Clonidine Therapy Research Articles

Effects of clonidine on 24-hour hormonal secretory patterns, cardiovascular hemodynamics, and central nervous function in hypertensive adolescents.

To assess the potential of antihypertensive drugs for interference with somatic growth and sexual development in hypertensive children, the effect of clonidine therapy on various endocrine, cardiovascular, and neuromuscular functions has been examined in five male adolescents with idiopathic hypertension. In studies done before and at the end of 4 weeks of twice-daily clonidine therapy, in an average daily dose of 0.31 mg, no significant effects were noted in the secretory patterns of growth hormone, luteinizing hormone, follicle-stimulating hormone, prolactin, cortisol, aldosterone, or testosterone, measured in blood obtained every 20 minutes for 24 hours. In blood obtained while the patients were supine and then erect, plasma renin activity and norepinephrine levels were significantly lowered after clonidine therapy. Cardiovascular responses to dynamic exercise were little altered beyond a 17% decrease in maximal oxygen consumption. The performance of fine motor skills was minimally altered. These data provide preliminary evidence that clonidine, an antihypertensive drug that affects the adrenergic nervous system, may not interfere with normal growth and maturation in adolescent males.

Changes in blood pressure, heart rate, and sympathetic activity on abrupt withdrawal of tiamenidine (HOE 440) in essential hypertension

A limitation of clonidine therapy is the syndrome of rebound hypertension and sympathetic overactivity after withdrawal. Ten patients, four male, six female, aged 28--64 years, with essential hypertension, were treated for one year with an imidazoline derivative, tiamenidine. Blood pressure fell from an average of 178/108 mm Hg pretreatment to 152/86 mm Hg after 1 year. Tiamenidine was then withdrawn in hospital, replaced by identical placebo under single blind conditions and observations made over 96 h. The study was interrupted in five patients (4 patients within 36 h) because blood pressure rose to greater than 30 mm Hg (systolic) or greater than 20 mm Hg (diastolic) above pretreatment values. For the group, blood pressure was maximal at 194/112 mm Hg, 18 h post withdrawal, significantly higher than pretreatment (p less than 0.005). Headache, tremor, flushing and insomnia were noted. Saliva production rose 100% at 24 h. Plasma noradrenaline rose within 24 h with an accompanying rise in urinary metanephrine and catecholamine excretion. Tiamenidine appears to share with other imidazolines rebound cardiovascular and autonomic effects following abrupt withdrawal.

An acute psychotic episode at the beginning of clonidine therapy

1. 1. A case of an acute behavioral-psychotic side effect to clondine therapy is presented. 2. 2. A possible mechanism of this psychotic side effect involving the adrenergic system, is suggested.

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.

Studies with clonidine (dixarit) in menopausal women.

Eleven women with menopausal symptoms were treated with 150 micrograms Clonidine (dixarit) daily. Before and during therapy, plasma estradiol-17 beta, LH, FSH and prolactin levels were measured by specific radio-immunoassays. In addition, each patient recorded the number of hot flushes a day and symptoms were monitored by the Kupperman-index. A highly significant fall in the number of hot flushes by day and night occurred during therapy (p less than 0.001) and the Kupperman-index similarly improved. Significant pulse and blood pressure changes were not noted and plasma hormone concentrations remained unaltered. Medication was well tolerated. Clonidine therapy would appear to be the treatment of choice for menopausal symptoms if estrogens are contraindicated.

Abrupt Discontinuation of Clonidine Therapy

Clonidine therapy was discontinued abruptly in seven patients. Blood pressure was recorded every hour or two hours throughout the study. Clonidine therapy was reinstituted 48 hours after its discontinuation in all except two patients, in whom it was reinstituted at 36 hours. During the withdrawal phase, blood pressure tended to return rapidly to nontreatment levels, but there was no "overshoot" in blood pressure. Apprehension, insomnia, palpitations, and sweating were experienced by two patients. These symptoms were relieved promptly by reinstituting clonidine therapy. In this prospective study, no blood pressure overshoot was noted with abrupt discontinuation of clonidine.

Abrupt discontinuation of clonidine therapy

Abrupt discontinuation of clonidine therapy

Reduced renovascular resistance by clonidine.

The antihypertensive effect of clonidine has been attributed to acute inhibition of sympathetic outflow from the central nervous system. This conclusion is derived from experiments with single doses of clonidine. The mechanism of the long-term blood pressure-lowering effect of clonidine has been less well characterized. Antihypertensive therapy may alter renal hemodynamics and these changes may ultimately affect systemic blood pressure. We studied the effect of long-term clonidine therapy on intrarenal hemodynamics, the renin-angiotensin system, and selected indices of sympathetic nervous system activity in 13 patients with essential hypertension to further elucidate its action. Long-term clonidine therapy resulted in decreased MAP and RVR associated with the suppression of supine but not upright PRA. RPF, RBF, FF, and WBV did not change. UKA, on index of the the putative vasodilating renal kallikrein-kinin system, was also not changed. Our findings suggest a role for PRA in modulating RVR during long-term clonidine therapy. This was associated with the reduction observed in MAP.

Preoperative and Postoperative Use of Clonidine with Neurolept Anaesthesia

The abrupt cessation of clonidine therapy can induce a withdrawal syndrome. This may also appear immediately after anaesthesia if clonidine medication is discontinued during the operation day. We studied (1) whether the withdrawal syndrome occurs postoperatively as often as otherwise when clonidine therapy is discontinued, and (2) the action of this clonidine withdrawal on the circulation as compared to patients who received clonidine without interruption during the operation day. During the recovery period in 2 out of 10 patients in whom clonidine medication was discontinued, a hypertensive crisis occurred, which was relieved by clonidine readministration. Clonidine given with premedication eliminated high rises in blood pressure during anaesthesia. During the recovery period, the regular intramuscular administration of the same dose of clonidine as the patients had used orally decreased blood pressure to almost normotensive levels. The slightly increased urinary catecholamine excretion and plasma renin activity in these patients might, however, indicate that the circulatory homeostasis was disturbed in some degree. The results suggest that it is important to give clonidine continuously, even during the operation day. The dose may be the same as, or preferably somewhat smaller than that which the patients have previously received orally.

Response of hypertensive adolescents to clonidine therapy: David E. Fixler, University of Texas Health Science Center, 5323 Harry Hines Blvd., Dallas, Texas 75235; W. Pennock Laird

Response of hypertensive adolescents to clonidine therapy: David E. Fixler, University of Texas Health Science Center, 5323 Harry Hines Blvd., Dallas, Texas 75235; W. Pennock Laird

Clonidine withdrawal. Mechanism and frequency of rebound hypertension.

1. The frequency and pathophysiology of the clonidine withdrawal syndrome was studied in fourteen hypertensive patients on chronic clonidine therapy. 2. After sudden cessation of clonidine (900 microgram daily) almost all of the patients showed an excessive increase of the heart rate and blood pressure. Seven of the fourteen patients had subjective symptoms, in three severe enough to require interruption of observation by therapeutic intervention 12 to 60 h after the last dose of clonidine. After clonidine withdrawal, NAE increased to abnormally high values in correlation with the blood pressure (P less than 0.01) and heart rate (P less than 0.001), whereas PRA even decreased initially, probably secondary to the rise of the blood pressure, and only rose, although not significantly, 48 h after withdrawal. PRA was not correlated with NAE, heart rate, or blood pressure. 3. It is concluded that the clonidine withdrawal phenomenon is a frequently occurring and potentially dangerous syndrome. Overactivity of the sympathetic nervous system is mainly responsible, without the mediation of the renin angiotensin system. This also explains our experience that adrenergic beta-receptor blocking drugs do not prevent the rise in BP, although they alleviate some of the symptoms.

Renin stimulation during clonidine therapy in "low renin" essential hypertension.

Plasma renin activity (PRA) was measured during the administration of clonidine (0.1 mg twice daily) to 11 patients with essential hypertension. After eigth weeks a trend toward an increase in PRA was noted. This increase was significant in "low renin" subjects (less than 1 ng Al/ml/hr, n = 7) in whom PRA (ng/ml/hr +/- SEM) rose from a control value of 0.7 +/- 0.1 to 2.0 +/- 1.1 at one week, 5.6 +/- 2.1 at four weeks, and 4.4 +/- 1.0 at eight weeks (p less than 0.05). In contrast, in a small group of "normal renin" patients (n = 4), PRA did not change significantly but tended to decrease on clonidine therapy from 9.2 +/- 3.4 at control to 3.3 +/- 2.0 at one week, 3.4 +/- 0.6 at four weeks, and 4.7 +/- 1.7 ng Al/ml/hr at eight weeks. Plasma renin substrate and serum and urinary electrolytes did not change significantly in either group and blood pressure reduction was comparable in the two groups. A strong negative correlation (r = -0.84, p less than 0.001) was found between changes in creatinine clearance and changes in PRA. Previous studies have implicated alpha-adrenergic receptors as the site of clonidine actions on blood pressure and renin release. The observed renin stimulation during chronic administration of clonidine to "low renin" patients with essential hypertension may imply an altered intrarenal alpha-receptor function in "low renin" essential hypertension.

Abrupt cessation of clonidine administration: A prospective study

In 20 patients with mild to moderate hypertension, the effects of abrupt cessation of clonidine therapy on blood pressure, heart rate and catecholamine excretion were evaluated. In a double blind, crossover study, placebo was substituted for clonidine after 3 days of therapy and again after 30 days. The results demonstrated no instances of clinically significant symptoms or overshoot in blood pressure or heart rate. There was an overshoot in norepinephrine excretion that approached the upper limits of normal. Thus, a clinical withdrawal syndrome associated with abrupt cessation of clonidine was not seen in this study of patients without severe hypertension who were given the drug without a diuretic agent.

Long-Term Treatment of Refractory Hypertensive Patients With Minoxidil

Twenty-nine hypertensive patients refractory to conventional medications were treated continuously with minoxidil, sympathetic suppressants, and diuretics for six months to five years (mean, 30 months). All had evidence of hypertensive end-organ damage before minoxidil therapy. Good blood pressure control was obtained in 21 (72%) of 29 patients when minoxidil was given in dosages up to 40 mg/day. No tolerance was found. In the remaining eight, good control was obtained in three when phenoxybenzamine therapy was added, and in one when clonidine therapy was added. Renal failure requiring hemodialysis developed in five of 29, one had temporary hemiparesis, and one had fatal cerebral hemorrhage. In the remainder, myocardial infarctions and strokes were effectively prevented. Patients receiving minoxidil and propranolol hydrochloride had elevated plasma norepinephrine levels while those receiving clonidine had normal plasma norepinephrine levels.

Withdrawal of Antihypertensive Therapy

Hypertensive crises were reported in three patients with hypertension associated with underlying renovascular occlusive disease during reduction of antihypertensive therapy. In each case, rebound hypertension was observed during clonidine hydrochloride withdrawal. Therapy with propranolol hydrochloride and diuretics had also been discontinued in two of the three patients. This and other reports of rebound hypertension during clonidine withdrawal are contrasted with the absence of reports of this syndrome in the setting of cessation of beta-adrenergic blockade therapy. This suggests that the discontinuation of clonidine therapy was primarily responsible for the hypertensive crises herein described. It is further concluded that rebound hypertension may follow gradual as well as abrupt reduction of clonidine dosage, and that patients with renovascular hypertension may be at greatest risk.

Clonidine

A double-blind crossover study to determine the effects on intraocular pressure (IOP) and blood pressure of topically instilled 0.125% and 0.25% solutions of clonidine hydrochloride by comparison with a 2% pilocarpine hydrochloride solution and placebo was carried out in a total of 21 patients with open-angle glaucoma, each of whom received a single drop of each preparation in the same glaucomatous eye on separate days. Both clonidine solutions were effective in lowering the IOP; the 0.25% solution was more effective than the 0.125% solution, and the former was slightly less potent than pilocarpine. Pupil diameter was essentially unchanged in all but one of the patients after clonidine. Pilocarpine reduced pupil diameter in all patients. One eye treated with placebo also showed a reduction in pupil size. Both systolic and diastolic blood pressure showed a statistically significant reduction after clonidine, but the magnitude of the change was small. We do not regard the minor blood pressure changes as being a threat to the optic nerve but further studies in this aspect of topical clonidine therapy are required.

Letter: Aspects of clonidine therapy.

Letter: Aspects of clonidine therapy.

Combined Clonidine-Chlorthalidone Therapy in Hypertension

The efficacy and safety of the antihypertensive drug, clonidine, were tested by open-label trial in 30 ambulatory, hypertensive patients who were concomitantly receiving the diuretic, chlorthalidone. This combined treatment followed several weeks of base line treatment with the diuretic alone. In both the recumbent and the upright position, clonidine potentiated the blood pressure-lowering effect of chlorthalidone to a noticeable degree; with combined treatment, the reductions in systolic and diastolic pressures were from 12.9% to 16.4% greater. Side-effects, consisting mostly of drowsiness and dryness of mouth, were mild and were observed mainly at the beginning of clonidine therapy. Orthostatic hypotension or weakness was experienced by 3 patients, but it subsided after dose adjustment in two of them. The drug combination was well suited for long-term management of patients with hypertension of all degrees of severity.

Letter: Dementia associated with clonidine therapy.

Letter: Dementia associated with clonidine therapy.