Rimiterol: A Review of its Pharmacological Properties and Therapeutic Efficacy in Asthma
Synopsis: Rimiterol1 is erythro-(3,4-dihydroxyphenyl)-2-piperidyl-methanol hydrobromide, and is a catecholamine. It is a selective β2-adrenoreceptor agonist, but is not effective as a bronchodilator by the oral route of administration. Rimiterol is available at present as an aerosol, though preliminary studies suggest that it may be of value in the intravenous therapy of severe asthma. Clinical studies in asthmatic patients have shown that inhaled rimiterol rapidly produces effective bronchodilatation. Its duration of action is similar to that of isoprenaline and shorter than those of salbutamol or terbutaline, though it may act faster than either of the latter drugs. At doses which produce equivalent maximum ventilatory responses, rimiterol produces lesser effects on cardiac or skeletal muscle than do isoprenaline or salbutamol. The short half-life of intravenous rimiterol, its relatively low cardiovascular toxicity, and the lack of resistance to aerosol rimiterol in patients given prolonged intravenous infusions of the drug, suggest that it may be useful in severe asthma either given alone by the intravenous route or combined with rimiterol given by intermittent positive pressure ventilation. Pharmacodynamic Studies: Inhaled or intravenous rimiterol produces bronchodilatation in animals and normal subjects, and also reverses bronchoconstriction induced by histamine or acetylcholine. Aerosol doses of rimiterol (500μg), isoprenaline (100μg), salbutamol (100μg), and orciprenaline (750μg) produced significant and equivalent reductions in the fall in ventilatory capacity induced in normal subjects by inhaled acetylcholine. Rimiterol appeared to be longer acting than isoprenaline against histamine-induced bronchospasm in normal subjects. Its β2-selectivity by the intravenous route is similar to that of salbutamol and about twice that of isoprenaline, but the potency of both drugs is about one-fifth of that of isoprenaline. Significant rises in heart rate followed inhaled isoprenaline 500 or 1,000μg and salbutamol 1,000μg, but not after rimiterol 500 or 1,000μg, in normal subjects. Administration by intermittent positive pressure ventilation (IPPV) showed no difference between 0.5 % rimiterol and saline in effects on heart rate, which was significantly increased by 0.5% salbutamol. Tremorogenic effects in normal subjects were similar after increasing intravenous doses of rimiterol, salbutamol or isoprenaline. Pharmacokinetic Studies: The pharmacokinetics of rimiterol are very similar to those of isoprenaline. Rimiterol has a short half-life (< 5 min) when given intravenously, is rapidly metabolised, to its 3-O-methyl derivative. When swallowed (oral or aerosol) 50% is excreted as rimiterol (free or conjugated), but after intravenous administration the majority (45 %) is excreted as 3-O-methylrimiterol (free or conjugated). The lung appears to metabolise rimiterol, following bronchoscopic administration. Therapeutic Trials: Inhaled rimiterol appears to be similar in potency and duration of action (11/2 to 3 hours) to inhaled isoprenaline. Dose-dependent bronchodilatation was produced by isoprenaline 80 to 1600μg or rimiterol 200 to 7200μg, but tachycardia was already severe following isoprenaline 800μg whereas rimiterol gave only insignificant effects on the heart at the highest dose levels. Rimiterol 500μg was equipotent by aerosol with salbutamol 200μg in bronchodilator efficacy, but the duration of action of salbutamol was more prolonged. Similarly, when given by IPPV, the peak bronchodilator effects of 0.5 % of 0.1 % rimiterol were equivalent to those of 0.5 % salbutamol but were significantly shorter in duration. Heart rate changes were of shorter duration after rimiterol than after equivalent bronchodilator doses of salbutamol by IPPV, but neither drug produced significant changes in heart rate by aerosol. Rimiterol 500μg and terbutaline 500μg were equivalent in peak bronchodilator effects, and neither affected heart rate. Rimiterol (400μg) was faster in onset but shorter in duration than terbutaline (400μg), though most chronic asthmatic patients preferred terbutaline. As would be expected none could subjectively detect the shorter onset of rimiterol, as such patients would be unable to detect the rapid onset of any aerosol bronchodilator. Intravenous rimiterol produced dose-dependent bronchodilatation and increases in heart rate and pulse pressure in asthmatic patients. Isoprenaline was about 8 and 5 times as potent as rimiterol and salbutamol in bronchodilator action, and approximately 16 and 12 times as potent in increasing heart rate. Prolonged, low-dose infusions of rimiterol produced dose-dependent increases in bronchodilatation (which were maintained by subsequent inhalations of drug), heart rate, pulse pressure and skeletal muscle tremor. Heart rate reached equilibrium earlier during the course of rimiterol infusion (0.05 to 0.2μg/kg/min) than salbutamol (0.025 to 0. μg/kg/min), and also declined more rapidly after they had stopped. Side-effects: There have been no reports of significant subjective side-effects following the acute administration of rimiterol by aerosol. Palpitations and skeletal muscle tremor have been observed after high or cumulative doses of inhaled rimiterol, and occur in a dose-related manner following intravenous administration. Contraindications and Precautions: There are no specific contraindications to rimiterol, but it should be given with care to patients with thyrotoxicosis, cardiovascular disease, diabetes mellitus, renal or hepatic dysfunction, and those who are hypersensitive to sympathomimetic substances. Caution is also advised in tnose receiving other sympathomimetic drugs or monoamine oxidase inhibitors. Dosage: Rimiterol is available in pressurised aerosols, which deliver 0.2mg, in each dose. One to three inhalations should be sufficient to provide relief in most cases. It should not be necessary for the patient to take further treatment for at least 30 minutes, or more than 8 treatments a day. Patients should be warned, with frequent reminders, of the dangers of overuse, and children should only be treated with a sympathomimetic aerosol under the supervision of a responsible adult. Preliminary studies suggest that intravenous infusions of 0.05 to 0.2μg/kg/minute of rimiterol may provide effective bronchodilatation in cases of severe asthma. The drug dose should then be monitored by the changes in heart rate in individual patients.