Source: Z-Index G-Standaard (NL) Revision Year: 2022 Publisher: Boehringer Ingelheim International GmbH, Binger Straße 173, D-55216 Ingelheim am Rhein, Germany
Pharmacotherapeutic group: Adrenergics in combination with anticholinergics for obstructive airway diseases
ATC code: R03AL01
Following inhalation, both active substances, fenoterol hydrobromide and ipratropium bromide, induce bronchodilatation within a few minutes. The bronchodilator effect persists for 3-5 hours for Fenoterol and up to 6 hours for ipratropium bromide. Due to the local effect in the airways the time course of plasma concentrations does not correlate with the pharmacodynamic time-response curve after inhalation.
Fenoterol hydrobromide is a ß2-sympathomimetic agent. The ß1-receptors are only stimulated with higher doses.
Fenoterol hydrobromide relaxes the smooth muscles in the bronchi and blood vessels. The relaxation of the smooth muscles is dose-dependent. It is induced via effects on the adenylate cyclase system in such a way that the binding of the ß-agonist to its receptor – mediated by guanosine-binding protein – leads to the activation of the adenylate cyclase. Increased intracellular cAMP then causes the smooth muscles to relax via protein phosphorylation (protein kinase A). In high doses fenoterol also affects the striated muscles (tremor). Furthermore, fenoterol inhibits mediator release from the mast cells. Increased mucociliary clearance is demonstrated after administration of fenoterol in a dose of 0.6 mg. There may be little or no effect in neonates or infants up to about 20 months.
Fenoterol has a positive isotropic and chronotropic (direct and/or reflex) effect on the heart. 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. The clinical significance has not been established.
The influence on lipid and sugar metabolism (lipolysis, glycogenolysis and hyperglycaemia) and relative hypokalaemia due to increased K+ uptake in the skeletal muscle are pharmacological effects which only occur with higher doses.
Due to the density of ß2-receptors in the myometrium, fenoterol also relaxes the uterine muscles. This effect is particularly pronounced in the pregnant uterus and at considerably higher doses.
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.
Preclinical and clinical evidence suggest no deleterious effect of ipratropium bromide on airway mucous secretion, mucociliary clearance or gas exchange.
The effects of fenoterol hydrobromide and ipratropium bromide interact through functional synergism. Therefore, the dose of fenoterol hydrobromide can be kept particularly low.
The delivery of active substances via inhalation is strongly dependent on the formulation, the device and the technique used. Generally approximately 10-30% of inhaled polar, water-soluble active substances reach the lower parts of the airways, while the remainder is deposited in the mouth and the upper part of the respiratory tract (oropharynx). In particular, after inhalation via Respimat, a lung deposition of fenoterol of 39% is experimentally observed. The oropharyngeal deposition is correspondingly decreased. The amount of the active substance deposited in the oropharynx is slowly swallowed and passes the gastrointestinal tract. Inhaled doses of fenoterol hydrobromide and ipratropium bromide follow this general pattern of distribution.
After oral administration, fenoterol hydrobromide is absorbed for approximately 60%. Due to first pass metabolism, the oral bioavailability of the swallowed portion is low (approximately 1.5%). Based on urinary excretion data, the total systemic bioavailability of inhaled doses of fenoterol hydrobromide is estimated at 7%.
Following intravenous administration, the apparent volume of distribution of fenoterol at steady state (Vdss) is approximately 189 L (≈2.7 L/kg). Fenoterol is bound to plasma proteins to approximately 40%-55%. Preclinical studies with rats revealed that fenoterol and its metabolites do not cross the blood-brain barrier.
Fenoterol is predominantly metabolised to sulphate conjugates in the liver.
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. 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 is barely absorbed by the respiratory tract (approximately 4%). The absorption of the swallowed portion is approximately 10%. Due to first pass metabolism, the oral bioavailability of the swallowed portion is low (approximately 2%).
Less than 20% of ipratropium bromide is bound to plasma proteins, and it does not pass the placenta or blood-brain barrier.
After intravenous administration approximately 60% of a dose is metabolised, the major portion probably in the liver by oxidation. Ipratropium bromide is metabolised in the liver to mainly 3 metabolites (α-phenylacrylic acid and the phenylacetic acid-N-isopropyl nortropine ester methobromide, and the N-isopropylnortropine methobromide). Binding of the main urinary metabolites to the muscarinic receptor is negligible.
Total clearance is approximately 2.3 l/min, 40% of which renal. Elimination occurs in approx. 1.6 hours. In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 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 occures via the kidneys. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.6 hours.
Animal tests have not produced evidence to suggest that there might be a safety risk for humans. This is based on data from pharmacological studies regarding safety, and data on toxicity following repeated administration, genotoxicity, carcinogenicity and reproduction studies.
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