Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

5.1   Pharmacodynamic properties
Pharmacotherapeutic group: Bronchodilators / antiasthmatic agents/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 Boehringer Ingelheim Israel                                                                          4 Atrovent                                                             Proposed prescribing information Boehringer Ingelheim                                                                  November 2020  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) is primarily local and specific to the lung and is not systemic in nature.

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

Clinical trials
Clinical trials with a treatment duration of up to 3 months in which the CFC formulation (Atrovent metered dose inhaler) and the CFC-free formulation (Atrovent metered dose inhaler) were compared in adult asthma and COPD patients and paediatric asthma patients have shown the two formulations to be therapeutically equivalent.

In controlled 90-day studies in patients with bronchospasm associated with chronic obstructive pulmo- nary 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.

In controlled 90-day studies in patients with bronchospasm associated with asthma, significant impro- vements in lung function (an increase of 15% in FEV1) occurred in 51% of the patients.

Pharmacokinetic Properties

5.2   Pharmacokinetic properties

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

Following inhalation, 10 - 30% of a dose is generally deposited in the lungs, depending on the formu- lation and inhalation technique. The majority 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 hours) of parent compound is approx. , 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 signific- antly to systemic exposure.

Distribution
Kinetic parameters describing the disposition of ipratropium were calculated from plasma concentra- tions after intravenous administration. A rapid biphasic decline in plasma concentrations was observ- ed. 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 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


Boehringer Ingelheim Israel                                                                           9 Atrovent                                                             Proposed prescribing information Boehringer Ingelheim                                                                  November 2020 
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 (incl- uding 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.