, Volume 35, Issue 1, pp 22–41


A Preliminary Review of its Pharmacological Properties and Therapeutic Efficacy in Reversible Obstructive Airways Disease
  • Heather A. Friedel
  • Rex N. Brogden
Drug Evaluation



Bitolterol is a β-adrenoceptor agonist which is hydrolysed to colterol by tissue esterases present at high concentrations in the lung. Animal studies indicate that bitolterol has significant β2-selectivity. In initial clinical trials transient cardiovascular effects have occurred in about 5% of patients. The spectrum of other adverse reactions with bitolterol is similar to that found with other β-adrenoceptor agonists.

Preliminary therapeutic trials of bitolterol administered by aerosol or nebuliser in adult patients with asthma have shown variable but significant improvements in forced expiratory volume in 1 second (FEV1) and a duration of action of up to 8 hours in some patients. Bitolterol has been shown to provide similar maximum increases in FEV1 to isoprenaline (isoproterenol) and to be significantly longer acting in long term comparative trials. Either alone or in combination with oral theophylline, bitolterol aerosol produces greater and more prolonged bronchodilation than oral theophylline alone but more consistently in non-steroid-dependent patients. Duration of bronchodilation with bitolterol in patients receiving steroids is less than in those who are not steroid dependent, perhaps due to more severe disease in the former group. More long term trials in larger groups of patients are clearly needed to assess the efficacy and safety of bitolterol in comparison with other long acting β-adrenoceptor agents, and to define the role of bitolterol in the combination regimens of antiasthmatic agents which are becoming increasingly popular. Nevertheless, bitolterol appears to be a well tolerated and relatively long acting alternative to other β-adrenoceptor agonists in the treatment of reversible obstructive airways disease.

Pharmacodynamic Studies

Bitolterol is a relatively selective β2-adrenoceptor agonist. Animal studies have shown a greater separation of bronchodilator and cardiovascular activities in comparison with salbutamol (albuterol) and terbutaline. In animals, bronchodilator response to bitolterol after histamine or carbachol challenge or injection of immune complexes is considerable, with effects lasting 4 to 5 hours. Cardiovascular response, on the other hand, is less than that seen with the other drugs studied and returns to baseline values while bronchodilation continues. In animals the separation of bronchodilator and cardiovascular effects has been explained by greater concentration of bitolterol and of esterase (to form the active metabolite colterol) in lung as opposed to heart tissue.

In adult asthmatic patients the onset of bronchodilator activity occurs within 3 to 5 minutes of bitolterol inhalation and a peak effect is attained at 30 to 90 minutes. Mean peak improvement in forced expiratory volume in 1 second (FEV1) following administration of 700 to 1100µg by aerosol and higher doses by nebuliser ranges from 20 to 56% and may be greater in non-steroid-dependent than in steroid-dependent patients. However, doses above 1000µg administered by closed nebuliser do not generally provide further improvement in FEV1. Duration of activity is also variable, ranging from 4 to 8 hours after a single inhaled dose, and is longer with higher doses and in patients not on steroids. Preliminary studies in small groups of paediatric patients suggest similar results. Preliminary results suggest that bitolterol is effective in preventing exercise-induced asthma but optimum dose and timing in relation to exercise, and duration of protective effect, have not been determined.

Cardiovascular effects of inhaled bitolterol during treatment of adult asthma patients for periods of up to 3 months have been generally mild and transient in nature. These have included small increases in heart rate (usually less than 10 beats/min), minor blood pressure changes, palpitations and chest discomfort. No cardiotoxicity, based on 24-hour electrocardiogram readings using Holter monitors, has been demonstrated during combined use with theophylline. However, only small numbers of fairly young, reasonably well controlled asthmatics have been studied. More work is needed to assess risks of toxicity in older patients and/or those with severe asthma or other intercurrent illness.


After oral dosing with bitolterol, both in animals and in human volunteers, partial hydrolysis to active colterol occurs in the gastrointestinal tract and liver during the absorption process. After 1 hour peak plasma colterol levels are reached and inactive metabolites are also present. In the rat the greatest tissue uptake is in the liver with little difference in uptake by blood, heart or lung tissue.

Upon intravenous dosing, on the other hand, bitolterol is preferentially distributed to lung tissue in both rat and dog. That, plus greater lung tissue esterase activity, is probably responsible for the good bronchodilator: cardiovascular separation ratio found in animals. It is not known whether these factors are present in humans. Nevertheless, upon aerosol administration in humans it is known that bitolterol is only slowly hydrolysed to colterol with serum concentrations of the latter too low to be measured by available methods.

By all routes of administration the pharmacological activity of bitolterol is terminated by further metabolism of colterol through methylation and subsequent conjugation. In healthy subjects over 85% of a dose of bitolterol is eliminated in the urine and 8% in the faeces over a period of 72 hours. No parent compound is recovered. Plasma elimination half-life is 3 hours.

Therapeutic Trials

In single-dose studies in adult patients with asthma, inhaled bitolterol has produced similar degrees of improvement in various parameters of respiratory function to that produced by salbutamol, orciprenaline (metaproterenol) and isoprenaline. Bitolterol aerosol 1050 and 1100µg was significantly longer acting than isoprenaline 250µg, and longer acting than salbutamol 180µg by the same route in some initial studies. The duration of action of a lower dose of bitolterol (700µg) was equal to that of orciprenaline in a single study.

In long term studies ( 1 to 3 months) comparing bitolterol administered by aerosol or nebuliser with isoprenaline given by the same route, in parallel groups of adult asthmatics, bitolterol was at least as effective as isoprenaline in improving FEV1 response and was significantly longer acting. Adverse effects were minor and not different between the 2 drugs. No data are available comparing bitolterol with other β-adrenoceptor agonists.

In 1 small study bitolterol aerosol, either alone or in combination with oral theophylline, produced a greater and more prolonged improvement in FEV1 than did oral theophylline alone in parallel groups of patients over a 6-week period. However, results were consistent only in patients not receiving inhaled corticosteroids concomitantly. In steroid-dependent patients, likely to have more severe disease, there was a smaller degree of bronchodilation and a shorter duration of effect, and one regimen was not clearly superior over another. There was no difference in the number of asthma attacks among all groups of patients studied. Acute bronchodilator studies may not adequately reflect the efficacy of slow release oral theophylline. Further work in much larger groups of patients is needed to adequately assess the long term efficacy of bitolterol relative to that of other β2-adrenoceptor agonists.

In one multicentre study in adult patients with chronic obstructive pulmonary disease, bitolterol aerosol 740µg produced a greater and more prolonged improvement in respiratory parameters than isoprenaline 170µg 3 times daily, which was maintained for the 3-month study period. Further studies are needed to determine the efficacy of bitolterol relative to that of established therapy in this type of patient.

Side Effects

The side effects most commonly associated with bitolterol therapy are tremor (14%), nervousness (5%), throat irritation (5%), headache (4%), cough (4%), dizziness (3%), light-headedness (3%), nausea (3%) and palpitations (3%). Cardiovascular effects (including palpitations) occur in about 5% of patients. Effects are usually mild and transient but are occasionally moderate to severe. However, few patients have required withdrawal from treatment.

Dosage and Administration

The usual aerosol dose for relief of bronchospasm is 2 inhalations (370 µg/actuation) given at an interval of 1 to 3 minutes and followed by a third inhalation if needed. For prevention of bronchospasm the usual dose is 2 inhalations every 8 hours but not exceeding 3 inhalations every 6 hours or 2 inhalations every 4 hours. By nebuliser the dose needed to produce maximum bronchodilation is 1.0 to 1.5mg using a closed intermittent flow system with an actuator valve and 2.5mg using an open continuous-flow system.


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Copyright information

© ADIS Press Limited 1988

Authors and Affiliations

  • Heather A. Friedel
    • 1
  • Rex N. Brogden
    • 1
  1. 1.ADIS Drug Information ServicesMairangi Bay, Auckland 10New Zealand

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