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

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Abstract
Epidural clonidine administration produces analgesia by a spinal action but may produce hemodynamic depression by activating other central or peripheral α2-adrenoceptors. To determine clonidine's distribution and cardiorespiratory effects 300 μg 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). Clonidine's 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 (>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 < 0.05) and intrathecal (93 ± 9 mmHg before, 79 ± 10 mmHg after; P < 0.05) injection. Blood pressure decreased earlier following intrathecal than following epidural injection, corresponding with higher CSF clonidine concentrations. Arterial PO1 decreased only following iv injection (from 97 ± 6 mmHg to 74 ± 7 mmHg; P < 0.05). These results support initial clinical experience with intraspinal clonidine administration, and provide a rationale for choice of route and method of administration.