Combipul Mechanism of Action

Bronchodilator.
Combipul solution for nebulization is a combination of ipratropium and salbutamol. Ipratropium bromide is an anticholinergic (parasympatholytic) agent which acts by inhibiting vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released from the vagus nerve. Salbutamol is a relatively selective β-adrenergic agonist whose activation leads to the increase in intracellular adenyl cyclase, the enzyme which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic, 5'-adenosine monophosphate (c-AMP). Combipul solution for nebulization provides the simultaneous delivery of ipratropium bromide and salbutamol sulfate allowing effects on both muscarinic and β-adrenergic receptors in the lung leading to increased bronchodilation over that provided by each single agent.
Pharmacology: Ipratropium bromide permits delivery of high doses to muscarinic receptors in the airways because the compound is poorly absorbed and does not readily enter the nervous system. Studies with this agent have shown that the degree of involvement of parasympathetic pathways in bronchomotor responses varies among subjects. In some, bronchoconstriction is inhibited effectively; while only modestly in others. The failure of higher doses of the muscarinic antagonist to further inhibit the response in these individuals indicates that the mechanisms other than parasympathetic reflex pathways must be involved.
Even in the subjects least protected by this antimuscarinic agent, however, the bronchodilation and partial inhibition of provoked bronchoconstriction is of potential clinical value, and antimuscarinic agents are valuable for patients intolerant of inhaled β-agonist agents. While antimuscarinic drugs appear to be slightly less effective than β-agonist agents in reversing asthmatic bronchospasm, the addition of ipratropium enhances the bronchodilation produced by nebulization with albuterol in acute severe asthma.
Salbutamol is a direct-acting symphatomimetic with predominantly β-adrenergic activity and selective action on β₂-receptors. The result in bronchodilating action being more prominent than its effect on the heart.
Pharmacokinetics: Following inhalation, only a small amount of ipratropium reaches the systemic circulation. Some ipratropium is inadvertently swallowed but it is poorly absorbed from the GIT. Ipratropium and its metabolites are eliminated in the urine and feces.
Salbutamol is readily absorbed from the GIT. It is subject to first-pass metabolism in the liver and possibly in the gut wall; the main metabolite is an inactive sulfate conjugate. Salbutamol is rapidly excreted in the urine as metabolites and unchanged drug; there is some excretion on the feces. Salbutamol does not appear to be metabolized in the lung, therefore its ultimate metabolism and excretion following inhalation depends upon the delivery method used, which determines the proportion of inhaled salbutamol relative to the proportion inadvertently swallowed. It has been suggested that the majority of inhaled dose is swallowed and absorbed from the gut.
The plasma half-life of salbutamol has been estimated to range from 4-6 hrs.