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Introduction
RILMENIDINE
Rilmenidine was proposed as a selective imidazoline receptor drug
rather than 2 adrenoreceptor drug (Bricca et al., 1989 and Ernsberger et
al., 1993). Verbeuren et al. (1990) and Trieb et al. (1995) reported that
rilmenidine causes marked centrally-mediated hypotension, whilst the
incidence of its adverse effects is quite low. Feldman et al. (1990) and
Haxhiv et al. (1992) reported that although rilmenidine needs to be able
to target imidazoline receptors in order to induce hypotension, its residual
affinity for 2 adrenoceptors may play a synergistic role in its hypotensive
action, however its affinity for 2 adrenoreceptors is low enough to avoid
the classical adverse effects associated with the first generation of
centrally acting antihypertensive drugs.
Structure:
Rilmendine’s chemical structure includes an oxazoline ring which
is very similar to the imidazoline ring, differing from it only by the
presence of an oxygen atom at the site of the second nitrogen atom in the
heteroring (Fig. 6) (Van Zwieten et al., 1988).
The similarity to imidazoline not only allows rilmenidine to bind to
imidazoline receptors, but also means that it does so with a high affinity
(Bousquet and Feldman, 1999).
Fig. (6): N-(Dicyclopropyl methyl)-4,5-dihydro-2 oxazolamine; 2-[N-dicyclopropylmethyl)
amino]- axazoline C10H6N2O (Bousquet and Guertzenstein 1973).
 35 
Introduction
Pharmacokinetic profile:
Because of low dosage administered, rilmenidine plasma levels
were assayed by combined gas chromatography and mass spectrometry
(GCMs) (Murray et al., 1985 and Ehrhardt, 1985). Genissel et al.
(1988) reported from radioabelled and bioavailability studies that
rilmenidine was rapidly and extensively absorbed with a bioavailability
factor close to I. The relative bioavailability factors of various
pharmaceutical forms (solution, tablet and capsules) were calculated,
showing their bioequivalence. It was demonstrated that food intake had
no significant effect on the bioavailability of rilmenidine. The main
pharmacokinetic parameters of rilmenidine are shown in table (6)
(Genissel et al., 1988).
Table (6): Pharmacokinetic parameters of rilmenidine in hypertensive
patients after oral administration. Comparison with healthy
subjects (Mean  SEM).
Healthy subjects
n=8
1 mg
Hypertensive patients
n = 11
1 mg
2 mg
Cmax (ng/ml-1)
3.25  0.26
3.28  0.21
7.85  0.70
T max (hr)
1.94  0.64
1.77  0.17
1.33  22
V/F (L)
332.92  32.49
286.08  12.78
246.55  12.47
t1/2, (hr)
7.00  0.86
7.29  0.54
6.85  0.50
CLR (ml/min-1)
-
311.00  40.65
313.97  42.49
Fe (%)
-
65.78  7.89
68.10  4.60
Cmax = maximum plasma concentration; Tmax = time needed to reach the maximum plasma
concentration; Fe = Fraction of the unchanged drug excreted in urine; t 1/2 = terminal half life,
V/F = apparent volume of distribution, CLR = total plasma clearance.(Genissel et al., 1986).
 36 
Introduction
Rilmenidine was weakly bound to plasma proteins (<10 percent).
The weak involvement of protein binding minimizes the risk of
pharmacokinetic
interactions
with
other
drugs
frequently
co-
administrated with this antihypertensive agent (Fourtillan, 1986).
Metabolism was poorly involved in the elimination process as
studies performed after administration of radiolabeled rilmenidine in
human showed that unchanged (14C) rilmenidine was the main product
identified in urine samples (Davies and Dolley, 1986 and Genissel et al.,
1986).
In urine, other minor products were found which represented no
more
than
5%
of
the
total
radioactivity,
among
them,
N-
dicycloprophylmethyl urea, N-(hydroxyethyl)-N’dicycloproply urea, and
2-(dicyclopropyl-methyl) amino-2-oxazoline-4 urea were identified and
two other products remained unidentified. These metabolites were devoid
of any recognized pharmacological activity. In the blood, rilmenidine was
the only product identified and no traces of metabolite were detectable by
any analytical method used (Genissel et al., 1987).
Poor involvement in the metabolism allows the assumption that no
hepatic first-pass effect occurs after oral administration, as confirmed by
the absolute bioavilability (Murrary et al., 1985).
Rilmenidine was mainly excreted via the kidneys as after
administration of single oral (DeBroe, 1986) or intravenous (Genissel et
al., 1987) dose of radiolabelled rilmenidine 1 mg to healthy subjects,
88.84% and 86.65  4%, respectively of the dose was recovered in urine
24 hours after dosing. After 7 days, 93  3% of the total radioactive dose
of rilmenidine was excreted in urine (DeBroe, 1986).
 37 
Introduction
Fecal elimination was very low, about 1% was excreted after 7
days. In an absolute bioavailability study performed by Singlas et al.
(1988).
Rilmenidine’s total clearance was about 460 ml/min, the renal
clearance of rilmenidine was 330  27 ml/min indicating that the renal
excretion is the major elimination process. The large free fraction and the
value of renal clearance indicate that rilmenidine undergoes not only a
glomerular filteration but also an active secretion processes superior to
that of an eventual reabsorption (Singlas et al., 1988).
Mean half-lives of rilmenidine have been calculated in the study
performed by Genissel et al. (1988) after administration of single oral
dose of 1mg in eight healthy subjects the half- life during the distribution
elimination phase was about 8 hours half-lives found after single (7.6 
0.8 hours) and repeated doses during 14 days (7.1  0.8 hours) were in
accordance.
Effects of essential hypertension and disease states on the
pharmaco-kinetics of rilmenidine:
As antihypertensive drugs are widely used not only in the elderly
but also in various physiopathologic hypertensive populations it was of
importance to verify the effects of various conditions e.g. age, renal
failure, hepatic insufficiency on the basic pharmacokinetic parameters of
rilmenidine found in healthy subjects (Reid 2000, 1990).
Essential hypertension was not found to influence the absorption,
distribution or elimination process of rilmenidine when compared with
healthy subjects (Table 6) (Singlas et al., 1988).
 38 
Introduction
In the elderly, the elimination rate was reduced as demonstrated by
a prolongation of the elimination half life (13  1h), and decreased total
clearance (Pelemans et al., 1994).
Singlas (1988) explained this reduction in the elimination rate by
the physiologic renal insufficiency in the elderly and so reduction of the
observed clearance and this fall in total clearance is responsible for the
rise in terminal elimination half life. These modifications in the
biodisposition of rilmenidine in the elderly do not require an adaptation
of the dosage regimen (Couet et al., 1987).
In patients with renal failure, the absorption of rilmenidine was not
modified except in patients with severe renal failure (creatinine clearance
5-15 ml/min) the elimination parameters were modified Tmax (2.17 
0.31 hours), Cmax (5.33  0.56 ng/ml), and elimination half life (34  3
hours) and these modifications are likely to be due to the decrease in
elimination and these elimination parameters were directly correlated to
the degree of renal failure (Singlas et al., 1988). Aparicio et al. (1994)
concluded that rilmenidine is contraindicated in patients presenting with
severe renal failure (creatinine clearance less than 15 ml/min) in the
absence of clinical data in this population.
Bauman
and
Singlas
(1986)
have
been
studied
the
pharmacokinetic profile of rilmenidine in patients with hepatocellular
failure without ascitis, encephalopathy or renal failure. The patients were
given single oral dose of 1mg rilmenidine, the study revealed that weak,
varations in absorption and distribution confirming that rilmenidine has a
minimal first-pass effect. The decrease in total clearance could be due to
an alteration in metabolic function owing to renal changes induced by
 39 
Introduction
liver disease (Singlas et al., 1988). No adaptation of the dosage regimen
is required (Singlas and Bourer, 1986).
Surveillance of rilmenidine plasma levels in long-term clinical
studies carried out by Beau et al. (1988) have never shown any
accumulation.
Pharmacodynamics of rilmenidine:
Mechanism of action:
Head and Burke (2000), reported that rilmenidine was more
effective when injected into the RVLM than into NTS, where it decreased
blood pressure only at higher doses. Reid (2000) reported that RVLM is a
major site for the rilmenidine-induced inhibition of renal sympathetic
tone. The major antihypertensive action of rilmenidine appears to be
through I1 receptors present in the RVLM which inhibit sympathetic
activity, Fig. (7) (Louis, 2000). In addition it selectively binds to I 1
receptors in the renal proximal convoluted tubules producing marked
inhibition of the Na+/K+ exchanger (Penner and Smyth, 1994 and Symth
et al., 1995).
Rilmenidine
Fig.(7):
Double
rilmenidine
pressure
impact
on
of
blood
regulation
systems RAAS, rennin –
angiotensin–aldosterone
system
(Penner
Smyth, 1994).
 40 
and
Introduction
Rilmenidine also binds to receptors in the adrenal cortex and
neurons in the CNS. The precise actions of these sites remain to be
clarified, but it is believed that in the CNS these receptors may be
neuroprotective and in the adrenal gland they may modify the secretion of
adosteron. Rilmenidine shows affinity for 2 adrenergic receptors with
relative high selectivity for the imidazoline receptors compared with 2
adrenoreceptors (Louis, 2000).
This specificity for imidazoline receptors results in the important
benefit that rilmenidine exhibits a minimal level of adverse effects
associated with 2 adrenoreceptor stimulation, thus avoiding drowsiness
and rebound hypertension (Head and Burke, 2000).
Pharmacologic characteristics:
Cardiovascular effects:
1- Haemodynamic effects:
Rilmenidine by acute intravenous administration induced a
transient hypertensive phase followed by a marked, durable and dose
dependent reduction in blood pressure and heart rate in genetically
spontaneously hypertensive rats (SHR) (Koeing et al., 1988). Following
oral administration in the rat, rilmenidine (0.15 to 0.30 to 0.60 mg/kg)
significantly induced a long lasting hypotensive action without modifying
heart rate (Koeing et al., 1988).
In anesthetized SHR after chronic administration, rilmenidine did
not modify renal function, including glomerular filteration rate (inulin
clearance), renal blood flow (para-aminohippuric acid [PAH] clearance)
and urinary output (Garattini et al., 1986).
 41 
Introduction
Rilmenidine reduced plasma renin activity in SHR (Garattini et al.,
1986) and in conscious normotensive dogs (Laubie et al., 1985).
Evidence for the central component of rilmenidine’s hypotensive
effect was noted following injection of low doses (10-30 ug/kg) into the
left thoracic vertebral artery of chlorase-anesthetized cats. However
similar and even higher doses, when administrated systemically,
remained virtually ineffective (Safar and Pannier, 1990).
Laubie et al. (1985) reported in their study of pithed and
vagotomized dogs that, rilmenidine prevented the tachycardiac response
to the electrical stimulation of the cardiac sympathetic nerves. In rats
similar results were obtained together with a decrease in the plasma
adrenalin concentration (Van Zwieten et al., 1986).
2- Reduction in left ventricular hypertrophy:
Callens et al. (1989) reported in their study that rilmenidine
reduced left ventricular weight of DOCA-salt treated rats, this effect
being associated with a reduction in the myocardial collagen content.
Callen et al. (1989) and Bobik et al. (1996) reported similar results
in other studies performed in SHR. A beneficial effect of rilmenidine has
therefore been demonstrated in the left ventricular hypertrophy associated
with essential hypertension in human.
3- Antiarrythmic properties:
Rilmenidine prevents epinephrine-induced arrhythmias in dogs
during halothan anesthesia and this action seems to be through the I 1
imidazoline receptors which regulate the activity of the autonomic
nervous system (Mammoto et al., 1995).
 42 
Introduction
In addition Sivot et al. (1995) reported in their study that
rilmenidine prevents cardiac arrythmias induced by electrical stimulation
in conscious and anesthetized rabbits. Mammoto et al. (1995) reported
that the anti-arrythmic action of rilmenidine appears to be more potent
than its antihypertensive action.
Central nervous system effects:
A very obvious difference between rilmenidine and clonidine was
rilmenidine’s lack of or minimal sedative activity in animal experiments.
In mice Van Zwieten (1986) and (1988) showed that in contrast to
clonidine (0.25 mg/kg I.P), rilmenidine (10 mg/kg IP) did not
significantly prolong the hexobarbiton-induced sleeping time.
In addition Koenig et al. (1988) showed that rilmenidine (10 mg/kg
I.P) did not induce any significant alteration of the sleeping time induced
by pentobarbiton whereas clonidine (0.125 mg/kg IP) produced a
significant increase of the sleeping time in rats.
Rilmenidine has demonstrated dose-dependent cerebral antiischemic properties as Maiese et al. (1992) reported that, rilmenidine can
partially reduce the size of focal ischemic infarctions by occlusion of the
middle cerebral artery in the rat. Rilmenidine elicited a maximal
reduction of infracted area by 33% which was dose-dependent. The
mechanism of reduction does not appear to be secondary to agonist action
on 2-adrenergic receptors, or variations in blood gases, heamatocrite,
mean arterial pressure, or local cerebral blood flow. Occupation of
imidazoline receptors, either in the ischemic zone or remote brain sites
may be responsible for neuroprotection of rilmenidine (Maiese et al.,
1992).
 43 
Introduction
Renal effects:
Rilmenidine’s activity in the kidney occurs via lowering of renal
sympathetic tone (Kline and Cechtto, 1993) as well as a direct action on
renal I1 imidazoline receptors (Smyth and Penner, 1994).
In rabbit proximal cells of the kidney rilmenidine showed a marked
inhibition of the Na+/H+ exchanger which may play a role in the overall
antihypertensive effect of the drug (Bidet et al., 1990 and Schlatter et al.,
1997).
Dollery et al. (1990) reported that patients with mild to
moderatehypertension who received chronic treatments with rilmenidine
showed reduced body weight suggesting that there was no sodium/water
retention with this drug. Another experimental study in anesthetized rats
showed that rilmenidine increase renal blood flow and produced slight
natriuresis. An effet which was associated with a marked decrease in
sympathetic renal nerve activity (Ghaemmaaghami et al., 1990 and
Kline and Cechetto, 1993).
In spontaneously hypertensive rats, the plasma antidiuretic
hormone level was shown to be reduced by rilmenidine (Hamilton,
1992).
Rilmenidine induced a fall in plasma rennin activity after acute
administration in healthy subjects (DeBroe et al., 1986) and repeated
administration in hypertensive patients (Zech and Prozet, 1986).
Effects on fluid volume state and electrolytes:
Acute and repeated administration of rilmenidine (1mg) in healthy
subjects significantly reduced blood pressure but did not modify water
 44 
Introduction
and electrolyte balance (Leary, 1989). After chronic administration in
hypertensive patients at the dose of 1mg/day or 1mg b.i.d rilmenidine
caused no variation in blood mass or weight and induced no variation in
urinary osmolarity, Na+/K+ ratio or electrolyte excretion rate (Zech and
Pozet, 1986). In contrast Bousquet and Feldman (2000) reported that
rilmenidine increased potassium excretion, just as it slightly increased
natriuresis in hypertensive and normotensive rats.
Endocrine and metabolic effects of rilmenidine:
Enjalbert (1986) reported that there is no modification of prolactin
level in conscious rats treated with rilmenidine. In healthy subjects
Grossman et al. (1987) and Kuhn and Wolf (1986) reported that growth
hormone increased briefly after acute oral administration of rilmenidine
and then returned to normal values; prolactin initially decreased and then
returned to normal values (Kuhn and Wolf, 1986). In hypertensive
patients plasma prolactin levels remained unchanged after a 12-week
period at administration of rilmenidine (1 mg once a day and 1 mg b.i.d)
(Grossman et al., 1987).
Rilmenidine had no influence on carbohydrate or lipid metabolism.
Duhault (1986) reported absence of lipid or glycemic modification after a
1-year treatment in rat.
In a comparison study versus atenolol over 12 weeks, Dallocchico
et al. (1994) reported that rilmenidine significantly reduced low-density
lipoprotein (LDL) and preserved high density lipoprotein (HDL) levels.
In contrast with atenolol treated group there was a significant reduction in
HDL and a tendancy to increase triglyceride. However in another study
 45 
Introduction
patients treated with rilmenidine showed small but statistically significant
reduction in total cholesterol (Fiorentini et al., 1989).
Reduction of microalbuminurea:
Rilmenidine has recently been compared with captopril in type 2
diabetics with placebo-resistant mild to moderate hypertension and
microalbuminurea (30 < microalbuminurea <300 mg/24 h). The median
microalbuminurea level reduction over 6 months with rilmenidine (160 to
56 mg/24 h) was similar to that observed for captopril (144 to 54
mg/24h). There was no significant difference between the two treatment
groups (Trimarco, 1999).
Improvement in insulin resistance:
Dupuy et al. (1999) studied the effects of rilmenidine in patients
with metabolic syndrome (syndrome x). Fifty-two patients with obesity,
hypertension, impaired glucose tolerance and hypertriglyceridemia (body
mass index 29 kg/m2, 95  DBP  114 mmHg, TG  2 mmol/L, fasting
plasma glucose  17.0 mmol/L were included. They were treated with
rilmenidine (1 to 2mg daily) for five months. Rilmenidine significantly
improved glucose metabolism as judged by the oral glucose tolerance test
by significant reduction in plasma glucose at 2h and in the area under the
curve.
Indications:
Rilmenidine is indicated in systemic hypertension. The dissociation
between antihypertensive activity and side effects, not found at
equihypotensive doses, supports rilmenidine as single therapy in
treatment of mild to moderate hypertension (Safar et al., 1989).
 46 
Introduction
Rilmenidine represents a useful treatment of hypertension in the
diabetics in whom sympathetic over activity associated with insulin
resistance
where
hyperinsulinemia
increases
peripheral
vascular
resistance and sodium reabsorption (Duppy et al., 2000).
Precautions:
Although no teratogenic or embryotoxic effects have been
observed in animal experiments, administration of rilmenidine during
pregnancy should be avoided. Because it is excreted in milk its
administration is not recommended for nursing mothers (Safar et al.,
1989). Rlimenidine should be avoided in children in the absence of
documented experiments.
Adverse effects:
Adverse effects at therapeutic doses with rilmenidine are rare,
benign and transient (Safar et al., 1989).
Grossman et al. (1987), showed that the incidence of side effects
was significantly lower with rilmenidine than that observed with
clonidine or methyl dopa, side effects were 4 to 8%, fatigue, insomnia,
drowsiness, dry mouth, palpitations, epigastric pain, diarrhea, skin rashes
and in expetional cases (<2 percent) cold extremities, orthostatic
hypotension, sexual disturbance, anxiety, depression, purities, edema
cramps, nusea, constipation and hot flushes.
 47 
Introduction
Contraindication:
Rilmenidine is contraindicated in cases of severe depression (Safar
et al., 1989) or severe renal insufficiency (creatinine clearance <15
ml/min) (Zech and Prozet, 1986).
Drug interactions:
Safar et al. (1989) study reported that concurrent treatment with
monamine oxidase inhibitors has not been investigated and is thus not
recommended. Combination with tricyclic antidepressants should be
carried out with caution because the antihypertensive activity of
rilmenidine may in this case be partly antagonized (Mahieusc et al.,
1988).
Leary (1989) study showed rilmenidine did not modify the urinary
effects of hydrochlorothiazides (25 mg) except for a counter action of
urinary excretion of magnesium induced by the diuretic.
 48 
Introduction
CLONIDINE
Clonidine (catapress) is a centrally acting antihypertensive agent
charactherized by its wide therapeutic range. Clonidine is an imidazoline
derivative, was originally developed as a nasal decongestant and
vasoconstrictor (Timmerman and Van Zewieten, 1982).
Its hypotensive and bradycardiac effects were first serendipitously
appreciated in 1962. It was introduced first in Europe in 1966 and
subsequently in the United states for use as antihypertensive agent (Van
Zwieten, 1999).
Structure:
Clonidine is a compound of the imidazoline group which exerts a
hypotensive action in very low doses. Its molecular weight is: 266.57 and
the
chemical
formula:
2-(2,6-dichorphenyl-amino)-2-imidazoline
hydrochloride (Koeing et al., 1988) (Fig. 8).
Fig. (8): Structure of clonidine (Bosquet and Feldman, 1999)
 49 
Introduction
Pharmacokinetic:
The pharmacologically active doses of clonidine are extremely
small, thus to facilitate detection in biochemical testes radio clonidine
(14C) was employed. Clonidine is rapidly absorbed from the
gastrointestinal tract, the onset of action occurs within 30 to 60 minutes,
with the peak antihypertensive effect occurring 2-4 hours after oral
administration. Peak plasma levels occur at 90 minutes and the plasma
half-life is 6 to 15 hours (Schmitt, 1979). Clonidine is metabolized
mainly by the liver, approximately 40 to 60 percent of an oral dose is
excreted unchanged in the urine within 24 hours (Stark and Altmann
1973).
Van Zwieten (1983) reported that, in cases of renal insufficiency,
renal clearance is markedly reduced, with 95% of excretion in the urine
and feces in 72 hours and total clearance in 5 days.
Clonidine is well absorbed through the skin, a trans-dermal
preparation releases clonidine at a constant rate for a 7-days period. A
micro porous polypropylene membrane controls rate of absorption from a
trans-dermal delivery system. It takes 2-3 days to attain a stable plasma
concentration after the adhesive patch has been applied. After a patch is
removed at the end of a week, the clonidine accumulated in the skin
reservoir is slowly absorbed, and the plasma level slowly declines
(Hieble and Kolpack, 1993).
If a new patch is applied to another site, absorption of the drug
from the old site plus the new site maintain a constant plasma level. Skin
permeability to clonidine varies slightly with the site used, the areas most
permeable to and from which the most constant absorption of clonidine
occurs, are the chest and upper outer arms (Isacc, 1980).
 50 
Introduction
Pharmacodynamics of clonidine:
Mechanism of action:
The mechanism of the antihypertensive action of clonidine appears
to be through stimulation of postsynaptic 2-adrenergic receptors in the
nucleus tractus solitari of the medulla oblongata. This inhibits basal
efferent sympathetic vasoconstrictor activity to the peripheral and renal
vasculature (Hieble and Kolpak, 1993).
However, a body of experimental evidence confirmed that a nonadrenergic mechanism underlies the hypotensive action of the
imidazoline like compounds (clonidine). Only imidazolines and analogue
substances induced hypotension when injected in the nucleus tractus
solitari, whereas catecholamines, the endogenous ligands for adrenergic
receptors, were unable to induce such an effect, hence the existence of
imidazoline receptors (Gyenet, 1997).
MacMillan et al. (1996) reported that the hypotensive action of
clonidine and various imidazoline compounds were abolished when 2adrenoreceptors were made inactive, this supports the view that the
integrity of 2 receptors is important for the hypotensive action of
clonidine like drugs (Bosquet and Feldman, 2000).
The same -adrenergic-stimulating properties that cause the
centrally mediated reduction of blood pressure have the opposite effect on
the peripheral vasculature. A biphasic blood pressure response has been
demonstrated in anathetized dogs after intravenous infusion of clonidine.
A brief initial increase in blood pressure is followed quickly by a
 51 
Introduction
prolonged period of lowered blood pressure and bradycardia (Koeing et
al., 1989).
Van Zwieten (1983) reported that a similar response to orally
administrated clonidine may be observed in hypertensive patients, within
minutes of an oral dose of clonidine there may be a small increase in
blood pressure universally followed by prolonged reduction in blood
pressure as the central antihypertensive effects quickly overwhelm the
peripheral pressor effect. However, Van Zwieten (1988) has suggested
that, this peripheral pressor effect may persist over a wide range of
clonidine blood levels than the central antihypertensive effect. The is the
centrally mediated antihypertensive action of clonidine may reach a
plateau stage, whereas the peripheral pressor effect may continue to
increase with increasing dosage. If this is correct, it is possible that with
very high doses of clonidine the peripheral pressor effect may lessen the
over all antihypertensive efficacy Mac Mahon et al., (1985).
Clonidine reduces sympathetic activity also via resetting the
sensitivity of carotid baroreceptors, this reversal of impaired baroreceptor
function has been demonstrated both in hypertensive animals and in
patients with hypertension (Guyente, 1997).
Van Zwieten (1988) suggested that the frequently observed
moderate decrease in heart rate during clonidine therapy is a result of
direct vagal stimulation or sinoatrial nodal inhibition. This comes about
as a result of reciprocal relationship between the sympathetic vasomotor
center and the dorsal motor nucleus of the vagus nerve i.e. with inhibition
of sympathetic ant flour, vagal tone is increased.
 52 
Introduction
In addition to its postsynaptic action, clonidine has presynaptic agonist activity. This presynaptic stimulating activity might inhibit
neurotransmitter release and contribute to the decrease in plasma
norepinephrine concentration found during clonidine therapy (Koieng et
al., 1988).
Haemodynamic effects:
Acute intravenous administration of clonidine reduces blood
pressure, heart rate, cardiac output and stroke volume without any
consistent change in calculated total peripheral resistance. The decrease
in cardiac output is due primarily to the reduction of heart rate and
venous return (due to venodilatation with no change in myocardial
contractility (Van Zwieten, 1988). Increases in cardiac output and heart
rate in response to exercise are preserved, probably because the central
sympathetic inhibitory action of clonidine is more prominent than
peripheral constrictor action, allowing peripheral effector mechanisms to
remain intact.
Ritz et al. (1998) reported that renal blood flow and glomerular
filteration rate are preserved during treatment with clonidine, allowing
renal autoregulation to compensate for the reduction in renal perfusion
pressure.
Chronic administration of clonidine results in decreases in blood
pressure and resting heart rate similar to those observed with acute
administration. The reduction in resting heart rate is seen in both the
supine and the upright positions (Boucher, 1997).
Supine and standing blood pressure are similar, and symptoms of
orthostatic hypotension are unusual with clonidine. Total peripheral
 53 
Introduction
resistance is reduced during chronic administration, but despite this
persistent reduction, cardiac output returns to normal within 4 to 6 weeks
(Head, 1995).
Cardiac effects:
Bousquet and Feldman (1984) reported that left ventricular
hypertrophy is a common manifestation of end-organ damage from
hypertension and may be an independent cardiovascular risk factor. Chan
et al. (1996) reported that left ventricular mass is correlated with plasma
norepinephrine concentrations is spontaneously hypertensive rats.
Therapy with sympathetic blocking agents can produce a reduction in left
ventricular mass in these rats.
In humans regression of left ventricular hypertrophy may be seen
with clonidine therapy with and without low dose diuretic (Bosquet and
Feldman, 1999).
Feng et al. (1994) reported that, diastolic left ventricular filling
which reflects diastolic ventricular function has been found to be
abnormal in hypertensive patients and may be improved by short-term
(12 weeks) clonidine therapy.
Chan et al. (1996) have been studied the effect of clonidine
therapy on patients with exertional angina, 48% of patients demonstrated
a decrease in anginal symptoms and the possible mechanisms include
reduction of heart rate and blood pressure, reduction of left ventricular
mass and possible vasodilatation.
Drolet et al. (1990) reported that there are no known direct
electrophysiologic
effects
of
clonidine,
 54 
any
demonstrable
Introduction
electrophysiologic effects may be attributed to decreased resting
sympathetic and increased resting parasympathetic tone.
Renal effects:
Clonidine decreases plasma renin activity, presumably as a result
of the decrease in sympathetic activity. However, it may directly inhibit
the renal release of renin (Ritz et al., 1998). The inhibition of renin
release contributes to the antihypertensive effect of clonidine (Smyth and
Penner, 1995) reported that a renin-independent anti-hypertensive effect
has also been demonstrated in patients with low renin levels in whome
clonidine did not cause changes in plasma renin activity.
Clonidine causes suppression of aldosteron production which
might also contributes to its blood pressure-lowering effects (Ritz et al.,
1998). There is lack of salt and water retention seen with clonidine
therapy is probably as a result of the inhibition of the renin-aldosteron
axis (Bidet et al., 1990).
Metabolic effects:
There is a growing susception that the metabolic effects of
antihypertensive agents may be related to the pathogenesis of
atherosclerosis and/or its complications, the metabolic effects of
clonidine and other antihypertensive agents have been increasingly
evaluated (Jeppesen, 1997, Schachter, 1997, Prichard and Granam,
2000 and Robert, 2000). The metabolic effects of clonidine are
controversial. The total serum cholesterol decreasing by 5 to 6 percent in
two studies (Goyal 1999, Pichard and Graham, 2000 ) and did not
significantly altered study performed by Luccioni (1995). Clonidine
therapy has been noted to reduce the atherogenic low-density lipoprotein
(LDL) concentrations without changing the cardioprotective high density
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Introduction
lipoprotein (HDL) concentrations, with a decrease in the LDL/HDL ratio
and a resultant decrease in predicted cardiovascular risk (Goyal, 1999).
However, Giugliano et al. (1998) reported that clonidine therapy
decreased both LDL, HDL and total cholesterol levels with a neutral
effect on cardiovascular risk. Clonidine does not adversely affect glucose
tolerance (Schachtler, 1999).
Clinical use:
a- Hypertension:
Clonidine is indicated in all form of hypertension; its clinical
efficacy has been well documented (Koeing et al., 1988, Van Zwieten,
1988 and van Zwieten, 1999).
Giugliano et al. (1998) reported that, when clonidine used as
monotherapy, clonidine reduces blood pressure to normal levels in about
one half of patients with mild hypertension, satisfactory control of blood
pressure can be attained with low doses of clonidine (0.4 mg or less in
many instances). Louis et al. (1994) reported that the combination of
clonidine and a diuretic is even more effective than monotherapy and the
combination will control blood pressure in more than 70 percent of
patients with mild to moderate hypertension. Clonidine is not indicated in
hypertensive emergencies when more rapidly acting and predictable
agents are available, however, rapid clonidine loading is useful in treating
hypertensive urgent situations or severe hypertension unaccompanied
with alterations in mental status or other signs of severe end organ
dysfunction (Van Zwieten, 1997). The initial dose is 0.1 to 0.2 mg PO,
followed by 0.1 mg hourly until blood pressure is reduced to safe levels,
or to a total dose of 0.5 mg. This approach is effective in 70 to 80 percent
of patients within 2 to 3 hours.
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Introduction
b- Prophylaxis of migrain headach :
Anonymous (1990) reported that, clonidine is a poor 1 st choice and
seemed unlikely to work even as a last resort. It has been used in patients
whose attacks may be precipitated by tyramine containing foods.
c- Menopausal disorders :
Although, hormone replacement therapy is generally regarded to be
the main stay of treatment for menopausal disorders, clonidine has been
found to be of some use in countering vasomotor symptoms in patients
who can not receive replacement therapy. (Young et al., 1990). In
addition to a reduction in amplitude and frequency of luteinising hormone
pulsations, clonidine was felt to influence hot flushes by peripheral
vascular effects.
d- Withdrawal syndrome of opioids:
Clonidine has been reported to be useful in controlling withdrawal
symptoms following abrupt discontinuation of opioids treatment is
required for about 10 days following methadone withdrawal and less for
withdrawal of herion. However, the tendency to cause hypotension by
clonidine may limit its usefulness in some patients (Keller and Frishman
2003).
e) Pain:
Food and Drug Administration (FDA) has been approved clonidine
as an epidural analgesic and analgesic co adjuvant (Carolyn et al., 1999).
f- Attention-deficit-hyperactivity- disorders (ADHD):
Clonidine had a moderate effect of 58  0.16% on symptoms of
ADHD so may be used as a 2nd choice for this disorder in children and
adult (Garcia et al.,1999).
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Introduction
Adverse effects:
Van Zwieten (1999) reported that the most frequent side effects
encountered with clonidine therapy are dry mouth (as many as 48% of
patients), drowsiness (about one third of patients) and sedation (about 8%
of patients). These manifestations are due to its central nervous system
actions. Approximately 7 percent of patients discontinue therapy because
of intolerable side effects.
The trans dermal patch to significantly reduce all the systemic side
effects, however a cutanous reaction directly under the patch occurs in up
to 20 percent of patients and this reaction range from a superficial
irritation to a localized contact dermatitis (Hieble and Kolpak, 1993).
Rare gastrointestinal, dermatologic and central nervous system adverse
reactions have been reported. Sexual dysfunctions frequently seen with
antihypertensive therapy, is an infrequent complications of clonidine
therapy (Bosquet and Feldman, 1999).
However, the withdrawal of clonidine therapy should be gradual as
sudden discontinuation may cause rebound hypertension, sometimes
sever. Symptoms of increased catecholamines release such as agitation,
sweating, tachycardia, headach, and nusea may also occur. Beta blockers
can excerbate the rebound hypertension, and if clonidine is being given
currently with a beta blocking agent, after the withdrawal of beta blockers
(DeQuattro, 2002).
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