Berodual MDI/Berodual F UDV

Berodual MDI/Berodual F UDV Mechanism of Action

ipratropium + fenoterol

Manufacturer:

Boehringer Ingelheim

Distributor:

Metro Drug
Full Prescribing Info
Action
Bronchodilator.
Pharmacology: Berodual/F UDV contains 2 active bronchodilating ingredients: Ipratropium bromide, exhibiting an anticholinergic effect and fenoterol HBr, a β-adrenergic agent.
Ipratropium bromide is a 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 cyclic guanosine monophosphate (cyclic GMP) caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
The bronchodilation following inhalation of ipratropium bromide is primarily a local, site-specific effect, not a systemic one.
In controlled 90-day studies in patients with bronchospasm associated with chronic obstructive pulmonary disease (chronic bronchitis and emphysema), significant improvements in pulmonary function (FEV1 and FEF25-75% increases of ≥15%) occurred within 15 min, reached a peak in 1-2 hrs, and persisted in the majority of patients up to 6 hrs.
In controlled 90-day studies in patients with bronchospasm associated with asthma, significant improvements in pulmonary function (FEV1 increases of ≥15%) occurred in 40% of the patients.
Preclinical and clinical evidence suggest no deleterious effect of ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange.
Fenoterol HBr is a 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. Occupation of β2-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 relaxes bronchial and vascular smooth muscles 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 higher doses of fenoterol.
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, increase in heart rate and contractility, are caused by the vascular effects of fenoterol, cardiac β2-receptor stimulation and, at supratherapeutic doses, by β1-receptor stimulation. 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.
In clinical studies, fenoterol was shown to be highly efficacious in manifest bronchospasm. It prevents bronchoconstriction following exposure to various stimuli eg, exercise, cold air and the early response following allergen exposure.
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 COPD, Berodual inhalation solution has been shown to be an efficacious bronchodilator not only after acute but also after chronic administration.
In patients with asthma and with COPD, studies with the metered aerosol have shown that Berodual is as efficacious as double the dose of fenoterol administered without ipratropium but is better tolerated in cumulative dose response studies. In adequately sized studies in patients with asthma and COPD, better efficacy compared to its components ipratropium or fenoterol was demonstrated.
In acute asthma, the combination of fenoterol and ipratropium is effective shortly after administration and has, in the majority of studies, been shown to be more efficacious than each of its components.
In acute bronchoconstriction, Berodual is effective shortly after administration and is therefore also suitable for treating acute attacks of asthma.
The effect of 4-times-daily domiciliary nebulized Berodual F UDV for 3 weeks was assessed in a placebo-controlled, randomized, double-blind, crossover study in 20 patients with a low bronchodilator response and steroid-resistant chronic obstructive pulmonary disease. Home expiratory flow rate rose from 164 L/min on saline to 196 L/min on Berodual F UDV. Secondary endpoint analysis revealed a fall in home inhaler usage and a rise in visual analogue scales for symptoms.
Pharmacokinetics: About 16% of the dose is deposited in the respiratory tract following inhalational administration. The remaining portion is being swallowed.
Fenoterol HBr and ipratropium bromide are absorbed very quickly from the respiratory tract. The peak plasma concentrations are reached only minutes after inhalation.
There is no evidence that the pharmacokinetics of both ingredients in combination differ from those of the mono-substance.
Fenoterol HBr: The swallowed portion is mainly metabolized to sulfate conjugates. The bioavailability following oral administration is low (approximately 1.5%). Following IV administration, 3 phases were observed, whereby the half-life of the terminal phase was approximately 3 hrs. Fenoterol and its conjugates are rapidly excreted renally (renal clearance: 267 mL/min). About 40-55% of the drug is bound to plasma proteins. In its nonmetabolized state, fenoterol HBr can slowly pass through the placenta and enter the maternal milk.
Ipratropium Bromide: The bioavailability of the swallowed portion is low (approximately 2%). Following IV administration, a rapid biphasic decline in plasma is noted for ipratropium. The half-life of the terminal elimination phase was about 1.6 hrs. The total clearance of the active ingredient is 2.3 L/min. Approximately 40% of the clearance is renal (0.9 L/min) and 60% nonrenal ie, mainly hepatometabolic. The main metabolites found in urine bind poorly to the muscarinic receptor. Renal excretion of the active ingredient is given as 46% of the dose after IV administration and 3-8% of the dose after oral inhalation. The swallowed portion is only poorly absorbed. The drug is minimally (<20%) bound to plasma proteins. The ipratropium ion does not cross the blood-brain barrier or the placental barrier.
Toxicology: In the acute toxicology studies with Berodual/F UDV in a ratio of 1:2.5 (ipratropium bromide:fenoterol HBr) in mice and rats using oral, IV and inhalation routes, the LD50 values revealed a low index of toxicity. They were determined more by the ipratropium bromide component than fenoterol HBr without any indication of potentiation.
After IV administration of Berodual/F UDV in dogs and inhalative administration in rats and dogs of up to 4 weeks, only minor toxic effects at concentrations up to several hundred times greater than that recommended in man were observed. Left ventricular myocardial scars were seen in only 1 animal from the highest treatment group of the IV dog study (84 mcg/kg/day). Thirteen-week studies in rats by oral and in beagle dogs by inhalative administration of Berodual/F UDV did not show any toxicological changes beyond those proportional to the individual components.
All of the toxicological systems appeared to be substance-related and were well-known out of the documentation of fenoterol HBr and ipratropium bromide. There was no indication of potentiation when ipratropium bromide and fenoterol HBr were administered concomitantly.
Teratogenicity: After inhalative administration of Berodual/F UDV in rats and rabbits, no teratogenic effects occurred. Also, no teratogenic effects were seen after ipratropium bromide and after fenoterol HBr, only after administration of extremely high (toxic) doses.
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