Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0085580 (essential hypertension)
 14,686 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although essential hypertension is usually defined as a hemodynamic disorder, it is expressed differently among individuals and varies during progression of the disease state. Therefore, various types of treatment can be envisioned. The use of selective I1-imidazoline-receptor agonists to modulate I1-imidazoline receptors involved in the central regulation of blood pressure has led to the introduction of a novel class of centrally acting antihypertensive drugs. Moxonidine, a representative molecule of this class, dissociates between a 10% alpha 2-adrenoceptor-agonist action linked with side effects such as fatigue or dry mouth, and a 90% specific antihypertensive action resulting from its selective agonistic action at I1-imidazoline receptors. Clinical experience is based on more than 2,000 patients and volunteers, and long-term efficacy has been demonstrated in about 500 patients who received a daily dose of moxonidine 0.2-0.4 mg. Moxonidine produces a pronounced reduction in peripheral vascular resistance without reflex tachycardia, accompanied by reduced plasma norepinephrine concentration and plasma-renin activity. Cardiovascular responses to exercise and standing remain nearly normal, and serious or life-threatening side effects, particularly the sympathetic overactivity that can occur on sudden withdrawal of other centrally acting agents, are never observed. In addition, moxonidine behaves neutrally with respect to plasma levels of cholesterol, potassium and glucose, glucose and lipid metabolism, and renal function, and can be administered without complication to patients with asthma or certain other diseases. Studies with magnetic resonance imaging have shown that moxonidine significantly reduces left ventricular mass, an indicator of left ventricular hypertrophy (LVH), within a 6-month treatment period, an effect that coincided with decreased plasma concentrations of catecholamines and renin. Comparisons between moxonidine and other well-established antihypertensive drugs such as nifedipine, atenolol, or angiotensin-converting enzyme inhibitors showed equal effectiveness in lowering blood pressure, whereas the adverse events profile always favored moxonidine. Considering its efficacy, safety, and specific effects (e.g., its ability to reduce LVH), moxonidine meets the criteria satisfied by other currently prescribed antihypertensive drugs. Because of its especially favorable benefit-to-risk ratio, moxonidine should be recommended as first-line treatment of hypertension and may also be useful in treating related problems such as LVH, coronary artery disease, and ventricular premature beats.
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PMID:I1-imidazoline-receptor agonists in the treatment of hypertension: an appraisal of clinical experience. 753 26

The influence of the sympathetic nervous system on blood pressure control was impressively demonstrated in 1940 by bilateral excision of sympathetic nerve fibers. Thereafter, the first generation of drugs lowering blood pressure by central modulation of the sympathetic outflow through alpha 2-adrenoceptor for stimulation, such as alpha-methyldopa, guanabenz, clonidine, and guanfacine, were marketed. However, these compounds were often tolerated poorly, because they caused orthostatic hypotension, sedation, tachycardia or bradycardia, dry mouth, and reduced cardiac output. The mode of action of the second generation centrally acting antihypertensive drugs moxonidine and rilmenidine is different from that of the first generation compounds (e.g., clonidine). Contrary to clonidine, the newer drugs bind more selectively to I1-imidazoline receptors rather than to alpha 2-adrenoceptors where first-generation drugs act. The high affinity and selectivity of these two drugs for this recently discovered new receptor class make it possible to discriminate between I1-imidazoline receptor-mediated blood pressure lowering, on the one hand, and alpha 2-adrenoceptor-mediated side effects, on the other. Discrimination of the two effects was substantiated either by studies using moxonidine alone or in interaction experiments with I1-imidazoline receptor or alpha 2-adrenoceptor antagonists. The high selectivity of moxonidine at the I1-imidazoline receptor allows discrimination between alpha 2-adrenoceptors and I1-imidazoline receptors and is reflected in man by the relatively low incidence of adverse drug events during moxonidine treatment. Concentration of endazoline, a specific mediator of I1-imidazoline receptors, is elevated in some patients with essential hypertension. Modulation of I1-imidazoline receptors by moxonidine could be interpreted as antagonism with regard to the endogenous agonistic effect of the endogenous "transmitter" endazoline. On the other hand, moxonidine acted directly as an agonist at the putative I1-imidazoline receptor. Therefore, to clear the ground, characterization as well as physiological function of the mediator for imidazoline receptors seems essential. The therapeutic relevance of using drugs selective for I1-imidazoline receptors for blood pressure reduction in hypertensive patients is substantiated by the finding that in human rostral ventrolateral medulla (RVLM), which is essential in central blood pressure regulation, the relation between alpha 2-adrenoceptors and I1-imidazoline receptors is about one to ten (1:10). Reduction of a long-lasting sympathetic overdrive may avoid the deteriorating effects on the heart and peripheral circulation. These recent findings give a rational explanation for the very low incidence of sedation and the absence of respiratory depression, orthostatic hypotension, and rebound hypertension that banned the former central acting antihypertensive drugs from first-line treatment despite the advantages of central mediated blood pressure control.
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PMID:Why imidazoline receptor modulator in the treatment of hypertension? 767 85

Centrally acting antihypertensive drugs are recognized to be safe and effective treatment for high blood pressure. Centrally mediated side effects, such as sedation, are commonly dose- and treatment-limiting events. Imidazoline-preferring receptors, while functionally similar to alpha 2 adrenoceptors, are distinguishable not only on the basis of in vitro radioligand binding but also in vivo in terms of side effects. Drugs with an imidazoline structure lower blood pressure but are less likely to impair psychomotor function. A placebo-controlled study compared moxonidine 0.1 mg with clonidine 0.1 mg orally in nine normal subjects. Both active drugs lowered blood pressure compared to placebo (clonidine more than moxonidine). However, psychomotor function and self-scored sedation and dry mouth were significantly affected only by clonidine. In a long-term (4 weeks) double-blind cross-over study in essential hypertension, rilmenidine was well tolerated and had similar effects to those of atenolol on erect and supine blood pressure. Rilmenidine had no effect on a wide range of autonomic and psychomotor tests or on responses to mental or physical stress. Atenolol, by contrast, had the predicted effects of a beta adrenoceptor antagonist on heart rate during exercise and the Valsalva maneuver. Imidazoline-preferring drugs offer a new and realistic approach to antihypertensive therapy with blood pressure reduction not limited by marked sedation within the therapeutic dose range.
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PMID:Clinical pharmacology of drugs acting on imidazoline and adrenergic receptors. Studies with clonidine, moxonidine, rilmenidine, and atenolol. 767 87

The objective of this study was to assess the efficacy and tolerability of transdermal clonidine in inner-city African-American and Hispanic-American patients with essential hypertension. A multiclinic open-label, prospective trial for 12 weeks was used. Dose titration was based on office blood pressure (BP) measurements of > 140/90 mm Hg. Clinical sites were community-based primary care centers. Untreated and treated hypertensive patients whose diastolic BP exceeded 90 mm Hg were administered transdermal clonidine at 0.1 mg or 0.2 mg delivery daily. The drug was titrated after 1 month if diastolic BP was greater than 90 mm Hg. At 12 weeks of treatment, change in blood pressure from baseline as well as adverse effects and patient satisfaction were assessed. A total of 357 patients entered the treatment phase of the study, and 315 patients (244 African-Americans, 67 Hispanic-Americans) had evaluable data. Transdermal clonidine significantly (P <.001) lowered BP in all patients by 15.7/12.8 +/- 18.1/9.6 mm Hg, and heart rate was reduced by 3 +/- 9 beats/min (P <.001). There were no differences in BP reduction according to race and ethnicity, gender, or age. The most common adverse effects were pruritus or discomfort at the patch site, dizziness, dry mouth, and fatigue. Eleven percent of the patients discontinued treatment because of one of these adverse effects. A large proportion of patients (67%) reported that transdermal clonidine was more convenient to use than oral therapy. Transdermal clonidine, alone or in combination with other antihypertensive therapies, significantly lowered BP and heart rate in inner-city hypertensive patients. The drug was generally well tolerated, with 89% of the patients remaining in the trial. Patient acceptability was high with the once-weekly treatment, which is an important feature for this particular hypertensive population.
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PMID:Clinical experience with transdermal clonidine in African-American and Hispanic-American patients with hypertension: evaluation from a 12-week prospective, open-label clinical trial in community-based clinics. 1042 43

Central regulation of the sympathetic nervous system plays an important role in the maintenance of blood pressure. In a subset of patients with essential hypertension, sympathetic activation may contribute to the development and maintenance of hypertension. Unlike the first generation of centrally active antihypertensive drugs, the second generation may be superior because of its selectivity to I1-imidazoline receptor and selective binding to the vasomotor center. Lack of a2 effects differentiates moxonidine from clonidine with respect to monoxidine"s superior side-effect profile (little or no sedation or dry mouth). Clinical trials show that moxonidine is as effective as angiotensin-converting enzyme inhibitors (eg, enalapril and captopril), b-blockers (e.g., atenolol), calcium-channel blockers (e.g., long-acting nifedipine), and diuretics (eg, hydrochlorothiazide) in lowering blood pressure and that it has superior tolerability. Thus, central modulation of the sympathetic nervous system has re-emerged as an exciting target for blood pressure reduction. Given the multiple adverse effects of sympathetic stimulation in various disease processes, including congestive heart failure, moxonidine may be the next therapeutic option for the management of hypertension and the prevention of target organ dysfunction.
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PMID:Centrally acting antihypertensive drugs: re-emergence of sympathetic inhibition in the treatment of hypertension. 1098 Oct 82


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