Pulmodual/Pulmodual MDI Mechanism of Action

Pharmacotherapeutic group: Selective beta-2-adrenoreceptor agonists and anticholinergics.
Pharmacology: Pulmodual: Ipratropium bromide is a synthetic quaternary anticholinergic (parasympatholytic) ammonium compound chemically related to atropine. It appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine. Anticholinergics prevent the increases in intracellular concentrations of cyclic guanosine monophosphate (cyclic GMP), which are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
The bronchodilation following inhalation is primarily a local, site-specific effect. Salbutamol sulfate is a direct-acting sympathomimetic with mainly beta-adrenergic activity and a selective action on beta₂ receptors (a beta₂ agonist) used to produce bronchodilation. It relieves reversible bronchospasm by relaxing the smooth muscles of the bronchioles in conditions associated with asthma, bronchitis, emphysema, or bronchiectasis.
Pulmodual MDI: Pharmacodynamics: Mechanism of Action: Salbutamol Sulphate and Ipratropium Bromide Inhalation contains salbutamol sulphate and Ipratropium bromide which have differing modes of action.
The respective mechanisms of action of both drugs are discussed as follows.
Salbutamol: Salbutamol is a short-acting, selective beta-2-adrenergic receptor agonist used in the treatment of asthma and COPD. It is 29 times more selective for beta2 receptors than beta1 receptors giving it higher specificity for pulmonary beta receptors versus beta1-adrenergic receptors located in the heart. Salbutamol is formulated as a racemic mixture of the R- and S-isomers. The R-isomer has 150 times greater affinity for the beta-2-receptor than the S-isomer and the S-isomer has been associated with toxicity. This lead to the development of levalbuterol, the single R-isomer of salbutamol. However, the high cost of levalbuterol compared to salbutamol has deterred wide-spread use of this enantiomerically pure version of the drug. Salbutamol is generally used for acute episodes of bronchospasm caused by bronchial asthma, chronic bronchitis and other chronic bronchopulmonary disorders such as chronic obstructive pulmonary disorder (COPD). It is also used prophylactically for exercise-induced asthma.
Salbutamol stimulates beta(2)-adrenergic receptors. Binding of Salbutamol to beta(2)-receptors in the lungs results in relaxation of bronchial smooth muscles. It is believed that salbutamol increases cAMP production by activating adenyl cycles, and the actions of salbutamol are mediated by cAMP. Increased intracellular cyclic AMP increases the activity of cAMP-dependent protein kinase A, which inhibits the phosphorylation of myosin and lowers intracellular calcium concentrations. A lowered intracellular calcium concentration leads to a smooth muscle relaxation and bronchodilation. In addition to bronchodilation, salbutamol inhibits the release of bronchoconstricting agents from mast cells, inhibits microvascular leakage, and enhances mucociliary clearance.
Ipratropium bromide: Ipratropium bromide is an anticholinergic (parasympatholytic) agent which, based on animal studies, appears to inhibit vagally mediated reflexes by antagonizing the action of acetylcholine, the transmitter agent released at neuromuscular junctions in the lung. Anticholinergics prevent the increases in intracellular concentration of cyclic guanosine monophosphate (cyclic GMP) which are caused by interaction of acetylcholine with the muscarinic receptor on bronchial smooth muscle.
In humans, ipratropium bromide has anti-secretory properties and, when applied locally, inhibits secretions from the seromucous glands lining the nasal mucosa. Ipratropium bromide is a quaternary amine that minimally crosses the nasal mucosa. Ipratropium bromide is a quaternary amine that minimally crosses the nasal mucosa. Ipratropium bromide is a quaternary amine that minimally crosses the nasal and gastrointestinal membrane and the blood-brain barrier, resulting in a reduction of the systemic anticholinergic effects (e.g., neurologic, opthalmic, cardiovascular, and gastrointestinal effects) that are seen with tertiary anticholinergic amines.
Pharmacokinetics: Salbutamol: Salbutamol is readily absorbed from the gastrointestinal tract. It is subjected to first-pass metabolism in the liver and possibly in the gut wall; the main metabolite is an inactive sulfate conjugate. It is rapidly excreted in the urine as metabolites and unchanged drug; there is some excretion in the faeces. Salbutamol does not appear to be metabolized in the lungs, 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.
Pulmodual: It has been suggested that most of an inhaled dose is swallowed and absorbed from the gut. The plasma half-life of salbutamol is 4 to 6 hours.
Pulmodual MDI: The plasma half-life of salbutamol has been estimated as 2 to 7 hours.
Ipratropium Bromide: Ipratropium bromide is minimally bound (≤ 9% (Pulmodual) or 0 to 9% (Pulmodual MDI) in vitro) to plasma albumin and α₁-acid glycoprotein. It is partially metabolized to inactive ester hydrolysis products.
Pulmodual: After inhalation, only a small amount of ipratropium reaches the systemic circulation from the nasal mucosa. Less than 20% of an 84 mcg per nostril dose is absorbed from the nasal mucosa, but the amount which is systemically absorbed from nasal administration exceeds the amount absorbed from inhalation solution (2% of a 500 mcg dose). Some ipratropium is advertently swallowed but it is poorly absorbed from the gastrointestinal tract. The elimination half-life is about 1.6 hours. Ipratropium and its metabolites are eliminated in the urine and faeces.
Pulmodual MDI: Ipratropium bromide is a quaternary amine. It is not readily absorbed into the systemic circulation either from the surface of the lung or from the gastrointestinal tract as confirmed by blood level and renal excretion studies.
Autoradiographic studies in rats have shown that ipratropium bromide does not penetrate the blood-brain barrier. The half-life of elimination is about 2 hours after inhalation or intravenous administration. Following intravenous administration, approximately one-half of the dose is excreted unchanged in the urine. Single doses of ipratropium bromide were administered intravenously, orally and by slow inhalation to ten healthy male volunteers. The plasma level after oral administration followed a low but a broad plateau persisting for several hours. After I.V. administration the kinetic parameters were: Vc = 25.9 L, V alpha = 13.1 L, V beta = 3.38 L, t1/2 alpha = 3.85 min, t1/2 beta = 98.4 min, AUC = 15.0 h.ng/mL, kel=11.8 L/h and total clearance is 2325 mL/min. The bioavailability was 3.3% (range 0.9-6.1%) on comparing the plasma AUCs following I.V. and 20 mg oral administration. The cumulative renal excretion (0-24 h) after I.V. administration was compared with that after oral administration and inhalation. Following oral administration, the apparent systemic availability was around 2%, and after inhalation it was 6.9%. In comparison with oral placebo administration, only after I.V. administration was there a significant change in heart rate (from 63.7 to 90.2 beats/min). The systolic blood pressure rose from 115.1 to 119.6 mm Hg and the diastolic blood pressure from 68.3 to 78.3 mm Hg.