Asthalin Mechanism of Action

Pharmacotherapeutic group: Andrenergics, inhalants. Selective beta-2-andrenoreceptor agonists. ATC code: R03A C02.
Pharmacology: Pharmacodynamics: Salbutamol is a sympathomimetic agent which has a selective action on β₂-adrenoceptors of bronchial muscle. At therapeutic doses, it acts on the β₂-adrenoceptors of bronchial muscle with little or no action on the β₂-adrenoceptors of cardiac muscle. Salbutamol provides short-acting (4-6 hour) bronchodilatation with a fast onset (within 5 minutes) in reversible airways obstruction.
Special Patient Populations: Children <4 years of age: Paediatric clinical studies conducted at the recommended dose (SB020001. SB030001. SB030002), in patients <4 years with bronchospasm associated with reversible obstructive airways disease, show that salbutamol has a safety profile comparable to that in children >4 years, adolescents and adults.
Pharmacokinetics: Absorption: The swallowed portion of an inhaled dose is absorbed from the gastrointestinal tract and undergoes considerable first-pass metabolism to the phenolic sulfate.
Distribution: After administration by the inhaled route, between 10 and 20% of the dose reaches the lower airways. The remainder is retained in the delivery system or is deposited in the oropharynx from where it is swallowed. The fraction deposited in the airways is absorbed into the pulmonary tissues and circulation, but is not metabolised by the lung. Salbutamol is bound to plasma proteins to the extent of 10%.
Biotransformation and elimination: On reaching the systemic circulation it becomes accessible to hepatic metabolism and is excreted, primarily in the urine, as unchanged drug and as the phenolic sulfate. Salbutamol administered intravenously has a half life of 4 to 6 hours and is cleared partly renally and partly by metabolism to the inactive 4'-O-sulfate (phenolic sulfate) which is also excreted primarily in the urine. The faeces are a minor route of excretion.
Both unchanged drug and conjugate are excreted primarily in the urine. Most of a dose of salbutamol given intravenously, orally or by inhalation is excreted within 72 hours.
Toxicology: Preclinical safety data: Salbutamol: In common with other potent selective β₂-agonists, salbutamol has been shown to be teratogenic in mice when given subcutaneously. In a reproductive study, 9.3% of fetuses were found to have cleft palate at 2.5 mg/kg dose. In rats, treatment at the levels of 0.5, 2.32, 10.75 and 50 mg/kg/day orally throughout pregnancy resulted in no significant fetal abnormalities. The only toxic effect was an increase in neonatal mortality at the highest dose level as the result of lack of maternal care. Reproductive studies in the rabbit at doses of 50 mg/kg/day orally (i.e. much higher than the normal human dose) have shown fetuses with treatment related changes; these included open eyelids (ablepharia), secondary palate clefts (palatoschisis), changes in ossification of the frontal bones of the cranium (cranioschisis) and limb flexure.
In an oral fertility and general reproductive performance study in rats at doses of 2 and 50 mg/kg/day, with the exception of a reduction in number of weanlings surviving to day 21 post partum at 50 mg/kg/day, there were no adverse effects on fertility, embryofetal development, litter size, birth weight or growth rate.
Propellant HFA 134a: In animal studies propellant HFA 134a has been shown to have no significant pharmacological effects other than at very high exposure concentrations, when narcosis and a relatively weak cardiac sensitising effect were found. The potency of the cardiac sensitisation was less than that of CFC-11 (trichlorofluoromethane).
In studies to detect toxicity, repeated high dose levels of propellant HFA 134a indicated that safety margins based on systemic exposure would be of the order 2200, 1314 and 381 for mouse, rat and dog with respect to humans.
There are no reasons to consider propellant HFA 134a as a potential mutagen, clastogen or carcinogen judged from in vitro and in vivo studies including long-term administration by inhalation in rodents.
Salbutamol sulphate - a CFC-free formulation: Safety studies with a salbutamol sulphate CFC-free formulation in rat and dog showed few adverse effects. These occurred at high doses and were consistent with the known effects of salbutamol inhalation.