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The effects of etilefrine on the ventral caudal artery of the rat have been examined in the presence of agents modifying sympathetic nerve function. Catecholamine levels were also measured in adjacent segments of artery to those studied pharmacologically and an attempt made to relate vascular response to etilefrine (and tyramine) with catecholamine content. Both guanethidine and reserpine produced significant attenuation of the vascular effects of etilefrine and tyramine. Pre-treatment with a monoamine oxidase inhibitor caused an increase in tissue catecholamine levels but, paradoxically, depressed the vascular response to etilefrine. The significance of some of the findings in terms of an indirect component to etilefrine's action are discussed.
Pharmacokinetic and metabolic studies with 3H-etilefrine were performed to assess the importance of a first-pass effect on the pharmacodynamic action of this sympathomimetic amine. Identical amounts of 3H-activity, ca. 80% of the dose, were excreted in the urine after intravenous or oral administration, which indicates complete enteral absorption of the drug. Comparison of the areas under the plasma curves of unchanged etilefrine after both routes of administration resulted in a bioavailability factor of 0.55, which can be explained by an extensive first-pass effect. The time curve of plasma levels of etilefrine was compatible with an open 2-compartment model characterized by a rather large volume of distribution (Vd, beta) of 160 1, and a predominant half life of 2 hours. The pharmacodynamic action corresponded to the amount of drug in the central compartment. The major pathway of metabolism of etilefrine was conjugation to form the phenolic sulphate, and a very minor proportion of the drug was excreted as the corresponding hydroxymandelic acid. This metabolic pattern seems to confirm our hypothesis that phenylalkylamines with hydroxyl group in the m-position of the benzene ring are predominantly conjugated in contrast to p-hydroxylated compounds which are mainly deaminated.
Intravenous etilefrine increases the pulse rate, cardiac output, stroke volume, central venous pressure and mean arterial pressure of healthy individuals. Peripheral vascular resistance falls during the infusion of 1-8 mg etilefrine but begins to rise at higher dosage. Marked falls in pulse rate, cardiac output, stroke volume and peripheral bloodflow, accompanied by rises in mean arterial pressure, occur when etilefrine is infused after administration of intravenous propranolol 2,5 mg. These findings indicate that etilefrine has both beta 1 and alpha adrenergic effects in man.
The suggested use of etilefrine in the treatment of patients with orthostatic hypotension is based on the premise that it has an action similar to that of noradrenaline (Miller, Wiener and Bloomfield, 1973). However, earlier work from this laboratory (Frost, Frewin and Gerke, 1977; Frost, Frewin, Gerke and Downey, 1978; Frost, Halloran, Frewin, Gerke and Downey, 1978) on blood vessels in the rat tail has suggested that the drug acts predominantly as an indirect sympathomimetic agent. The present study examined the action of etilefrine on the central artery of the rabbit ear. This vessel is known to have a rich sympathetic innervation (de la Lande, Frewin and Waterson, 1967) and has the added advantage that it can be surgically denervated. It therefore became possible to examine the effects of etilefrine on both normal and denervated arteries and to quantitate the extent to which the drug relied on the symphathetic nerves for its vasoconstrictor effects.
Etilefrine was found to constrict blood vessels in the rat tail through a mechanism which was partly dependent on the sympathetic nerves present in these vessels. The response to the drug was enhanced by pretreagment with noradrenaline and cocaine, and totally abolished by the alpha-receptor antagonist phentolamine. When compared with several other sympathomimetic agents which were tested on the vessel, etilefrine appeared to have a low order of vasoconstrictor activity. These findings would seem to have considerable relevance to the clinical situation where an attempt has been made to use etilefrine in the treatment of patients with orthostatic hypotension.
The action of etilefrin (Effortil Depot Perlongets) was compared with placebo in a double-blind study in 24 female geriatric patients with sympathicotonic orthostatic hypotension. After determining the basic values, all patients were treated with the active substance in a titration phase lasting one week (dosage 2-3 Perlongets/day). The decrease in systolic blood pressure and the increase in pulse rate while standing were then statistically significant lower (p less than (p less than 0.001) when compared with the basic values. In 17 out of 21 cases of collapse which occured while standing before therapy was commenced no further collapse occurred (p less than 0.005). Following the titration phase treatment with etilefrin was continued in 12 patients in a double-blind study while the remaining 12 patients were changed over to placebo as a withdrawal study. The effect continued in those patients treated with the active ingredient and the average values and incidence of effects improved further. On the other hand, in the placebo group there was one again a marked decrease in systolic blood pressure and increase in pulse rate as observed in the basic values. The symptomatology, particulary episodes of collapse increased again. There was a statistically significant difference between the action of etilefrin and placebo for all criteria (both objective and subjective parameters). Side-effects were not observed.
According to the results obtained under the described conditions it can be stated that after i.v. administration Adyston induces a dose-dependent rise in systolic and diastolic blood pressure, in comparison with etilefrin the new product Adyston shows a greater potency in rising the systolic and diastolic blood pressure; Adyston induced rise of blood pressure is in general of longer duration in comparison with that induced by etilefrin, it is interesting that in the dose of 0.01 mg/kg Adyston increases the arterial blood pressure but at the same time slightly decreases the heart rate; this is not the case after administration of etilefrin which at the same dose increases both arterial blood pressure and heart rate.
In an attempt to elucidate the function of an aorto-coronary bypass in patients with coronary artery obliterative disease, intravenous injection of etilefrine was used to bring about variations of central hemodynamics. Etilefrine proved to cause a significant increase of cardiac output (QPA), mean systemic blood pressure and aorto-coronary bypass flow. Calculations of peripheral myocardial resistance showed a rather pronounced decrease in all vascular regions studied. There was no change of central venous pressure. The decrease of the myocardial vascular resistance, as shown by the increase of aorto-coronary bypass flow, is indicative of the myocardial vascular capacity. Hence, it may be of value as a prognostic test.
Systolic blood pressure, heart rate and concentrations of adrenaline, noradrenaline and dopamine as well as plasma dopamine-beta-hydroxylase (DBH) were measured in 22 subjects in recumbency and on standing up. Six subjects each had previously been given intravenously dihydroergotamine (0.5 mg) or etilefrine (0.25 mg/min) or a placebo. It was demonstrated that orthostasis leads to an increased activity of the sympathetic nervous system and the adrenal system. After administration of dihydroergotamine there was a diminished reaction of the sympathetic nervous system with an increase of venous tone which counteracted the decrease in cardiac output. Etilefrine, on the other hand, inhibited the sympatho-adrenal reaction on orthostasis and decreased the liberation of adrenaline. It acts directly via stimulation of alpha-and beta-receptors and is thus predominantly indicated if there is insufficient response of the baroreceptor reflex at its efferent limb.
The indirect sympathomimetic activity of etilefrine has been examined using the ventral caudal artery of the rat. This vessel has a rich sympathetic innervation and lends itself to studies on [3H]noradrenaline efflux from these sites. Etilefrine possessed significant indirect activity on the artery and this action, although less than that of tyramine, was equivalent to that caused by ephedrine. Pretreatment of the vessels with a mixture of iproniazid, doca, cocaine and UO521 (3',4'-dihydroxy-2-methyl propiophenone) significantly enhanced[3H]-noradrenaline efflux from the artery.
In 20 female and 40 male subjects with circulatory instability, the response of pulse rate and blood pressure to blood loss and orthostasis was studied under the condition of protective pretreatment with drugs known to improve venous return by increasing the tone of capacitance vessels. Before blood loss (420 ml), in a cross-over double-blind procedure, each subject obtained 10 mg etilefrin or 2 mg dihydroergotamine, both administered orally. The procedure was repeated after at least 8 weeks. At this time, the subject obtained the drug which was not given in the first examination. By comparison of pulse rate and blood pressure taken after pretreatment, the statistical evaluation did not reveal any differences in the effectiveness of one or the other drug on the response to hypovolemic and orthostatic conditions. Patients preferred etilefrin.
ST 1059, the pharmacologically active metabolite of midodrine, is a powerful vasoconstrictor compound, acting by stimulation of alpha-receptors. It elicited 80% of noradrenaline-induced contraction of human veins.
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Studies in normal volunteers documented the positive inotropic effects of Etilefrin-HCL, a direct sympathomimetic drug, with increases of systolic blood pressure, renal blood flow and glomerular filtration rate. Sodium and potassium excretion as well as serum potassium decreased. After an additional injection of Metoprolol, a beta 1-sympatholytic drug, blood pressure, renal blood flow and glomerular filtration rate normalized, whereas electrolyte excretion decreased further. Renin release was decreased during administration of Etilefrin as well as during combined Etilefrin and Metoprolol application. Reziprocal to changes of blood pressure, plasma norepinephrine concentration decreased during Etilefrin and increased during combined administration of Etilefrin and Metoprolol. The results lead to the following interpretation: Changes of blood pressure and renal hemodynamics are mediated by beta 1-adrenergic effects of Etilefrin, whereas the electrolyte excretion is influenced by beta 2-adrenergic effects. Renin release seems to be influenced by beta 1 as well as beta 2-adrenergic receptors.