Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2018 Publisher: Mylan Products Ltd, Station Close, Potters Bar, Hertfordshire, EN6 1TL, United Kingdom
Pharmacotherapeutic group: DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES, ADRENERGICS INHALANTS; Selective beta-2-adrenoreceptor agonists
ATC-Code: R03AC02
Salbutamol is a beta2-selective adrenoceptor agonist, which has a selective action on bronchial beta2-receptors and little effect on cardiac beta1-receptors at therapeutic doses. Following inhalation, salbutamol exerts a stimulating action on beta2-receptors on bronchial smooth muscle, and thus ensures rapid bronchodilatation which becomes significant within a few minutes and persists for 4 to 6 hours. The drug also causes vasodilatation leading to reflex chronotropic effect and metabolic effects, including hypokalaemia.
After inhalation, 20-47% of the active substance based on the delivered dose passes into the deeper bronchial airways, while the remainder deposits in the mouth and the upper section of the respiratory tract and is swallowed. The fraction deposited in the airways is absorbed into the pulmonary tissues and circulation, but is not metabolised by the lung. 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 sulphate.
The swallowed portion of an inhaled dose is well absorbed from the gastrointestinal tract and undergoes considerable first-pass metabolism to the phenolic sulphate. 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. Approximately 10% of the salbutamol is bound to plasma proteins.
Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential and toxicity to reproduction.
Effects seen in toxicity studies were related to the beta-adrenergic activity of salbutamol.
In common with other potent selective beta2-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 2.5mg/kg dose. In rats, treatment at the levels of 0.5, 2.32, 10.75 and 50mg/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.
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