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PubMed1985

Prenalterol: a partial beta 1-adrenoceptor agonist or a beta-blocker with intrinsic activity?

Hemodynamic studies have demonstrated a significantly reduced beta 1-adrenoceptor stimulating effect of prenalterol compared to dobutamine suggesting a partial agonism on the receptor. In order to prove this hypothesis we administered 80 micrograms/kg of prenalterol within 5 minutes in 8 healthy volunteers during a continuous infusion of dobutamine (15 micrograms/kg/min). In addition to heart rate, blood pressure and the double product, the systolic time intervals QS2I, PEP and LVET and the echocardiographically determined parameters FS and Vcf were measured for evaluation of ventrical function. The injection of prenalterol caused a distinct attenuation of the cardiostimulating effects of dobutamine: there was a prompt fall in heart rate and systolic blood pressure and a typical negative inotropic effect on the parameters of left ventricular function. In the experimental conditions selected, the effects of prenalterol were those of a beta-sympatholoytic agent. Prenalterol should therefore be classified as a partial beta 1-adrenoceptor agonist or as a beta-blocking agent with pronounced intrinsic sympathomimetic activity. The beta 1-stimulating potency of prenalterol amounts to about 60% of a full agonist.

Adrenergic beta-Agonists↗
PubMed1985

Decrease in beta-receptor density explaining the development of pindolol- and prenalterol-tolerance in orthostatic hypotension.

A 58-year-old woman with diabetic autonomic dysfunction was well treated for orthostatic hypotension with pindolol. After eight months however, symptoms recurred in spite of continued treatment with pindolol. Addition of prenalterol, a beta-blocking agent with very high intrinsic sympathomimetic activity, had a marked clinical effect on her orthostatic hypotension. Before treatment with prenalterol, stroke volume and left ventricular enddiastolic volume markedly decreased during tilt, as demonstrated by radionuclide angiography. After short-term prenalterol treatment, the orthostatic decreases of stroke volume and left ventricular end-diastolic volume were less pronounced. During continued prenalterol treatment, both symptoms and haemodynamic changes recurred in the erect position. Beta-receptor density in her lymphocytes decreased from elevated levels before prenalterol to subnormal levels, when the clinical effect had disappeared. The data suggest that the tolerance development to prenalterol may be explained by the decrease in beta-adrenergic receptor density.

Adrenergic beta-Agonists↗
PubMedDate not supplied

The metabolic disposition of the selective beta 1-adrenoceptor agonist prenalterol in mice, rats, dogs, and humans.

The metabolic routes of the selective beta 1-adrenoceptor agonist prenalterol have been studied in mice, rats, dogs, and humans after oral administration. The drug was well absorbed from the gastrointestinal tract and most of the administered radioactivity was excreted in urine from all species within 24 hr. Prenalterol was metabolized to a varying extent in the species studied. About 20% of the 10-mg dose was recovered unchanged in man, the corresponding figures being 1.8% in the mouse, 7% in the rat, and 54% in the dog at 0.263 mg/kg (1 mumol/kg). Three metabolites were characterized and quantified by thin-layer chromatography, high-performance liquid chromatography, nuclear magnetic resonance (1H and 13C), and gas chromatography-mass spectrometry. Pronounced species variations in the metabolic pattern were observed. The phenolic sulfate ester of prenalterol was the main urinary metabolite in man, important in the dog, minor in the rat but not detectable in the mouse. Prenalterol glucuronide was formed in significant amounts in the animals and, in addition, beta-4(hydroxyphenoxy)lactic acid was present in dog urine. In the rat and the mouse the degree of biotransformation of prenalterol was significantly decreased at high oral doses of 2630 mg/kg (10 mmol/kg). The synthesis of prenalterol sulfate ester with use of ion pair extraction techniques is described.

Administration, Oral↗
PubMed1984

Relative efficacy of prenalterol and pirbuterol for beta-1 adrenoceptors: measurement of agonist affinity by alteration of receptor number.

Both prenalterol and pirbuterol are partial agonists (when compared to isoproterenol) in rat left atria. Schild analysis with the beta-1 adrenoceptor selective antagonist atenolol indicated that all three agonists stimulate beta-1 adrenoceptors in this preparation. Atria from rats implanted with mini-osmotic pumps which delivered isoproterenol (400 micrograms kg-1 hr-1) s.c. for 4 days were 9 times less sensitive than control, to isoproterenol, and produced no responses to either prenalterol or pirbuterol. Schild analysis with atenolol on these desensitized atria indicated a homogeneous population of beta-1 adrenoceptors. In the desensitized atria, both prenalterol and pirbuterol functioned as competitive antagonists of responses to isoproterenol and Schild analysis yielded estimates of the equilibrium dissociation constants (Kp) of prenalterol (0.09 micron) and pirbuterol (2 micron) in these tissues. The estimates of Kp were utilized to calculate the relative efficacy of pirbuterol and prenalterol; pirbuterol was shown to have 2.3 times the efficacy of prenalterol on beta-1 adrenoceptors. The implications of this method as a means of calculating the Kp for partial agonists are discussed. These data also serve as a caveat to the use of pirbuterol in the determination of functional cardiac beta adrenoceptor subtypes in experimental animals and in man.

Adrenergic beta-Agonists↗
PubMed1984

Prenalterol in the treatment of orthostatic hypotension in Shy-Drager syndrome.

The effects of prenalterol, a selective beta 1-adrenoreceptor agonist, were studied in a patient with the Shy-Drager syndrome, presenting with incapacitating orthostatic hypotension. The main haemodynamic defect was an impressive postural fall in stroke volume and cardiac output pointing to denervation of the capacitance vessels. Prenalterol 4 X 30 mg orally produced a marked increase in supine and standing blood pressure, along with substantial symptomatic improvement. Notable positive chronotropic and inotropic effects were observed. Association of fludrocortisone 0.5 mg/day resulted in further haemodynamic and symptomatic improvement, presumably due to plasma volume expansion. Haemodynamically, prenalterol and fludrocortisone resulted in a substantial increase in standing cardiac output, primarily due to the chronotropic effects of prenalterol. In addition to the haemodynamic effects, prenalterol stimulated the renin-aldosterone system and restored the normal diurnal pattern of water and sodium excretion, the latter may have contributed to the improvement of orthostatic tolerance. Prenalterol could be a valuable adjunct to the existing treatment schedules of neurogenic orthostatic hypotension.

Adrenergic beta-Agonists↗
PubMed1984

Ventilatory effects of selective beta 1-(prenalterol) or beta 2-(salbutamol) adrenoceptor agonism in man.

We compared the ventilatory effects of prenalterol (beta 1-selective adrenoceptor agonist) with those of salbutamol (beta 2-selective adrenoceptor agonist) in 6 healthy volunteers. Two intravenous doses of prenalterol (1 mg/60 min, 2 mg/60 min) and of salbutamol (300 micrograms/60 min, 600 micrograms/60 min) were given in random order in 4 separate sessions of 60 minutes each. Pulmonary ventilation per minute (V'E) increased only on the high dose of salbutamol. Mouth occlusion pressure (P0.1) did not vary either on prenalterol or on salbutamol. Only the high dose of salbutamol induced (1) an increase in tidal volume (VT) without changes in respiratory rate (RR), (2) an increase in mean inspiratory flow (VT/Ti) without changes in the fraction of inspiratory time to total cycle duration (Ti/Ttot). During forced expiration, salbutamol elicited a small bronchodilating effect at the level of both large (FEV1, FEF25-75, FEF50) and small (FEV3, FEF75-85, FEF75) airways. Prenalterol induced a very small dilatation of the large airways, and a somewhat more pronounced effect at the level of the small airways. Neither the indexes of ventilatory pattern nor those of bronchial tone showed any statistical or biological differences between values on prenalterol and values on salbutamol. However, both the former and the latter indexes showed a trend to be higher on salbutamol than on prenalterol. Results suggest that salbutamol-induced increase in pulmonary ventilation per minute in subjects without bronchial obstruction is likely the result of a reduced bronchomotor tone at rest, leading to an increase in tidal volume because of the rise in the VT/Ti ratio.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Agonists↗
PubMed1984

Dose-response relationship in normal subjects of prenalterol, a beta-adrenergic agonist with positive inotropic and resistance lowering effects.

The acute haemodynamic effects of increasing doses of parenterally administered prenalterol-a beta-adrenergic stimulating drug-were assessed in normal subjects by means of radionuclide ventriculography. Prenalterol induced dose-related increases in the left ventricular ejection fraction and the systolic pressure end-systolic volume ratio. Left ventricular end-systolic and end-diastolic volumes decreased to the same extent accounting for an unchanged stroke volume. Cardiac output increased due to a rise in the heart rate. Systolic blood pressure increased, whereas diastolic and mean blood pressure remained unchanged. Calculated total peripheral resistance decreased significantly. The maximum effect of prenalterol on cardiac performance occurred with a dose of 18 to 36 micrograms/kg. Plasma concentrations of prenalterol showed large interindividual variations. In conclusion, prenalterol improves the pump function of the normal heart and causes a fall in peripheral vascular resistance, implying a reduction of the load on the heart. These effects may prove beneficial in the treatment of acute heart failure.

Adrenergic beta-Agonists↗
PubMed1981

Pharmacokinetic studies in man of the selective beta 1-adrenoceptor agonist, prenalterol.

The pharmacokinetics of prenalterol, a selective beta 1-adrenoceptor agonist, has been studied in healthy subjects, by following the plasma concentration and urinary excretion of the unchanged compound and its total radioactive metabolites after oral and intravenous administration. Each of six healthy subjects received a single i.v. dose (2.5 mg) and three oral doses (2.5, 5.0 and 10 mg) of prenalterol. The oral dose was administered as a solution. Three of the subjects received the intravenous and oral doses of 2.5 mg as tritiated drug. Prenalterol was rapidly and completely absorbed after oral administration. The peak plasma concentration was attained after about 0.5 h. About 25% of prenalterol reached the systemic circulation. Prenalterol was extensively distributed to extravascular tissues with a half-life of the distribution phase close to 7 min. About 90% of the dose was excreted in urine within 24 h irrespective of the route of administration, indicating complete absorption of the drug. On average 60% of the i.v. and 13% of the oral doses were excreted as unchanged drug. The elimination half-life of the compound was 1.8 h, and the decline in the plasma concentration of the metabolites indicated a slower elimination rate than for the unchanged drug. Dose-dependent kinetics were not observed after the oral doses examined.

Administration, Oral↗
PubMedDate not supplied

Interaction in healthy volunteers between prenalterol, a selective beta 1-adrenoceptor agonist, and metoprolol or propranolol.

We studied the hemodynamic effects of the selective beta 1-adrenoceptor agonist prenalterol in healthy subjects before and after intravenous infusion of the nonselective beta-adrenoceptor blocker propranolol or the beta 1-selective adrenoceptor blocker metoprolol. Intravenous infusions of 0.1, 0.25, and 0.5 mg prenalterol induced a dose-dependent decrease in total electromechanical systole and pre-injection period, whereas left ventricular ejection time remained unchanged. Stoke volume as determined by impedance cardiography was not changed, but a dose-dependent increase in cardiac output due to an increase in heart rate was observed. Systolic blood pressure was significantly increased, but diastolic blood pressure remained unchanged. After intravenous administration of either 10 mg propranolol or 20 mg metoprolol, prenalterol was infused in a 10 times higher dose than before. The hemodynamic effects were similar to those observed before the beta-blockers. Whether propranolol or metoprolol was administered did not influence the effects induced by prenalterol. It is suggested that prenalterol might be a useful drug to counteract undesired hemodynamic effects of beta-adrenoceptor blockers.

Adrenergic beta-Agonists↗
PubMed1982

Pharmacokinetics of prenalterol in healthy subjects and patients with congestive heart failure.

1. Prenalterol is rapidly and completely absorbed after oral administration with peak concentrations reached after 30 minutes. 2. Prenalterol is rapidly distributed to extravascular tissues after intravenous administration. 3. The extent of bioavailability after administration of prenalterol as a solution is about 25% of an intravenous dose. After administration of 20 mg prenalterol in a controlled release preparation the bioavailability is increased to about 45%. 4. The half-life of the elimination phase is close to 2 hours. 5. 60% of an intravenous dose and 15% of an oral dose is eliminated unchanged by renal excretion. The rest is mainly excreted as the sulphate ester of prenalterol.

Administration, Oral↗
PubMed1982

Haemodynamic effects of intravenously administered prenalterol in patients with severe heart failure.

The acute haemodynamic effects of prenalterol 75-225 micrograms/kg i.v. were studied at rest and during exercise in the supine position in 12 patients with chronic congestive heart failure secondary to myocardial infarction (6 pts), chronic valvular disease with valvular replacement (4 pts), ischaemic cardiomyopathy (1 pt) and post myocarditis (1 pt). In 5 of the 6 AMI patients the effect of prenalterol on myocardial oxygen consumption at rest was measured. Pulmonary artery end-diastolic pressure decreased significantly from 17 to 10 mm Hg at rest and from 31 to 21 mm Hg during exercise. Resting heart rate increased from 78 to 90 at rest but was unchanged during exercise. MVO2 in the 5 patients was unchanged or lower in 4 patients and increased in one in whom angina developed after prenalterol. In general, dyspnoea and angina during exercise were less pronounced after prenalterol. The calculated triple product was lower after prenalterol, especially during exercise, indicating lower myocardial oxygen consumption and probably less myocardial ischaemia.

Adrenergic beta-Agonists↗
PubMed1982

Dose-dependent haemodynamic response to prenalterol in patients with congestive heart failure.

The effect of three doses of prenalterol, 12.5, 25 and 50 micrograms, on cardiac index (CI), pulmonary artery pressure (PAP), heart rate (HR), and stroke volume index (SVI) was investigated in 18 patients with congestive heart failure (CHF). Twelve patients received only prenalterol, while 6 patients received prenalterol 1 hour after an oral dose of hydralazine and isosorbid dinitrate. In 7 out of 12 patients a dose-dependent increase in HR was observed. The response of HR was inversely correlated to resting catecholamine levels; patients with high resting catecholamines--these are patients with severe CHF--did not show any increase in HR. CI increased in 8 out of 12 patients (average 1 . 1/min m) and SVI in 5 out of 12 patients. This inconsistent response was not dependent on left ventricular ejection fraction or plasma catecholamines at rest. Pretreatment with vasodilators did not improve the haemodynamic response to prenalterol. Four out of 17 patients demonstrated an increase in severity of arrhythmias suggestive of arrhythmogenic properties of prenalterol.

Administration, Oral↗
PubMed1984

Prenalterol as long-term therapy for chronic congestive heart failure. A randomized cross-over trial.

Ten patients with severe chronic congestive heart failure (CHF) due to ischaemic heart disease treated with digitalis and diuretics were randomly allocated to oral treatment with prenalterol (100-200 mg daily in addition to their basal treatment) or to intensified treatment with diuretics in a cross-over trial. A wash-out period of 1-4 weeks was allowed between the two modes of treatment. Most of the patients demonstrated subjective improvement during prenalterol therapy, but this improvement could not be verified objectively by exercise test, echocardiography, chest X-ray or weight measurements. No serious side-effects of either mode of treatment were observed. Heart rate was significantly lower during exercise when the patients were treated with prenalterol than during the control periods or during intensified conventional treatment, indicating that prenalterol acts as a beta-adrenergic receptor blocker during exercise in this patient group. The results indicate that prenalterol is a partial beta-receptor agonist without superior beneficial effects compared to those of intensified conventional treatment in patients with chronic, severe CHF.

Adrenergic beta-Agonists↗
PubMed1980

Hemodynamic and cardiometabolic effects of prenalterol in patients with gram negative septic shock.

The hemodynamic effects of prenalterol, a new inotropic agent, were investigated in 10 patients with gram negative septic shock. In four of the patients, coronary sinus blood flow (CSF) and myocardial oxygen and lactate extraction were also determined. After baseline hemodynamic measurements, prenalterol was infused intravenously over a 10-min period to a total dose of 150 micrograms/kg. All patients responded within 15 min after completion of prenalterol infusion by increasing mean arterial pressure from 57 +/- 11 to 75 +/- 20 mmHg (7.58 +/- 46 to 9.97 +/- 2.66 kPa), (+32%), (P less than 0.01) and cardiac index from 2.65 +/- 0.40 to 3.80 +/- 0.47 1.min-1.m-2, (+44%) (P less than 0.001). There was no change in heart rate or systemic vascular resistance, nor were any arrhythmias recorded. The urinary output increased significantly. After prenalterol, CSF increased from 185 +/- 14 to 246 +/- 14 ml.min-1, (+33%), (P less than 0.001) and myocardial oxygen and lactate extraction rose from 19.8 +/- 2.1 to 26.6 +/- 2.1 ml O2.min-1, (+34%) (P less than 0.001) and from 33.2 +/- 2.3 to 44.7 +/- 2.1 mumol.min-1, (+35%), (P less than 0.001), respectively. The total body oxygen consumption increased from 287 +/- 13 to 348 +/- 23 ml O2.min-1, (+21%), (P less than 0.01) and the arterial lactate concentration decreased from 5.61+/- 0.55 to 3.94 +/- 0.16 mmol.l-1, (-30%), (P less than 0.01), suggesting improved tissue perfusion. The results demonstrate that prenalterol is a potent, highly selective inotropic agent inducing the same magnitude of increase in blood pressure and cardiac output as reported for dopamine in septic shock.

Adult↗
PubMed1982

The haemodynamic effects of dopamine and prenalterol in patients after cardiac valve surgery.

The haemodynamic effects of prenalterol and dopamine were compared in 10 patients about 4 h after cardiac valve replacement during a phase of temporarily depressed myocardial function. The rate of infusion was adjusted to give similar increases in stroke volume with the two drugs (dopamine + 17% and prenalterol + 18%). Both drugs produced marked inotropic and chronotropic effects with significant increases in heart rate, cardiac output, arterial blood pressure, and left and right ventricular stroke work. The arterial blood pressure and the left ventricular stroke work increased significantly more with dopamine than with prenalterol, however. The systemic vascular resistance decreased significantly with prenalterol, whereas it was unchanged with dopamine. The effects of prenalterol could be traced after 90 min, whereas the effects of dopamine vanished within 15 min.

Adrenergic beta-Agonists↗
PubMed1989

A comparison of the properties of prenalterol and corwin at beta 1- and beta 2-adrenoreceptors in vitro.

1. The affinities and efficacies (relative to isoprenaline) of prenalterol and corwin at beta 1- and beta 2-adrenoreceptors, have been determined in isolated cardiac and vascular tissues respectively. 2. Prenalterol and corwin have similar affinities for cardiac beta 1-adrenoreceptors. The affinity of prenalterol for beta 2-adrenoreceptors is approximately 10 times lower than for beta 1-adrenoreceptors; that for corwin is approximately 100 times lower than for beta 1-adrenoreceptors. 3. The efficacies of prenalterol and corwin, relative to isoprenaline, at beta 1 and beta 2-adrenoreceptors, are similar. 4. The greater selectivity of corwin compared with prenalterol, as an agonist at beta 1-adrenoreceptors, is a reflection of its lower affinity for beta 2-adrenoreceptors.

Adrenergic beta-Agonists↗
PubMed1986

The immediate haemodynamic and electrophysiological response to prenalterol during fixed rate pacing in patients with chronic ischaemic heart disease.

The immediate haemodynamic and electrophysiologic effects of intravenous prenalterol 2.5-75 micrograms/kg in patients with coronary heart disease without clinical heart failure were investigated during fixed rate atrial pacing. Right ventricular peak dP/dt increased pronounced and serum concentration dependent after prenalterol concomitant with an increase in stroke volume and a moderate decrease in peripheral vascular resistance. The effects on haemodynamics after prenalterol were thus serum concentration dependent but with marked interindividual variation. AV nodal conduction velocity increased significantly. It is concluded that prenalterol possess pronounced inotropic properties. The haemodynamic response to prenalterol intravenously is to a lesser degree dependent on the chronotropic effects of the drug and it is often unpredictable.

Aged↗
PubMed1984

Acute haemodynamic effects of oral prenalterol in severe heart failure.

The acute haemodynamic effects of oral prenalterol were studied in 14 patients with severe heart failure (NYHA class III) due to ischaemic heart disease. All had received treatment with digoxin, diuretics, and in most cases vasodilators. Prenalterol was administered at two hourly intervals to give cumulative doses of 20, 50, and 100 mg and mean plasma concentrations of 53, 97, and 175 nmol/l. Haemodynamic measurements were made two hours after each dose with Swan-Ganz catheterisation; cardiac output was measured by thermodilution. There were no significant changes in heart rate, mean arterial pressure, or pulmonary artery diastolic pressure after the drug. Cardiac index rose significantly after 50 mg and 100 mg prenalterol. Oral prenalterol has a beneficial short term haemodynamic effect in patients with severe heart failure. If this effect is sustained prenalterol may be of value in the long term management of patients with this disabling condition.

Adrenergic beta-Agonists↗