Combimist Mechanism of Action

Pharmacotherapeutic group: Adrenergics in combination with anticholinergics for obstructive airway diseases.
Pharmacology: Mode of action: Ipratropium bromide has anticholinergic (parasympatholytic) properties. In non-clinical studies, it appears to inhibit vagally mediated reflexes by antagonising the action of acetylcholine, the transmitter agent released from the vagus nerve.
Pharmacodynamics: The bronchodilation following inhalation of ipratropium bromide is primarily local and site specific to the lung and not systemic in nature.
Salbutamol 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 bronchoconstrictor challenges. Ipratropium + Salbutamol provide the simultaneous delivery of ipratropium bromide and salbutamol sulfate allowing effects on both muscarinic and beta2-adrenergic receptors in the lung leading to increased bronchodilation over that provided by each agent singly.
Paediatric population: Ipratropium + Salbutamol has not been studied in the paediatric population.
Pharmacokinetics: Absorption characteristics of the combination ipratropium bromide-salbutamol sulfate: Co-administration of ipratropium bromide and salbutamol sulfate does not potentiate the systemic absorption of either component and therefore the additive activity of Ipratropium + Salbutamol is due to the combined local effect on the lung following inhalation.
Ipratropium: Absorption: Based on a cumulative excretion value (CRE0-24h) of about 3-13%, the range of total systemic bioavailability of inhaled doses of ipratropium bromide is estimated at 7 to 28%.
Distribution: Kinetic parameters describing the disposition of ipratropium bromide 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. Non-clinical 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 administration via inhalation approximately 87%-89% of a dose is metabolised, the major portion probably in the liver by oxidation.
Elimination: Ipratropium has a total clearance of 2.3 L/min and a renal clearance of 0.9 L/min.
After administration via inhalation about 3.2% of drug related radioactivity, i.e. parent compound and metabolites, is eliminated in urine. Total radioactivity excreted via the faeces was for this route of administration. The half-life for elimination of drug-related radioactivity following inhalation is 3.2 hours.
Salbutamol: Absorption: Salbutamol is rapidly and completely absorbed following oral administration either by the inhaled or the gastric route and has an oral bioavailability of approximately 50%. Mean peak plasma salbutamol concentrations of 492 pg/mL occur within three hours after inhalation of Ipratropium + Salbutamol.
Distribution: 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 non-clinical 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-sulfate. The R(-)-enantiomer of salbutamol (levosalbutamol) is preferentially metabolised and is therefore cleared from the body more rapidly than the S(+)-enantiomer. After oral administration urinary excretion of unchanged drug and sulfate conjugate were 31.8% and 48.2% of the dose, respectively.