Jaime Diaz

Pharmacokinetics and pharmacodynamics of vecuronium in the obese surgical patient

The effect of obesity on the disposition and action of vecuronium was studied in 14 surgical patients. After induction of anesthesia with thiopental and maintenance of anesthesia by inhalation of nitrous oxide and halothane, seven obese patients (93.4 ± 13.9 kg, 166% ± 30% of ideal body weight, mean ± SD) and seven control patients (60.9 ± 12.3 kg, 93% ± 6% of ideal body weight) received 0.1 mg/kg of vecuronium. Plasma arterial concentrations of muscle relaxant were determined at 1, 3, 5, 10, 15, 20, 30, 45, 60, 90, 120, 150, 180, 210, 240, 300, and 360 min by a spectrofluorometric method. Simultaneously, neuromuscular blockade was assessed by stimulation of the ulnar nerve and quantification of thumb adductor response. Times to 50% recovery of twitch were longer in the obese than in the control patients (75 ± 8 versus 46 ± 8 min) as were 5%-25% recovery times (14.9 ± 4.0 versus 10.0 ± 1.7 min) and 25%-75% recovery times (38.4 ± 13.8 versus 16.7 ± 10.3 min). However, vecuronium pharmacokinetics were similar for both groups. When the data were calculated on the basis of ideal body weight (IBW) for obese and control patients, total volume of distribution (791 ± 303 versus 919 ± 360 mL/kg IBW), plasma clearance (4.65 ± 0.89 versus 5.02 ± 1.13 mL-min−1·kg IBW−1), and elimination half-life (119 ± 43 versus 133 ± 57 min) were not different between groups. Only when total volume of distribution and clearance are divided by patient weight (a larger value for the obese) and expressed per kilogram of actual body weight do these values appear smaller in the obese (473 ± 142 versus 993 ± 401 mL/kg and 2.83 ± 0.54 versus 5.36 ± 1.14 mL·min−1·kg−1, respectively). As obesity did not alter the distribution or elimination of vecuronium, the prolonged action seen at 0.1 mg/kg is due to an overdose when vecuronium is administered on the basis of total body weight. Clinically, ideal body weight should be used for dose calculation in the obese patient.

Consequences of Electroencephalographic-suppressive Doses of Propofol in Conjunction with Deep Hypothermic Circulatory Arrest

Background Some patients who undergo cerebral aneurysm surgery require cardiopulmonary bypass and deep hypothermic circulatory arrest. During bypass, these patients often are given large doses of a supplemental anesthetic agent in the hope that additional cerebral protection will be provided. Pharmacologic brain protection, however, has been associated with undesirable side effects. These side effects were evaluated in patients who received large doses of propofol. Methods Thirteen neurosurgical patients underwent cardiopulmonary bypass and deep hypothermic circulatory arrest to facilitate clip application to a giant or otherwise high-risk cerebral aneurysm. Electroencephalographic burst suppression was established before bypass with an infusion of propofol, and the infusion was continued until the end of surgery. Hemodynamic and echocardiographic measurements were made before and during the prebypass propofol infusion and again after bypass. Emergence time also was determined. Results Prebypass propofol at 243 plus/minus 57 micro gram *symbol* kg sup -1 *symbol* min sup -1 decreased vascular resistance from 34 plus/minus 8 to 27 plus/minus 8 units without changing heart rate, arterial or filling pressures, cardiac index, stroke volume, or ejection fraction. Propofol blood concentration was 8 plus/minus 2 micro gram/ml. Myocardial wall motion appeared hyperdynamic at the end of cardiopulmonary bypass, and all patients were weaned therefrom without inotropic support. After bypass, vascular resistance decreased further, and cardiovascular performance was improved compared to baseline values. Nine of the 13 patients emerged from anesthesia and were able to follow commands at 3.1 plus/minus 1.4 h. Three others had strokes and a fourth had cerebral swelling. Conclusions Propofol infused at a rate sufficient to suppress the electroencephalogram does not depress the heart or excessively prolong emergence from anesthesia after cardiopulmonary bypass and deep hypothermic circulatory arrest.

Cocaine, norcocaine, ecgonine methylester and benzoylecgonine pharmacokinetics in the rat

Abstract We have compared the pharmacokinetics of bolus dose cocaine administration with that of its three most important metabolites; norcocaine, ecgonine methylester, and benzoylecgonine and assessed whether kinetics are dose dependent at two equimolar doses equivalent to cocaine hydrochloride 2.5 and 5 mg kg respectively. Forty-nine male Sprague-Dawley rats were randomly divided into 8 groups to receive iv either high (14.7 umol kg ) (HI) or low (7.3 umol kg ) (LO) bolus doses of cocaine or one of its metabolites. Arterial blood samples for cocaine and metabolite analysis were taken repetitively over the next 3 h. Equimolar bolus doses of these congeners showed biexponential plasma concentration decay curves which were fitted to a two compartment model and subjected to noncompartmental analysis. The plasma concentration time profiles were significantly different for the HI and LO doses administered for each congener. The elimination half-lives of cocaine and norcocaine were similar (28–33 min), that for ecgonine methylester (60–71 min) was approximately twice this and for benzoylecgonine was 40–44 min. Cocaine clearance (155–158 ml/kg/min) was found to be in the range found in other rat studies. Ecgonine methylester clearance and benzoylecgonine clearance were found to be one quarter and one eighth of this value respectively. The pharmacokinetic profile of these congeners was not dose dependent when the two doses administered were compared.

Pharmacokinetics and pharmacodynamics of pipecuronium bromide (Arduan) in elderly surgical patients

The neuromuscular response to pipecuronium bromide (Arduan), 70 μg/kg, was studied in 20 elderly (>70 yr) and 10 younger Patients (<60 Yr) during nitrous oxide, fentanyl, and droperidol anesthesia. The adductor Pollicis response to single 0.2-ms suparamaximal pulses was recorded. Although all younger patients were completely paralyzed, 2 of 20 elderly patients did not attain paralysis. Onset time in the elderly was prolonged (6.9 ± 2.6 vs 4.3 ± 1.5 min, P < 0.02). Spontaneous recovery was similar in both groups, with 75% recovery occurring at 133 ± 52 min in the elderly and 146 ± 46 min in the younger patients. The pharmacokinetic variables were similar for the two groups, and pharmacodynamic analysis revealed a similar sensitivity at the neuromuscular junction. The pharmacologic actions of pipecuronium in otherwise healthy patients do not differ between young and elderly adults.

Are all effects of esmolol equally rapid in onset

The purpose of this study was to compare the time course of the bradycardic and hypotensive effects of esmolol.Ten patients undergoing craniotomy requiring hypotension were anesthetized with nitrous oxide and isoflurane. During steady state anesthesia, the response to an infusion of esmolol 500 micro gram centered dot kg (-1) centered dot min-1 for 90 s followed by 300 micro gram centered dot kg (-1) centered dot min-1 was measured over 60 min. Heart rate (HR), mean arterial pressure (MAP), and plasma renin activity (PRA) responses did not occur with equal rapidity. The half-time for the 14% decrease in HR (81 +/- 13 bpm to 70 +/- 9 bpm) was 1.2 min. MAP decreased by 26% (85 +/- 7 mm Hg to 63 +/- 6 mm Hg) with a 17.8 min half-time. This delay in MAP response may, in part, be related to the gradual 44% decline in PRA (9.5 +/- 4.5 ng centered dot mL-1 centered dot h-1 to 5.3 +/- 2.5 ng centered dot mL-1 centered dot h-1) occurring with a half-time of 11.9 min. The times to attainment of 90% maximum decreases were 4.8 +/- 3.0 min for HR, 42.5 +/- 8.9 min for MAP, and 32.1 +/- 15.0 min for PRA. Thus although esmolol has an ultrashort kinetic half-life, only the HR effect can be considered to have an ultrashort onset. (Anesth Analg 1995;81:297-300)

Cardiac performance preserved despite thiopental loading.

BackgroundSome cerebral artery aneurysms require cardiopulmonary bypass and deep hypothermic circulatory arrest to be clipped safely. During bypass these neurosurgical patients often are given large doses of thiopental in the hope that additional cerebral protection will be provided. However, thiopental loading during bypass has been associated with subsequent cardiac dysfunction in patients with heart disease. This study was undertaken to determine how patients without concomitant heart disease would respond to thiopental loading. MethodsTwenty-four neurosurgical patients with giant cerebral aneurysms and little or no cardiac disease were anesthetized with fentanyl, nitrous oxide, and isoflurane. Thiopental was titrated to achieve electroencephalographic burst-suppression before bypass, and the infusion was continued until after separation. Prebypass hemodynamic and echocardiographic measurements were obtained during a stable baseline and 15 min after thiopental loading began. They were repeated after bypass. ResultsPrebypass thiopental loading increased heart rate from 61 ± 11 to 72 ± 13 beats/min and decreased stroke volume from 43 ± 10 to 38 ± 8 ml. beat−1. m-2, but arterial and filling pressures, vascular resistance, cardiac index, and ejection fraction remained the same. Before bypass, thiopental plasma concentration measured 28 ± 8

The effect of chronic cocaine administration on hemodynamic stability and neurohumoral mediators during isoflurane anesthesia and shock in rats

mUg/ml. Loading continued for 2–3 h until after bypass was terminated, and the overall infusion rate was 18 ± 5 mg. kg−1. h−1. All patients were easily separated from bypass without inotropic support. Following bypass, vascular resistance was decreased; heart rate, filling pressures, and cardiac index were increased; stroke volume had returned to its baseline; and ejection fraction was unchanged. ConclusionsIt was concluded that if preoperative ventricular function is good, thiopental loading to electroencephalographic burst-suppression causes negligible cardiac impairment and does not impede separation from cardiopulmonary bypass.

Chronic continuous cocaine infusion in rats: effect on urine cocaine, ecgonine methylester and benzoylecgonine concentrations and bolus-dose cocaine pharmacokinetics.

Background: The aim of this investigation was to determine whether chronic cocaine administration altered endogenous vasoconstrictor secretion in response to hypotension from isoflurane anesthesia and blood loss in rats.

Influence of infused catecholamines on the pharmacokinetics of cocaine and benzoylecgonine formation after bolus dose or continuous cocaine administration in the rat.

The aim of this study was to determine the effect of chronic cocaine infusion on urine cocaine, ecgonine methylester and benzoylecgonine concentrations to establish if they varied with dose and duration of cocaine administration.

DOSE-RESPONSE COCAINE, NORCOCAINE, ECGONINE METHYLESTER AND BENZOYLECGONINE PHARMACOKINETICS IN THE RAT

The purpose of this study was to determine whether a catecholamine infusion administered to simulate a stress state could alter the pharmacokinetics of administered cocaine and effect the formation of benzoylecgonine, its major metabolite, in the rat. In a previous investigation we determined that catecholamine infusion enhanced the toxicity of continuous cocaine infusion by reducing the time before the onset of convulsions and respiratory arrest. We postulated that this enhanced toxicity was an effect of catecholamines on the pharmacokinetics of cocaine.