Torsade de pointes induced by N-acetylprocainamide.

N-Acetylprocainamide (NAPA), a class III antiarrhythmic drug, caused torsade de pointes in a 72 year old woman who had this arrhythmia on two previous occasions while being treated with quinidine and disopyramide. Initial evaluation with an intravenous infusion of NAPA indicated a favorable antiarrhythmic response. The QTC interval was prolonged, but the 2.4 ms/microgram per ml incremental QTC interval lengthening caused by NAPA was not greater than usual. During subsequent oral therapy with NAPA, torsade de pointes developed at plasma levels of this drug that appeared to be well tolerated during the initial evaluation.

Kinetics of epsilon-aminocaproic acid distribution, elimination, and antifibrinolytic effects in normal subjects.

The kinetics of epsilon-aminocaproic acid (EACA) distribution and elimination were studied in six normal subjects after a single 10-gm iv dose. Steady-state distribution volume averaged 30.01 or 0.39 l/kg. Mean elimination t 1/2 was 294 min and the elimination clearance was 0.19 l/min. Renal excretion of unchanged EACA accounted for 68% of its elimination and renal EACA clearance averaged 115% of creatinine clearance. EACA antifibrinolytic effect kinetics were also characterized in five of the subjects by the monitoring of clot lysis times in whole blood and platelet-rich plasma. Peak antifibrinolytic effects were observed 15 to 60 min after peak EACA plasma concentrations were attained. A model of maximal fibrinolysis inhibition (Emax) was used to estimate a half-maximal inhibition (IC50) of 63 +/- 19.7 microgram/ml. This agrees with the value of 0.55 mM or 72 microgram/ml that has been reported for the dissociation constant of the EACA-plasminogen complex and is consistent with the proposed biochemical mechanism of EACA action.

Kinetics of cocaine distribution, elimination, and chronotropic effects.

The pharmacokinetics of cocaine were studied in five subjects with histories of drug abuse who were otherwise healthy. A two-compartment system was used to model the distribution kinetics of the drug. The steady-state volume of distribution averaged 131.8 L or 1.96 L/kg, elimination clearance was 2.10 L/min, and the t 1/2 was 48 minutes. Cocaine concentrations in a hypothetic biophase were estimated to correlate the chronotropic effects of this drug with its pharmacokinetics. The experimentally determined kinetic parameters indicate that the peak chronotropic effect would occur 7.3 minutes after intravenous bolus injection of cocaine, and that biophase cocaine concentrations would initially accelerate the heart rate by 0.3 bpm for each 1 ng/ml. The kinetic analysis also demonstrated that the chronotropic effects of cocaine decline more rapidly than either plasma levels or biophase concentrations. This progressive attenuation in intensity of the chronotropic effect of a given biophase cocaine concentration could be modeled as a first-order process and is compatible with either the intervention of homeostatic reflex mechanisms or the phenomenon of acute tolerance.

Pressor responses to tyramine and norepinephrine after subchronic administration of fluoxetine to man.

The effects of subchronic, oral administration of fluoxetine (60 mg daily for 45 days) were studied in three healthy male volunteers. The pressor responses to intravenous bolus tyramine injections or norepinephrine infusions were assessed during the one-week placebo period, periodically after daily fluoxetine dosing, and then for 11 days post-fluoxetine dosing. The dose-pressor responses, determined from the incremental elevation of systolic blood pressure, were unchanged in each of the three dosing intervals. These results indicate that fluoxetine does not significantly impair the catecholamine uptake mechanism in the peripheral adrenergic neuron on acute or subchronic dosing, nor is any rebound-increased sensitivity evident after subchronic administration. Further, fluoxetine does not appear to demonstrate peripheral alpha-adrenolytic properties in man.

Urea distribution kinetics analyzed by simultaneous injection of urea and inulin: demonstration that transcapillary exchange is rate limiting.

The kinetics of urea and inulin were studied after simultaneous i.v. injection in six anesthetized dogs. The distribution of both compounds was characterized by a three-compartment model. The initial volume of urea distribution averaged 2.21 +/- 0.39 liters (+/- S.D.) and was similar to the expected volume of intravascular space. Although the 0.66 +/- 0.05 liters/kg of total volume of urea distribution corresponds to total body water, transcapillary exchange between intravascular space and rapid and slow equilibrating interstitial fluid spaces is the rate-limiting step in urea distribution and accounts for the three-compartmental structure of the system used to model the distribution kinetics of both urea and inulin. The free-water diffusion coefficient ratio of urea and inulin and the intercompartment clearances calculated after the simultaneous injection of these compounds were used to estimate blood flows to the fast and slow equilibrating interstitial fluid compartments. The sum of these flows averaged 97% of measured cardiac output (range, 83-113%) and was not significantly different from cardiac output. These studies suggest that the rate of urea removal during dialysis may be affected by hemodynamic factors, as we have shown previously for drugs.

The pharmacokinetics of d-tubocurarine with surgery involving salvaged autologous blood.

The disposition of d-tubocurarine (dTc) was assessed when a bolus and infusion dosage regimen was used to obtain relaxation during major orthopedic surgery on the spine. Renal clearance of dTc was 0.63 +/- 0.23 ml X min-1 X kg-1 and was correlated with creatinine clearance. Total plasma clearance of 1.21 +/- 0.40 ml X min X -1 X kg-1 was lower than that found in many previous studies, and the predetermined continuous dTc infusion produced an apparent plateau in plasma concentrations of 1.8 +/- 0.3 micrograms X ml-1. Despite the operative blood loss, these concentrations were greater than anticipated and were associated with a more intense neuromuscular blockade than the infusion was designed to produce. Autologous blood transfusion was used to reduce the reliance on homologous donor blood, and the erythrocytes from the 2.2 +/- 1.2 1 of blood loss during the procedure were reinfused after intraoperative salvage, washing, and centrifugation. With 80 +/- 23 mg dTc administered, 1.4 +/- 0.8% was recovered from the fluid discarded after centrifugation. These results indicate that even massive intraoperative blood loss will not entail a significant reduction in the amount of dTc present in the body.

Reduction in slow intercompartmental clearance of urea during dialysis.

The kinetics of urea and inulin were analyzed in five anesthetized dogs during sequential 2-hour periods before, during, and after hemodialysis. The distribution of both compounds after simultaneous intravenous injection was characterized by three-compartment models, and the total volumes of urea (0.66 +/- 0.05 L/kg) and inulin (0.19 +/- 0.01 L/kg) distribution were similar to expected values for total body water and extravascular space, respectively. Intercompartmental clearances calculated before dialysis were used to estimate blood flows to the fast and slow equilibrating compartments. In agreement with previous results, the sum of these flows was similar to cardiac output, averaging 101% of cardiac output measured before dialysis (range 72% to 135%). Dialysis was accompanied by reductions in the slow intercompartmental clearances of urea (81%) and inulin (47%), which reflected a 90% attenuation in blood flow supplying the slow equilibrating compartments. This was estimated to result in a 10% average reduction in the efficiency with which urea was removed by dialysis (range 2.0% to 16.4%). Mean arterial pressure fell by less than 5% during dialysis, but total peripheral resistance increased by 47% and cardiac output fell by 35%. In the postdialysis period, total peripheral resistance and cardiac output returned toward predialysis values, but blood flow to the slow equilibrating peripheral compartment was still reduced by 80%. These changes parallel activation of the renin-angiotensin system, but further studies are required to establish causality.