Maria I. Castro

Pharmacokinetics and Dynamics of Intravenous, Intrathecal, and Epidural Clonidine in Sheep

Epidural clonidine administration produces analgesia by a spinal action but may produce hemodynamic depression by activating other central or peripheral alpha 2-adrenoceptors. To determine clonidines distribution and cardiorespiratory effects 300 micrograms clonidine was injected epidurally, intrathecally, and intravenously in six chronically prepared sheep, and cerebrospinal fluid (CSF) and arterial plasma clonidine were measured. Dural transfer of epidurally administered clonidine was rapid and extensive: time to maximal concentration (Tmax) in CSF was 32 +/- 8 min, bioavailability in CSF was 14 +/- 4% of the administered dose, and maximal CSF concentrations following epidural administration (820 +/- 30 ng/ml) were three orders of magnitude greater than those following iv injection (0.71 +/- 0.06 ng/ml). Systemic absorption of epidurally administered clonidine occurred rapidly: Tmax in plasma was 34 +/- 6 min and plasma concentrations were similar to those following iv injection at all time points beyond 20 min. Elimination half-lives from plasma were similar for all three routes of administration (81-95 min). Clonidines effect on blood pressure differed with route of administration. Blood pressure increased and heart rate decreased following iv injection when plasma clonidine concentrations were high (greater than 2 ng/ml). Clonidine, following all routes of administration, numerically decreased blood pressure, but this decrease was significant only following epidural (mean arterial pressure = 97 +/- 6 mmHg before, 86 +/- 6 mmHg after; P less than 0.05) and intrathecal (93 +/- 9 mmHg before, 79 +/- 10 mmHg after; P less than 0.05) injection. Blood pressure decreased earlier following intrathecal than following epidural injection, corresponding with higher CSF clonidine concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Epidural clonidine analgesia in obstetrics: sheep studies

Epidural clonidine administration produces analgesia by a nonopiate, spinal mechanism, and offers advantages over other epidural agents for labor analgesia. To examine clonidines acute maternal and fetal effects, the authors injected clonidine, 300 micrograms, epidurally in seven chronically prepared, near term ewes. Unlike epidural saline injection, clonidine increased maternal and fetal serum glucose (by 178 +/- 30% and 190 +/- 30%, respectively; mean +/- SEM, P less than .01) 1 h following injection. Maternal and fetal serum cortisol and arterial blood gas tensions were unchanged following clonidine. Epidural clonidine injection produced minor decreases (10-15%) in heart rate in ewe and fetus, without altering maternal and fetal blood pressure, intra-uterine pressure, or uterine blood flow. Maternal and fetal serum clonidine concentrations peaked at 58 +/- 8 and 73 +/- 5 min following injection, respectively, and declined with similar half-lives. Heart rate correlated negatively with serum clonidine concentration in both ewe and fetus (P less than .05). Apart from hyperglycemia, which does not occur in humans, these results in sheep suggest that epidurally administered clonidine does not adversely affect the fetus and may be evaluated as an analgesic in obstetrics.

Maternally administered esmolol produces fetal β-adrenergic blockade and hypoxemia in sheep

Although esmolol may be a useful therapeutic agent in obstetrics and obstetric anesthesia, concerns about fetal safety have limited its use. To assess acute fetal hemodynamic effects of maternally administered esmolol, saline or esmolol (4-200 micrograms.kg-1.min-1 in a stepped manner) was infused into maternal venous catheters in nine chronically prepared pregnant ewes, and the degree of beta-adrenergic blockade was assessed by isoproterenol challenge. In control experiments saline infusion and repeated isoproterenol challenges did not alter measured parameters, although maternally administered isoproterenol (0.1 micrograms) transiently decreased uterine blood flow by 20 +/- 5% (mean +/- SEM; P less than 0.05). Esmolol produced a dose-dependent decrease in maternal blood pressure and fetal heart rate (maternal blood pressure decreased by 22 +/- 8% and fetal heart rate decreased by 27 +/- 7% following esmolol, 200 micrograms.kg-1.min-1; P less than 0.05). Fetal arterial PO2 decreased from 18.2 +/- 1.2 mmHg before to 14.1 +/- 1.5 mmHg following esmolol, 200 micrograms.kg-1.min-1 (P less than 0.05). Maternally administered esmolol produced similar dose-dependent beta-adrenergic blockade in both ewe and fetus, with complete blockade following the 80 and 200 micrograms.kg-1.min-1 doses. Thirty minutes following cessation of esmolol infusion, fetal resting heart rate and maternal and fetal isoproterenol-stimulated heart rate remained below control values. These results suggest that maternally administered esmolol may produce adverse fetal effects, limiting its usefulness in the obstetric setting.

Intravenous clonidine hydrochloride toxicity in pregnant ewes

Administration of intravenous clonidine hydrochloride has been advocated to rapidly control blood pressure in severe preeclampsia. To examine clonidines acute maternal and fetal effects were intravenously injected 300 micrograms clonidine in eight chronically prepared normotensive near term ewes. Unlike intravenous saline solution injection, clonidine produced significant toxicity--intraamniotic pressure increased 97 +/- 27% (p less than 0.05), uterine blood flow decreased 55 +/- 7% (p less than 0.001), maternal and fetal serum glucose increased 158 +/- 23% and 249 +/- 91%, respectively (p less than 0.001), and maternal and fetal Po2 decreased to 44 mm Hg +/- 4 mm Hg and 13 mm Hg +/- 1 mm Hg, respectively (p less than 0.05). Maternal and fetal blood pressure and serum cortisol were unaffected by clonidine, whereas heart rate decreased. No adverse maternal or fetal effects were noted with serum clonidine concentrations less than 1.0 ng/ml. Direct fetal infusion of clonidine did not lower fetal arterial Po2 levels, although heart rates decreased and serum glucose levels increased. The multiple effects of clonidine infusion are best explained by actions on alpha 2-adrenergic receptors. These results suggest that intravenous administration of clonidine may adversely affect the fetus by direct actions and by alterations in maternal physiology.