Enalapril and baroreflex function in normotensive subjects.
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Enalapril↗
Biomedical subjects
A Berdeaux
Publications and source records attributed to A Berdeaux.
Effect of mechanical ventilation on hepatic drug pharmacokinetics.
Mechanical ventilation was able to induce a decrease in cardiac output and regional blood flow, especially hepatic flow. Thus, hepatic elimination of drugs with a high hepatic-extraction ratio, which was linked to alteration in hepatic blood flow, could be reduced during mechanical ventilation. The aim of this work was to determine the effect of mechanical ventilation on pharmacokinetic parameters of lidocaine, which is a well-known nonrestrictive elimination drug at the hepatic level. Five patients (mean age, 58 years) with normal hepatic function and quite similar gasometric parameters before and after weaning from mechanical ventilation were studied. With a washout period of 48 hours between mechanical ventilation and spontaneous ventilation, each patient was submitted to the following protocol: lidocaine in a bolus (1.5 mg/kg intravenously), followed by infusion (1.0 to 1.7 mg/min for 120 minutes). The results were that the peak plasma concentration after the bolus during mechanical ventilation was 3.22 +/- 0.37 mg/L (mean +/- SE) vs 2.40 +/- 0.35 mg/L during spontaneous ventilation (p less than 0.02). Steady-state plasma concentration during mechanical ventilation was 2.10 +/- 0.20 mg/L vs 1.64 +/- 0.16 mg/L during spontaneous ventilation (p less than 0.01). Total clearance was 604.2 +/- 87.0 ml/min during mechanical ventilation vs 775.0 +/- 112.1 ml/min during spontaneous ventilation (p less than 0.01). Elimination half-life was 245.2 +/- 50.6 minutes during mechanical ventilation vs 160.0 +/- 40.6 minutes during spontaneous ventilation (p less than 0.05). Distribution volume was 188.6 +/- 50.2 L during mechanical ventilation and 183.0 +/- 50.8 L during spontaneous ventilation (not significant). These preliminary data clearly demonstrated a decrease in lidocaine elimination in patients submitted to mechanical ventilation, but the magnitude of dosage adjustment of such a highly hepatic-extracted drug in patients submitted to mechanical ventilation remains to be investigated.
Adult↗
[Rational use of inotropic sympathomimetic amines in resuscitation].
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Acute Disease↗
Vasodilating beta-adrenoceptor blocking drugs do not redistribute myocardial flow during acute coronary ligation in dogs.
The effects of two nonselective beta-adrenoceptor blocking drugs, additionally endowed with vasodilating properties with different mechanisms: labetalol which blocks alpha-adrenoceptors, and bucindolol which nonspecifically relaxes vascular smooth muscle, were investigated on regional myocardial blood flow (RMBF) distribution in ischemic and nonischemic areas and on ST-segment elevation in ischemic areas during intermittent coronary artery occlusion in dogs. Both labetalol and bucindolol reduced heart rate, arterial blood pressure and myocardial oxygen consumption. However, they did not affect coronary vascular resistance and did not induce any favorable coronary blood flow redistribution phenomenon either from the epicardium to the endocardium or from the nonischemic to the ischemic areas. These results indicate that the inability of labetalol and bucindolol to favorably redistribute RMBF was due to the fact that their vasodilating properties counteract one major determinant of RMBF redistribution. i.e. the beta-adrenoceptor blockade-induced increase in regional coronary vascular resistance. Finally, both labetalol and bucindolol dose dependently decreased ST-segment elevation in ischemic myocardial areas.
Adrenergic beta-Antagonists↗
Vasodilator synchronized retroperfusion: quantitative assessment of flow-function relation in acutely ischemic canine myocardium.
To investigate whether addition of vasodilator drugs can increase the beneficial effects on the ischemic myocardium of diastolic synchronized retroperfusion (DSR), low doses of verapamil (2 micrograms/kg/min) or nitroglycerin (0.7 microgram/kg/min) were infused through DSR in open-chest dogs undergoing 180 minutes of proximal left anterior descending coronary artery occlusion. Verapamil-DSR (n = 6), nitroglycerin-DSR (n = 6) or DSR alone (n = 8, controls) were started 10 minutes after the onset of occlusion and maintained for 170 minutes. Regional myocardial blood flow (MBF) (microspheres) and left ventricular function (endocardial ultrasonic crystals) were simultaneously assessed in nonischemic and ischemic zones in the 3 groups, before and after 10 and 180 minutes of coronary occlusion. DSR alone significantly increased ischemic regional MBF, endocardial/epicardial flow ratio and endocardial segmental length shortening. Verapamil DSR increased both nonischemic and ischemic regional MBF but reduced the endocardial/epicardial flow ratio and worsened ischemic contractile function. Nitroglycerin DSR did not modify ischemic transmural flow compared with DSR alone, but abolished the beneficial endocardial/epicardial blood flow redistribution, resulting in no additional improvement of contractile function. Thus, ischemic MBF and function are not improved by addition of small amounts of verapamil or nitroglycerin to the arterial retroperfusate in this model of acute myocardial ischemia.
Acute Disease↗
Comparative beta-adrenoceptor blocking effect and pharmacokinetics of bucindolol and propranolol in man.
The beta-adrenoceptor blocking properties and pharmacokinetics of bucindolol 150 mg were compared to those of propranolol 80 mg and a placebo in a double-blind trial in 6 healthy volunteers. Heart rate (HR), systolic (SBP) and diastolic (DBP) blood pressures and peak expiratory flow rate (PEFR) at rest and during vigorous exercise, and plasma renin activity (PRA) at rest, were measured before and at intervals up to 24 h after oral administration of the drugs. Bucindolol reduced exercise tachycardia and decreased exercise PEFR, thus behaving as a non-selective beta-adrenoceptor blocking drug. In contrast to propranolol, bucindolol did not reduce resting HR and PRA, probably because of its intrinsic sympathomimetic activity. It decreased resting DBP in relation to its peripheral vasodilator properties. The effects of bucindolol developed as early as 30 min after administration and lasted up to 24 h, whereas its Tmax and T 1/2 were 1.6 and 3.6 h respectively. Comparison of the time courses of plasma bucindolol and the cardiac beta-adrenoceptor blockade strongly suggests that in man bucindolol undergoes an extensive first-pass effect, leading to the formation of one or more active metabolites.
Adrenergic beta-Antagonists↗
Prospective study of the potentiation of acenocoumarol by amiodarone.
The influence of oral amiodarone on the anticoagulant effect of the coumarin derivative acenocoumarol has been investigated prospectively in 10 patients with normal renal, hepatic and haematological function and who were not in cardiac failure. The daily dose of acenocoumarol was sufficient to produce a prothrombin activity of 25 to 35%. When the prothrombin time had become stable amiodarone 600 mg/d was administered for 1 week followed by 400 mg/d for the next 3 weeks. A decrease in prothrombin activity from 30.5 to 20.2% was observed, associated with a decrease in vitamin K coagulation factors, after a mean of 4 days following commencement of amiodarone. In 6 patients a prothrombin activity less than 20% required a 60% reduction in the dose of acenocoumarol after 1 week of amiodarone 600 mg, and a 33% reduction after 3 weeks of amiodarone 400 mg. There was no correlation between the plasma amiodarone and the decrease in prothrombin activity. Inhibition of acenocoumarol metabolism by amiodarone is the most likely explanation of these findings.
Acenocoumarol↗
Ventilatory response to CO2 following intravenous and epidural lidocaine.
The authors determined the effects of intravenous infusion and epidural administration of lidocaine on the control of ventilation in two groups of eight healthy unpremedicated subjects. In the intravenous group, an injection of 1.5 mg/kg lidocaine was followed by an infusion at a rate of 60 micrograms X kg-1 X min-1 for 30 min. The slope of the ventilatory response to CO2 was significantly increased (P less than 0.05) from its control value (2.65 +/- 1.22 1 X min-1 X mmHg-1 [mean +/- SD]) at the end of the infusion (58%), while plasma lidocaine level was at 3.14 +/- 0.82 microgram/ml. The correlation between individual plasma lidocaine levels and the changes in the slope of the ventilatory response to CO2 was significant (r = 0.58, n = 24, P less than 0.01). In the epidural group, after the administration of 5 mg/kg of lidocaine, the slope of the ventilatory response to CO2 increased significantly (P less than 0.05) from its control value (1.52 +/- 0.75 1 X min-1 X mmHg-1) at 15 (+22%) and 25 min (+42%), while plasma lidocaine levels were at 1.79 +/- 0.42 and 2.22 +/- 0.47 microgram/ml, respectively. In both groups, resting minute ventilation and end-tidal CO2 values remained unchanged. These results suggest that epidural lidocaine has a stimulating effect on the ventilatory control mechanisms that results from the systemic effect of the drug.
Adult↗
Bupivacaine in children: pharmacokinetics following caudal anesthesia.
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Anesthesia, Caudal↗
The effect of enalapril on baroreceptor mediated reflex function in normotensive subjects.
The effects of enalapril, 20 mg orally, on the responses to baroreflex activation and deactivation by respectively phenylephrine and nitroglycerin were investigated in normotensive subjects on a normal sodium diet, with simultaneous measurement of plasma renin activity (PRA), converting enzyme activity (PCEA), aldosterone and catecholamines. Enalapril, 4 h after administration, lowered artificial blood pressure without modifying heart rate and plasma catecholamines. PCEA was abolished, PRA increased and plasma aldosterone decreased. Enalapril (a) displaced to the left the baroreflex set-point, (b) did not affect baroreflex sensitivity since the slopes of the RR-interval/systolic blood pressure regression lines remained unchanged during both activation and deactivation and (c) did not modify baroreflex efficacy since the maximal RR-interval responses as well as the overall RR-interval-time products to identical blood pressure variations were not modified. Thus, enalapril induced a resetting of the baroreflex, which probably accounts for the lack of reflex tachycardia observed during the drug-induced fall in blood pressure.
Adult↗
Attenuation by diltiazem of arterial baroreflex sensitivity in man.
The effect of oral diltiazem 120 mg, on the responses to baroreflex activation and deactivation by phenylephrine and nitroglycerin, respectively, were investigated in normotensive subjects, with simultaneous measurement of plasma catecholamine levels. Diltiazem significantly reduced the tachycardia induced by bolus injections of nitroglycerin and abolished the concomitant increase in plasma noradrenaline. It also significantly decreased the bradycardiac response to phenylephrine infusion. Diltiazem reduced, although not significantly so, the bradycardia induced by boluses of phenylephrine. The overall reduction in baroreflex sensitivity, which might contribute to the limited tachycardiac effect of diltiazem in man, is consistent with the drug-induced attenuation of the sympathetic and also of the parasympathetic components of the baroreceptor reflex.
Adolescent↗
Pharmacokinetics of lignocaine in children following caudal anaesthesia.
The time course of the plasma lignocaine concentration, following caudal anaesthesia, was studied in 11 healthy children (3.5-9 yr). Plasma lignocaine concentrations were measured for up to 6 h after administration (5 mg kg-1). Peak plasma concentration was 2.05 +/- 0.08 micrograms ml-1 and occurred at 28.2 +/- 2.9 min after administration. Pharmacokinetic parameters determined from a two-compartmental model were similar to those observed after the i.v. or extradural administration of lignocaine in adults, except for a longer half-life of elimination (155 +/- 32 min). Since the total body clearance of lignocaine was similar in children (15.4 +/- 1.2 ml min-1 kg-1) to that in adults, the longer half-life of elimination was attributed to a larger volume of distribution in the children (3.05 +/- 0.40 litre kg-1).
Anesthesia, Caudal↗
Tissue extraction of amiodarone and N-desethylamiodarone in man after a single oral dose.
The hepatic extraction of amiodarone and N-desethylamiodarone has been investigated in seven patients following catheterization of the portal and hepatic veins under general anaesthesia. Amiodarone (600 mg) was administered orally 4 h before regional blood sampling. Concentrations of amiodarone and N-desethylamiodarone, determined by h.p.l.c., were about twice as high in the portal vein compared with those in the hepatic vein, the calculated hepatic extraction ratios of both compounds being 0.39 +/- 0.07 and 0.34 +/- 0.03, respectively. The presence of N-desethylamiodarone in the portal vein in higher concentrations than in the hepatic vein strongly suggests that N-dealkylation of amiodarone occurs in the gut wall or lumen, a finding which might account for the low and highly variable intersubject amiodarone bioavailability.
Administration, Oral↗
Influence of heart rate on the effects of prenalterol on regional myocardial blood flow and function during coronary stenosis in dogs.
The effects of prenalterol, a selective beta 1-adrenoceptor agonist with potent cardiac positive inotropic properties have been investigated on regional myocardial blood flow (RMBF) (microspheres) and contractile function (ultrasonic crystals) during partial circumflex coronary artery stenosis in 8 open-chest anaesthetized dogs. Prenalterol was investigated at two intravenous doses: 5 micrograms kg-1, which increased myocardial contractility (dP/dt max: +29%) more than heart rate (+12%, up to 150 beats min-1) and 20 micrograms kg-1 which induced almost similar increases in contractility (+35%) and heart rate (+31% up to 175 beats min-1). The induced modifications of regional flow and function were then compared to those produced in another series of 6 dogs by atrial pacing at 150 and 175 beats min-1 respectively. Prenalterol significantly increased RMBF and segment length (SL)-shortening in a dose-dependent manner in the nonischaemic zone. In the ischaemic zone, RMBF was maintained and SL-shortening increased with prenalterol, 5 micrograms kg-1 whereas both RMBF and contractile function were severely decreased with prenalterol, 20 micrograms kg-1. Atrial pacing had almost no effect on RMBF and SL-shortening in the nonischaemic zone. In the ischaemic zone, atrial pacing rate-dependently decreased both RMBF and SL-shortening. Thus, a significant increase in contractility, associated with little tachycardia (prenalterol, 5 micrograms kg-1), induces beneficial effects on RMBF and function in both the nonischaemic and ischaemic myocardium. In contrast, a strong tachycardia, whether accompanied by positive inotropic effects (prenalterol, 20 gig kg-') or not (atrial pacing at 175 beats min-1) induces deleterious effects on RMBF and cardiac function in the ischaemic myocardium.
Adrenergic beta-Agonists↗
[A new family of anti-angina agents].
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Angina Pectoris↗
Effects of propranolol on regional myocardial blood flow and function during severe coronary stenosis in dogs.
The effects of propranolol alone or associated with atrial pacing were studied on regional myocardial blood flows (RMBF) and regional contractility (sonocardiometry) in non-ischemic, moderately and severely ischemic areas of the canine myocardium. In non-ischemic areas, propranolol reduced both epicardial and endocardial flows, increased the endo/epi ratio and decreased regional contractility. The reductions in subendocardial flow and function were correlated. In moderately and severely ischemic areas, propranolol increased subendocardial flow, reduced subepicardial flow, increased the endo/epi ratio and preserved or even slightly improved regional contractility. There was a good correlation between the propranolol-induced protective effects on regional contractility and the drug-induced increase in subendocardial flow since under atrial pacing subendocardial flow no longer increased and regional function dropped dramatically.
Animals↗
Diastolic synchronized retroperfusion versus reperfusion: effects on regional left ventricular function and myocardial blood flow during acute coronary occlusion in dogs.
The effects of 170 minutes of diastolic synchronized retroperfusion of the coronary sinus with arterial blood during 180 minutes of coronary artery occlusion on regional myocardial contractility (ultrasonic crystals) and blood flow (microspheres) were investigated in open-chest dogs. These effects were compared with those of 180 minutes of coronary occlusion and those of 170 minutes of anterograde reperfusion after 10 minutes of coronary occlusion in separate groups of dogs. Retroperfusion was able to almost restore transmural blood flow in the moderately ischemic zones and to increase it back to 47% of its preocclusion value in the severely ischemic zones with, in both zones, a favorable redistribution of flow toward the endocardium. Simultaneously, retroperfusion significantly improved segment length shortening in the moderately ischemic zones and significantly reduced the extent of paradoxical bulging in the severely ischemic zones. These partial recoveries in regional contractility and blood flow during retroperfusion were intermediate between those induced by 170 minutes of anterograde reperfusion and those of 180 minutes of coronary artery occlusion. Thus, in the presence of coronary artery occlusion, retroperfusion appears to exert a beneficial effect by improving both regional perfusion and function in the ischemic zones and may be proposed as a medical circulatory support to the jeopardized myocardium.
Acute Disease↗
[Redistribution of the coronary blood flow, functional improvement of the ischemic myocardium and reduction of the size of an experimental infarction by molsidomine].
Molsidomine is able to restore a better balance between myocardial oxygen supply and demand during myocardial ischaemia, by inducing a prolonged decrease in the left ventricular wall pressure, by reducing the venous return to the heart and by dilating the large coronary trunks. Molsidomine is also able to redistribute the coronary blood towards the deep sub-endocardial layers during a transient or permanent coronary occlusion, by complex changes in the metabolic autoregulation, by dilatation of the transmural coronary arteries and by reduction of the extravascular compression forces. Finally, by inhibiting platelet aggregation and by a possible action thromboxane A2/prostacyclin synthesis, molsidomine exerts a real anti-thrombotic effect which helps reduce ventricular arrhythmia, improve segmental contractility and reduce the size of the post-stenotic infarct.
Animals↗