Pharmacotherapeutic group: Adrenergics in combination with anticholinergics for obstructive airway diseases. ATC code: R03AL01
Pharmacology: Pharmacodynamics: BERODUAL contains two active bronchodilating ingredients: ipratropium bromide, exhibiting an anticholinergic effect and fenoterol hydrobromide a beta-adrenergic agent.
Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical 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 bronchodilatation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one.
Non-clinical and clinical evidence suggest no deleterious effect of ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange.
Fenoterol hydrobromide is a direct acting sympathomimetic agent, selectively stimulating beta2-receptors in the therapeutic dose range. The stimulation of beta1-receptors comes into effect at a higher dose range. Occupation of beta2-receptors activates adenyl cyclase via a stimulatory Gs-protein.
The increase in cyclic AMP activates protein kinase A which then phosphorylates target proteins in smooth muscle cells. This in turn leads to the phosphorylation of myosin light chain kinase, inhibition of phosphoinositide hydrolysis, and the opening of large-conductance calcium-activated potassium channels.
Fenoterol hydrobromide relaxes bronchial and vascular smooth muscle and protects against bronchoconstricting stimuli such as histamine, methacholine, cold air, and allergen (early response). After acute administration the release of bronchoconstricting and pro-inflammatory mediators from mast cells is inhibited. Further, an increase in mucociliary clearance has been demonstrated after administration of doses of fenoterol (0.6 mg).
Higher plasma concentrations, which are more frequently achieved with oral, or even more so, with intravenous administration inhibit uterine motility. Also at higher doses, metabolic effects are observed: Lipolysis, glycogenolysis, hyperglycaemia and hypokalaemia, the latter caused by increased K+-uptake primarily into skeletal muscle.
Beta-adrenergic effects on the heart such as increase in heart rate and contractility are caused by the vascular effects of fenoterol, cardiac beta2-receptor stimulation, and at supratherapeutic doses, by beta1-receptor stimulation. As with other beta-adrenergic agents, QTc prolongations have been reported. For fenoterol pressurised inhalation, solutions these were discrete and observed at doses higher than recommended. However, systemic exposure after administration with nebulisers (nebuliser solution, nebuliser solution in unit dose vials) might be higher than with recommended pressurised inhalation, solution doses. The clinical significance has not been established. Tremor is a more frequently observed effect of beta-agonists. Unlike the effects on the bronchial smooth muscle, the systemic effects on skeletal muscle of beta-agonists are subject to the development of tolerance.
Concurrent use of these two active ingredients dilates the bronchi by affecting different pharmacological sites of action. The two active substances thus complement each other in their spasmolytic action on the bronchial muscles and allow a broad therapeutic use in the field of bronchopulmonary disorders associated with constriction of the respiratory tract. The complementary action is such that only a very low proportion of the beta-adrenergic component is needed to obtain the desired effect, facilitating individual dosage suited to each patient with a minimum of adverse reactions.
Clinical efficacy and safety: In patients with asthma and COPD, better efficacy compared to its components ipratropium or fenoterol was demonstrated. Two studies (one with asthma patients, one with COPD patients) have shown that BERODUAL is as efficacious as double the dose of fenoterol administered without ipratropium but was better tolerated in cumulative dose response studies.
In acute bronchoconstriction BERODUAL is effective shortly after administration and is therefore also suitable for treating acute episodes of bronchospasm.
Pharmacokinetics: The therapeutic effect of the combination ipratropium bromide and fenoterol hydrobromide is produced by a local action in the airway. The pharmacodynamics of the bronchodilation are therefore not related to the pharmacokinetics of the active constituents of the preparation.
Following inhalation, 10 to 39% of a dose is generally deposited in lungs, depending on the formulation, inhalation technique and device, while the remainder of the delivered dose is deposited in the mouthpiece, mouth and the upper part of the respiratory tract (oropharynx). A similar amount of the dose is deposited in the respiratory tract following inhalation by metered aerosol with HFA 134a propellant. In particular after inhalation of the aqueous solution via the RESPIMAT inhaler, a more than 2-fold higher lung deposition is experimentally observed as compared to the metered aerosol inhaler. The oropharyngeal deposition is correspondingly decreased and is significantly lower for the RESPIMAT inhaler as compared to the metered aerosol inhaler. The portion of the dose deposited in the lungs reaches the circulation rapidly (within minutes). The amount of the active substance deposited in the oropharynx is slowly swallowed and passes the gastrointestinal tract. Therefore the systemic exposure is a function of both oral and lung bioavailability.
There is no evidence that the pharmacokinetics of both ingredients in the combination differ from those of the mono-substance.
Fenoterol hydrobromide: The swallowed portion is mainly metabolised to sulphate conjugates. The absolute bioavailability following oral administration is low (approx. 1.5%).
After intravenous administration, free fenoterol and conjugated fenoterol are approximated to 15% and 27% of the administered dose in the cumulative 24-hour urine. After inhalation via BERODUAL metered dose inhaler approximately 1% of an inhaled dose is excreted as free fenoterol in the 24-hour urine. Based on these data, the total systemic bioavailability of inhaled doses of fenoterol hydrobromide is estimated at 7%.
Kinetic parameters describing the disposition of fenoterol were calculated from plasma concentrations after i.v. administration. Following intravenous administration, plasma concentration-time profiles can be described by a 3-compartment model, whereby the terminal half-life is approximately 3 hours. In this 3-compartment model the apparent volume of distribution of fenoterol at steady state (Vdss) is approximately 189 L (≈2.7 L/kg). (For nebuliser solution)
About 40% of the drug are bound to plasma proteins.
Preclinical studies with rats revealed that fenoterol and its metabolites do not cross the blood-brain barrier. Fenoterol has a total clearance of 1.8 L/min and a renal clearance of 0.27 L/min.
In an excretion balance study cumulative renal excretion (2 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 65% of dose after intravenous administration and total radioactivity excreted in faeces was 14.8% of dose. Following oral administration, total radioactivity excreted in urine was approximately 39% of dose and total radioactivity excreted in faeces was 40.2% of dose within 48 hours.
Ipratropium bromide: Cumulative renal excretion (0-24 hrs) of ipratropium (parent compound) is approximated below 1% of an oral dose and approximately 3 to 13% of an inhaled dose via BERODUAL metered dose inhaler. 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.
Kinetic parameters describing the disposition of ipratropium were calculated from plasma concentrations after i.v administration. A rapid biphasic decline 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. Preclinical studies with rats and dogs, revealed that the quarternary amine ipratropium does not cross the blood-brain barrier.
The half-life of the terminal elimination phase is approximately 1.6 hours. Ipratropium has a total clearance of 2.3 L/min and a renal clearance of 0.9 L/min. After intravenous administration, approximately 60% of a dose is metabolised, the major portion probably in the liver by oxidation.
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 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. Binding of the main urinary metabolites to the muscarinic receptor is negligible and the metabolites have to be regarded as ineffective.