Pharmacotherapeutic group: Adrenergics in combination with anticholinergics for obstructive airway diseases. ATC Code: R03AL02.
Pharmacology: Mode of action and pharmacodynamics: Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In nonclinical studies, it appears to inhibit 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++ 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 bronchodilation following inhalation of ipratropium bromide is primarily local and site specific to the lung and not systemic in nature.
Salbutamol sulphate is a beta2-adrenergic agent which acts on airway smooth muscle resulting in relaxation. Salbutamol relaxes all smooth muscle from the trachea to the terminal bronchioles and protects against all bronchoconstrictor challenges.
COMBIVENT provides the simultaneous release of ipratropium bromide and salbutamol sulphate allowing the additive effect on both muscarinic and beta2-adrenergic receptors in the lung resulting in a bronchodilation which is superior to that provided by each single agent.
Paediatric population: COMBIVENT has not been studied in the paediatric population.
Clinical trials: Controlled studies in patients with reversible bronchospasm have demonstrated that COMBIVENT has a greater bronchodilator effect than either of its components and there was no potentiation of adverse events.
Pharmacokinetics: From a pharmacokinetic perspective, the efficacy observed in the COMBIVENT pressurized inhalation, suspension pulmonary clinical trials is due to a local effect on the lung following inhalation.
Following inhalation 10 to 39% of a dose is generally deposited in the 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). 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.
Coadministration of ipratropium bromide and salbutamol sulphate does not potentiate the systemic absorption of either component and therefore the additive activity of COMBIVENT is due to the combined local effect on the lung following inhalation.
Ipratropium: Absorption: Cumulative renal excretion (0-24 hrs) of ipratropium (parent compound) is approximated to 46% of an intravenously administered dose, below 1% of an oral dose and approximately 3-13% of an inhaled dose. 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.
Distribution: 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. Nonclinical data indicate that the quaternary amine ipratropium does not cross the placental or the blood-brain barrier. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.
Biotransformation: After intravenous administration approximately 60% of a dose is metabolised, the major portion probably in the liver by oxidation.
Elimination: 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. 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. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.6 hours.
Salbutamol: Absorption and Distribution: Salbutamol is rapidly and completely absorbed following oral administration either by the inhaled or gastric route and has an oral bioavalability of approximately 50%. Mean peak plasma salbutamol concentrations of 492 pg/mL occur within three hours after inhalation of COMBIVENT. Kinetic parameters were calculated from plasma concentrations after i.v. administration. The apparent volume of distribution (Vz) is approximately 156 L (≈ 2.5 L/kg). Only 8% of the drug is bound to plasma proteins. In nonclinical trials, levels of approximately 5% of the plasma level of salbutamol are found in the brain. However, this amount probably represents the distribution of the substance in the extracellular water of the brain.
Biotransformation and Elimination: Following this single inhaled administration, approximately 27% of the estimated mouthpiece dose is excreted unchanged in the 24-hour urine. The mean terminal half-life is approximately 4 hours with a mean total clearance of 480 mL/min and a mean renal clearance of 291 mL/min.
Salbutamol is conjugatively metabolised to salbutamol 4'-O-sulphate. The R(-)-enantiomer of salbutamol (levosalbutamol) is preferentially metabolised and is therefore cleared from the body more rapidly than the S(+)- enantiomer. Following intravenous administration, urinary excretion was complete after approximately 24 hours. After oral administration urinary excretion of unchanged drug and sulphate conjugate were 31.8% and 48.2% of the dose, respectively.