Rhea Ipratropium + Salbutamol Mechanism of Action

Pharmacotherapeutic group: Adrenergics in combination with anticholinergics for obstructive airway diseases. ATC code: R03AL02.
Pharmacology: Pharmacodynamics: Mode of Action: 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 sulfate 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.
Ipratropium bromide + salbutamol provides the simultaneous release of ipratropium bromide and salbutamol sulfate 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.
Clinical Trials: Controlled studies in patients with reversible bronchospasm have demonstrated that ipratropium bromide + salbutamol 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 ipratropium bromide + salbutamol 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 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).
Coadministration of ipratropium bromide and salbutamol sulphate does not potentiate the systemic absorption of either component and therefore the additive activity of ipratropium bromide + salbutamol 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 3-4% 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 9% 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 (V_dss) 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.
Biotransformation: 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. After intravenous administration approximately 60% of a dose is metabolised, the major portion probably in the liver by oxidation.
Elimination: In an excretion balance study cumulative renal excretion (6 days) of drug-related radioactivity (including parent compound and all metabolites) accounted for 72.1% after intravenous administration, 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. Regarding the excretion of drug-related radioactivity after intravenous administration, the main excretion occurs via the kidneys. The half-life for elimination of drug-related radioactivity (parent compound and metabolites) is 3.6 hours. The main urinary metabolites bind poorly to the muscarinic receptor and have to be regarded as ineffective.
Salbutamol: Absorption and Distribution: Salbutamol is rapidly and completely absorbed following oral administration either by the inhaled or 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 bromide + salbutamol. 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-sulfate. 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. The majority of the dose was excreted as parent compound (64.2%) and 12.0% were excreted as sulfate conjugate. After oral administration urinary excretion of unchanged drug and sulfate conjugate were 31.8% and 48.2% of the dose, respectively.
Toxicology: The acute toxicity of ipratropium bromide + salbutamol after single inhalation administration was tested in rats and dogs. Up to the highest technically feasible dose (rat: 887/5397 mcg/kg ipratropium bromide/salbutamol, dog: 164/861 mcg/kg ipratropium bromide/salbutamol) there were no indications of systemic toxic effects, the combination was locally well tolerated. The approximate LD₅₀ after intravenous administration was calculated for the individual substances to be between 12 and 20 mg/kg for ipratropium bromide and between 60 and 73 mg/kg for salbutamol sulfate depending on the species tested (mouse, rat, dog).
Two 13-week inhalation toxicity studies in rats and dogs, have been performed with the combination of ipratropium bromide and salbutamol sulfate. In these studies, the heart proved to be the target organ. In the rat at dosages of 34/197 to 354.5/2604 mcg/kg /day ipratropium bromide/salbutamol sulfate, a non dose dependent increase in heart weights was present, however without any histopathological correlate. In the dog at doses of 32/198 to 129/790 mcg/kg/day ipratropium bromide/salbutamol sulfate, slightly increased heart rate and, at higher dosages, histopathologically detectable scars and/or fibrosis in the papillary muscle of the left ventricle, sometimes accompanied with mineralisation, were observed.
The cardiovascular findings obtained in the previously mentioned studies must be regarded as well known effects of beta-adrenergics such as salbutamol. The toxicological profile of ipratropium bromide is also well known for many years and characterised by typical anticholinergic effects as dryness of the mucosal membranes of the head, mydriasis, keratoconjunctivitis sicca (dry eye) in dogs only, reduction in tone and inhibition of motility in the gastrointestinal tract (rat).
Reproduction toxicity studies are available for the two individual components of ipratropium bromide + salbutamol. Salbutamol sulfate caused cleft palates at high subcutaneous dosages in mice, starting at dosages in the range of the inhalation Maximum Recommended Human Daily Dose (MRHDD) (based on mg/m²). However this phenomenon is well known and occurs also after the administration of other beta-adrenergic compounds. Today it is assumed that this effect is caused by an increase in the maternal corticosterone level and might be regarded as a result of general stress not relevant for other species. Apart from these findings, the studies performed with salbutamol sulfate and with ipratropium bromide revealed only marginal effects, if any, on embryos, foetuses and pups and these only in the range of maternal toxicity.
Ipratropium bromide did not affect fertility of male or female rats at oral doses up to 50 mg/kg (approximately 3,400 times the MRHDD on a mg/m² basis). Reproduction studies in rats with salbutamol revealed no evidence of impaired fertility.
Both individual substances were tested in numerous in vivo and in vitro genotoxicity tests. Neither salbutamol sulfate nor ipratropium bromide showed any evidence of mutagenic properties. In addition ipratropium bromide + salbutamol did not show genotoxic activity in in vitro assays.
Salbutamol sulfate and ipratropium bromide were tested individually for neoplastic properties in several carcinogenicity studies. After oral administration of salbutamol sulfate in rats, but not in mice, hamsters and dogs, an increased incidence of leiomyomas of the mesovarium was observed at dosages about ≥ 20-fold higher than inhalation MRHDD. The development of the leiomyomas was found to be preventable by simultaneous administration of beta-blockers. These findings were assessed to be species specific and therefore without clinical relevance, consequently not leading to any restriction of the clinical use of salbutamol sulfate.
Ipratropium bromide revealed no carcinogenic potential when tested orally in mice and rats.
No evidence was found of any immunotoxicological effect caused by ipratropium bromide + salbutamol or its individual active ingredients.