DURACLON clinical pharmacology

# Clinical Pharmacology

## Mechanism of Action
Epidurally administered clonidine produces dose-dependent analgesia not antagonized by opiate antagonists. The analgesia is limited to the body regions innervated by the spinal segments where analgesic concentrations of clonidine are present. Clonidine is thought to produce analgesia at presynaptic and postjunctional alpha-2-adrenoceptors in the spinal cord by preventing pain signal transmission to the brain.

## Pharmacokinetics
Following a 10 minute intravenous infusion of 300 mcg clonidine HCl to five male volunteers, plasma clonidine levels showed an initial rapid distribution phase (meanSD t12=119 minutes) followed by a slower elimination phase (t12=92 hours) over 24 hours. Clonidines total body clearance (CL) was 21992 mL/min.
Following a 700 mcg clonidine HCl epidural dose given over five minutes to four male and five female volunteers, peak clonidine plasma levels (4.41.4 ng/mL) were obtained in 1927 minutes. The plasma elimination half-life was determined to be 2215 hours following sample collection for 24 hours. CL was 19070 mL/min. In cerebral spinal fluid (CSF), peak clonidine levels (418255 ng/mL) were achieved in 2611 minutes. The clonidine CSF elimination half-life was 1.30.5 hours when samples were collected for 6 hours. Compared to men, women had a lower mean plasma clearance, longer mean plasma half-life, and higher mean peak level of clonidine in both plasma and CSF.
In cancer patients who received 14 days of clonidine HCl epidural infusion (rate=30 mcg/hr) plus morphine by patient-controlled analgesia (PCA), steady state clonidine plasma concentrations of 2.21.1 and 2.41.4 ng/mL were obtained on dosing days 7 and 14, respectively. CL was 279184 and 272163 mL/min on these days. CSF concentrations were not determined in these patients.

## Distribution
Clonidine is highly lipid soluble and readily distributes into extravascular sites including the central nervous system. Clonidines volume of distribution is 2.10.4 L/kg. The binding of clonidine to plasma protein is primarily to albumin and varies between 20 and 40% in vitro. Epidurally administered clonidine readily partitions into plasma via the epidural veins and attains systemic concentrations (0.5 - 2.0 ng/mL) that are associated with a hypotensive effect mediated by the central nervous system.

## Excretion
Following an intravenous dose of 14C-clonidine, 72% of the administered dose was excreted in urine in 96 hours of which 40-50% was unchanged clonidine. Renal clearance for clonidine was determined to be 13366 mL/min. In a study where 14C-clonidine was given to subjects with varying degrees of kidney function, elimination half-lives varied (17.5 to 41 hours) as a function of creatinine clearance. In subjects undergoing hemodialysis only 5% of body clonidine stores were removed.

## Metabolism
In humans, clonidine metabolism follows minor pathways with the major metabolite, p-hydroxy-clonidine, being present at less than 10% of the concentration of unchanged drug in urine.

## Special Populations
The pharmacokinetics of epidurally administered clonidine has not been studied in the pediatric population or in patients with renal or hepatic disease.