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Alpha-adrenergic receptors play an important role in the regulation of blood pressure (BP). There are 2 principal types of alpha receptors, alpha 1 and alpha 2, and both participate in circulatory control. Alpha 1 receptors are the classic postsynaptic alpha receptors and are found on vascular smooth muscle. They determine both arteriolar resistance and venous capacitance, and thus BP. Alpha 2 receptors are found both in the brain and in the periphery. In the brain stem, they modulate sympathetic outflow. Their function in the periphery is not yet fully understood, but they may contribute both to control of sympathetic tone and to local and regional blood flow. Drugs that enhance central alpha 2 activity, such as clonidine, guanfacine and the active metabolite of methyldopa, can significantly lower BP and are effective in the long-term control of hypertension, either alone or in combination with other drugs. While central alpha agonists, as a class, share a common pharmacologic mode of action, side effects, e.g., sedation and drowsiness, occur to different degrees with different drugs, and the individual agents also vary in terms of their propensity for causing withdrawal hypertension. The use of low-dose regimens or of newer drugs, such as guanfacine, with its longer half-life and duration of action, may reduce the likelihood of adverse reactions associated with this class of drugs.

Three clinical studies examined the effects of guanfacine as monotherapy. Study 1 was a double-blind, randomized, parallel trial with a placebo control with 26 patients with mild essential hypertension treated with 1-mg guanfacine or matching placebo daily at bedtime for 8 weeks. Pretreatment and posttreatment determinations of plasma volume, plasma aldosterone and blood pressure (BP) were made in all 26 patients. There were no significant differences between guanfacine and placebo with regard to changes in plasma volume or plasma aldosterone, but a significant decrease (p = 0.001) in both diastolic and mean BPs was seen with the active drug. No side effects were reported. From this study, it was concluded that guanfacine monotherapy is an effective and well-tolerated initial treatment for mild essential hypertension with no effect on either plasma volume or plasma aldosterone. Study 2 was a double-blind, randomized, parallel clinical study with placebo control with 42 patients with mild essential hypertension treated with either guanfacine (1 mg/day) or matching placebo at bedtime for 8 weeks. Pretreatment and posttreatment evaluations of serum cholesterol, triglycerides, low density lipoproteins, very low density lipoproteins and high density lipoproteins revealed no significant differences between the treatment and the placebo groups. A statistically significant (p less than 0.0001) decrease in diastolic BP was seen in the guanfacine group compared with those patients who received placebo. Guanfacine monotherapy was again shown to be an effective initial treatment for mild essential hypertension with no adverse influence on serum lipids.(ABSTRACT TRUNCATED AT 250 WORDS)

To assess the long-term efficacy and safety of guanfacine, a centrally acting alpha-adrenergic agonist, 580 mild, moderate and severe hypertensive subjects were treated with the drug for 1 year. Mean ages of both the 257 women and 323 men were 52 years. Most had essential hypertension; 55 patients had renal, 22 renovascular and 4 endocrine-related hypertension. When possible, 1- to 3-week washout periods were used before and after treatment. Doses up to 20 mg/day were used in some patients. Diuretics, beta blockers, vasodilators or some combination thereof were used in some patients. After the 1-year study, 169 patients were continued on therapy for another year, and 54 were evaluated for 5 to 7 years. Normalized blood pressures (BPs) were achieved in 54%, 66% and 63% of patients in the first, second, and 5- to 7-year groups, respectively. Guanfacine, alone and in combination, proved safe and effective. Once- and twice-a-day doses were superior to 3-times-a-day dosing. Lower doses were more effective and produced fewer side effects. Large-scale, open-field studies evaluated the effect of low-dose therapy in 1,234 Belgian, 3,504 French and 4,627 German patients, with average BPs of 180/103 mm Hg. The average BP reduction during treatment was 16%. Most Belgian (56%) and French (74%) patients received 2 mg/day; 60% of German patients received 1 mg/day throughout the study. BPs normalized in 71% of Belgian, 58% of French and 61% of German patients.

Control of hypertension (ie, reduction of blood pressure to less than or equal to 160/90 mmHg) in 40 mild to moderate hypertensives not responding adequately to hydrochlorothiazide was achieved by the addition of guanfacine (once daily) or methyldopa (twice daily) in a 16-week, double-blind, parallel-group trial. Control occurred after two weeks (at 1 mg/day) in 50% of the guanfacine-treated patients and in most patients within four to six weeks of treatment. The final mean doses were 2.5 mg/day of guanfacine or 763 mg/day of methyldopa. Sixteen patients maintained control of hypertension with continued guanfacine therapy for one year.

Guanfacine, an alpha-adrenoceptor agonist, may exhibit distinct dose-related curves for efficacy and adverse effects in the step-2 therapy of essential hypertension. To determine the lowest clinically effective safe dose, 462 newly or previously diagnosed subjects were admitted to a 5-week prerandomization phase at 8 centers. Patients were weaned from any current antihypertensive drugs and placed on 25-mg chlorthalidone, daily, in the morning. At the end of the 5-week weaning period, 362 patients with seated diastolic blood pressures (BPs) between 95 and 114 mm Hg qualified for the 12-week postrandomization phase. Subjects were randomized to receive either an indistinguishable placebo or 0.5, 1, 2 or 3 mg of guanfacine. Chlorthalidone was changed to bedtime administration and taken with the study medications. Guanfacine was started at the lowest dose in all subjects and increased (if scheduled, according to the randomization code) to the next higher dose at biweekly intervals. Of the 362 randomized patients, 278 completed the study. The 1-mg guanfacine dosage produced a 14/13 mm Hg decrease in BP (p less than 0.0125 compared with placebo). Doses of guanfacine at 2 and 3 mg/day were not more effective than the 1 mg/day dose; 0.5 mg/day was not better than placebo. There was an increase in the frequency of side effects possibly or probably associated with 2 and 3 mg/day guanfacine. Only 3.2% of the patients in the 1 mg/day group dropped out of the study because of side effects. We conclude that when added to a diuretic, 1 mg/day guanfacine at bedtime is the lowest safe and therapeutically effective dose.

Guanfacine, an alpha 2-adrenoceptor agonist, was compared with clonidine as step-2 therapy of mild to moderate essential hypertension in a 24-week, double-blind, randomized, parallel evaluation to determine efficacy, safety and occurrence of withdrawal syndrome. During a 5-week period, patients were weaned from current antihypertensives, if any, and stabilized on step-1 therapy with 25 mg of chlorthalidone once a day. Those with a diastolic blood pressure (BP) from 95 to 114 mm Hg while taking chlorthalidone were randomized to treatment. The 2 agents had equal efficacy; 149 of 270 patients treated with guanfacine (55%) and 164 of 276 treated with clonidine (59%) achieved goal diastolic BP of less than or equal to 90 mm Hg. Terminations because of adverse effects were relatively low. Dry mouth (30% of guanfacine and 37% of clonidine groups) and somnolence (21% of guanfacine and 35% of clonidine groups, p less than 0.05) were reported most frequently. Nonsyncopal dizziness was reported in 11% of guanfacine-treated and 8% of clonidine-treated patients. This difference was not statistically significant. To evaluate the occurrence of a withdrawal syndrome in 316 outpatients and 156 inpatients, vital signs were monitored at least twice a day for up to 7 days after the end of therapy. Segmented 24-hour urine studies were performed on inpatients. Abrupt withdrawal of clonidine produced a rapid increase in diastolic and, especially, systolic BP, whereas guanfacine withdrawal produced more gradual increases. The differences were significant over the first 3 withdrawal days. It is concluded that guanfacine is a safe, effective, second-generation alpha 2-adrenoceptor agonist.(ABSTRACT TRUNCATED AT 250 WORDS)

The 24-hour duration of the antihypertensive effect of guanfacine, a centrally acting alpha 2-adrenoceptor agonist administered once a day, was demonstrated in a 12-week, multicenter, double-blind, placebo-controlled study. Two hundred and forty-nine patients who remained mildly to moderately hypertensive following a 5-week period, during which they had been weaned from previous antihypertensive medications and stabilized on 25-mg chlorthalidone taken once a day, were involved. Of the 249 patients, 126 received guanfacine as a step-2 agent and 123 received placebo. Both groups were further subdivided so that blood pressure (BP) measurements were determined either 12 or 24 hours after dosing. The initial dose of guanfacine was 1 mg/day, which could be raised 1 mg at 2-week intervals to a maximum daily dose of 3 mg/day at the discretion of each investigator. The daily dose could also be lowered by 1 mg at 2-week intervals, depending on patient response. The mean 24-hour reductions with guanfacine in sitting diastolic BP (-11 mm Hg), systolic BP (-14 mm Hg) and mean arterial pressure (-12 mm Hg) were statistically significant (p less than 0.01) compared with the reductions in BP with placebo. Heart rate also decreased with guanfacine, but no clinically relevant bradycardia (less than 60 beats/min) was observed. Dry mouth (47%), constipation (16%), fatigue (12%) and drowsiness (4%) were the most frequently reported side effects. The highly acceptable side-effects profile of guanfacine was also indicated by the small percentage of patients (7%) who prematurely left the study because of adverse reactions.

More than 5,000 primary-care physicians enrolled more than 22,000 patients with mild to moderate hypertension in a postmarketing study in which guanfacine hydrochloride, a centrally acting antihypertensive agent, was given for 28 days. The objectives of the evaluation were: (1) to obtain broad experience with guanfacine for the management of essential hypertension in a clinical practice setting; (2) to obtain information on patient acceptance of guanfacine, 1 mg HS, for the control of essential hypertension; and (3) to obtain more information on the drug's safety in clinical practice. Patients had to be at least 21 years of age, to be receiving a thiazide-type diuretic, and to have a sitting diastolic blood pressure of 95 to 114 mmHg. Women who were pregnant or lactating or planning to become pregnant during the evaluation were excluded. Blood pressure and heart rate were measured before guanfacine was started and at the completion of the study. Adverse on-therapy events were reported at the return visit. The average blood pressure in the general patient population decreased by 17/12 mmHg, that is, from 164/100 to 147/88 mmHg in four weeks. The magnitude of the reduction was not significantly influenced by age, race, sex, duration of hypertension, or the use of concomitant antihypertensive therapy. Adding guanfacine to another antihypertensive regimen resulted in mean reductions of 11 to 15 mmHg diastolic pressure, and the substitution of guanfacine for another antihypertensive agent resulted in mean reductions of 10 to 11 mmHg diastolic pressure. The most common side effect reported was dry mouth in 6% of patients, followed by dizziness, somnolence, fatigue, headache, and nausea, each reported in fewer than 3% of patients. More than 80% of the participants continued to receive guanfacine after the study. Of the total patient population, 7% discontinued guanfacine because of lack of efficacy, 10% because of side effects, and 3% for other reasons. The results of this large postmarketing study confirmed the results of controlled clinical trials conducted prior to marketing.