A. ß2-Adrenoceptor Agonists

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Introduction

ß2-adrenoceptor agonists are probably the commonest prescribed medication in respiratory practice. They are used in the treatment of asthma and the reversible element of airways obstruction commonly found in chronic obstructive airways disease (COAD). Although there are several different types of ß2-agonist, most are pharmacologically similar and all are used in a similar fashion. The group will therefore be discussed as a whole with individual differences highlighted. The two commonest ß2-agonists prescribed in the UK are salbutamol (Ventolin®, Ventodisk®) and terbutaline sulphate (Bricanyl®). Other less common drugs include fenoterol hydrobromide (Berotec®), rimiterol hydrobromide (Pulmadil®), pirbuterol (Exirel®), reproterol hydochloride (Bronchodil®) and tulobuterol hydrochloride (Brelomax®). There is no place for the use of orciprenaline and isoprenaline in current practice as they are not ß2 selective and therefore, they will not be discussed.

Pharmacology

Salbutamol, terbutaline and fenoterol have a similar molecular structure based on the isoprenaline molecule, but rimiterol is not. All 4 agents are selective ß2-adrenoreceptor agonists with effects on smooth and skeletal muscle, which include bronchodilatation, relaxation of the uterus and tremor. Both salbutamol and terbutaline are highly ß2-receptor selective, fenoterol less so and rimiterol 20 times less than fenoterol. Therefore, both fenoterol and rimiterol may stimulate the ß1-receptors as well, causing an increase in heart rate and myocardial contractility. Both salbutamol and terbutaline will also increase the heart rate, but this may be due to a reflex response following relaxation of vascular smooth muscle resulting in vasodilation rather than stimulation of ß1-receptors. Smooth muscle relaxation is thought to occur following stimulation of the ß2-receptor in the cell membrane causing conversion of ATP to cAMP, which then activates protein kinase. This leads to phosphorylation of proteins which then bind intracellular calcium reducing its availability for actin-myosin cross-linkage and therefore relaxation of the muscle. ß2-agonists also have mild anti-inflammatory activity because they have been shown to inhibit the release of bronchoconstrictor mediators from mast cells in vitro and the release of mediators into the circulation following provocation challenge testing in vivo. ß2-agonist have also been shown to enhance mucociliary clearance and have metabolic effects such as raising free fatty acid, glucose and insulin concentrations. Hypokalaemia also occurs commonly, especially following intravenous administration, and is thought to be related to linkage of ß2-receptors to Na+/K+-ATPase.

Pharmacokinetics

All ß2-agonists are commonly administered by inhalation of the drug as an aerosol (either from a metered dose inhaler (MDI) or a nebulizer) or as a powder. Salbutamol and terbutaline are also available as oral slow release tablets, syrups and intravenous preparations. Metered dose inhalers deliver an aerosol containing particles of drug with a mean median aerodynamic diameter of 2-3 µm which should reach the peripheral airways of the lung. Using indirect labelling techniques, it was previously thought that only about 10 per cent of the inhaled aerosol dose actually entered the lungs, the remainder being swallowed. However, recent studies using directly labelled drugs suggest a much higher percentage deposition in the region of 20 per cent in both normal subjects and patients with asthma, and the percentage distribution to the periphery of the lungs can be improved by use of a large volume spacer device (Volumatic® or Nebuhaler®), which also greatly reduces the swallowed dose. The maximal therapeutic effect is seen within 15 minutes of inhalation which suggests a local action within the lungs as the peak plasma concentration of the drug occurs after about 3 hours after inhalation. When given as a nebulised solution, an initial peak plasma concentration is seen within 30 minutes which is probably due to absorption from the lungs. Oral preparations of salbutamol are well absorbed (approximately 85 per cent), and terbutaline slightly less so (25-80 per cent), both being probably being affected by food in the gastrointestinal tract, and both undergoing significant first pass metabolism. Oral salbutamol is now only available as Volmax®, a specially designed capsule, which osmotically controls release of the drug by holding it within a core surrounded by a semi-permeable membrane with a single pore 250 µm in diameter and produces peak plasma levels 5-6 hours after ingestion. The plasma half-life of both drugs is about 2.5-5 hours although the terminal half life of terbutaline is much longer being 14-18 hours. When administered intravenously, because of the avoidance of first pass metabolism, both salbutamol and terbutaline circulate mostly as unchanged drug. Because of their local effect within the lungs, none of the currently available ß2-agonists show any relation between plasma concentrations and efficacy when inhaled. However, there is a dose dependent response when salbutamol or terbutaline are administered orally or intravenously, although assay of levels is not relevant in clinical respiratory practice. Salbutamol, terbutaline and fenoterol, unlike isoprenaline and rimiterol, are not substrates for metabolism by catechol-O-methyl-transferase (COMT), and are metabolised by conjugation to the sulphate although some terbutaline is also conjugated as the glucuronide. The main route of excretion is by the kidneys. Rimiterol is metabolised by COMT and the product conjugated by the liver, and as a consequence, has the shortest duration of action of the 4 agents.

Therapeutic Use

These agents are used as for their bronchodilator properties in the management of asthma and the reversible airflow element of chronic obstructive bronchitis. Salbutamol and terbutaline are also used in obstetric practice for their tocolytic properties in the management of premature labour. In the treatment of mild asthma, the agents are given by inhalation as the aerosol or powder for the relief of symptoms or prior to exercise to prevent exercise induced asthma. Recent studies suggest that better control of symptoms may be obtained by "as required" rather than regular dosing. If symptoms dictate the use of the inhaler more than twice a day then prophylactic therapy in the form of an inhaled corticosteroid or mast cell stabilising agent should be considered. Oral preparations of ß2-agonists are useful in patients unable to use the inhaled forms of therapy, although with the introduction of spacer devices and easy to use powder delivery systems, this is uncommon. Oral therapy is also useful for the control of troublesome nocturnal symptoms and also daytime symptoms not controlled by high dose inhaled corticosteroid therapy. In the management of acute severe asthma, the nebulised route is preferred because there are fewer systemic side effects and a more prolonged effect than when ß2-agonists are given parenterally. Nebulisers can deliver an aerosol with the particle size range of 2-5 µm, similar to the MDI. The nebulised dose of both salbutamol(2.5-5mg) and terbutaline (5-10mg) is equivalent to 25-50 puffs of the equivalent MDI and some studies have shown that 25 puffs from an MDI given via a spacer device has an equivalent clinical effect in acute severe asthma. Nebulisers can be driven by oxygen for patients with asthma or air for patients with chronic bronchitis and suspected carbon dioxide retention. Nebulised doses can be given safely every 2-4 hours and in very severe cases, even hourly doses can be used, although in this situation the patient may have too small a tidal volume and assisted ventilation should be considered. In ventilated patients, nebulised drug can be given via the ventilator circuit and may be especially useful prior to physiotherapy. Both salbutamol and terbutaline may be administered intravenously in acute severe asthma, but has no significant advantages over the inhaled route. Salbutamol can be given as a slow bolus of 250 µg initially followed by an infusion of 5-20 µg/min according to response. Terbutaline is given as a slow bolus of 250-500 µg followed by an infusion 1.5-5 µg/min. The most common side effects of intravenous therapy are tachycardia and tremor which may limit the dosage given. Hypokalaemia is also more common during intravenous therapy. Some patients with chronic bronchitis respond only to very large doses of bronchodilator and in this group, home nebulisation using an air compressor has been useful and may replace the MDI. Continuous subcutaneous infusion of terbutaline or salbutamol has also been used in some patients with very variable ("brittle") asthma. In emergencies, both salbutamol and terbutaline can be given as subcutaneous injection, and some patients with a history of sudden catastrophic attacks of asthma may carry preloaded syringes. Recent surveys into the high mortality rate amongst asthmatics in New Zealand may have found links with the use of fenoterol. It is now recommended that patients presently using fenoterol should use an alternative ß2-agonist until the matter has been clarified.

Side effects and Overdosage

ß2-agonist have proved extremely safe and free from serious toxic effects. The main side effect that may limit usage is fine tremor although switching to an alternative agent usually works. Other side effects include muscle cramps, anxiety and headache. Both tremor and palpitations are more commonly seen when oral dosing or high dose nebulisers are used. Theoretically, care should be taken in patients with ischaemic heart disease or a history of cardiac dysrhythmias when high doses or parenteral treatment are used. Significant hypokalaemia may be seen, especially when parenteral therapy is used, although whether this is clinically significant has not been determined. No fatalities have been reported with overdosage, the main effects being tremor, anxiety, tachycardia, flushing and hypokalaemia and the treatment is mainly supportive.

A. ß2-Adrenoceptor Agonists

A. ß2-Adrenoceptor Agonists

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Introduction

Pharmacology

Pharmacokinetics

Therapeutic Use

Side effects and Overdosage

Further Reading

A. ß2-Adrenoceptor Agonists

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