Amrinone A Preliminary Review of its Pharmacological Properties and Therapeutic Use

Publisher Website
Google Scholar
Abstract
Synopsis: Amrinone1 is a bipyridine derivative with positive inotropic effects and vasodilatory properties. However, in the clinical setting of congestive heart failure, the relative contribution of these factors remains a matter of conjecture. Its mode of action appears to be related to alterations in extracellular and intracellular calcium balance, probably mediated by increased levels of tissue cyclic adenosine monophosphate and possibly involving a sodium-dependent pathway. Clinical experience has mostly been short term and is limited to a relatively small number of patients with severe congestive heart failure, refractory to conventional treatment. Amrinone rapidly improves cardiac performance by decreasing systemic vascular resistance (afterload), decreasing the determinants of left ventricular filling pressure (preload) and improving the cardiac contractility. Improvements in exercise performance and clinical symptomatology occur without an increase in heart rate or decrease in mean arterial pressure. Amrinone has been compared with dopamine, dobutamine, pirbuterol and prazosin in preliminary short term studies in patients with severe congestive heart failure, although more studies are needed before any relative clinical advantages or disadvantages can be ascribed to amrinone. Initial experience suggests that the addition of vasodilators such as hydralazine and isosorbide dinitrate to amrinone therapy may confer additional haemodynamic benefits. Preliminary medium term studies suggest that tolerance to the haemodynamic effects of amrinone does not usually occur, but long term studies are needed to determine whether amrinone alters the normal progression of the disease and whether overall mortality is affected. Amrinone has usually been administered as intravenous bolus doses (totalling 1.5 to 3.6 mg/kg/day) and/or continuous intravenous infusion, with varied results. Generally, an oral dose greater than the intravenous dose is required to achieve an equivalent level of response. Reversible, usually asymptomatic, thrombocytopenia occurs in about 20% of patients treated with amrinone. Arrhythmias and gastrointestinal disturbances have been reported, but wider clinical experience is required to determine the side effect profile of the drug. Pharmacodynamic Studies: Amrinone at concentrations of 3 to 1000 μg/ml produces dose-related inotropic effects in isolated atrial and ventricular papillary tissues from cats, rabbits and guinea-pigs. Tolerance to the inotropic effects does not occur with repeated doses over a short period. However, amrinone produced inotropic effects only in human isolated cardiac tissue from patients with mild, but not severe, cardiac failure. Prolonged exposure to high concentrations, in vitro, has produced occasional arrhythmias and increased thresholds for response. Amrinone increases maximum rate of depolarisation and ‘overshoot’ of slow responses in depolarised tissues. Amrinone does not appear to significantly affect aftercontractions but does augment those induced by acetylstrophanthidin. Increased chronotropy has occurred in isolated guinea-pig atria and in anaesthetised dogs. Pretreatment with reserpine, tetrodotoxin, phentolamine, β-blockers and histamine antagonists does not generally affect the inotropic responses to amrinone, although, depending on the tissue or haemodynamic variable being monitored, occasional inhibition of inotropic activity is observed. Amrinone potentiates the inotropic effects of isoprenaline, dopamine and histamine. Amrinone increases cardiac work indexes, coronary flow and taurine influx, and reverses the negative inotropic actions of verapamil in Langendorff guinea-pig heart preparations, but not in rat hearts. Single intravenous bolus doses or continuous infusion in anaesthetised or conscious healthy dogs influences most haemodynamic parameters, but not cardiac output. Heart rate and blood pressure are influenced only at high doses (10 mg/kg or 100 μg/kg/min). Sustained inotropic effects in conscious healthy dogs following infusion (80 μg/kg/min) for 2 hours are also accompanied by marked hypotensive effects. Intravenous administration of amrinone to conscious or anaesthetised dogs with experimentally induced cardiac failure improves cardiac output as well as other haemodynamic measurements, although slight changes in heart rate or blood pressure occur in some animals. Mean arterial pressure is decreased by amrinone in dogs with cardiac failure caused by coronary artery occlusion, but not in other models. These results are consistent with the reduced preload and afterload seen with amrinone. Regional blood flow studies in animals with experimentally induced congestive heart failure indicate that amrinone stimulates flow to the left ventricle, kidney (cortex and medulla), liver and spleen, possibly for sustained periods, although evidence suggests that underperfusion of the left ventricular myocardium is not necessarily corrected. Dose-related, nonspecific relaxation of vascular and respiratory smooth muscle has been seen in vitro and in vivo in both human and animal studies. Therapeutic doses of amrinone produced decreased forearm vascular resistance and increased venous compliance in congestive heart failure patients, and dose-related relaxation of isolated human umbilical arterial muscle. In 2 studies on anaesthetised dogs, amrinone was a less potent tracheodilator and vasodilator than isoprenaline, but infusion of amrinone (300 μg/kg/min) produced greater vasodilation than dopamine, prenalterol (5 μg/kg/min), dobutamine (10 μg/kg/min) or saline. Cell studies of the effects of amrinone on calcium uptake indicate that drug effects may be dependent on intracellular calcium release or influx of extracellular calcium via a sodium-dependent mechanism, and that calcium may mediate the actions of amrinone. The effects of calcium on the responses to amrinone in isolated tissue preparations appear to vary according to the species or tissue studied. The majority of data indicate that increased myocardial contractility induced by amrinone is associated with raised tissue cyclic AMP concentrations and inhibition of phosphodiesterase (possibly only phosphodiesterase III). Pharmacokinetic Studies: The pharmacokinetics of amrinone have been studied following single-dose oral or intravenous administration. Initial multiple-dose studies suggest that the pharmacokinetic profile of amrinone does not change with repeated doses. Peak plasma concentrations of 4 μg/ml are attained 0.5 to 3 hours following 3.5 mg/kg orally, but do not increase further despite increased doses. ‘Constant levels’ of 1.7 μg/ml were measured after an intravenous bolus of 1.5 mg/kg followed by infusion of 5 μg/kg/min over 10 hours. In most studies there is a strong correlation between plasma amrinone concentrations and improvements in cardiac index after intravenous administration, but this association is less evident after oral administration. Interpatient variation in pharmacokinetic handling and cardiac baseline status account for variable haemodynamic responses to standard doses. Elimination half-life of amrinone is about 2.6 hours in healthy subjects following oral or intravenous administration of 0.8 to 2.2 mg/kg, but is extended after higher oral doses. In patients with congestive heart failure, half-lives of about 5 to 8 hours are seen, with considerable interpatient variation (3 to 15 hours). The indication of the presence of a ‘deep’ compartment (prolonged half-lives without increased plasma levels after a certain dose) reiterates the need for multiple-dose studies. The apparent volume of distribution following oral doses in normal volunteers was 1.43 L/kg, and in congestive heart failure patients was 0.64 to 1.2 L/kg. Inexplicably, a considerably smaller volume of distribution (41.2 ml/kg) and rapid distribution half-life (1 to 4 minutes) was seen after a single intravenous bolus dose. Tissue concentrations of amrinone remain to be studied. Between 10 and 40% of an oral dose is recovered in the urine in 24 hours in humans. Amrinone is metabolised via conjugative, but not oxidative, pathways. Plasma clearance after oral administration is approximately 220 to 250 ml/min in congestive heart failure patients, and 392 ml/min in healthy subjects. Therapeutic Trials: Amrinone has so far been used only in the treatment of severely disabling congestive heart failure (New York Heart Association Functional classes III and IV), in small numbers of patients refractory to conventional therapy. Patients have usually continued with digoxin and diuretics, but not vasodilator therapy. Single-dose and short term oral and intravenous studies show dose-related improvements in cardiac index and left ventricular stroke work index (40 to 80%), left ventricular end-diastolic pressure (40%), pulmonary capillary wedge pressure (16 to 53%), pulmonary arterial pressure (17 to 33%), right atrial pressure (16 to 44%), left ventricular ejection fraction (50%) and systemic and peripheral vascular resistance (23 to 50%) at rest. Heart rate and mean arterial pressure are not significantly affected. In patients with obstructive coronary artery disease and ischaemic disease, amrinone treatment was associated with decreased myocardial oxygen demands, coronary blood flow and arterial lactate levels, without evidence of ECG changes. Oral administration requires higher doses than those given intravenously to achieve equivalent results. After intravenous administration, peak response occurs after 5 minutes and lasts about 1 hour, whereas after oral administration, peak effects occur at 1 to 4 hours and last for 4 to 6 hours. Continuous intravenous infusion, and repeated oral or intravenous bolus administration over a short period have revealed no evidence of tolerance to the haemodynamic effects of amrinone. Considerable improvements in exercise capacity are achieved, along with increased stroke volume and cardiac output following single and repeated doses of intravenous and oral amrinone. Pulmonary capillary wedge pressure is reduced, particularly in those with severe disease. Amrinone does not affect heart rate and mean arterial pressure responses to exercise. Myocardial oxygen uptake is increased in some patients, and this change may be sustained during longer term oral therapy. Long term therapy (20 to 72 weeks) produced continued improvements in exercise performance in 4 patients, although the peak improvements were not maintained. However, drug withdrawal precipitated rapid deterioration in all patients, and cardiac size had increased (although other studies record decreased cardiac size) in this study, suggesting that disease progression, rather than drug tolerance occurred. In contrast, in another trial, amrinone was withdrawn in a double-blind manner after 4 weeks’ therapy, but no worsening of symptoms or changes in left ventricular size or function of patients with congestive heart failure were seen during a 3-month follow-up period of placebo therapy. Other medium term studies (2 to 12 weeks) confirm that the favourable effects of amrinone on exercise haemodynamics are maintained without increases in rhythm disturbances and are accompanied by reduced clinical symptoms. In a comparison of the acute effects of amrinone (100mg), hydralazine (75 to 175mg) and amrinone plus hydralazine, the haemodynamic improvement with combination therapy was significantly greater than with amrinone alone. With the combination, cardiac index increased by 68%, stroke volume index by 73%, and pulmonary capillary wedge pressure decreased by 36%. The respective changes with amrinone were 47%, 50% and 22%. Amrinone tended to produce better results than hydralazine, although only the differential decrease in pulmonary capillary wedge pressure reached significance. Exercise tolerance after combination therapy was improved from 6.1 to 12.6 minutes after 3 weeks, although the impressive results achieved with low doses may reflect a less severe condition, or a training effect. A comparative study of amrinone (10 μg/kg/min) and dobutamine (11.8 μg/kg/min) given by infusion showed that although initial haemodynamic improvements tended to favour dobutamine the haemodynamic effects of amrinone were maintained over 24 hours, whereas tolerance to the effects of dobutamine was evident over an 8-hour period. In primarily ischaemic patients, amrinone (2.5 mg/kg infusion over 60 minutes) produced significantly greater haemodynamic improvement than prazosin (1 to 6 mg/kg orally) and, to a lesser extent, pirbuterol (20 to 30mg orally). Both inotropic agents also reduced myocardial oxygen demand, although amrinone had a more marked effect. In another study, similar improvements in haemodynamic effects were achieved with single-dose administrations of amrinone (100mg orally) and pirbuterol (20mg orally). In this study, the further haemodynamic improvement after the addition of isosorbide dinitrate suggested that the activity of amrinone may be augmented by the addition of nitrate therapy. Side Effects: The side effects noted so far may not represent the complete profile for amrinone, due to the limited duration of most studies, the possibly inappropriate doses in some trials, and the relatively small number of patients treated. From preliminary studies conducted to date, it seems that the primary problem likely to be associated with long term amrinone is reversible thrombocytopenia, which has appeared in about 20% of patients but which may occur in a higher proportion during long term amrinone therapy. The mean decrease in platelet numbers is usually 70,000 to 90,000/mm3 and appears to be related to dosage. Thrombocytopenia is usually asymptomatic, responds to reduced dosage and may be transient. Patients with congestive heart failure may be receiving other drugs with a potential to cause thrombocytopenia. Ventricular arrhythmias have been reported, as have appetite and weight change, and gastrointestinal disturbances. One retrospective study reported a decreased cumulative survival rate in amrinone-treated patients. Because this study employed inadequate control measures and was not well documented there is a need for suitably designed long term prospective studies of the adverse effects of amrinone in patients with severe congestive heart failure. Dosage and Administration: As yet, there is no definitive dosage regimen for treatment with oral or intravenous amrinone in patients with congestive heart failure. However, recent unpublished studies indicate that 0.5 mg/kg intravenous bolus followed by a maximum total infusion of 10 mg/kg over 24 hours, and 100mg oral bid initially, rising to a maximum of 600 mg/day according to response may become the recommended dosage regimens.