[Blood levels of phenytoin. Pharmacokinetics and individualization of dosages in controlled children with crises and with persistence of crises]. / Niveles séricos de fenitoína. Farmacocinética e individualización de dosis en niños con crisis controlados y con persistencia de las crisis.

The pharmacokinetics of phenytoin was evaluated using the Michaelis-Menten technique in children with seizures seen at the Outpatient Ward, in order to adjust their medication dosages based on a clinical-pharmacological relation. The children were divided into two groups: Group A (controlled seizures) and group B (persistent seizures). Each group of children were orally given 7 mg/kg of phenytoin. Their serum levels were measured using enzymatic immunoassay at one, two, four, eight and 12 hours after taking the medication. There was a significant correlation (P less than 0.05) between the average saturation constant (Km) and the maximum speed (Vmax) with age and the doses administered in group A, which showed a lesser metabolic capacity than group B. There was also a significant correlation (P less than 0.05) when predicting the levels in each group. Clinically, the patients group A were controlled while those in group B witnessed a lesser frequency and intensity of the seizures in six patients, two were controlled and two others remained the same. The data shows a clinical-pharmacological correlation in children difficult to control, and improves the dosaging criteria used each individuals needs.

Electrocardiographic alterations induced by repeated electrical stimulation of the heart at low intensity.

Repeated, low-intensity electrical stimulation of the heart gradually leads to the development of electrocardiographic abnormalities that culminate in cardiac arrhythmias, mainly A-V block in the isolated heart frog and ventricular and supraventricular tachyarrhythmias in the canine heart in situ. The pattern of development of these alterations shows some characteristics similar to the kindling phenomenon. Blockade of adrenergic influences on the heart offered complete protection against the development of cardiac arrhythmias. These results support the idea that a kindling-like effect can be induced by the periodic electrical stimulation of structures other than the CNS.

Reversal by hypothermia of vasodilator-induced tachycardia in anesthetized rats.

The normal cardiovascular response to hydralazine in urethane-anesthetized rats, i.e. hypotension and tachycardia, was changed to hypotension and bradycardia if the body temperature of the animals was not maintained constant by external heating, but was allowed to decrease spontaneously throughout the experiment. A similar phenomenon was observed with diazoxide. In rats maintained at a rectal temperature of 31 degrees C, hydralazine bradycardia was partially blocked by a low dose of atropine and was reversed to tachycardia by a high dose of this agent; mecamylamine failed to influence heart rate lowering in this condition. Heart rate responses in unheated animals to acetylcholine and isopropylarterenol were respectively potentiated and depressed when compared to responses in heated rats. These findings suggest that cold-induced reciprocal changes in reactivity of cardiac muscarinic and beta-adrenoceptors may be responsible for reversal of hydralazine or diazoxide tachycardia in urethane-anesthetized hypothermic rats. As a result, cardiac stimulation by the sympatho-adrenal discharge induced by hypotension is inhibited, while cardiac depression which is apparently also induced by hypotension, is facilitated. It is speculated that vasopressin, released as a consequence of the blood pressure fall, could be this negative chronotropic factor.

Repeated administration of adenosine increases its cardiovascular effects in rats.

Hypotensive and negative chronotropic responses to adenosine in anesthetized rats increased after previous administration of the nucleoside. Bradycardia after adenosine in the isolated perfused rat heart was also potentiated after repeated administration at short intervals. This self-potentiation could be due to extracellular accumulation of adenosine and persistent stimulation of receptors caused by saturation or inhibition of cellular uptake of adenosine.

Role of the sympatho-adrenal system in the reflex tachycardia produced by hydralazine in the anesthetized rat.

The role of the sympatho-adrenal system in the production of tachycardia accompanying the hypotensive response to hydralazine was studied in urethane-anesthetized rats subjected to previous bilateral adrenal demedullation or to pretreatment with 6-hydroxydopamine and compared with intact control animals. The prolonged hypotension induced by the vasodilator was not affected by these maneuvers, but the slowly developing tachycardia was reversed to bradycardia, which in the demedullated group was followed after 60 min by a moderate increase in heart rate. In the chemically sympathectomized rats, the cardiac depressant response was completely blocked by pretreatment with atropine. In additional experiments, previous administration of methylatropine enhanced hydralazine tachycardia, but atropine partially inhibited this response and changed its time course to mirror that of the hypotension. These results indicate that in urethane-anesthetized rats, hydralazine tachycardia is mediated by sympatho-adrenal activation and that it is accompanied by a simultaneous heart rate-lowering parasympathetic discharge normally masked by the predominant tachycardia. They further suggest that the tachycardia is facilitated by a muscarinic mechanism which modulates central sympathetic influences on cardiovascular function.

The influence of cyclo-oxygenase inhibitors on the cardiovascular effects of hydralazine in rats.

In order to explore the postulated role of prostaglandins in the vasodilator effects of hydralazine, blood pressure and heart rate responses to the drug were determined in anesthetized and conscious rats with and without pretreatment with indomethacin or aspirin. Changes in rectal temperature were also measured. In control animals, hydralazine produced an almost immediate fall in blood pressure and a slowly developing tachycardia which bore no temporal relation with the hypotension. These effects were accompanied by a moderate increase in temperature. Pretreatment with the cyclo-oxygenase inhibitors did not reduce the blood pressure response, but completely blocked and in some cases reversed the tachycardia. The hyperthermic response was also reversed. These results can be taken as evidence for a role of prostaglandins in the tachycardia and hyperthermia, but not in the hypotension elicited by hydralazine in rats. In the absence of direct measurements of prostaglandin synthesis and release, however, no firm support for this possibility is offered by the present findings and alternative explanations are considered.