Chemical formula: C₁₁H₁₇NO₃ Molecular mass: 211.258 g/mol PubChem compound: 4086
Pharmacologically, the action of orciprenaline sulphate is one of beta stimulation. Receptor sites in the bronchi and bronchioles are more sensitive to the drug than those in the heart and blood vessels, so that the ratio of bronchodilating to cardiovascular effects is favourable. Consequently, it is usually possible clinically to produce good bronchodilation at dosage levels which are unlikely to cause cardiovascular side effects.
Orciprenaline sulphate is a bronchodilating agent. The bronchospasm associated with various pulmonary diseases-chronic bronchitis, pulmonary emphysema, bronchial asthma, silicosis, tuberculosis, sarcoidosis and carcinoma of the lung, has been successfully reversed by therapy with orciprenaline sulphate.
In guinea-pigs and dogs, orciprenaline sulphate has a marked relaxing effect on bronchospasm induced by histamine, acetylcholine, or serotonin. When administered orally, orciprenaline sulphate protects guinea-pigs from histamine-induced asthma. In dogs, orciprenaline sulphate is better absorbed and acts longer than isoproterenol. In dogs in which bronchospasm has been induced with morphine or pilocarpine, 1 mg/kg isoproterenol and 30 mg/kg orciprenaline sulphate administered intravenously, have the same degree of bronchodilator action; however, the effect of orciprenaline sulphate lasts considerably longer than that of isoproterenol.
The rate of clearance of colloidal silver iodide from rat lung in vivo was not adversely affected by orciprenaline sulphate aerosol. Nor did orciprenaline sulphate interfere with muco-ciliary transport in a rabbit tracheal preparation in vitro.
Orciprenaline sulphate administered intravenously to anesthetized dogs in equivalent bronchodilator doses tends to have less effect on blood pressure and heart rate than isoproterenol. In dogs, with small intravenous doses there is occasionally a fall in diastolic pressure and, because of the increase in the cardiac output, there is an increase in systolic pressure with a consequent increase in pulse pressure. The ratio between intramuscular and oral effects is 1:67 for orciprenaline sulphate and 1:333 for isoproterenol. Thus the oral absorption of orciprenaline sulphate in dogs is approximately 5 times better than that of isoproterenol.
In various isolated heart preparations, orciprenaline sulphate has positive inotropic and chronotropic effects. In the spontaneously beating right atrium (cat) a dose of orciprenaline sulphate 41 times greater than that of isoproterenol is required to achieve the same inotropic effect but with electrically stimulated atrium and papillary muscle, concentrations only 1.2 and 2.7 times greater were required respectively. Thus in heart preparations which lack a pacemaker, the effects of orciprenaline sulphate and isoproterenol are similar whereas when a pacemaker is present, as in the right atrium, the effect of orciprenaline sulphate is much less than that of isoproterenol. It can be concluded that orciprenaline sulphate, like isoproterenol, acts mainly on the sinus node in the right atrium and that the affinity of orciprenaline sulphate for the pacemaker is appreciably less than that of isoproterenol. In heart preparations which ordinarily do not beat spontaneously, orciprenaline sulphate induced spontaneous activity much less frequently than isoproterenol. In guinea-pigs, doses of orciprenaline sulphate from 1 to 100 mg/kg intravenously failed to induce any cardiac arrhythmia. On the other hand, orciprenaline sulphate provided protection against arrhythmias experimentally induced by adrenaline. For example, 30 minutes to 2 hours after 30-100 mg/kg of orciprenaline sulphate had been administered intravenously, arrhythmias were not induced by doses of adrenaline from 3 to 30 times greater than those which formerly produced arrhythmias.
Orciprenaline sulphate produces an inhibitory effect on the smooth muscle of the gastrointestinal tract, as demonstrated by its action on histamine and acetylcholine-induced contractions of the isolated guinea-pig ileum and on serotonin-induced spasm of the rat duodenum. The inhibitory effect on the gastrointestinal tract was further demonstrated by studying charcoal meal progression in the guinea-pig.
A mild mydriatic effect has been shown in mice and on the enucleated eyes of cattle.
Consequently, it is usually possible clinically to produce good bronchodilation at dosage levels which are unlikely to cause cardiovascular side effects.
The efficacy of the bronchodilator after both oral and inhalation administration has been demonstrated by pulmonary function studies (spirometry, and by measurement of airways resistance by body plethysmography).
Rapid onset of action follows administration of orciprenaline sulphate inhalants, and the effect is usually noted immediately. Following oral administration, the effect is usually noted within 30 minutes.
The peak effect of bronchodilator activity following orciprenaline sulphate generally occurs within 60 to 90 minutes, and this activity lasts for 3 to 6 hours.
Orciprenaline sulphate taken orally potentiates the action of a bronchodilator inhalant administered 90 minutes later, whereas no additive effect occurs when the drugs are given in reverse order.
Patients have not developed tolerance to the drug during prolonged therapy.
No toxic effects on the liver, kidneys or hematologic system have been reported in the long–term use of orciprenaline sulphate in man.
Excretion studies in humans with the orally administered labelled compound have demonstrated that an average of approximately 40% of the drug is absorbed. The drug is excreted primarily as glucuronic acid conjugates. Animal studies (rat, rabbit and monkey) have also demonstrated good absorption as evidenced by recovery of substantial amounts in the urine. The major metabolite in animals is also the conjugated form of the drug. The concentration of radioactivity in blood plasma was determined in rabbits following intravenous administration of radiolabelled orciprenaline sulphate. Radioactivity decreased in two phases of different velocity. During the first phase, the decrease is linear on the semilogarithmic scale with a half–life of about 40 minutes. This may represent tissue penetration. The second phase is considerably slower and has a half-life of approximately 15 hours.
The toxic effects of orciprenaline sulphate have been studies in 5 species: rat, mouse, rabbit, dog and monkey. In acute and subchronic studies, orciprenaline sulphate was given by various routes including oral, inhalation, intravenous, intraperitoneal, and subcutaneous and in doses ranging from 0.2 mg to 500 mg/kg.
The following table compares the LD50's in various species for oral orciprenaline sulphate.
| Species | LD50 (mg/kg) |
|---|---|
| Rat | 4420-5276 |
| Mouse | 4800-8130 |
| Rabbit | 3114-5000 |
| Dog | 50-900 |
| Monkey | 4000 |
The oral LD50 ranges represent values found by different investigators. In mice, for an oral LD50 of 4800 mg/kg, the subcutaneous LD50 is 200 mg/kg and the intravenous LD50 is 114 mg/kg. Depending upon the species and the dosage, the toxic signs included decreased activity followed by hyperpnea and salivation, which proceeded to ataxia, and finally, prostration or convulsions before death. Animals which survived the toxic dose had uneventful recoveries.
Orciprenaline sulphate has been studied for various periods in rats, dogs and monkeys. In rats given up to 25 times (4.5, 13.5, 40.5 mg/kg/day) the recommended maximum human dose orally for 3 months, there were only increases in the weights of the hearts and livers. In dogs given orciprenaline sulphate for 3 months in doses of 6.25, 25 and 100 mg/kg/day, there were no dose-related toxic effects, although one dog in each of the three drug level groups died following the first dose. In monkeys, doses of orciprenaline sulphate of 10, 30 and 100 mg/kg/day for six months had no demonstrable toxic effects and all the animals survived.
Hemorrhages occurred in the myocardium and bladder mucosa of 2 of 6 dogs that received 0.5- 0.6 mg of orciprenaline sulphate aerosol/kg/day for 3 months. Three of 6 dogs that received a single dose of 11 to 13 mg of drug per kg had endocardial and/or renal hemorrhages; one of these also had a small hemorrhage in the circle of Willis. Petechial hemorrhages were observed in the coronary groove and auricles of a dog that died, and suspicious macroscopic lesions occurred in the hearts of 6 other dogs that received doses of orciprenaline sulphate aerosol ranging from 125 to 455 mg/kg.
Questionable macroscopic lesions also occurred in kidneys and hearts of monkeys given 250-750 mg/kg. However, isoproterenol also causes myocardial hemorrhages and infarcts in dogs and rats. Subcutaneous doses as small as 2.5 and 0.8 mg/kg produced these effects in dogs and rats respectively; minimal hemorrhage-producing doses were not investigated in the canine experiment.
The teratogenicity of orciprenaline sulphate has been studied in rabbits, rats, mice and monkeys. In rabbits and rats, the drug was given orally and parenterally; in mice it was given only parenterally; in monkeys it was given only orally. The results of these studies indicate that orciprenaline sulphate has no appreciable teratogenic effects even at dosages considerably higher than the recommended human dose. At extremely high dosage levels in the rabbit, all sympathomimetic amines studied (ephedrine, isoproterenol, orciprenaline sulphate, and phenylephrine) caused abnormalities such as limb flexures, agenesis of digits, hydrocephalus, agenesis of mouth, cleft palate and polycystic liver, in a proportion of the test animals. At the high dosage levels used in these studies, there was a decreased conception rate suggesting maternal toxicity. There was also suggestive evidence that the pregnant rabbit was more susceptible to the toxic effects which occur at extremely high dosage levels, than non–pregnant animals.
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