Effects of milrinone on systemic hemodynamics and regional circulations in dogs with congestive heart failure: comparison with dobutamine

Milrinone is a new bipyridine inotropic agent with direct vasodilator properties. To determine the role of the vasodilator action in mediating systemic and regional hemodynamic responses to milrinone, we administered two equipotent inotropic doses of either milrinone or dobutamine to dogs with chronic congestive right heart failure produced by tricuspid avulsion and pulmonary artery stenosis. Similar increases in cardiac output, right and left ventricular dP/dt, and left ventricular dP/dt/P were produced by milrinone and dobutamine; however, heart rate increased and mean aortic pressure decreased only with milrinone infusion. In addition, while total peripheral vascular resistance decreased with both agents, the decrease was greater with milrinone. Regional blood flows were measured by a radioactive microsphere method. Milrinone and dobutamine produced similar increases in myocardial blood flow and left ventricular oxygen consumption. Dobutamine infusion decreased quadriceps muscle vascular resistance and had no effect on renal and splanchnic circulations. In contrast, milrinone infusion increased vascular resistance in quadriceps muscle and decreased it in renal and splanchnic beds. Thus, when milrinone was used in inotropic doses similar to those of dobutamine, the responses in systemic and regional hemodynamics in congestive heart failure differed. Milrinone produced a greater decline in total peripheral, renal, and splanchnic vascular resistances, probably resulting from its direct vasodilator action.     

Amrinone. A preliminary review of its pharmacological properties and therapeutic use

Amrinone 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 terms 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.     

Comparative haemodynamic dose-response effects of dobutamine and amrinone in left ventricular failure complicating acute myocardial infarction

The comparative haemodynamic dose-response effects of intravenous (i.v.) amrinone and dobutamine were evaluated in 20 male patients with haemodynamic (pulmonary artery occluded pressure (PAOP) greater than 20 mm Hg) and radiographic left heart failure following a recent myocardial infarction. Following a 1-h control period, 10 patients were each randomised to amrinone (800, 1,600, or 3,200 micrograms/kg/h) or dobutamine (200, 400, or 800 micrograms/kg/h) sequentially infused for 30 min at each dose level; haemodynamic parameters were recorded at the end of each infusion period. Amrinone reduced systemic arterial blood pressure and vascular resistance index with a moderately increased heart rate; PAOP (-10 mm Hg; p less than 0.01) fell substantially without change in cardiac or stroke work indices. Dobutamine increased systemic arterial blood pressure, heart rate, and stroke work index at an unchanged PAOP; cardiac index (+0.7 L/min/m2; 25%; p less than 0.01) increased. Systemic vascular resistance index was significantly reduced by both drugs. Thus, dobutamine increased cardiac index at an unchanged PAOP; myocardial stroke work increased. Amrinone had lesser effect on cardiac pumping but reduced PAOP (preload) at an unchanged stroke work. The implications of these differential actions for the clinical therapy of myocardial infarction deserves further evaluation.     

Haemodynamic dose-response effects of intravenous amrinone in left ventricular failure complicating acute myocardial infarction

The haemodynamic dose-response effects of intravenous amrinone were measured in 16 male patients, aged 40-65 years, with radiographic and haemodynamic evidence of left ventricular failure 4-18 h after acute myocardial infarction. After a l-h control period to confirm stable haemodynamic baseline variables, patients were randomised to either low-dose (200-400-800 micrograms/kg/h) or high-dose (800-1600-3200 micrograms/kg/h) intravenous amrinone. Each of the three infusions was given consecutively over 30 min (total infusion time 90 min) in each group, and haemodynamic measurements were made at the end of each infusion step. No arrhythmias or other untoward side effects, including haematological changes, were observed during the infusions. In both groups, intravenous amrinone reduced the pulmonary artery-occluded pressure (PAOP) (p less than 0.01), increased the cardiac output (p less than 0.05), and reduced the systemic vascular resistance (p less than 0.05). The reductions in PAOP and systemic arterial diastolic pressure and the increase in heart rate were directly dose-related, but the changes in cardiac output and systemic vascular resistance were not. These results suggest that peripheral vasodilation, particularly of venous capacitance vessels, as well as positive inotropic stimulation, may play a role in the haemodynamic changes induced by intravenous amrinone in acute ischaemic left ventricular failure.     

Haemodynamic advantages of a combined inotropic/venodilator regimen over inotropic monotherapy in acute heart failure

The haemodynamic influence of positive inotropic therapy with dobutamine, both alone and when combined with isosorbide dinitrate, was evaluated in 10 consecutive patients admitted to Coronary Care with acute left ventricular failure (pulmonary artery occluded pressure greater than 20 mm Hg) complicating myocardial infarction. Dobutamine increased systemic arterial blood pressure and heart rate without reduction in the left heart filling pressure; cardiac index (+0.9 L/min/m2; p less than 0.01) was substantially increased. Thus, consequent on these effects, dobutamine could increase myocardial oxygen requirements. The addition of intravenous isosorbide dinitrate reduced systemic arterial pressure and left heart filling pressure; the augmented cardiac index following therapy with dobutamine alone was maintained. Combined dobutamine/nitrate therapy, therefore, appeared haemodynamically superior to dobutamine monotherapy, in that it improved cardiac stroke volume at a normalised left ventricular filling pressure. These data suggest that combined dobutamine/nitrate therapy may prove useful as an adjunct to the treatment of normotensive heart failure complicating acute myocardial infarction.     

Modulation of inotropic therapy by venodilation in acute heart failure: a randomised comparison of four inotropic agents, alone and combined with isosorbide dinitrate.

The effects of four inotropic agents with differing ancillary properties [a cardiac glycoside (digoxin), a combined alpha- and beta-adrenergic agonist (dobutamine), a beta-adrenergic agonist (prenalterol), and a phosphodiesterase inhibitor (amrinone)] alone and with subsequent addition of isosorbide dinitrate were compared in 48 consecutive acute myocardial infarction patients with radiographic and haemodynamic (pulmonary artery occluded pressure greater than 18 mm Hg) left ventricular failure. All agents with the exception of dobutamine reduced the elevated left heart filling pressure; only digoxin and dobutamine augmented the cardiac stroke volume index. All drugs except digoxin reduced the SVRI; an arteriolar constrictor response was evident 60 min after digoxin and a tachycardia resulted after combined alpha- and beta- and beta-adrenergic stimulations (dobutamine and prenalterol, respectively). The addition of isosorbide dinitrate reversed the inotrope-induced elevations of systemic arterial pressure and resulted in additional reductions in left heart filling pressure. These data suggest that, in the absence of substantial venodilator properties in an inotropic compound, reduction in elevated left heart filling pressure is not achieved with inotropic therapy alone in acute left ventricular failure and combining a venodilator may be haemodynamically advantageous.     

Cardiotonic activity of milrinone, a new and potent cardiac bipyridine, on the normal and failing heart of experimental animals

Milrinone (Win 47203) is a potent cardiac bipyridine with inotropic and vasodilator properties. Its effects were studied in anesthetized and unanesthetized dogs and in isolated cardiac tissues from guinea pigs. In the anesthetized dog, the intravenous injection of milrinone (0.01-0.1 mg/kg) increased cardiac contractile force (CF) (23 +/- 6.1 to 87 +/- 8.9%), maximum left ventricular pressure development (24 +/- 5.8 to 119 +/- 16.1%), and cardiac output (16 +/- 4.5 to 33 +/- 8.9%), with less than a 30% increase in heart rate (HR). Significant decreases in systolic and diastolic blood pressures were seen at 0.3-3 mg/kg i.v. Oral doses of milrinone (0.1-1.0 mg/kg), in unanesthetized dogs, increased cardiac CF by 35 +/- 7.0 to 99 +/- 17.0%, with a maximum increase in HR of 40 +/- 7.1% and no significant change in blood pressure. Milrinone was effective in the presence of ouabain and dopamine without enhancing their arrhythmogenic properties. It was also effective in reversing propranolol-, verapamil-, or pentobarbital-induced heart failure. The inotropic response does not seem to involve the stimulation of the autonomic receptors, the release of endogenous catecholamines, histamine, or prostaglandins, or the inhibition of Na+,K+-adenosine triphosphatase. Milrinone is an inhibitor or cardiac adenosine 3',5'-monophosphate (cAMP) phosphodiesterase, with resultant increases in cardiac cAMP levels. However, the time course for this increase does not seem to correspond to the increase in muscle developed tension, and, therefore, it is unlikely to be responsible for the initiation of the inotropic response. Milrinone is a potent cardioactive agent which should be beneficial in the treatment of acute and chronic congestive heart failure.     

Biochemical mechanisms for the inotropic effect of the cardiotonic drug milrinone

Milrinone is a new inotropic agent for the treatment of refractory congestive heart failure. Our understanding of the mechanisms(s) of action of this synthetic cardiotonic drug is incomplete. We examined the effects of milrinone and the parent compound amrinone on sarcoplasmic reticulum function (45Ca-uptake and Ca-ATPase); radioligand binding to adenosine, beta-adrenergic, and cholinergic muscarinic receptors; cyclic AMP accumulation; and inhibition of various forms of cyclic AMP phosphodiesterases. Comparisons were made to observe how these effects correlate with the inotropic response of heart. Milrinone was shown to be a potent phosphodiesterase inhibitor that was 40 times more potent than amrinone and 10 times more potent at inhibiting the high-affinity (Km = 0.23 microM) form (Ki = 22 microM) than the low-affinity (Km = 140 microM) form (Ki = 225 microM) of cyclic AMP phosphodiesterase in heart. The potency of milrinone as a phosphodiesterase inhibitor was the same in the presence and absence of calcium. Concentrations of milrinone that increased cyclic AMP accumulation also produced positive inotropy. A comparison of milrinone with amrinone and methylxanthines revealed the order of potency to be isobutylmethylxanthine greater than milrinone greater than theophylline greater than caffeine greater than amrinone. Milrinone and amrinone had no effect on 45Ca-uptake or Ca-ATPase activity in myocyte sarcoplasmic reticulum. However, milrinone did bind weakly to adenosine receptors (KD = 466 microM) but not to cholinergic muscarinic or beta-adrenergic receptors. Also, in combination with isoproterenol high concentrations of milrinone blocked the negative inotropic response to the adenosine agonist phenylisopropyladenosine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Milrinone, a new agent for the treatment of congestive heart failure

The chemistry, pharmacology, pharmacokinetics, dosage, clinical efficacy, and adverse effects of milrinone are reviewed. Milrinone, which is structurally similar to amrinone, is an oral agent under investigation for the treatment of congestive heart failure. The drug produces positive inotropic and vasodilating effects through unknown mechanisms. Milrinone is well absorbed orally and has a duration of action of three to six hours. The major route of elimination is through the kidneys. The usual initial dosage of milrinone is 2.5-5 mg every six hours; patients whose condition is deteriorating may require 50 mg of the drug per day. Although most patients report that early in therapy the drug relieves the symptoms of congestive heart failure, these benefits are not always sustained. Milrinone does not check the natural progression of disease. Complaints of side effects are rare, although diarrhea, hyperthyroidism, aggravation of angina pectoris, worsening of muscle weakness, and increased fluid retention have been reported. There is evidence to suggest that milrinone may cause or aggravate arrhythmias, worsen congestive heart failure, and shorten the length of survival. Experience with milrinone indicates that the drug may be of limited usefulness in the treatment of congestive heart failure.     

The pharmacokinetics and pharmacodynamics of newer inotropic agents

In the past few years an intense effort has been directed toward the development of new inotropic agents for the treatment of chronic cardiac failure. Traditionally, therapy of this disease has included treatment with digitalis glycosides, diuretics, sodium restriction and vasodilators. While digitalis has proven to be an effective inotropic agent, it possesses a low therapeutic index and many patients remain symptomatic or 'refractory' despite its inotropic effects. This review focuses on the pharmacokinetics and pharmacodynamics of newer inotropic agents that have been developed or which are currently undergoing investigation. Amrinone and milrinone are two bipyridine derivatives which have been shown to be effective in the short term treatment of cardiac failure. Milrinone is currently being evaluated for its long term efficacy. The mechanism of action of amrinone and milrinone appears to be unrelated to the cardiac glycosides and sympathomimetic agents, and they are rapidly and well absorbed following oral administration. The bioavailability of milrinone appears to be somewhat reduced in patients with chronic cardiac failure. The distribution of these drugs to extravascular tissues is very rapid; the volume of distribution suggests that they are not extensively bound to tissues. While the volume of distribution of amrinone appears to be unaffected by the presence of heart failure, that of milrinone appears to be somewhat enhanced. The major route of elimination of both drugs appears to be excretion into urine as unchanged drug. A substantial fraction of the amrinone dose, however, undergoes hepatic metabolism to many metabolites, including an N-acetyl derivative. Clearance of amrinone and milrinone is dramatically reduced in patients with chronic cardiac failure compared with normal volunteers, resulting in proportionate increases in the serum half-lives of these drugs. Studies examining the acute and chronic disposition of these agents in cardiac failure patients have not demonstrated changes in their pharmacokinetics secondary to improvements in cardiocirculatory function. Both drugs show strong correlations between mean improvements in haemodynamics and drug serum concentrations, although considerable intrapatient variability may exist. It is currently unclear as to whether the site for the pharmacological action of amrinone is pharmacokinetically distinguishable from plasma. Enoximone and its sulphoxide metabolite, piroximone, are two compounds currently undergoing investigation for the treatment of chronic cardiac failure.(ABSTRACT TRUNCATED AT 400 WORDS)     

Physiologic assessment of milrinone therapy in severe heart failure patients.

To assess the inotropic, vasodilator, and after-load-reducing effects of intravenous milrinone in patients with severe congestive heart failure, a simple noninvasive echocardiographic study coupled with a right catheterization was performed in 12 patients. Milrinone was administered intravenously as a 50 micrograms.kg-1 bolus followed by a 24-h milrinone infusion at a rate of 0.5 mg.kg-1.min-1 [corrected]. Echocardiographic left ventricular end-diastolic diameter (Ded), end-systolic diameter (Des), and wall thickness were measured at baseline and at 24 h of milrinone infusion, before and after a sublingual nitrate administration (0.8 mg of nitroglycerin) that induced load variations. Hemodynamic measurements were performed simultaneously. Left ventricular end-systolic meridional wall stress (Ses) was then calculated. The slopes of percent fractional shortening (percent FS)/Ses and Ses/Des, obtained during sublingual nitrate administration, were traced. Both end-systolic relations are an index of the contractile state. Milrinone therapy improved hemodynamics in all patients, resulting in stabilized hemodynamic conditions between 12 and 24 h of continuous milrinone infusion. At these times, the cardiac index increased to 30% while the capillary pulmonary wedge pressure and systemic vascular resistance decreased to 26 and 24%, respectively (all p less than 0.01). The average slope of Ses/Des shifted upward from 47.5 +/- 30 to 69.25 +/- 34 (p less than 0.05) and the average slope of (percent FS)/Ses shifted from -0.032 +/- 0.025 to -0.082 +/- 0.061 (p less than 0.01), both variations attesting the inotropic effect of milrinone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential effects of OPC-18790, amrinone and dobutamine on cardiac function and energy metabolism in the guinea-pig isolated ischaemic heart.

1. The effects of OPC-18790, a novel positive inotropic agent, on cardiac function and myocardial energy metabolism in the guinea-pig isolated heart with ischaemia were studied by 31P-magnetic resonance spectroscopy (MRS) and compared with those of amrinone and dobutamine. 2. Cardiac ischaemia was induced by intracoronary infusion of 15 microns microspheres to reduce coronary perfusion flow (CPF) by 50%. Microsphere embolisation caused a 40% decrease in left ventricular systolic pressure (LVSP), cardiac contractility measured by peak of ventricular pressure development (LVdP/dt) and slightly reduced heart rate. There was also a decrease in ATP and creatine phosphate (PCr) by 20%, an increase in inorganic phosphate (Pi) by 25% and an acidic shift of intracellular pH in the ischaemic heart. 3. In the ischaemic heart, OPC-18790, amrinone and dobutamine were applied at concentrations which increased LVdP/dt by about 60%. These compounds increased LVP by 15% to 30% and increased CPF by about 10%. Amrinone and dobutamine but not OPC-18790 increased heart rate. When these drugs produced the haemodynamic changes described above, amrinone and dobutamine reduced ATP and PCr, increased Pi and produced further intracellular acidosis, whereas, OPC-18790 did not change these parameters. 4. Cardiac pacing at 285 beats min-1 produced decreases in LVP, LVdP/dt and CPF by about 30%, 20%, 5%, respectively and an increase in Pi, decreases in PCr and ATP, and intracellular acidosis. 5. These results suggest that degradation of high energy phosphate compounds closely relates to increase in heart rate in the ischaemic heart. Positive inotropic agents without chronotropic action seem to be beneficial in support of the ischaemic heart.     

Cardiac and hemodynamic effects of intravenous R80122, a new phosphodiesterase III inhibitor, in a canine model of myocardial ischemia and heart failure.

The cardiac and hemodynamic effects of R80122, a new specific phosphodiesterase III inhibitor, were studied in a closed-chest canine model of acute global left ventricular ischemia complicated by heart failure. The results obtained were compared with those obtained with milrinone. Intravenous infusion of the compounds (0.005 mg/kg/min for both) was started when stable heart failure had developed and was continued for 50 min followed by a washout period of 60 min. Both R80122 and milrinone improved the function of the acutely failing heart, as indicated by the increase in the values of the variables related to left ventricular function, but differences existed. The most striking differences were the normalization of the left ventricular external mechanical efficiency with R80122, but not with milrinone, and the maintenance of aortic blood pressure during infusion of R80122, which decreased during infusion of milrinone. Milrinone tends to induce ventricular tachycardia more frequently than R80122. It can be concluded that R80122 and milrinone improve the function of the acutely failing heart, but that the changes induced by R80122 are better balanced, i.e., enhancement of external mechanical efficiency with maintenance of aortic blood pressure.     

Improvement of postischemic contractile dysfunction of dog heart by MCI-154, a novel cardiotonic agent

The effects of MCI-154, a cardiotonic agent which has direct effects on cardiac myofilaments, on postischemic contractile dysfunction were studied in dog heart subjected to a 30-min occlusion of the left anterior descending coronary artery followed by reperfusion, and compared with the effects of milrinone and dobutamine, that have largely cyclic AMP-dependent mechanisms of action. Regional myocardial contractility (segment shortening) and tissue ATP levels were severely depressed in reperfused myocardium. MCI-154 (0.3 and 1 microgram/kg per min) improved the regional function of postischemic myocardium and decreased left ventricular end-diastolic pressure and systemic aortic pressure when infused i.v. from 30 min after reperfusion. The improvement of regional function caused by MCI-154 (1 microgram/kg per min) was more pronounced than that caused by milrinone (1 microgram/kg per min) or dobutamine (1 microgram/kg per min), although the drugs produced an equal increase in cardiac performance (peak positive left ventricular dP/dt). These results suggest that MCI-154 produces a more pronounced improvement of regional myocardial function than milrinone and dobutamine, presumably by increasing the responses of the contractile protein system to Ca2+. In this respect, MCI-154 would be of much benefit for the treatment of postischemic left ventricular dysfunction.     

Comparative effects of dobutamine and corwin, a beta 1-adrenergic partial agonist, in experimental left ventricular failure

Corwin is a new, long-acting beta 1-adrenergic partial agonist for oral and intravenous (i.v.) use. The effects of corwin were compared with those of dobutamine in acute ischemic left ventricular failure in dogs. Failure was produced by embolization of the left main coronary artery with 50 micron plastic microspheres. This induced severe depression in left ventricular function, as evidenced by a marked increase in left ventricular end-diastolic pressure, reduction in left ventricular dP/dtmax, and cardiac output. After 45 min was allowed for stabilization, the 27 dogs were randomly assigned to three groups: control (n = 9), dobutamine-treated (5-10 micrograms/kg/min i.v., n = 9), and corwin-treated (0.025-0.10 mg/kg i.v., n = 9). The doses of dobutamine and corwin were adjusted to give an increase in left ventricular dP/dtmax of 50%. Both drugs similarly increased cardiac output (p less than 0.01), lowered left ventricular end-diastolic pressure (p less than 0.01) and total peripheral vascular resistance (p less than 0.01), but did not affect the heart rate. Only dobutamine increased the mean arterial pressure (p less than 0.01). Both drugs also increased the arterial concentrations and myocardial uptake of fatty acids (p less than 0.05) but caused only a small and nonsignificant increase in myocardial oxygen consumption. Our findings indicate that the hemodynamic and metabolic profiles of corwin and dobutamine are similar, and both drugs should be of special value in the treatment of congestive heart failure. Since corwin can be given orally and has a longer duration of action, it is potentially useful in the long-term treatment of heart failure.     

Current status of phosphodiesterase inhibitors in the treatment of congestive heart failure.

The phosphodiesterase inhibitors have been recognised as potent inotropic and vasodilating drugs. In acute congestive heart failure they increase cardiac output, decrease left pulmonary capillary wedge pressure, and reduce total peripheral resistance with an improvement in loading conditions of the failing heart. Their potency in reversal of symptoms of acute congestive heart failure is quite similar to, or even better than, treatment with intravenous catecholamines and sodium nitroprusside. In chronic congestive heart failure, however, these agents increase mortality and have deleterious effects in the outcome of patients with severe left ventricular dysfunction.     

Intravenous glyceryl trinitrate (nitroglycerin). A review of its pharmacological properties and therapeutic efficacy

The recently introduced preparation of intravenous glyceryl trinitrate (nitroglycerin) provides a rapid steady therapeutic blood concentration of nitrates during continuous infusion. Intravenous glyceryl trinitrate causes venodilation at low doses, but at higher doses dilates both arteries and veins. Its principal haemodynamic effects at therapeutic dosages include a decrease in blood pressure in preload (left ventricular filling pressure) and in determinants of afterload, and a decrease in myocardial oxygen demand. Human pharmacokinetic data are few and difficult to interpret due to wide interstudy and interindividual variation. There is no close correlation between infusion rate, blood concentration and haemodynamic effects. The nature of the patient population treated with intravenous glyceryl trinitrate has largely precluded the use of a placebo, but in open trials the drug has been used successfully in the treatment of unstable angina, left ventricular failure accompanying acute myocardial infarction and in the control of hypertension associated with cardiac surgery at dosages titrated to achieve a specific end-point. Favourable haemodynamic responses have been achieved in very short term studies in congestive heart failure, and preliminary studies suggest that institution of intravenous glyceryl trinitrate early after acute myocardial infarction may limit ischaemic damage. However, use of the drug in acute myocardial infarction remains controversial. Intravenous glyceryl trinitrate is generally well tolerated, although hypotension and headache occur occasionally, and sinus tachycardia and bradycardia less frequently. Careful titration of dosage is required (beginning at 5 micrograms/min), and if the infusion sets contain polyvinylchloride, the delivered dose is lower than that calculated, because of adsorption of glyceryl trinitrate onto the plastic tubing.     

Comparison of the cardiovascular actions of Cordemcura, isoprenaline and dobutamine in cats

A comparative study was made of the closed-chest cardiovascular effects of Cordemcura (amrinone), isoprenaline, and dobutamine in anaesthetized cats (n = 17). The haemodynamic parameters used for this purpose include: maximum rate of both left ventricular pressure rise (dp/dtmax) and decline (dp/dtmin), heart frequency (HFR), arterial blood pressure, both systolic (Ps) and diastolic (Pd). The maximum changes of the haemodynamic parameters after increasing iv. bolus injections of the test substances were used to plot the dose-effect curves of the single parameters for each substance. All the 3 pharmaceuticals caused dp/dtmax to rise, with quantitative differences being found. Moreover, quantitatively different positive chronotropic effects have been found. The influence on the remaining haemodynamic parameters was different both in the quantitative and in the qualitative sense. The results were discussed with regard to comparing the cardiovascular effects of Cordemcura with isoprenaline and dobutamine.     

Pharmacokinetics and pharmacodynamics of intravenous inotropic agents

Positive inotropic drugs have various mechanisms of action. Long-term use of cyclic adenosine monophosphate (cAMP)-dependent drugs has adverse effects on the prognosis of heart failure patients, whereas digoxin has neutral effect on mortality. There are, however, little data on the effects of intravenous inotropic drugs on the outcome of patients. Intravenous inotropic agents are used to treat cardiac emergencies and refractory heart failure. beta-Adrenergic agonists are rapid acting and easy to titrate, with short elimination half-life. However, they increase myocardial oxygen consumption and are thus hazardous during myocardial ischaemia. Furthermore they may promote myocyte apoptosis. Phosphodiesterase (PDE) III inhibiting drugs (amrinone, milrinone and enoximone) increase contractility by reducing the degradation of cAMP. In addition, they reduce both preload and afterload via vasodilation. Short-term use of intravenous milrinone is not associated with increased mortality, and some symptomatic benefit may be obtained when it is used in refractory heart failure. Furthermore, PDE III inhibitors facilitate weaning from the cardiopulmonary bypass machine after cardiac surgery. Levosimendan belongs to a new group of positive inotropic drugs, the calcium sensitisers. It has complex pharmacokinetics and long-lasting haemodynamic effects as a result of its active metabolites. In comparative trials, it has been better tolerated than the most widely used beta-agonist inotropic drug, dobutamine. The pharmacokinetics of the intravenous inotropic drugs might sometimes greatly modify and prolong the response to the therapy, for example because of long-acting active metabolites. These drugs display considerable differences in their pharmacokinetics and pharmacodynamics, and the selection of the most appropriate inotropic drug for each patient should be based on careful consideration of the clinical status of the patient and on the pharmacology of the drug.     

米力农治疗难治性心力衰竭56例

目的：评价米力农治疗难治性心力衰竭（RHF）的疗效。方法：对56例患者给予米力农5mg加入5％葡萄糖或0．9％氯化钠注射液250mL,静脉滴注,qd,7d为1个疗程,观察患者治疗前后症状、体征、血压、心率及心功能指标。结果：①米力农治疗难治性心力衰竭总有效率85．75;②治疗后左室身血分数（LVEF）、左室短轴缩短率（FS）均明显增加（P＜0．01）,舒张早期最大充盈速度（E）与舒张晚期最大充盈速度（A）比值（E／A）明显增加（P＜0．05）。结论：米力农治疗RHF有较好的疗效,不仅能改善患者患者心脏收缩功能,而且能改善舒张功能。