Pharmacology: Ipratropium bromide is a quaternary ammonium compound with anticholinergic (parasympatholytic) properties. In preclinical 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 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 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.
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: Ipratropium bromide is quickly absorbed after oral inhalation. The systemic bioavailability after inhalation is estimated to be less than 10% of the dose. Renal excretion of ipratropium bromide is given as 46% of the dose after intravenous administration. The half-life of the terminal elimination phase is about 1.6 hours as determined after intravenous administration.
The half-life for elimination of drug and metabolites is 3.6 hours, as determined after radio labeling. Ipratropium bromide does not penetrate the blood brain barrier.
Salbutamol sulphate is rapidly and completely absorbed following oral administration either by the inhaled or gastric route. Peak plasma salbutamol concentrations are seen within three hours of administration and is excreted unchanged in the urine after 24 hours. The elimination half-life is 4 hours. Salbutamol will cross the blood brain barrier reaching concentrations amounting to about five percent of the plasma concentrations.
It has been shown that co-nebulisation of ipratropium bromide and salbutamol sulphate does not potentiate the systemic absorption of either component and that therefore the additive activity of COMBIVENT is due to the combined local effect on the lung following inhalation.