Excess repeat use of inhalations may produce adverse effects such as tachycardia, CNS stimulation, tremor, hypokalaemia and hyperglycaemia.
Treatment consists of discontinuation of salbutamol together with appropriate symptomatic therapy. The preferred antidote for overdosage with salbutamol is a cardioselective beta-blocking agent, but beta-blocking drugs should be used with caution in patients with a history of bronchospasm. Hypokalaemia may occur following overdose with salbutamol. Serum potassium levels should be monitored. If hypokalaemia occurs potassium replacement via the oral route should be given. In patients with severe hypokalaemia intravenous replacement may be necessary.
Excess repeat use of inhalations may produce adverse effects such as tachycardia, CNS stimulation, tremor, hypokalaemia and hyperglycaemia.
Treatment consists of discontinuation of Aerolin together with appropriate symptomatic therapy. The preferred antidote for overdosage with Aerolin is a cardioselective beta-blocking agent, but beta-blocking drugs should be used with caution in patients with a history of bronchospasm. Hypokalaemia may occur following overdose with Aerolin. Serum potassium levels should be monitored. If hypokalaemia occurs potassium replacement via the oral route should be given. In patients with severe hypokalaemia intravenous replacement may be necessary.
The most common signs and symptoms of overdose with salbutamol are transient beta agonist pharmacologically mediated events, including tachycardia, tremor, hyperactivity and metabolic effects including hypokalaemia and lactic acidosis.
Hypokalaemia may occur following overdose with salbutamol. Serum potassium levels should be monitored. Lactic acidosis has been reported in association with high therapeutic doses as well as overdoses of short-acting beta-agonist therapy, therefore monitoring for elevated serum lactate and consequent metabolic acidosis (particularly if there is persistence or worsening of tachypnea despite resolution of other signs of bronchospasm such as wheezing) may be indicated in the setting of overdose.
None known.
The undesirable effects caused by normally used inhaled doses of salbutamol are mild, typical for sympathomimetic agents, and they usually disappear with continued treatment.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common, (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
|
| Common | Uncommon | Rare | Very Rare |
| Immune System disorders | hypersensitivity reactions (angioedema, urticaria, hypotension and collapse) | |||
| Metabolism and nutrition disorders | hypokalaemia | |||
| Nervous system disorders: | Headache | hyperactivity, restlessness, dizziness | ||
| Cardiac disorders | palpitations | myocardial ischaemia Cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles | ||
| Vascular disorders | peripheral vasodilatation, and as a result small increase in heart rate | |||
| Respiratory, thoracic and mediastinal disorders | bronchospasm , cough, irritation of mouth and throat which may be prevented by rinsing the mouth after inhalation. | |||
| Musculoskeletal and connective tissue and bone disorders: | tremor | muscle cramps, |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
The undesirable effects caused by normally used inhaled doses of Aerolin are mild, typical for sympathomimetic agents, and they usually disappear with continued treatment.
Adverse events are listed below by system organ class and frequency. Frequencies are defined as: very common (>1/10), common, (>1/100 and <1/10), uncommon (>1/1000 and <1/100), rare (>1/10,000 and <1/1000), very rare (<1/10,000) and not known (cannot be estimated from the available data).
|
| Common | Uncommon | Rare | Very Rare |
| Immune System disorders | hypersensitivity reactions (angioedema, urticaria, hypotension and collapse) | |||
| Metabolism and nutrition disorders | hypokalaemia | |||
| Nervous system disorders: | Headache | hyperactivity, restlessness, dizziness | ||
| Cardiac disorders | palpitations | myocardial ischaemia Cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles | ||
| Vascular disorders | peripheral vasodilatation, and as a result small increase in heart rate | |||
| Respiratory, thoracic and mediastinal disorders | bronchospasm , cough, irritation of mouth and throat which may be prevented by rinsing the mouth after inhalation. | |||
| Musculoskeletal and connective tissue and bone disorders: | tremor | muscle cramps, |
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
Adverse events are listed below by system organ >
Immune system disorders
Very rare:
Hypersensitivity reactions including angioedema, urticaria, bronchospasm, hypotension and collapse
Metabolism and nutrition disorders
Rare:
Hypokalaemia.
Potentially serious hypokalaemia may result from beta2 agonist therapy.
Unknown:
Lactic acidosis
Nervous system disorders
Common:
Tremor, headache.
Very rare:
Hyperactivity.
Cardiac disorders
Common:
Tachycardia.
Uncommon:
Palpitations
Very rare:
Cardiac arrhythmias including atrial fibrillation, supraventricular tachycardia and extrasystoles
Unknown:
Myocardial ischaemia*
Vascular disorders
Rare:
Peripheral vasodilatation.
Respiratory, thoracic and mediastinal disorders
Very rare:
Paradoxical bronchospasm.
Gastrointestinal disorders
Uncommon:
Mouth and throat irritation.
Musculoskeletal and connective tissue disorders
Uncommon:
Muscle cramps.
* reported spontaneously in post-marketing data therefore frequency regarded as unknown
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme at: www.mhra.gov.uk/yellowcard.
The short term toxicity has been tested in different animal species - the mouse, the rat and the dog - at doses extending to several thousand fold higher than the intended human therapeutic dose - maximally in the region of 15 µg/kg daily. The lethal doses via the intravenous route in the rodents range from 50mg/kg, via the peroral route to around 2000 mg/kg and even higher. Thus the agent exhibits low acute systemic toxicity.
Local toxicity on the airway has not been exclusively studied, but the historical evidence based on long clinical use suggests good airway tolerance.
Reported findings in repeated dose studies such as tachycardia, increases in heart weight and hypertrophy of muscle fibres are common to all potent selective beta2-agonists and are an expression of excessive beta-stimulant action. The safety margin for these effects is not known.
The subacute toxic effects on the cardiac muscle are seen at doses ranging from 0.2 to 3mg/kg. This is a manifestation of the pharmacodynamics of salbutamol at grossly elevated doses.
The doses administered in subchronic toxicity studies have been in the milligram ranges per kilogram - 0.15 to 50 - via the oral route or by inhalation. The species have been the rat (p.o. administration), and the dog (p.o. and inhalation). The toxic signs and symptoms exhibited were, as noted in the paragraph above, related to the mode of action on the adrenergic receptor.
The chronic toxicity, again, is manifested as exaggerated pharmacodynamic effects in animals.
Animal data on reproductive toxicity is quite limited. Sympathomimetics, including salbutamol, are widely used in clinical medicine in patients of fertile age. In spite of this fact, no adverse reproductive effects attributable to salbutamol are reported in the literature.
Embryotoxicity in animal studies seems to be related only to the mouse. In this species the union of the flat bones of the lower part of the skull seem to be involved. The specific mechanism of this has not been fully elucidated.
Foetal toxicity at high single or elevated chronic doses are related to energy metabolism from glycogen. Catecholamines liberate energy in the form of glucose from glycogen stored in liver and muscle. This action is mediated by glycogen synthase and phosphorylase of these tissues. Elevated foetal insulin and glucose levels suggest a higher sensitivity of the foetal pancreas to this stimulation of ß-adrenergic receptors.
The classic airways of mutagenic potential by which this agent has been tested have exhibited no increase in the incidence of mutations.
The potential of increase in the number of neoplasms shows a species and even a strain specificity, as did the effect on the delay in union flat jaw bones. Ovarian leiomyomas, benign tumours of smooth muscle, occur with a significantly higher frequency in the rat, particularly of the Spraque-Dawley strain. The other rodent species do not appear to be affected, suggesting a difference in the susceptibility of the uterine muscle of Spraque-Dawley to ß-adrenergic stimulation.
The short term toxicity has been tested in different animal species - the mouse, the rat and the dog - at doses extending to several thousand fold higher than the intended human therapeutic dose - maximally in the region of 15 µg/kg daily. The lethal doses via the intravenous route in the rodents range from 50mg/kg, via the peroral route to around 2000 mg/kg and even higher. Thus the agent exhibits low acute systemic toxicity.
Local toxicity on the airway has not been exclusively studied, but the historical evidence based on long clinical use suggests good airway tolerance.
Reported findings in repeated dose studies such as tachycardia, increases in heart weight and hypertrophy of muscle fibres are common to all potent selective beta2-agonists and are an expression of excessive beta-stimulant action. The safety margin for these effects is not known.
The subacute toxic effects on the cardiac muscle are seen at doses ranging from 0.2 to 3mg/kg. This is a manifestation of the pharmacodynamics of Aerolin at grossly elevated doses.
The doses administered in subchronic toxicity studies have been in the milligram ranges per kilogram - 0.15 to 50 - via the oral route or by inhalation. The species have been the rat (p.o. administration), and the dog (p.o. and inhalation). The toxic signs and symptoms exhibited were, as noted in the paragraph above, related to the mode of action on the adrenergic receptor.
The chronic toxicity, again, is manifested as exaggerated pharmacodynamic effects in animals.
Animal data on reproductive toxicity is quite limited. Sympathomimetics, including Aerolin, are widely used in clinical medicine in patients of fertile age. In spite of this fact, no adverse reproductive effects attributable to Aerolin are reported in the literature.
Embryotoxicity in animal studies seems to be related only to the mouse. In this species the union of the flat bones of the lower part of the skull seem to be involved. The specific mechanism of this has not been fully elucidated.
Foetal toxicity at high single or elevated chronic doses are related to energy metabolism from glycogen. Catecholamines liberate energy in the form of glucose from glycogen stored in liver and muscle. This action is mediated by glycogen synthase and phosphorylase of these tissues. Elevated foetal insulin and glucose levels suggest a higher sensitivity of the foetal pancreas to this stimulation of ß-adrenergic receptors.
The classic airways of mutagenic potential by which this agent has been tested have exhibited no increase in the incidence of mutations.
The potential of increase in the number of neoplasms shows a species and even a strain specificity, as did the effect on the delay in union flat jaw bones. Ovarian leiomyomas, benign tumours of smooth muscle, occur with a significantly higher frequency in the rat, particularly of the Spraque-Dawley strain. The other rodent species do not appear to be affected, suggesting a difference in the susceptibility of the uterine muscle of Spraque-Dawley to ß-adrenergic stimulation.
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.
Pharmacotherapeutic group: Selective beta2-adrenoreceptor agonists.
ATC code: R03AC02.
Salbutamol is a selective ß2-adrenergic receptor agonist. The pharmacological effects of salbutamol are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3',5',-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. Salbutamol also stimulates mucous secretion and mucociliary transport in the respiratory tract. Bronchial effects of inhaled salbutamol can be detected after a few minutes and duration of action is normally 4-6 hours.
Like other ß2-adrenoceptor agonists salbutamol also has cardiovascular effects in some patients as measured by changes in pulse rate, blood pressure, symptoms and ECG changes. These effects can especially be detected after oral and intravenous administration of salbutamol. Furthermore oral and intravenous salbutamol causes reduction in uterine tonicity which has been associated with pain relief in pregnancy. In addition, salbutamol has some metabolic effects. Especially intravenous and nebulised salbutamol decreases serum potassium concentrations although the effect is generally mild and transient. Salbutamol has also lipolytic effects and it has been shown to cause increases in blood glucose and insulin probably by stimulating glycogenolysis and having a stimulatory effect on ß2-receptors in pancreas cells.
Pharmacotherapeutic group: Selective beta2-adrenoreceptor agonists.
ATC code: R03AC02.
Aerolin is a selective ß2-adrenergic receptor agonist. The pharmacological effects of Aerolin are at least in part attributable to stimulation through beta-adrenergic receptors of intracellular adenyl cyclase, the enzyme that catalyses the conversion of adenosine triphosphate (ATP) to cyclic-3',5',-adenosine monophosphate (cyclic AMP). Increased cyclic AMP levels are associated with relaxation of bronchial smooth muscle and inhibition of release of mediators of immediate hypersensitivity from cells, especially from mast cells. Aerolin also stimulates mucous secretion and mucociliary transport in the respiratory tract. Bronchial effects of inhaled Aerolin can be detected after a few minutes and duration of action is normally 4-6 hours.
Like other ß2-adrenoceptor agonists Aerolin also has cardiovascular effects in some patients as measured by changes in pulse rate, blood pressure, symptoms and ECG changes. These effects can especially be detected after oral and intravenous administration of Aerolin. Furthermore oral and intravenous Aerolin causes reduction in uterine tonicity which has been associated with pain relief in pregnancy. In addition, Aerolin has some metabolic effects. Especially intravenous and nebulised Aerolin decreases serum potassium concentrations although the effect is generally mild and transient. Aerolin has also lipolytic effects and it has been shown to cause increases in blood glucose and insulin probably by stimulating glycogenolysis and having a stimulatory effect on ß2-receptors in pancreas cells.
Pharmacotherapeutic group: Andrenergics, inhalants. Selective beta-2-andrenoreceptor agonists
ATC code: R03AC02
Salbutamol is a selective β2-agonist providing short-acting (4-6 hour) bronchodilation with a fast onset (within 5 minutes) in reversible airways obstruction. At therapeutic doses it acts on the β2-adrenoceptors of bronchial muscle. With its fast onset of action, it is particularly suitable for the management and prevention of attack in asthma.
Absorption
Orally administered salbutamol is well absorbed with peak plasma concentrations occurring 1 to 4 hours after administration.
Distribution
The major proportion of inhaled Salbutamol is swallowed. The fraction that is distributed to the lung (approx. 10-25%) is rapidly seen in the circulation as free unmetabolised drug. The remainder is retained in the delivery system or is deposited in the oropharynx from where it is swallowed. The swallowed portion of an inhaled dose is absorbed from the gastrointestinal tract and undergoes considerable first-pass metabolism.
Elimination
The plasma concentrations of inhaled Salbutamol are, however, lower than those produced by usual oral doses. Salbutamol and its metabolites are rapidly excreted in the urine and faeces with about 80% of the dose being recovered in urine within 24 hours. The elimination half-life of Salbutamol is 2.7 - 5.5 hours after oral and inhaled administration.
Absorption
Orally administered Aerolin is well absorbed with peak plasma concentrations occurring 1 to 4 hours after administration.
Distribution
The major proportion of inhaled Aerolin is swallowed. The fraction that is distributed to the lung (approx. 10-25%) is rapidly seen in the circulation as free unmetabolised drug. The remainder is retained in the delivery system or is deposited in the oropharynx from where it is swallowed. The swallowed portion of an inhaled dose is absorbed from the gastrointestinal tract and undergoes considerable first-pass metabolism.
Elimination
The plasma concentrations of inhaled Aerolin are, however, lower than those produced by usual oral doses. Aerolin and its metabolites are rapidly excreted in the urine and faeces with about 80% of the dose being recovered in urine within 24 hours. The elimination half-life of Aerolin is 2.7 - 5.5 hours after oral and inhaled administration.
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. Most of a dose of salbutamol given intravenously, orally or by inhalation is excreted within 72 hours. Salbutamol is bound to plasma proteins to the extent of 10%.
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. 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.
The swallowed portion of an inhaled dose is absorbed from the gastrointestinal tract and undergoes considerable first-pass metabolism to the phenolic sulfate. Both unchanged drug and conjugate are excreted primarily in the urine.
The nebulised solution may be inhaled through a face mask, T-piece or via an endotracheal tube. Intermittent positive pressure ventilation (IPPV) may be used but is rarely necessary. When there is a risk of anoxia through hypoventilation, oxygen should be added to the inspired air.
As many nebulisers operate on a continuous flow basis, it is likely that some nebulised drug will be released into the local environment. Aerolin should therefore be administered in a well-ventilated room, particularly in hospitals when several patients may be using nebulisers at the same time.
Dilution: Aerolin may be diluted with sterile normal saline. Solutions in nebulisers should be replaced daily.
