Differential pharmacologic sensitivities of phosphodiesterase-3 inhibitors among human isolated gastroepiploic, internal mammary, and radial arteries.

UNLABELLED: Systematic investigations of the actions of phosphodiesterase (PDE)-3 inhibitors on different human vascular tissues have not been performed. We investigated the effects of specific PDE-3 inhibitors (olprinone, milrinone, and amrinone) on contracted human gastroepiploic arteries (n = 70), internal mammary arteries (n = 72), and radial arteries (n = 70) harvested from a total of 134 patients, all of whom were undergoing coronary artery bypass surgery. Each of these PDE-3 inhibitors dose-dependently diminished the contractile responses to 10(-6) mol/L norepinephrine and to either 10(-9) or 10(-8) mol/L of the thromboxane A2 analog U46619. In inducing vasorelaxations, these inhibitors were significantly more potent in norepinephrine-contracted rings than in those contracted with U46619. Further, at concentrations similar to the maximum therapeutic plasma concentrations (10(-7) mol/L olprinone; 10(-6) mol/L milrinone; 10(-5) mol/L amrinone) olprinone and milrinone were more potent at inducing relaxations than amrinone in gastroepiploic arteries and radial arteries, whereas in internal mammary arteries milrinone was more potent than the others. These results suggest different activities for the three PDE-3 inhibitors among human arteries located in different regions and may be informative about the effectiveness of these inhibitors in preventing spasms in the various arterial grafts used in revascularization. IMPLICATIONS: Because three phosphodiesterase-3 inhibitors (milrinone, olprinone, and amrinone) differed in their vasodilator potencies (against the contractile response to either norepinephrine or a thromboxane A2 analog) among human arteries removed from different parts of the body, their vascular relaxation profiles should be considered before they are used clinically.

Pharmacokinetics of amrinone in neonates and infants.

OBJECTIVE: To evaluate the pharmacokinetics of amrinone and its metabolites in neonates and infants after reconstructive surgery for congenital heart disease. DESIGN: Prospective study. SETTING: Pediatric intensive care unit in a university hospital. PARTICIPANTS: Fifteen neonates aged less than 1 month with transposition of the great arteries and 14 infants aged 2 to 6 months with complete atrioventricular septal defect. INTERVENTIONS: Amrinone, loading dose of 2 mg/kg, was administered before weaning from cardiopulmonary bypass, followed by a maintenance infusion of 7.5 microg/kg/min. MEASUREMENTS AND MAIN RESULTS: Blood samples to determine plasma concentrations of amrinone, N-acetylamrinone, and N-glycolylamrinone were drawn before amrinone administration, frequently after the loading dose, every 6 hours during the maintenance infusion, and until 48 hours after the end of the infusion. Amrinone clearance was 2.4 +/- 0.9 mL/kg/min in neonates and 3.2 +/- 1.2 mL/kg/min in infants (p < 0.05). The volume of distribution at steady-state was smaller (p < 0.05) in neonates than in infants. The elimination half-life of amrinone was 10.7 +/- 6.7 hours in neonates and 6.1 +/- 1.4 hours in infants (p < 0.05). There was a linear correlation between the clearance of amrinone and the body surface area (r = 0.67; p < 0.05). The ratio of the plasma concentration of N-acetylamrinone to that of amrinone did not differ between neonates and infants. CONCLUSIONS: Amrinone is eliminated at a slower rate in neonates than in infants. The rate of acetylation of amrinone appears to be similar; the differences in the elimination capacity of amrinone are mainly due to the immature renal function in neonates.

Clinical pharmacokinetics of vasodilators. Part II.

Stimulating cardiac beta 1-adrenoceptors with oxyfedrine causes dilatation of coronary vessels and positive inotropic effects on the myocardium. beta 1-adrenergic agonists increase coronary blood flow in nonstenotic and stenotic vessels. The main indication for the use of the phosphodiesterase inhibitors pamrinone, mirinone, enoximone and piroximone is acute treatment of severe congestive heart failure. Theophylline is indicated for the treatment of asthma, chronic obstructive pulmonary disease, apnea in preterm infants ans sleep apnea syndrome. Severe arterial occlusive disease associated with atherosclerosis can be beneficially affected by elcosanoids. These drugs must be administered parenterally and have a half-life of only a few minutes. Sublingual or buccal preparations of nitrates are the only prompt method (within 1 or 2 min) of terminating anginal pain, except for biting nifedipine capsules. The short half-life (about 2.5 min) of nitroglycerin (glyceryl trinitrate) makes long term therapy impossible. Tolerance is a problem encountered with longer-acting nitric oxide donors. Knowledge of the pharmacokinetic properties of vasodilating drugs can prevent a too sudden and severe blood pressure decrease in patients with chronic hypertension. In considering the administration of a second dose, or another drug, the time necessary for the initially administered drug to reach maximal efficacy should be taken into account. In hypertensive emergencies urapidil, sodium nitroprusside, nitroglycerin, hydralazine and phentolamine are the drugs of choice, with the addition of beta-blockers during catecholamine crisis or dissecting aortic aneurysm. Childhood hypertension is most often treated with angiotensin-converting enzyme (ACE) inhibitors or calcium antagonists, primarily nifedipine. Because of the teratogenic risk involved with ACE inhibitors, extreme caution must be exercised when prescribing for adolescent females. The propagation of health benefits to breast-fed infants, combined with more women delaying pregnancy until their fourth decade, has entailed an increase in the need for hypertension management during lactation. Low dose hydrochlorothiazide, propranolol, nifedipine and enalapril or captopril do not pose enough of a risk of preclude breastfeeding in this group. The most frequently used antihypertensive agents during pregnancy are methyldopa, labetalol and calcium channel antagonists. Methyldopa and beta-blockers are the drugs of choice for treating mild to moderate hypertension. Prazosin and hydralazine are used to treat moderate to severe hypertension and hydralazine, urapidil or labetalol are used to treat hypertensive emergencies. The use of overly aggressive antihypertensive therapy during pregnancy should be avoided so that adequate uteroplacental blood flow is maintained. Methyldopa is the only drug accepted for use during the first trimester of pregnancy.

Hemodynamic effects of amrinone in children after Fontan surgery.

After Fontan repair in children, we performed a prospective, open-label study to evaluate the effect of amrinone on pulmonary vascular resistance (PVRI). Eight patients who underwent the Fontan repair had baseline arterial pressure, left atrial pressure, central venous pressure, and cardiac output measured postoperatively. Hemodynamic measurements were repeated after amrinone 4.5 mg/kg. The PVRI tended to decrease, but the change was not statistically significant. Although the systemic vascular resistance decreased to 802 +/- 222 from 941 +/- 191 dynes.s.cm-5.m-2 (P < 0.05), mean arterial blood pressure was unchanged. Cardiac index (3.8 +/- 1.2 to 4.7 +/- 1.6 L.min-1.m-2) and stroke volume index (23.6 +/- 6.7 to 30.5 +/- 8.1 mL.beat-1.m-2) increased, and heart rate decreased (160 +/- 21 to 151 +/- 24 bpm) (P < 0.05). Colloid transfusion during amrinone bolus administration was 13.9 mL/kg. The mean serum amrinone concentration was 4.2 micrograms/mL at the end of bolus and clearance was 2.24 mL.kg-1.min-1. Arrhythmias and thrombocytopenia were not noted. We conclude that amrinone administration is effective in increasing cardiac output in children who have undergone a Fontan repair.

Amrinone loading during cardiopulmonary bypass in neonates, infants, and children.

OBJECTIVES: To determine whether amrinone is bound to cardiopulmonary bypass circuits. When amrinone is administered to children during cardiopulmonary bypass, determine whether measured amrinone concentrations differ from those predicted based on a reported volume of distribution of 1.6 L/kg. DESIGN: In vitro study: Uptake of amrinone by cardiopulmonary bypass circuits was determined. Clinical study: Prospective, open label investigation. SETTING: University-affiliated tertiary children's hospital. PARTICIPANTS: Clinical study: 27 children participated, including 5 neonates and 9 infants. INTERVENTIONS: In vitro study: Waste blood was circulated within seven pediatric cardiopulmonary circuits. Amrinone was administered, and blood was serially assayed for amrinone levels. Clinical study: Amrinone (mean dose 4.9 mg/kg) was loaded during cardiopulmonary bypass and amrinone concentrations in pump blood were determined at termination of bypass. Amrinone measured by high-performance liquid chromatography. MEASUREMENTS AND MAIN RESULTS: Cardiopulmonary bypass circuit uptake reduced amrinone concentrations to 79% of predicted. After correcting for circuit uptake, serum amrinone levels in patients were significantly higher than predicted. The levels, expressed in the ratio of measured: predicted amrinone concentration, did not differ among neonates, infants, and children older than 1 year of age. CONCLUSIONS: When amrinone is administered to children during cardiopulmonary bypass, about 20% of the dose becomes bound to the circuit. Available drug is distributed within a smaller volume than predicted. This may be the consequence of the physiologic perturbations of hypothermic cardiopulmonary bypass.

Elimination of amrinone during continuous veno-venous haemofiltration after cardiac surgery.

We studied the elimination of amrinone during continuous veno-venous haemofiltration (CVVHF) in three anuric patients after cardiac surgery. The patients had developed low cardiac output followed by acute prerenal failure. Plasma amrinone levels measured by HPLC were fitted to a two-compartment model. We found significant amrinone clearance, with a mean sieving coefficient (S) of 0.44%, which correlates with the protein-unbound, pharmacologically effective fraction of amrinone. The AUC of the arterial plasma concentration-time curve was decreased by 49.8%. All pharmacokinetic parameters showed wide interindividual variation. To ensure the therapeutic effect of amrinone and to avoid toxic adverse effects monitoring of plasma amrinone levels is necessary.

Age-related amrinone pharmacokinetics in a pediatric population.

OBJECTIVES: To measure the plasma concentrations of amrinone and N-acetyl-amrinone achieved using current pediatric dosing recommendations. To examine the pharmacokinetics of amrinone in an extended age range of pediatric patients. To examine any age-related differences in the relative contribution of hepatic metabolism vs. renal elimination of amrinone. DESIGN: Prospective study. SETTING: A pediatric intensive care unit in a tertiary care teaching hospital. PATIENTS: Thirty-one patients aged 4 days to 15 yrs who required a constant infusion of amrinone. INTERVENTIONS: Blood samples were obtained 15 mins after each 0.75 mg/kg loading dose, and every 6 hrs during a constant infusion of amrinone to measure plasma amrinone, N-acetyl-amrinone and N-glycolyl-amrinone concentrations by high-performance liquid chromatography. Blood samples to measure amrinone, N-acetyl-amrinone, and N-glycolyl-amrinone concentrations during elimination were also obtained at regular intervals after discontinuation of the infusion. Six-hour urine collections were obtained to measure amrinone renal clearance. MEASUREMENTS AND MAIN RESULTS: Plasma amrinone concentrations > or = 2 micrograms/mL were obtained in 13 of 14 patients after a 3-mg/kg loading dose. There was a six-fold variability in steady-state plasma amrinone concentrations in patients receiving the same ordered infusion rate. There was a significant (p = .001) difference between the ordered and measured amrinone infusion rates. Six (19.4%) of 31 patients had steady-state plasma amrinone concentrations of < or = 2 micrograms/mL. There was a large variability in the volume of distribution, clearance, and elimination half-life which did not appear to be age-related. Renal clearance of amrinone ranged between 0.4 and 2.18 mL/kg/min, and did not increase with age. There was no increase in the proportion of children with a high plasma steady-state N-acetyl-amrinone/amrinone ratio over time from 1 to 24 months of life. CONCLUSIONS: Administering a 3-mg/kg amrinone loading dose in four divided doses over 1 hr resulted in relatively rapid therapeutic plasma concentrations without excessively high concentrations and good clinical tolerance. The wide interindividual variation in clearance and volume of distribution resulted in a variable dose-concentration relationship; children receiving lower amrinone infusion rates may-have subtherapeutic plasma steady-state concentrations. There did not appear to be any age-related change in renal clearance or hepatic metabolism of amrinone in children aged 1 to 24 months.

Amrinone in cardiac surgical patients with left-ventricular dysfunction. A prospective, randomized placebo-controlled trial.

STUDY OBJECTIVE: To evaluate the efficacy of amrinone for facilitating weaning from cardiopulmonary bypass (CPB). DESIGN: Prospective, randomized, double-blind, placebo-controlled trial with epinephrine as "rescue" therapy. SETTING: Operating room of a large, metropolitan tertiary-care center. PATIENTS: Thirty-nine patients with preoperative left ventricular dysfunction undergoing cardiac surgery. Thirty-three patients underwent aortocoronary bypass grafting; six patients underwent valve replacement for severe mitral or aortic regurgitation. INTERVENTIONS: Patients received either amrinone (1.5 mg/kg loading dose plus 10 micrograms/kg/min maintenance infusion; n = 20) or placebo (n = 19) in a randomized double-blind fashion shortly (median, 10.5 min; range, 2 to 24 min) before separation from CPB. Inotropic drugs (other than the study drug) were withheld prior to separation from CPB unless safety considerations demanded that the protocol be broken. Patients who could not be weaned from CPB, as well as those with a cardiac index of 2.2 L/min/m2 or less after weaning from CPB, received epinephrine (60 to 120 ng/kg/min) by infusion. MEASUREMENTS AND RESULTS: Fourteen of 19 patients receiving placebo but only 1 of the 20 patients receiving amrinone (p = 0.00001) required epinephrine infusion to separate from bypass. The cardiac index of 4 patients receiving placebo (but no patients with amrinone) failed to exceed 2.2 L/min/m2 despite epinephrine infusion, requiring the protocol to be broken (p < 0.08). Blood concentrations of amrinone determined (only in the amrinone group) after separation from CPB confirmed that the dosage of amrinone produced an effective blood concentration. Fourteen of 19 patients receiving placebo and 17 of 20 patients receiving amrinone required an infusion of phenylephrine titrated to maintain systolic blood pressure less than 90 mm Hg. Seven patients (four with amrinone and three with placebo) required antiarrhythmic drug therapy. The outcome at 3 months was similar in the 2 groups. CONCLUSIONS: Amrinone by itself is an effective agent to facilitate weaning from CPB, and therapy with amrinone reduced the need for individualized titration of epinephrine. Amrinone is as effective as individualized titration of epinephrine (after CPB) to improve cardiac function. Patients in the group receiving amrinone had no greater need for vasoconstricting agents than did patients in the group receiving placebo; however, proactive administration of amrinone before separation from CPB appears to offer no greater benefit to high-risk patients than selective administration of drugs (epinephrine) only to those patients who demonstrate the need for drug support at the time of weaning.

Hemodynamic effects of amrinone and colloid administration in children following cardiac surgery.

Amrinone was used as the sole vasoactive medication in 9 of 14 children (aged 5 months to 8.25 years) given the drug following open repair of congenital cardiac lesions. Four children received a concomitant dopamine infusion and one infant had the infusion stopped after 5 hours for low mean arterial pressure (49 mmHg). In the 10 children receiving only amrinone, cardiac index increased 21% (range, 0 to 94%) after a total loading dose of 4.5 mg/kg given over 1 hour. Four of 14 patients (29%) required dopamine infusions to maintain mean arterial pressure over 55 mmHg and in these children cardiac index increased from baseline and was maintained during the amrinone infusion. Preload was held constant by administration of whole blood or plasmanate during amrinone loading; a decrease in systemic vascular resistance index was seen resulting in a stable arterial blood pressure. Minimal chronotropic effect was seen and no arrhythmias occurred. The sole child with postoperative pulmonary hypertension had a beneficial decrease in pulmonary artery pressure, increase in cardiac index, and stable systemic blood pressure during amrinone use. Cardiac index changes during amrinone loading in these children were variable and less clearly related to serum levels than reported in adults. Pharmacokinetic analysis in 12 children showed a clearance of 3.4 mL/min/kg, a volume of distribution of 1.65 L/kg, and an elimination half-life of 5.75 hours. Decreases in platelet counts were seen in 6 children and platelet transfusion was needed in 1; thus, serial platelet counts should be monitored.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of continuous arteriovenous haemofiltration on pharmacokinetics of amrinone.

This case report details the pharmacokinetic adjustments of an amrinone infusion in a paediatric patient who developed multiorgan system failure with anuric renal failure and was prescribed continuous arteriovenous haemofiltration. A significant proportion of clearance of amrinone is nonrenal. Near normal amrinone clearance can occur in patients with hepatic and renal dysfunction if continuous arteriovenous haemofiltration is used. Hepatic dysfunction with renal failure may require a reduction in the continuous amrinone infusion rate as previously reported for neonates.

Amrinone-associated thrombocytopenia: pharmacokinetic analysis.

Amrinone-associated thrombocytopenia is thought to result from nonimmune-mediated peripheral platelet destruction. Platelet destruction may be a concentration-dependent toxic effect of amrinone or its principal metabolite N-acetylamrinone. Eighteen children receiving amrinone after heart surgery were prospectively evaluated to correlate the pharmacokinetics of amrinone and N-acetylamrinone with thrombocytopenia. Amrinone and N-acetylamrinone plasma concentrations were determined by HPLC during loading, infusion, and terminal elimination, with concurrent monitoring of platelet counts. Thrombocytopenia developed in eight patients (platelet count, 66 +/- 17 x 10(9) platelets/L [mean +/- SD]). Peak and steady-state amrinone plasma concentration, amrinone total dose, duration of amrinone exposure, and amrinone area under curve (AUC) were similar between patients with and without thrombocytopenia. N-Acetylamrinone peak concentration, steady-state concentration, N-acetylamrinone AUC, and ratio of N-acetylamrinone to amrinone were greater in patients with thrombocytopenia. This association suggests that N-acetylamrinone, and not amrinone, may be the mediator of thrombocytopenia in children receiving amrinone.

Perioperative experience with amrinone.

Amrinone is the only phosphodiesterase fraction III inhibitor currently available in the USA for the treatment of perioperative biventricular failure. Patients with chronic congestive heart failure (CHF) show down-regulation of the beta 1-adrenergic receptor with a decrease in receptor density and altered responses to catecholamines. Intravenous administration of amrinone can transiently restore beta 1-adrenergic responses in patients who have CHF. Amrinone's mechanism of vasodilatation, independent of the beta 1-adrenergic receptor, nitrates, and calcium entry blockers, proves an important therapeutic option for pulmonary hypertension. The elimination half-life of amrinone in volunteers is 2.6-4.1 h, and 3.5 h when administered into the cardiopulmonary bypass (CPB) circuit. Different loading and infusion doses have been reported for amrinone. Investigators have demonstrated that increases in cardiac output following amrinone administration are directly related to plasma concentration. In cardiac surgical patients, following a dose of 0.75 mg kg-1 administered into the CPB circuit, plasma concentrations are subtherapeutic after 10 min. We believe that, when using amrinone to facilitate separation from CPB, a bolus dose of 1.5 mg kg-1 or more should be administered. If therapeutic levels need to be maintained in patients with biventricular failure, an infusion should also be administered after the bolus dose. Additive effects have been demonstrated when catecholamines are administered concomitantly with amrinone and other PDE III inhibitors to increase cyclic AMP in cardiac muscle and improve contractility. The use of amrinone with catecholamines is also important clinically, because together they attenuate the vasoconstrictive effects of catecholamines alone, while the catecholamines support perfusion pressure. Amrinone represents a novel drug for managing biventricular dysfunction in cardiac surgical patients.

Pharmacokinetics of amrinone during cardiac surgery.

Amrinone is a nonglycosidic noncatecholamine with both vasodilator and positive inotropic effects that may be administered to patients undergoing cardiac surgery. As an initial step toward elucidating the optimal dosage of amrinone for cardiac surgical patients we studied the pharmacokinetics of amrinone during and after cardiac surgery requiring cardiopulmonary bypass. The study population comprised 35 adult patients, each receiving a single dose of amrinone (0.75, 1.5, 2.0, or 2.5 mg/kg) administered into the venous reservoir near the end of cardiopulmonary bypass. Additionally, 15 of the 35 patients also received intravenous infusions of either 5 or 10 micrograms.kg-1.min-1. Arterial blood was sampled over the next 22 h, and plasma concentrations of amrinone were determined by high-performance liquid chromatography. Protein binding of amrinone, assayed by equilibrium dialysis, was 21.6 +/- 2.5%. The decay of amrinone concentrations in plasma over time was fit to a biexponential equation by nonlinear least-squares regression. The manufacturer's recommended dose of 0.75 mg/kg followed by an infusion of 10 micrograms.kg-1.min-1 was inadequate to maintain the plasma concentration within the therapeutic range based on the pharmacodynamics of amrinone in patients with chronic congestive heart failure. This was due to significant redistribution of amrinone in the body after the loading dose. To maintain a therapeutic plasma concentration of 1.5-2.0 micrograms/ml, a larger loading dose or a supplemental loading dose as well as a continuous infusion is required.

Amrinona intravenosa en insuficiencia cardíaca refractaria: efectos clínicos, hemodinámicos y metabólicos / Amrinone in refractory congestive heart failure

En el presente trabajo se estudió si el beneficio de la infusión de Amrinona en pacientes con Insuficiencia Cardíaca Crónica Refractaria (ICCR) se relacionaba con modificación de la congestión visceral o de la perfusión tisular. Se estudiaron 10 pacientes (7 hombres, edad entre 52 y 77 años). La cardiopatía de base fue miocardiopatía dilatada idiopática en 7 pacientes, enfermedad coronaria en 1 y enfermedad reumática en 2 pacientes. El protocolo consistió en la infusión por 72 horas de Amrinona iv (promedio 10.2 ug/kg/min), además de diuréticos y digital. Se midieron antes e inmediatamente después de la administración de Amrinona diferentes parámetros: score clínico (SC), hemodinamia, dimensiones cardíacas (ECO 2D), índices de congestión visceral (peso corporal, congestión pulmonar radiológica y Volemia Plasmática), índices de perfusión tisular (ácido láctico arterial, clearance de creatinina y Flujo Plasmático Renal) y noradrenalina plasmática. Luego de la infusión de Amrinona mejoró el SC (12.8 ñ 0.5 vs 5.4 ñ 2.4, p < 0.009), y disminuyeron el peso (65.6 ñ 8.1 vs 63 ñ 9.5 kg, p < 0.05), Volemia Plasmática (2839 ñ 581 vs 2582 ñ 693 ml, p < 0.04) y la Presión Capilar Pulmonar (27.2 ñ 3.7 vs 17.9 ñ 7.0 p < 0.01). Aumentó el débito cardíaco (4.0 ñ 1.4 vs 5.1 ñ 2.1 lt/min, p < 0.05). No se observaron cambios significativos en el tamaño cardíaco, presión venosa central, resistencia vascular sistémica, flujo plasmático renal ni en noradrenalina plasmática. En estos pacientes, la terapia con Amrinona asociada a la terapia convensional, aumentó el gasto cardíaco, redujo la volemia y los parámetros de congestión visceral, lo que se asoció a mejoría clínica objetiva. Por otra parte, no observamos cambios significativos en los parámetros de perfusión tisular

Amrinone: pharmacokinetics and pharmacodynamics.

Amrinone is a selective inhibitor of phosphodiesterase fraction 3 in both cardiac and smooth muscle. Intravenous administration in humans produces increased contractility and vasodilation of venous capacitance and arterial conductance vessels. The elimination half-life in healthy patients is reported to be 2.6 to 4.1 hours, making it the only long-acting positive inotropic agent available that can be administered either as an intravenous bolus or by infusion. A low incidence of side effects, often minor, has been reported with intravenous use. Thrombocytopenia does not seem to be a problem with short-term use. Amrinone represents a new approach in the pharmacologic therapy for ventricular dysfunction following cardiac surgery.