Hexoprenaline: A Review of its Pharmacological Properties and Therapeutic Efficacy with Particular Reference to Asthma

Abstract

Synopsis: Hexoprenaline¹, N,N-[2-(3,4-dihydroxyphenyl)-2-hydroxyethyl] hexamethylenediamine, sulphate is a selective β₂-adrenoreceptor agonist which is active in man as a bronchodilator by the oral or intravenous routes and by inhalation. It is indicated for use in the treatment of bronchospasm associated with obstructive airways diseases, including asthma, bronchitis and emphysema.

Clinical experience and double-blind studies have established that hexoprenaline is an effective bronchodilator. Its major advantage over many other brochodilators of equal efficacy is its generally low production of side-effects, particularly tremor, palpitations, and tachycardia. In comparative trials, it has generally been rated as superior to orciprenaline or trimeto-quinol, but comparisons with salbutamol have provided equivocal results. Oral hexoprenaline was superior to fenoterol as long-term maintenance therapy in asthma, principally because its somewhat lesser bronchodilatory effects were more than compensated for by a lesser incidence of side-effects.

Pharmacodynamic Studies: Both in animals and humans, hexoprenaline is markedly longer in action than other catechol-containing β₂-agonists, such as isoprenaline and rimiterol. It protects asthmatic patients against bronchoconstriction induced by histamine, acetylcholine and allergens. Hexoprenaline is effective by inhalation and by the oral and intravenous routes, and is similar to salbutamol in onset and duration of action. Significant effects on the cardiovascular system are seen after oral or inhaled doses, only at levels several fold greater than those required for significant bronchodilatation, though a pronounced increase in heart rate occurs a few minutes after intravenous administration, and a moderate increase may occur after repeated oral dosage. Hexoprenaline has been given to asthmatic patients with hypertension of all grades of severity, and to others with cardiac disease, by all three routes of administration without causing adverse cardiovascular effects. Like other sympathomimetic amines, hexoprenaline has a lipolytic and glycogenolytic effect, but this does not apparently interfere significantly with glucose utilisation in diabetic patients inhaling the drug or receiving it intravenously. In general, hexoprenaline does not affect blood-gas values or acid-base status, though one trial reported a significant hypoxemia following inhalation of 400pg hexoprenaline. Its inhibition of uterine activity, which reflects activity at β₂-adrenoreceptors, in the absence of significant cardiovascular effects, may have therapeutic application in the suppression of labour contractions, at least by the intravenous route.

Pharmacokinetics Studies with tritium-labelled hexoprenaline in rats have shown that it is rapidly absorbed after intratracheal or intramuscular administration, and is also absorbed from the intestine. Hexoprenaline undergoes only slow O-methylation compared with isoprenaline, but its long duration of action may also be due to the initial 3-O-methyl metabolite being an effective bronchodilator. Excretion is mainly in the urine in the form of sulphates and glucuronides of the mono- and di-3-O-methyl derivatives, although unchanged hexoprenaline predominates initially.

Therapeutic Trials: Single- and multiple-dose studies of oral hexoprenaline in asthmatic patients have shown the drug to have superior bronchodilator properties to placebo and tri-metoquinol, but to be not significantly different from orciprenaline. Direct, comparison suggests that hexoprenaline by metered aerosol is more selective than orciprenaline or salbutamol, producing less cardiac stimulation for a greater or similar degree of bronchodilatation. Inhaled solutions of hexoprenaline at concentrations of 0.025% and 1 % are at least as effective as orciprenaline or isoprenaline 2%, with fewer side-effects and a greater degree of bronchodilation. Intravenous hexoprenaline 5μg was as effective as orciprenaline at 100 times this dose, and produced significantly fewer side-effects and a lesser degree of tachycardia.

In long-term studies, patients have usually been treated initially, and particularly in severe or hospitalised cases, by intravenous hexoprenaline. Oral hexoprenaline has then been substituted for maintenance therapy, supplemented in many patients by inhaled drug from metered aerosols. The average long-term improvement in pulmonary function has been about 20 to 25%. In a 1-year study, oral hexoprenaline was significantly better than fenoterol in terms of fewer side-effects, though fenoterol produced a greater degree of improvement in pulmonary function; hexoprenaline was particularly suitable in a sub-group of patients with cardiac disease, who experienced tachycardia, anginal pain and palpitations with fenoterol but not with hexoprenaline. Hexoprenaline alone is not recommended in status asthmaticus, by any route of administration, though it may be given intravenously together with aminophylline and corticosteroids for severe acute attacks of asthma. Subsequent maintenance therapy can then be carried out with oral and/or inhaled drug.

Side-effects: There have been few reports of significant side-effects following the acute administration of hexoprenaline by inhalation. An initial transient mild tachycardia may occasionally occur, which is usually not subjectively apparent to the patient. After intravenous injection, and sometimes after inhalation, a transient reddening of the skin may be observed in particularly sensitive vascular areas. Palpitations and skeletal muscle tremor have been observed after high or cumulative doses of oral or inhaled hexoprenaline over a short period of time, and occur in a dose-dependent manner following intravenous administration. Over-dosage may produce fine tremor, general unrest, dizziness, and perspiration but gastrointestinal effects are rare.

Contraindications and Precautions: There are no specific contraindications to hexoprenaline, though the same precautions as to its use apply as they do to other sympathomimetic substances. It should be used with caution in patients with thyrotoxicosis, hypertension, cadiac disease, diabetes mellitus, and renal or hepatic dysfunction, and in those who are hypersensitive to sympathomimetic drugs.

Dosage and Administration: Hexoprenaline can be given by metered aerosol in doses of 200 to 400μg, up to 5 times daily. Children may receive half the adult dose. Frequent repetition of dosage should be avoided, in view of the long duration of action of inhaled hexoprenaline. The drug is also available for inhalation as a 0.02% solution, for use in compressed air or ultrasound aerohalers. Dosage of the undiluted solution is 1 to 20 breaths, several times daily, but inhalation may be continued for up to 10 minutes depending upon respiratory rate and quantity delivered by the inhaler. Hexoprenaline solution may also be used for damp inhalation with air-humidifying substances in a plastic tent.

By the oral route, hexoprenaline should be given in doses of 0.5 to 1.0mg, 3 times daily, 30 minutes before meals, though some patients may require up to 1.0mg 4 times daily. Infants and babies should receive about 1/4 of the adult dose, preferably dissolved in milk, and older children about 1/2 of the adult dose. Symptoms of overdosage may only become apparent after several days of oral treatment, due to the prolonged action of the drug. Initial side-effects may subside with continuing treatment.

The dose by the intravenous route is 5 to 10μg, injected slowly over 2 minutes. Up to 15 or 20μg may be given during 24 hours, though some patients may require 30μg. Infants and babies may receive 1 to 3μg, 1 to 3 times daily, with older children receiving 3 to 4μg, 1 to 3 times daily.