Possible involvement of an endogenous opioid in the antihypertensive effect of clonidine in patients with essential hypertension

The effect of naloxone on the hypotensive and bradycardiac action of clonidine was studied in 27 hospitalized patients with uncomplicated mild-to-moderate essential hypertension. In a double-blind, crossover study, clonidine, 0.3 mg/day orally for 3 days, significantly reduced systolic and diastolic blood pressure and heart rate, whereas placebo was ineffective. Naloxone, 0.4 mg given intravenously on the third day of clonidine treatment, caused a rapid increase in blood pressure and heart rate in 14 patients (reacting group), but was ineffective in the remaining 13 patients (nonreacting group). Naloxone given during the placebo period was ineffective in all patients. Both the clonidine-induced hypotension and the rebound increase in blood pressure after cessation of clonidine were significantly greater in the reacting than in the nonreacting group. These observations suggest that release of an endogenous opioid contributes to the antihypertensive action of clonidine; this mechanism may be also involved in the discontinuation syndrome after cessation of clonidine.     

Blood pressure crisis following withdrawal of clonidine (Catapres, Catapresan), with special reference to arterial and urinary catecholamine levels, and suggestions for acute management

In five patients with severe essential hypertension, placebo was substituted after 24 to 48 months of treatment with clonidine and a diuretic. In the present study, four of the patients developed a marked blood pressure rise following withdrawal of clonidine which was rapidly reversed by intravenous administration of propranolol 0.2 mg. per kilogram of body weight and phentolamine 20 to 30 mg. The fifth patient was pretreated with reserpine 2.0 mg. intramuscularly for three days prior to withdrawal of clonidine, and the blood pressure rise which he experienced was far less impressive. All patients experienced similar “withdrawal” symptoms, consisting of headaches, insomnia, restlessness, tremor, and nausea.Catecholamines were determined in arterial blood and urine, before and during the overshoot. They revealed a marked increase, particularly in the urine samples, consistent with the appearance of a hyperadrenergic state.     

Clinical experience with rate-controlled delivery of antihypertensive therapy by a transdermal system

The efficacy of transdermal clonidine, alone and in combination with diuretics, has been demonstrated in several studies involving patients with mild to moderate essential hypertension. In one 3-month open study, 64% of patients (wearing one to three 3.5 cm2 transdermal patches) achieved sustained blood pressure reductions throughout the treatment period. In this large study, side effects requiring discontinuation of drug were not observed. Transdermal clonidine reduced plasma renin activity and urinary aldosterone excretion to the same extent as that reported for oral clonidine. Renal function or serum electrolytes were not affected during therapy with transdermal clonidine. Another study showed that patients receiving oral clonidine and hydrochlorothiazide experienced comparable blood pressure reductions when switched to transdermal patches. Plasma drug concentrations measured during treatment with the transdermal patches were similar to the trough levels observed during treatment with oral clonidine. The equipotency of oral and transdermal therapy in combination with hydrochlorothiazide was also demonstrated in two remaining studies. In one of these studies it was suggested that daily variations in blood pressure induced by the peak and trough drug levels of the oral form were minimized by the stable drug levels characteristics of the transdermal device.     

Clonidine,a centrally acting sympathetic inhibitor,as monotherapy for mild to moderate hypertension

Sixteen patients with uncomplicated essential hypertension were treated with 0.2 mg of clonidine three times daily as the sole antihypertensive drug. Blood pressure decreased from 167 ± 4/105 ± 2 to 139 ± 3/89 ± 2 mm Hg (mean ± standard error of the mean) after 1 week (p < 0.001) and remained at 140 ± 3/90 ± 2 mm Hg after 3 months of therapy. There were no significant changes in cardiac output, blood volume, renal blood flow or glomerular filtration rate during clonidine therapy. Clonidine significantly decreased plasma catecholamines and there was a linear correlation between the change in blood pressure and decreases in plasma catecholamine concentration (r = 0.61, p < 0.001). There was also a significant correlation between the decreases in heart rate and blood pressure (r = 0.78, p < 0.001). It is concluded that clonidine can be used effectively and safely as the sole agent in the treatment of mild to moderate hypertension.     

Abrupt and Gradual Change from Clonidine to Beta Blockers in Hypertension

ABSTRACT. Elective change of antihypertensive therapy from clonidine to β-blockers was studied in 18 hypertensive inpatients on diuretic treatment. An abrupt cessation of clonidine (0.3 mg t.i.d.) and start of treatment 12 hours later with atenolol (50 mg b.i.d.) resulted, within 24–36 hours, in severe rise of blood pressure and intolerable symptoms of clonidine withdrawal in all 4 patients studied. Plasma noradrenaline levels were elevated 18–24 hours after the last dose of clonidine. Halving the previous daily clonidine dose (0.15 mg t.i.d.) and discontinuing it after three days on concomitant treatment with atenolol or timolol in increasing doses proved successful and caused only few side-effects in 14 hypertensive inpatients.     

Effects of a Dual L/N-Type Calcium Channel Blocker Cilnidipine on Blood Pressure,Pulse Rate,and Autonomic Functions in Patients with Mild to Moderate Hypertension

The current study was conducted to examine the effects of cilnidipine, a dual L/N-type calcium channel blocker, on blood pressure, pulse rate, and autonomic functions in patients with mild-to-moderate hypertension. Sixteen patients with mild-to-moderate hypertension (8 males and 8 females; 44–72 years of age) were treated with cilnidipine (10 mg/day) for 3 months. Before and after the treatment, the following measurements were conducted; beat-to-beat blood pressure during late phase II and overshoot phase of the Valsalva maneuver, the Valsalva ratio, heart rate response to deep breathing, systolic and diastolic blood pressure, and pulse rate. The head-up tilt test was also performed before and after the treatment. Cilnidipine significantly decreased either the systolic or diastolic blood pressure from 151 ± 15 mmHg to 129 ± 14 mmHg or 84 ± 11 mmHg to 71 ± 9 mmHg, respectively. For pulse rate, there were no significant changes during therapy. Beat-to-beat blood pressure during late phase II and overshoot phase of the Valsalva maneuver indicated significant improvements in both figures. The heart rate response to deep breathing and the Valsalva ratio indicated no significant differences during therapy. Before and after the treatment, no orthostatic hypotension was observed during the head-up tilt test. The current study revealed that cilnidipine significantly decreases blood pressure with improving autonomic functions while having no adverse effects on heart rate response and pulse rate.     

Drugs five years later: clonidine

Clonidine represents the prototype of a new class of centrally acting antihypertensive agents, classed as partial alpha-adrenergic antagonists. Blood pressure reduction is characterized, hemodynamically, by reduced cardiac output with unchanged peripheral vascular resistance at rest. Reflex control of blood pressure during orthostasis and exercise appears to be unimpaired, and orthostatic hypotension is uncommon. As with most other antihypertensive agents, satisfactory reduction of blood pressure with clonidine given as a sole agent is limited to patients with relatively mild hypertension; an additive or synergistic effect of diuretic administration has been well documented. Abrupt withdrawal of clinidine has been reported to be followed, within 24 to 36 h, by rebound hypertension, tachycardia, cardiac arrhythmias, and other changes suggestive of sympathetic overactivity. The incidence and clinical significance of rebound hypertension after abrupt cessation of clonidine therapy, and indeed the profile of blood pressure responses to varying physical activity during therapy, remain to be evaluated.     

Centrally Acting Alpha-Adrenoceptor Agonists in Hypertension: Mechanisms and their Role in Therapy

Summary: Centrally acting alpha-adrenoceptor agonists in hypertension: Mechanisms and their role in therapy. C. T. Dollery, Aust. N.Z. J. Med. , 1976, 6 , pp. 88–94.
Experimental work in animals has shown that both methyldopa and clonidine lower the blood pressure predominantly by an action on the central nervous system. This action is due to alpha-adrenoceptor stimulation by clonidine and by alpha-methyl-noradrenaline. The evidence for a central site of action for these drugs in man is indirect but persuasive. Both drugs lower blood pressure and heart rate without causing much postural or exercise hypotension. Sympathetic responses like the overshoot of pressure following Valsalva's manoeuvre are reduced but not abolished. Failure of ejaculation in the male is much less common than with drugs that are known to blockade sympathetic adrenergic neurones in the periphery.     

Rebound hypertension after discontinuation of transdermal clonidine therapy

Three (and possibly all four) elderly hypertensive patients who were followed sequentially after discontinuation of transdermal clonidine monotherapy manifested a rapid rise in blood pressure to levels above control (pre- and post-therapy) readings. No signs of an "overshoot" in plasma norepinephrine levels or symptoms of beta-adrenergic overactivity were seen. Such rebound hypertension suggests hypersensitivity to alpha-adrenergic receptor stimulation and could pose a heretofore unreported potential hazard to elderly or otherwise compromised patients who discontinue transdermal clonidine therapy.     

Prevention of propranolol withdrawal mechanism by prolonged small dose propranolol schedule

Abrupt withdrawal of propranolol may be followed by a "propranolol withdrawal syndrome "due, at least in part, to enhanced beta adrenergic sensitivity. Tapering propranolol dosage is frequently used in the hope of preventing adverse withdrawal events but the success of such a maneuver has not been shown. The rationale for the dose tapering schedule in this study was based on earlier observations after abrupt withdrawal of propranolol. Nine hypertensive patients were gradually withdrawn from long-term propranolol therapy, either by serial dose reduction for 6 to 9 days (n = 3) or by reduction to a prolonged small dose (30 mg daily) for 2 weeks before complete withdrawal (n = 6). During dose reduction of propranolol and for 2 additional weeks of placebo therapy, serial measurements were made of cardiac sensitivity to isoproterenol, heart rate at rest, blood pressure, plasma catecholamines, serum thyroxine (T4) and triiodothyronine (T3) and symptoms. Serial dose reduction decreased but did not prevent cardiac hypersensitivity in two of three patients. The prolonged small dose therapy largely prevented cardiac hypersensitivity and overshoot in heart rate, blood pressure and plasma catecholamines and symptoms. Serum T4 decreased significantly and T3 tended to increase during and after prolonged small dose treatment. These results indicate that prolonged administration of small dose propranolol before complete withdrawal in hypertensive patients prevents enhanced cardiac beta adrenergic sensitivity and other adverse events.     

Home Blood Pressure Monitoring and Changes in Plasma Catecholamines During Once or Twice Daily Treatment with Atenolol in Patients with Mild Hypertension

Summary: Home blood pressure monitoring and changes in plasma catecholamines during once or twice daily treatment with atenolol in patients with mild hypertension. B. P. McGrath, L. J. Beilin, T. Schofield, C. R. Benedict, N. P. Barker and R. Cooper, Aust. N.Z. d. Med., 1979, 9, pp. 374–381.
1. The effects of atenolol on diurnal blood pressure control, heart rate and plasma catecholamines were studied in nine hypertensive, six of whom also received diuretics. The patients completed a double-blind trial in which the effects of once and twice daily administration of atenolol were compared with placebo.
2. Atenolol (100 mg) given once a day produced significant reduction in diurnal blood pressures recorded at home but the effect was slightly less than either 50 mg given twice a day or 200 mg once a day.
3. Effects on heart rate and blood pressure were seen within 36 hours of the first dose, and were near maximal at 72 hours. After cessation of the drug, mean resting heart rate increased gradually and reached pre-treatment levels five days later, suggesting strong tissue binding of atenolol. Blood pressure increased more slowly over 8–10 days.
4. Plasma noradrenaline levels were increased at rest with atenolol. This argues strongly against the antihypertensive effect of atenolol being due to a reduction of sympathetic nerve activity.
5. Once daily administration of atenolol in this group of patients with mild hypertension produced satisfactory diurnal blood pressure control and beta blockade without "rebound" hypertension on cessation of therapy.     

Beta blockers in hypertension

Beta-adrenoceptor antagonists are effective in the management of patients with mild-to-moderate hypertension. Noncardioselective agents, cardioselective agents and beta blockers with intrinsic sympathomimetic activity (ISA) are equally effective, provided they are used in equipotent doses. Beta blockers can be used as first-line therapy in the management of hypertension and can be safely combined with diuretics, vasodilators, or both, for a better control of blood pressure. The exact mechanism by which beta blockers decrease blood pressure remains speculative, but they all reduce cardiac output during long-term therapy; drugs with ISA lower cardiac output and heart rate less than do drugs without ISA. Pharmacokinetic properties of beta blockers differ widely; drugs metabolized by the liver have shorter plasma half-lives than drugs primarily excreted by the kidneys. Although many of the side effects of various beta blockers are similar, differences in water and lipid solubility account for a higher incidence of central nervous system side effects with lipid-soluble drugs (such as propranolol and metoprolol) than with hydrophilic drugs (such as atenolol and timolol). The incidence of cold extremities has been reported to be less with drugs with ISA, and the incidence of bronchospasm less with cardioselective drugs. In the management of uncomplicated mild-to-moderate hypertension, all beta blockers are equally effective and produce less troublesome side effects than alternative antihypertensive agents. For effective therapy beta blockers can be used in 2 divided daily doses or even once daily.(ABSTRACT TRUNCATED AT 250 WORDS)     

Rebound hypertension following abrupt cessation of clonidine and metoprolol. Treatment with labetalol

Abrupt withdrawal of adrenergic blockers in a hypertensive subject may result in acute hypertensive crisis. This crisis results from marked increase in adrenergic discharge and upregulation of adrenoceptors. In a patient with hypertensive crisis following abrupt cessation of clonidine hydrochloride and metoprolol tartrate, intravenous administration of labetalol hydrochloride rapidly reduced blood pressure and heart rate to precrisis levels. The patient was subsequently maintained in a normotensive state by continued oral use of labetalol. This case study demonstrates that alpha- and beta-blocking activities of labetalol may be particularly beneficial in a hyperadrenergic state following abrupt withdrawal of adrenergic blockers.     

Role of renin and aldosterone suppression in the antihypertensive mechanism of clonidine

The hypothesis that clonidine decreases blood pressure by suppression of the renin-angiotensin II-aldosterone system was investigated in 20 hypertensive patients during a constant sodium and potassium intake. A significant decrease in mean arterial pressure (MAP), from 123 ± 3 to 102 ± 3 mm Hg (P < 0.001) was observed in 15 patients (responders) during treatment with clonidine. In these patients, plasma renin activity (PRA) was decreased by clonidine from 9.9 ± 3.9 to 5.4 ± 1.6 ng/ml/hour (P < 0.05). The decrease in MAP correlated with the decrease in PRA (r = 0.685, P < 0.02) and with the pretreatment PRA (R = 0.596, P < 0.05). The aldosterone excretion was decreased by clonidine by 29 per cent (from 16 ±4 to 11 ± 2 μg/24 hours), but not significantly. However, the changes in PRA were significantly correlated with the changes in aldosterone (r = 0.645, P < 0.05). Among the responders to clonidine, those with the higher pretreatment PRA levels showed the greatest fall in blood pressure. A common characteristic of the nonresponders to clonidine (five patients) was the presence of moderate to severe renal insufficiency. Moreover, in the nonresponders, PRA and urinary aldosterone were not significantly suppressed by clonidine.In order to evaluate further the role of renin suppression as an antihypertensive mechanism during clonidine treatment, the renin (angiotensin II) dependency of hypertension was tested prior to the administration of clonidine by giving an infusion of the angiotensin II competitive antagonist, saralasln to eight patients. In four of the eight patients blood pressure was decreased by both clonidine and saralasin, whereas in three patients clonidine decreased MAP, but saralasin elicited a pressor response. Finally one nonresponder to clonidine exhibited a depressor response to saralasin. Thus, clonidine decreased blood pressure in patients with nonrenin-dependent hypertension.Over-all results indicate that although the decrease in blood pressure is related to renin suppression during treatment with clonidine, another antihypertensive mechanism (or mechanisms) still exists in hypertension without renin dependency.     

The chronic effect of rilmenidine on heart rate variability in patients with mild hypertension

The purpose of this study was to evaluate the chronic effect of rilmenidine on time domain indexes of heart rate variability in patients with mild hypertension. Twenty patients (12 males, eight females; mean age, 47 yr; age range, 38-55 yr), with untreated and newly diagnosed mild hypertension were studied. There was no evidence of diseases other than hypertension. All patients received 1 mg of rilmenidine once daily. If the diastolic blood pressure was still greater than 90 mm Hg after 4 weeks of active treatment, the dose was increased to 2 mg once daily. Twenty-four hour ambulatory electrocardiograms were recorded before, and 4 and 12 weeks after the start of therapy. Time domain parameters of heart rate variability were calculated. Rilmenidine therapy determined a marked decrease in blood pressure. At 4 weeks, rilmenidine induced a significant reduction in systolic and diastolic blood pressure and a further reduction was observed after 12 weeks. At 4 and 12 weeks, time domain parameters of heart rate variability and heart rate were not significantly different in the data obtained before therapy. In conclusion, this study demonstrated that the administration of rilmenidine to patients with mild essential hypertension induced significant reductions in blood pressure, without any significant changes in time domain parameters of heart rate variability.     

Renin and aldosterone suppression in the antihypertensive action of clonidine

In 18 hypertensive patients receiving a constant (100 mEq/day) sodium diet, treatment with clonidine (0.3 mg/day for 5 days) decreased blood pressure in 11 patients with high and normal renin levels and 7 with low renin levels. The high and normal renin group had early and rapid reductions in blood pressure and plasma renin activity. In contrast, the low renin group had a more gradual hypotensive response and only a small absolute decrease in plasma renin. For all patients, pretreatment renin levels were related to the initial decrease in blood pressure but not to the reductions measured after 5 days. Thus, two mechanisms of action of clonidine are possible, one related to acute inhibition of the renin-angiotensin system in patients with high and normal renin levels and another that is independent of renin mechanisms and occurs in all hypertensive patients. In six additional patients with high renin levels induced by prior sodium depletion (10 mEq/day sodium diet), clonidine did not reduce blood pressure or renin, thus indicating that the suppressive action of this agent on renin presser mechanisms occurs only in patients whose elevated renin levels are intrinsic to hypertension and unrelated to sodium depletion.Of the 18 patients receiving a normal sodium diet, 13 were classified as responding to treatment (decrease in both systolic and diastolic pressures of at least 10 percent). The five nonresponders had a greater weight gain and higher values for aldosterone excretion. For all patients, there was a significant correlation between decrements in blood pressure and in aldosterone, suggesting that the countervailing effects of fluid accumulation on blood pressure in nonresponding patients resulted from a failure of aldosterone to be suppressed. Changes in aldosterone, in turn, correlated significantly with changes in renin. Thus, the antirenin effect of clonidine enhances its antihypertensive action not only by acutely ablating renin-angiotensin pressor mechanisms, but also by inhibiting aldosterone production and thereby minimizing longer-term reactive volume retention during treatment.     

Acute and chronic haemodynamic and renal effects of carvedilol in patients with cirrhosis

BACKGROUND/AIMS: Recent reports have suggested that the vasodilating beta-blocker carvedilol may have beneficial acute haemodynamic effects in cirrhotic portal hypertension. However, no data exist on chronic use or renal effects in this patient group. The aim of this study was to assess the acute and chronic haemodynamic and renal effects of carvedilol in cirrhotic patients. METHODS: Seventeen cirrhotic patients (mean age 55.2+/-2.8, mean Child-Pugh score 7.4+/-0.5) were studied. Hepatic venous pressure gradient, cardiac output, systemic vascular resistance, mean arterial pressure, heart rate and hepatic blood flow were measured before and 1 h after 25 mg carvedilol. After 4 weeks of therapy with carvedilol 25 mg daily, these measurements were repeated before and after rechallenge with carvedilol. Urine volume, sodium excretion and creatinine clearance were also measured before and after 4 weeks of therapy. RESULTS: Seven patients did not complete the 4-week carvedilol therapy due to hypotension or poor compliance. Hepatic venous pressure gradient fell by 20.8% acutely (p<0.001) and by 16.3% after 4 weeks of therapy (p<0.002). Heart rate, mean arterial pressure and cardiac output fell after acute administration of carvedilol, but only heart rate fell significantly after 4 weeks of treatment. Hepatic blood flow, urine volume, sodium excretion and creatinine clearance remained unchanged after therapy. CONCLUSION: Carvedilol has beneficial effects on splanchnic haemodynamics following acute and chronic administration in cirrhosis, without compromising hepatic blood flow or renal function. However, a substantial number of patients cannot tolerate 25 mg daily.     

Effects of interferon on circadian changes in blood pressure and heart rate variability in patients with chronic hepatitis.

We have determined the effects of interferon therapy on circadian changes in blood pressure and heart rate variability in normotensive hospitalized patients with chronic active hepatitis. Body temperature and pulse rate increased for the initial few days of interferon therapy without significant change in casual or ambulatory blood pressure. Interferon therapy failed to elicit any significant changes in the power spectrum of R-R intervals. In addition, urinary excretion of norepinephrine did not differ between before and during the therapy. These results suggest that interferon therapy caused transient increases in body temperature and pulse rate, but that it did not change either sympathetic or parasympathetic outflow, or the circadian rhythm of blood pressure and heart rate variability, in normotensive subjects.     

Shortened platelet survival time and enhanced heart rate responses after abrupt withdrawal of propranolol from normal subjects

Although clinical observations suggest that abrupt discontinuation of propranolol therapy may precipitate myocardial ischemia and infarction in patients with coronary occlusive disease, the physiologic consequences of propranolol withdrawal are not fully understood. Platelet survival times and heart rate responses to exercise, upright tilt and isoproterenol were therefore examined in 14 normal subjects before and after abrupt withdrawal of propranolol. Propranolol, 80 to 240 mg/day, was given for 24 to 79 days; its effect was confirmed by a lower heart rate during exercise and during infusion of isoproterenol. In 10 subjects, the mean survival time of chromium-51-tagged blood platelets decreased from 10.0 days before propranolol to 7.8 days after its withdrawal (p <0.05). One day after withdrawal, the rise in heart rate with exercise or tilt was slightly increased from values before propranolol therapy. Two days after withdrawal of propranolol the mean peak heart rate during exercise (165 beats/min) was 12 beats/min higher (p <0.01) than the value before propranolol. On this same day heart rate increased more after tilt without medication (+6 beats/min, p <0.05) and more after tilt following vagal blockade (+8 beats/min, p <0.02) than before treatment with propranolol. Seven days after propranolol withdrawal, heart rate responses to exercise or tilt remained increased. Isoproterenol-induced heart rate responses (5 to 40 ng/kg per min, n = 14), white blood cell beta receptor function (cyclic adenosine monophosphate production after isoproterenol and ³H-I-dihydroalprenolol binding, n = 9) and plasma norepinephrine values at rest and during exercise (n = 7) were each unaltered after propranolol.The results suggest that abrupt withdrawal of propranolol is accompanied by a shortening of platelet survival and enhancement of sympathetically mediated reflex increases in heart rate. These changes may each play a role in the increased incidence of ischemic episodes observed after withdrawal of propranolol from patients with coronary occlusive disease. However, the number of beta receptors and their sensitivity to adrenergic agonists do not seem to be changed uniformly after abrupt withdrawal of propranolol.     

Clonidine and carotid baroreflex in essential hypertension

Clonidine is believed to reduce blood pressure by a neural action and animal experiments suggest that this consists in potentiation of baroreflexes. In 16 patients with essential hypertension we studied the effects of alterations in carotid sinus baroreceptor activity (neck chamber technique) on arterial blood pressure (catheter measurements) and heart rate, before and after intravenous administration of 150 microgram and 300 microgram of clonidine. The magnitude of the reflex responses was assessed by the slope of the linear regressions relating applied increase and decrease in tissue pressure at the carotid sinus (and therefore applied decrease and increase in carotid sinus transmural pressure) and resulting changes in mean arterial pressure and R-R interval. Clonidine caused a marked reduction in mean arterial pressure (-26 +/- 3 mm Hg) and a slight but significant reduction in heart rate (-5 +/- 1 b/min). There was no evidence for a potentiation of the baroreceptor influence on blood pressure, although a slight potentiation of the baroreceptor influence on heart rate was observed in few instances. We conclude that in man clonidine can exert a pronounced hypotensive effect without potentiating baroreceptor influence on blood pressure. Therefore this mechanism does not play a prominent role in the clinical antihypertensive action of the drug.