Berodual Mechanism of Action

Trials with treatment duration of up to 3 months involving adult asthmatics and chronic obstructive pulmonary disease (COPD) patients, and asthmatic children, in which the hydrofluroalkane (HFA) formulation and the chlorofluorocarbon (CFC) formulation have been compared, have shown the 2 formulations to be therapeutically equivalent.
Berodual contains 2 active bronchodilating ingredients: Ipratropium bromide, exhibiting an anticholinergic effect and fenoterol HBr, a β-adrenergic agent.
Ipratropium bromide: Quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical studies, it inhibits 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⁺⁺ caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle, Ca++ release is mediated by the 2nd messenger system consisting of IP3 (inositol triphosphate) and DAG (diacylglycerol).
The bronchodilatation following inhalation of ipatropium bromide is primarily a local, site-specific effect, not a systemic one.
Preclinical and clinical evidence suggest no deleterious effect of ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange.
Fenoterol hydrobromide: Direct-acting sympathomimetic agent, selectively stimulating β₂-receptors in the therapeutic dose range. The stimulation of β₁-receptors comes into effect at a higher dose range (eg, as administered in tocolysis). Occupation of β₂-receptors activates adenyl cyclase via a stimulatory G_S-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 eg, 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 IV administration, inhibit uterine motility. Also, at higher doses, metabolic effects are observed: Lipolysis, glycogenolysis, hyperglycemia and hypokalemia, the latter caused by increased K⁺-uptake primarily into skeletal muscle. Beta-adrenergic effects on the heart eg, increased heart rate and contractility are caused by the vascular effects of fenoterol, cardiac β₂-receptor stimulation, and at supratherapeutic doses, by β₁-receptor stimulation. As with other β-adrenergic agents, QT prolongations have been reported. For fenoterol MDIs, these were discrete and observed at doses higher than recommended. However, systemic exposure after administration with nebulisers (UDVs, solution for inhalation) might be higher than with recommended metered dose inhalers (MDI) doses. The clinical significance has not been established. Tremor is a more frequently observed effect of β-agonists. Unlike the effects on the bronchial smooth muscle, the systemic effects of β-agonists are subject to the development of tolerance.
Concurrent use of these 2 active ingredients dilates the bronchi by affecting different pharmacological sites of action. The 2 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 β-adrenergic component is needed to obtain the desired effect, facilitating individual dosage suited to each patient with a minimum of adverse reactions.
In patients with asthma and with chronic obstructive pulmonary disease (COPD), better efficacy compared to its components ipatropium or fenoterol was demonstrated. Two studies (1 with asthma patients, 1 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 attacks of asthma.