Prenalterol

Abstract

Prenalterol (H133/22) is the hydrochloride salt of the levorotatory (-) isomer of l-(4-hydroxyphenoxy)-3-isopropyl-amino-2-propanol (Fig. 1). The compound has a molecular weight of 261.75 and a melting point of 125" C. It is freely soluble in water. The pKa values are 9.5 (amine) and 10.0 (phenolic).Prenalterol has been characterized as a selective PI-adrenoceptor agonist. Pharmacologic studies have shown that it has positive inotropic as well as chronotropic effects. At lower doses, the positive inotropic effect is associated with a minimal effect on heart rate; at effective inotropic doses, the drug appears to have less tendency to cause arrhythmias than either cardiac glycosides or other sympathomimetic amines. Clinical studies have shown the utility of prenalterol as a padrenoceptor agonist. It is anticipated that prenalterol will be used in the management of patients with congestive heart failure, myocardial ischemia, and coronary artery disease and in postoperative cardiac surgery. ANIMAL PHARMACOLOGY Cardiovascular Effects lnotropic and Chronotropic PropertiesThe pharmacologic activity of several p-adrenoceptor agonists, including prenalterol, was studied in the norepinephrine-depleted anesthetized cat. Prenalterol increased heart rate but did not dilate the hindlimb vasculature. Isoproterenol and terbutaline caused a dose-dependent increase in heart rate as well as a dilation of the hindlimb vasculature. The ratios of the ED5,, for vasodilation to the ED50 for heart rate for isoproterenol, terbutaline, and prenalterol were 0.3, 0.1, and >600, respectively. These values indicate that prenalterol has a high degree of selectivity for cardiac P-adrenoceptors, while isoproterenol and particularly terbutaline have a higher affinity for vascular p-adrenoceptors (13). PRENALTEROLPrenalterol and terbutaline differed in their relative inotropic and chronotropic activities in the cat. The ratios of the ED5& for heart rate to the maximum dpldt for prenalterol and terbutaline were 0.93 and 0.16, respectively. The ED,, ratio for isoproterenol did not differ significantly from that for prenalterol. Thus it was possible to differentiate between P-agonists with primarily a positive chronotropic or inotropic effect. Terbutaline, a @,-selective agonist, at 36 nmoles/kg i.v., increased heart rate to a greater extent than the contractile force; prenalterol, a PIselective agonist, at 9 nmolesikg i.v., had equal positive inotropic and chronotropic effects.It was hypothesized that both PIand P,-adrenoceptors are present in the sinoatrial (SA) node and in the myocardium of the ventricles, but that their relative distribution differed. The ratio of the 6,to the P,-adrenoceptors appeared to be higher in the ventricle than in the SA node. Terbutaline, therefore, a @,-selective agonist, was more effective on the SA node than on the ventricle, and the chronotropic response to terbutaline was more pronounced than the inotropic response. Prenalterol, on the other hand, produces equal chronotropic and inotropic effects because of its hi...