours.

Ipratropium has a total clearance of 2.3 l/min and a renal clearance of 0.9 l/min.
After inhalation of ipratropium bromide with HFA 134a as the propellant, cumulative renal excretion over 24 hours was approx. 12%.
In an excretion balance study, cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) was 9.3% after oral administration and 3.2% after inhalation. Total radioactivity excreted via the faeces was, 88.5% after oral administration and 69.4% after inhalation. Drug-related radioactivity after intravenous administration is excreted mainly via the kidneys. The elimination half-life of drug-related radioactivity (parent compound and metabolites) is 3.6 hours.