A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Catapres Pharmacology, Pharmacokinetics, Studies, Metabolism - Clonidine
Catapres Pharmacology, Pharmacokinetics, Studies, Metabolism - Clonidine
CLINICAL PHARMACOLOGY
Tablet
Clonidine hydrochloride
acts relatively rapidly. The patient's blood pressure declines within
30 to 60 minutes after an oral
dose, the maximum decrease occurring within 2 to 4 hours. The plasma
level of clonidine hydrochloride peaks in approximately 3 to 5 hours
and the plasma half-life
ranges from 12 to 16 hours. The half-life
increases up to 41 hours in patients with severe impairment
of renal function. Following
oral administration
about 40-60% of the absorbed dose
is recovered in the urine
as unchanged drug in 24 hours. About 50% of the absorbed dose
is metabolized in the liver.
Clonidine stimulates alpha-adrenoreceptors in the brain
stem, resulting in reduced sympathetic
outflow from the central
nervous system
and a decrease in peripheral
resistance: at a 45° tilt there is a smaller reduction in cardiac
output and a decrease
of peripheral resistance.
During long-term therapy, cardiac
output tends to return
to control values, while
peripheral resistance remains decreased. Slowing of the pulse
rate has been observed
in most patients given clonidine, but the drug
does not alter normal
hemodynamic response to exercise.
Other studies in patients have provided evidence
of a reduction in
plasma renin activity
and in the excretion
of aldosterone and
catecholamines, but the exact relationship of these pharmacologic
actions to the antihypertensive effect has not been fully elucidated.
Clonidine acutely stimulates growth
hormone release
in both children and adults, but does not produce a chronic
elevation of growth
hormone with long-term use.
Tolerance may develop in some patients, necessitating a reevaluation
of therapy.
Epidural Injection
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 (mean±SD
t½ = 11±9 minutes) followed by a slower
elimination phase (t½ = 9±2 hours) over
24 hours. Clonidine's total body
clearance (CL) was
219±92 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 (4.4±1.4 ng/ml) were obtained in 19±27 minutes.
The plasma elimination
half-life was determined to be 22±15 hours following sample
collection for 24 hours. CL was 190±70 ml/min. In
cerebral spinal fluid
(CSF), peak clonidine levels (418±255 ng/ml) were achieved
in 26±11 minutes. The clonidine CSF
elimination half-life
was 1.3±0.5 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 2.2±1.1 and 2.4±1.4 ng/ml were obtained
on dosing days 7 and 14 respectively. CL was 279±184 and
272±163 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. Clonidine's
volume of distribution
is 2.1 ±0.4 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 133 ±66 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 was removed.
Metabolism: In
humans, clonidine metabolism follows minor
pathways with the major metabolite,
p-hydroxyclonidine, 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.
CLINICAL STUDIES
Epidural Injection
In a double-blind, randomized study of cancer
patients with severe intractable pain below the C4 dermatome
not controlled by morphine, 38 patients were randomized to an epidural
infusion of clonidine
HCl plus epidural morphine,
whereas 47 subjects received epidural
placebo plus epidural
morphine. Both groups were allowed rescue doses of epidural
morphine. Successful analgesia, defined as a decrease in either
morphine use or Visual
Analog Score (VAS) pain, was significantly more common with epidural
clonidine than placebo (45% vs 21%, p=0.016). Only the subgroup
of 36 patients with ``neuropathic'' pain, characterized by the investigator
as well-localized, burning, shooting, or electric-like pain
in a dermatomal or peripheral
nerve distribution had
significant analgesic
effects relative to placebo
in this study.
The most frequent adverse events with clonidine were hypotension
(45% vs 11% for placebo,
p<0.001), postural
hypotension (32%
vs 0%, p<0.001), dizziness (13% vs 4%, p=0.234), anxiety
(11% vs 2%, p=0.168) and dry mouth (13% vs 9%, p=0.505). Both mean
blood pressure
and heart rate
were reduced in the clonidine group. At
the conclusion of the two week study period in the clinical
trial, all patients were abruptly withdrawn from study drug or placebo.
Four patients of the clonidine group
suffered rebound hypertension upon withdrawl of clonidine; one of
these patients suffered a cerebrovascular
accident. Asymptomatic bradycardia
was noted in one clonidine patient.
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