Prostaglandin mediation of hemodynamic responses to pulmonary microembolism in rabbits: effects of ibuprofen and meclofenamate.

The effect of the cyclooxygenase inhibitors ibuprofen and meclofenamate were studied to assess the role of prostaglandin release in mediating the hemodynamic response to acute pulmonary microembolism in awake rabbits. In Group I (n = 10), a control group receiving only saline infusion, there was no change in pulmonary artery pressure, thermodilution cardiac output, or pulmonary vascular resistance. Group II (n = 12) received sequential intravenous doses of polyacrylamide microspheres averaging 34 mu in diameter, and demonstrated a progressive decrease in cardiac output and stroke volume and increases in pulmonary artery pressure and pulmonary vascular resistance. Pretreatment with either ibuprofen (Group III; n = 10) or meclofenamate (Group IV; n = 9) resulted in no change in resting hemodynamics and only minimally altered the effect of microembolism on pulmonary artery pressure. However, both ibuprofen and meclofenamate abolished the microembolism-induced decrease in cardiac output and stroke volume and blunted the increases in pulmonary artery pressure and pulmonary vascular resistance. The hemodynamic consequences of pulmonary microembolism in awake rabbits, particularly the decrease in cardiac output, are partly mediated by prostaglandin release, which alters pulmonary vascular tone and/or myocardial function.

Comparison of the electrocardiographic and hemodynamic responses to ionic and nonionic radiocontrast media during left ventriculography: a randomized double-blind study.

The ECG and hemodynamic responses to a standard ionic radiographic contrast agent (diatrizoate) were measured and compared to those induced by iopamidol, a newly developed nonionic agent, during left ventriculography. Studies were performed using randomized double-blind techniques in 46 patients with suspected coronary artery disease who were scheduled for cardiac catheterization. A nuclear probe was used to measure left ventricular ejection fraction and relative ventricular volume before and immediately after left ventriculography. Bolus injections of diatrizoate and iopamidol induced similar significant decreases in left ventricular end-diastolic and end-systolic volume and similar significant increases in both left ventricular end-diastolic pressure (p less than 0.05) and systolic ejection fraction (p less than 0.01 vs baseline). Both agents induced modest increases in heart rate, but only the increase induced by diatrizoate was significant (p less than 0.01). The maximal rate of left ventricular pressure rise was not significantly altered by either agent. Iopamidol induced a slight increase in QRS duration (p less than 0.05); neither agent effected a significant change in QT duration. We conclude that the hemodynamic effects during left ventriculography using diatrizoate and iopamidol are similar. These findings do not justify the large-scale substitution of more expensive nonionic radiographic contrast agents for standard ionic agents such as diatrizoate in left ventriculography.

Vasodilator effect on right ventricular function in congestive heart failure and pulmonary hypertension: end-systolic pressure--volume relation.

The right ventricular (RV) end-systolic pressure-volume relation during vasodilator administration was studied in 10 patients with pulmonary arterial (PA) hypertension, most of whom had biventricular failure. RV end-systolic volumes were estimated from equilibrium radionuclide RV counts and forward cardiac output. Simultaneous radionuclide and hemodynamic values were measured at rest and during nitroglycerin and nitroprusside infusion. Vasodilator administration resulted in decreases in PA mean and systolic pressures in all 10 patients, with an average decrease in end-systolic pressure (p less than 0.001) from 48 +/- 11 to 38 +/- 9 and 35 +/- 10 mm Hg during nitroglycerin and nitroprusside administration, respectively. In each patient, a direct linear relation was observed between the vasodilator-induced decrease in PA end-systolic pressure and in RV end-systolic volume. Average RV end-systolic volume decreased (p less than 0.001), from 130 +/- 69 ml/m2 at baseline to 108 +/- 62 and 102 +/- 55 ml/m2 during nitroglycerin and nitroprusside infusion, respectively. The slope of the RV end-systolic pressure-volume relation was directly related to RV ejection fraction. Thus, the vasodilator-induced decrease in PA systolic pressure is accompanied by a linear decrease in RV end-systolic volume, with a slope which is dependent on RV systolic function. This linear relation is analogous to the left ventricular end-systolic pressure-volume relation.

Pharmacokinetics, central nervous system uptake, and lipid solubility of propranolol, acebutolol, and sotalol.

The relation of in vitro lipophilicity, based on octanol:buffer partition ratio and on reverse-phase liquid chromatographic retention, to in vivo pharmacokinetics and central nervous system entry was evaluated for the beta-blockers propranolol, acebutolol, and sotalol. Anesthetized cats received single intravenous doses, following which plasma kinetics, cerebrospinal fluid (CSF) kinetics and brain tissue uptake were determined over the next 4 h. Propranolol, by far the most lipophilic beta-blocker in vitro, had the highest in vivo metabolic clearance and volume of distribution (Vd), the most rapid entry into CSF, and the highest brain:plasma uptake ratio (38.0). Sotalol, the most hydrophilic drug in vitro, had the lowest in vivo clearance and Vd, the slowest CSF entry, and the lowest brain:plasma ratio (0.52). Acebutolol had slightly greater in vitro lipophilicity than sotalol, intermediate values of in vivo plasma kinetics and CSF entry rate, and a slightly greater brain:plasma uptake ratio (0.71). Thus, differences among beta-blockers in lipid solubility are associated with predictable differences in plasma kinetics, and rate of entry into CSF. Furthermore, the relative extent of entry into brain is lower for hydrophilic as opposed to lipophilic beta-blockers.

In vitro correlates of benzodiazepine cerebrospinal fluid uptake, pharmacodynamic action and peripheral distribution.

Factors influencing the rate and extent of benzodiazepine uptake into cerebrospinal fluid (CSF), peripheral tissue distribution and electroencephalographic (EEG) effects were evaluated in a model utilizing anesthetized male cats. A single (0.25-10 mg/kg) dose of the following eight benzodiazepines was administered i.v.: diazepam, desmethyldiazepam, midazolam, lorazepam, alprazolam, triazolam, flunitrazepam and clobazam. Multiple samples were simultaneously drawn from arterial blood and cisternal CSF over the next 4 hr and the EEG was continuously monitored. Concentrations of benzodiazepines in plasma and CSF samples were measured by electron-capture gas-liquid chromatography and plasma protein binding determined by equilibrium dialysis. Physicochemical properties of lipophilicity of each benzodiazepine were determined by measurement of the octanol/buffer partition ratio at physiologic pH and by the high-pressure liquid chromatographic (HPLC) retention on a reverse-phase C18 column at neutral pH. Disappearance of all benzodiazepines from plasma was consistent with a linear sum of two or three exponential terms. After correction for individual differences in protein binding, volume of distribution (Vd) of unbound drug was highly correlated with HPLC retention (r = 0.91), but not significantly related to octanol/buffer partition coefficient. Diazepam and midazolam, having the longest HPLC retention also had the largest unbound Vd. All benzodiazepines rapidly entered CSF, with peak concentrations usually attained within 15 min of dosage. More lipophilic drugs tended to enter CSF most rapidly, but associations of entry rate and in vitro lipophilicity were not significant. After distribution equilibrium was attained, disappearance of benzodiazepines from both plasma and CSF occurred in parallel. Equilibrium CSF/total plasma concentration ratios of all drugs were much less than unity.(ABSTRACT TRUNCATED AT 250 WORDS)

Benzodiazepines protect mice from local anesthetic convulsions and deaths.

Median convulsant (CD50) and median lethal (LD50) doses of intraperitoneal lidocaine, bupivacaine, and etidocaine were determined in 149 mice. Another 496 mice were pretreated with intramuscular diazepam, lorazepam, or midazolam, 1 mg/kg. Fifteen minutes later, lidocaine, bupivacaine, or etidocaine was given intraperitoneally and the incidence of convulsions and deaths recorded. Benzodiazepines significantly reduced the incidence or convulsions. For instance, etidocaine, 54.9 mg/kg, produced 50% convulsions in untreated mice compared to 6.9%, 3.4%, and 3.4% after diazepam, lorazepam, or midazolam, respectively. Benzodiazepines also enhanced survival, as shown by significant increases in the LD50s. The bupivacaine LD50, for example, increased from 58.7 mg/kg in untreated mice to 75.2, 79.1, and 83.6 mg/kg after diazepam, lorazepam, or midazolam, respectively. Similarly, bupivacaine, 58.7 mg/kg, killed 50% of untreated mice, but only 1.2%, 9.7%, and 4.5% of mice treated with diazepam, lorazepam, or midazolam, respectively. It is concluded that premedication with a benzodiazepine significantly reduces the incidence of convulsions in mice and lowers the mortality rate as well. In equal intramuscular doses, midazolam proved to be the most effective anticonvulsant and diazepam the least. Etidocaine and bupivacaine convulsions were more difficult to suppress than those induced by lidocaine. On the other hand, the lethality of lidocaine was least reduced by these benzodiazepines.

Mixtures of local anesthetics are no more toxic than the parent drugs.

Mixtures of local anesthetics can combine the best features of both components. The authors assayed the systemic toxicity of local anesthetic mixtures given subcutaneously to mice. Convulsions regularly preceded death. The median convulsant dose (CD50) of bupivacaine was one-fourth that of lidocaine, and one-seventh that of chloroprocaine. The median lethal dose (LD50) of chloroprocaine was twice the CD50, whereas the LD50 of bupivacaine was but little greater than the CD50. Hence, the more potent the agent, the greater is the chance of death from a convulsant dose of local anesthetic. Conversion to lidocaine-equivalent doses permitted comparisons between mixtures. None of the mixtures were more convulsant or more lethal than their parent components; lidocaine-containing mixtures were significantly less lethal than the lidocaine norm. Mixing increased the distance between convulsant and lethal doses, with survival from convulsions induced by bupivacaine-containing mixtures enhanced in particular. It is concluded that local anesthetic toxicity is essentially additive.

Local anesthetics: injection route alters relative toxicity of bupivacaine.

Site of injection affects the toxicity of local anesthetics, perhaps because differences in tissue binding, vascular uptake, and hepatic clearance affect drug disposition. Three local anesthetics with different physical and pharmacologic properties were given intraperitoneally or subcutaneously to mice assay median convulsant (CD50) and median lethal (LD50) doses. The toxicity of bupivacaine, a long-acting, tightly tissue-bound local anesthetic agent was increased only 30% to 40%, whereas the toxicities of lidocaine and chloroprocaine were increased 300% to 400%, by giving the drugs intraperitoneally rather than subcutaneously. Because of this, bupivacaine appeared to be 13 times more toxic than chloroprocaine when subcutaneously, but only 4.5 times more toxic relative to chloroprocaine when assayed intraperitoneally. We conclude that a drug's therapeutic index (ratio of potency to toxicity) relative to a standard drug is affected considerably by route of extravascular administration.

Deaths from local anesthetic-induced convulsions in mice.

Median convulsant (CD50) and median lethal (LD50) doses of three representative local anesthetics were determined in adult mice to evaluate the threat to life of local anesthetic-induced convulsions. The CD50 and LD50, respectively, were 57.7 and 58.7 mg/kg for bupivacaine, 111.0 and 133.1 mg/kg for lidocaine, and 243.4 and 266.5 mg/kg for chloroprocaine. When given intraperitoneally, bupivacaine thus was only about twice as toxic as lidocaine and four times as toxic as chloroprocaine. Convulsions always preceded death, except after precipitous cardiopulmonary arrest from extreme doses. A CD50 dose of local anesthetic (causing convulsions in 50% of mice) was fatal in 90% of bupivacaine-induced seizures, in 57% of the chloroprocaine group, and in 6% of the lidocaine group. The narrow gap between convulsant and lethal doses of local anesthetics indicates that untreated convulsions present much more of a threat to life than heretofore appreciated.