* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Aishea omar youiens elkady_rev 1
Survey
Document related concepts
Adherence (medicine) wikipedia , lookup
Discovery and development of beta-blockers wikipedia , lookup
Drug interaction wikipedia , lookup
Discovery and development of angiotensin receptor blockers wikipedia , lookup
Intravenous therapy wikipedia , lookup
Neuropsychopharmacology wikipedia , lookup
Plateau principle wikipedia , lookup
Pharmacokinetics wikipedia , lookup
Neuropharmacology wikipedia , lookup
Theralizumab wikipedia , lookup
Psychopharmacology wikipedia , lookup
Transcript
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, 88.84% 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 55 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. 56 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). 57 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). 58