Salbutamol in the 1980s
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Salbutamol (albuterol) is a β2-selective adrenoceptor agonist which accounts for its pronounced bronchodilatory, cardiac, uterine and metabolic effects.
During the intervening years since salbutamol was first reviewed in the Journal (1971), it has become extensively used in the treatment of reversible obstructive airways disease. Numerous studies in this disease (including severe acute, childhood and exercise-induced asthma) have confirmed the bronchodilatory efficacy of salbutamol, and it has been shown to be at least as effective as most of the currently available bronchodilators, if not more effective.
The onset of maximum effect of salbutamol is dependent on the formulation used and the route by which it is administered. In most patients inhaled salbutamol is a first-line therapy, since it offers rapid bronchodilation, usually relieving bronchospasm within minutes. Although oral salbutamol has often proved to be less efficacious than the inhaled formulation, it still affords clinically significant bronchodilation, and it is particularly useful in those patients unable to coordinate the use of inhalers. Parenteral formulations of salbutamol are generally reserved for the treatment of severe attacks of bronchospasm and they are one of the treatments of choice in these life-threatening situations.
Studies of the concomitant use of salbutamol and other agents such as anticholinergics, methylxanthines and beclomethasone dipropionate have usually shown a complementary response in the majority of patients, as might be expected from the different mechanisms of action of these groups of drugs.
Salbutamol is generally well tolerated and any side effects observed are a predictable extension of its pharmacology. Since the frequency of side effects is dose related, and therefore dependent on the route of administration, it is not surprising that they are much more common following intravenous and oral rather than inhalation therapy. Tremor, tachycardia and hypokalaemia are the most frequently reported adverse effects.
After nearly 20 years of use, salbutamol is well established as a ‘first-choice’ treatment in reversible obstructive airways disease. Indeed, throughout this time many new bronchodilatory agents have been studied but none have proved more effective. Clinical evaluation of salbutamol in the treatment of premature labour, hyperkalaemia and cardiac failure awaits further studies, although to date some encouraging results have been reported.
Salbutamol is a β2-selective adrenoceptor agonist which has demonstrated considerable bronchodilatory effects. In studies in healthy volunteers, inhaled salbutamol caused a rapid and significant bronchodilation by reducing bronchomotor tone in both the large and small airways, as reflected by increases in sGaw, FEV1, FEF25–75, FEF50, FEV3, FEF75–88 and FEF75, and effectively inhibited histamine-induced bronchospasm. As would be expected, the bronchodilatory effects of salbutamol are greatly diminished following coadministration of non-selective β-blockers such as propranolol, betaxolol and tertatolol. The selective β-blocker atenolol had no such effect. Lower doses of inhaled salbutamol are required to bring about maximum bronchodilation in normal volunteers than in asthmatic patients. Although salbutamol has effective antitussive properties, its clinical application in this area requires further investigation.
In common with other β2-adrenoceptor agonists, salbutamol demonstrated vasodilatory and inotropic effects in healthy volunteers, and in patients with reversible obstructive airways disease or cardiovascular disease, particularly after intravenous administration. However, the clinical efficacy of salbutamol in the treatment of heart failure remains to be established.
Intravenous salbutamol causes a marked reduction in uterine tonicity in women suffering from primary dysmenorrhoea, and this was associated with pain relief in pregnancy. Furthermore, salbutamol by intravenous infusion reduced uteroplacental blood flow by 18 to 50%.
Salbutamol exerts a number of metabolic effects. Intravenous and nebulised salbutamol decrease serum potassium concentrations, although the effect is generally mild and transient. However, intravenous salbutamol has been used to treat hyperkalaemia in renal failure patients. Salbutamol possesses lipolytic activity which is manifested as significant increases in non-esterified fatty acid and high density lipid-cholesterol. Oral and intravenous salbutamol cause increases in blood glucose and insulin, by stimulating glycogenolysis in the liver and having a direct stimulatory effect on β2-receptors in insulin secretory pancreas cells. Studies in animals and humans indicate that maternally administered salbutamol exerts some effects on fetal metabolism, but the only change reported to date which could be of clinical significance is an increase in growth hormone levels.
Salbutamol possesses antidepressant properties, although the mechanism by which it exerts this activity is unclear. Other reported CNS effects in animals include anorexia, induced by mechanisms involving β-adrenergic sites in the brain of rats, and increased vasopressin levels in the cerebrospinal fluid of dogs.
Salbutamol has demonstrated some antiallergic activity. In vitro, salbutamol produces dose-related inhibition of histamine release from lung fragments. However, it has little or no effect on allergen-induced histamine release from leucocytes obtained from allergic patients and only weak activity at inhibiting anti-IgE-induced histamine release from human skin slices. Inhaled and oral salbutamol are potent inhibitors of mast cell mediator release; in addition, both effectively inhibit inhaled allergen-induced bronchoconstriction.
As with other β2-adrenoceptor agonists, salbutamol stimulates mucus secretion and mucociliary transport. Nebulised solutions of salbutamol increase mucociliary rates by up to 36% in obstructive airways disease patients and 16% in healthy volunteers.
The mechanism of action of salbutamol is thought to be mediated via the stimulation of the production of cyclic adenosine-3′ 5′-monophosphate (cAMP) by activation of the enzyme adenyl cyclase. Cyclic AMP is then capable of triggering a sequence of intracellular events that ultimately leads to the physiological effects associated with salbutamol therapy.
Despite its widespread use, pharmacokinetic information on salbutamol is limited, particularly with respect to newer formulations, and further studies are needed to fully define its pharmacokinetic profile in humans. The major portion of an inhaled dose of salbutamol is swallowed and handled orally; the small fraction that is delivered to the lung (approximately 10%) rapidly appears in the circulation as free drug. Salbutamol is well absorbed following oral administration, with peak plasma concentrations occurring between 1 and 4 hours later. However, due to extensive presystemic metabolism in the gut wall its systemic bioavailability is only 50%. After multiple oral doses of salbutamol 4mg 4 times daily, steady-state plasma concentrations are attained by the third day of administration. Additionally, salbutamol 2mg 4 times a day was found to be bioequivalent to a controlled release formulation given at a dosage of 4mg twice daily over a 5-day period
In animal studies it has been shown that salbutamol is rapidly cleared from all tissues. In addition, the drug undergoes placental transfer from maternal to fetal plasma, and slightly penetrates the blood-brain barrier. The apparent volume of distribution of salbutamol in humans is 156L, indicating extensive extravascular uptake. The plasma protein binding of salbutamol over the concentration range 0.05 to 2.0 mg/L is 7 to 64%. The blood/plasma concentration ratio of salbutamol is about 1.
Salbutamol and its metabolite(s) are rapidly excreted in the urine and faeces, with about 80% of a dose being recovered in urine within 24 hours, irrespective of the route of administration.
Unchanged salbutamol accounts for approximately 30% of the excreted dose following oral and inhaled administration, and about 65% after intravenous administration. Unchanged salbutamol appears to undergo active tubular secretion. Salbutamol is almost exclusively metabolised by conjugation to a 4′-O-sulphate ester in the gastrointestinal tract and liver. The metabolite possesses little or no β-adrenergic activity. The elimination half-life of salbutamol is 2.7 to 5.5 hours after oral and inhaled administration, and 2.4 to 4.2 hours after intravenous administration. The pharmacokinetic profile of salbutamol was generally very similar in patients receiving the drug for prevention of preterm labour, although renal clearance was significantly lower.
Many short and several long term studies have confirmed the therapeutic efficacy and good tolerability of salbutamol in reversible obstructive airways disease irrespective of the formulation or route of administration. Single and multiple doses of salbutamol were significantly superior to placebo in terms of improving respiratory function and, overall, inhaled salbutamol (usually 200 or 400µg) would seem to be the formulation of choice for the majority of patients with reversible obstructive airways disease. Inhalation produces peak bronchodilation within 10 minutes and the improvement in lung function has been reported to last for up to 6 hours. A similar bronchodilatory effect is obtained with nebulised salbutamol (usually 2.5mg); indeed, no significant difference was observed between inhaled and nebulised salbutamol, although a greater incidence of dose-related adverse effects occurred with the nebulised formulation. Peak bronchodilation after oral salbutamol (most frequently 4mg) usually occurred at about 2 hours, and lasted for up to 8 hours. After parenteral administration of salbutamol, rapid and effective bronchodilation occurred within 15 minutes and lasted for up to 3 hours, but this route of administration is often associated with cardiovascular-related side effects and is reserved for treating life-threatening attacks of severe acute asthma. A large number of short term studies comparing the efficacy of salbutamol and alternative bronchodilators in patients with reversible obstructive airways disease have been reported. Salbutamol was more effective than isoprenaline and isoetharine, and in general there were no major clinical differences compared with bitolterol, broxaterol, clenbuterol, fenoterol, orciprenaline (metaproterenol), procaterol, terbutaline and tulobuterol. Although some of these agents had longer durations of action than salbutamol, this was often offset by the rapid onset of bronchodilation and fewer adverse effects associated with the latter drug. In single-dose trials comparing salbutamol and anticholinergic drugs in reversible obstructive airwaysa disease, salbutamol was superior to atropine methonitrate and oxitropium, equivalent to atropine and ipratropium bromide, but, as might be expected, inferior to ipratropium bromide administered in combination with the β2-adrenoceptor agonist fenoterol. There have been few well-designed clinical trials comparing salbutamol with methylxanthine therapy in the long term management of reversible obstructive airways disease. In those studies that have been reported, usual oral doses of salbutamol (4mg 3 times daily) appeared to be as effective as oral aminophylline, choline theophyllinate and a combination of theophylline and hydroxyzine.
Studies evaluating the efficacy of salbutamol in combination with anticholinergic drugs or other agents such as theophylline or beclomethasone dipropionate have generally recorded superior improvements with combination therapy compared with the individual components alone, but such differences were not always statistically or clinically significant. Further well-designed studies are needed to confirm the apparent improvement in efficacy associated with combination therapy and to determine the most appropriate dosages for obtaining the greatest benefit.
Clinical studies in patients with severe acute asthma have confirmed that both nebulised and parenteral salbutamol are efficacious and relatively safe. Indeed, comparative studies in patients with severe acute asthma have shown that salbutamol is more effective than adrenaline (epinephrine) or aminophylline and equally as effective as terbutaline and ipratropium bromide.
Salbutamol has been successfully used in the treatment of childhood asthma and in short and long term studies it improved respiratory function to a significantly greater extent than placebo. Other comparative studies demonstrated that salbutamol was superior to isoprenaline, and at least as effective as terbutaline and fenoterol. Combination therapy with salbutamol and theophylline or ipratropium bromide was generally synergistic in childhood asthma.
Salbutamol administered by inhalation is a very effective agent in the prophylaxis of exertional asthma. In terms of protection against exercise-induced asthma, inhaled salbutamol was superior to sodium cromoglycate, theophylline, orciprenaline and ipratropium bromide, and it was at least as effective as terbutaline and fenoterol.
Clinical evaluation of salbutamol in the treatment of premature labour has tended to be of a preliminary nature, generally in uncontrolled trials. Firm conclusions regarding its relative efficacy await further research, although some encouraging results have been reported.
Salbutamol is a well-tolerated treatment for the majority of patients suffering from reversible obstructive airways disease. The most common adverse effects are dose related, and therefore dependent upon formulation and route of administration, and are characteristic of the sympathomimetic agents. Usual inhaled doses of salbutamol do not appear to produce significant adverse reactions. The principal adverse effects of the drug are mild skeletal muscle tremor and cardiovascular-related effects, including tachycardia, palpitations and peripheral oedema. Reported metabolic adverse effects include significant increases in plasma glucose and insulin, and dose-related decreases in plasma potassium concentrations, especially following intravenous therapy. The decrease in potassiuin concentrations is usually transient and supplemental potassium therapy is rarely required. The weight of evidence suggests that absolute clinical tolerance to the bronchodilatory effects of salbutamol does not develop, although some attenuation of bron-chodilatory response has been documented.
Dosage and Administration
Salbutamol is available in a wide range of formulations for the management of the various forms of reversible airways disease (in infants, children and adults) and threatened premature labour. The recommended dosage instructions are summarised in table VIII in section 6.
KeywordsSalbutamol Forced Vital Capacity Terbutaline Fenoterol Ipratropium Bromide
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