Clinical experience with guanfacine in long-term treatment of hypertension. Part II: adverse reactions to guanfacine.
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Antihypertensive Agents↗
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Guanfacine hydrochloride: a centrally acting antihypertensive agent.
The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of guanfacine hydrochloride are reviewed. Guanfacine lowers blood pressure by activating CNS alpha adrenoreceptors, which results in sympathetic outflow leading to reduced vascular tone. However, initial hypotensive response to guanfacine may be caused by stimulation of peripheral presynaptic receptors that inhibit sympathetic nerve function. Guanfacine is rapidly and completely absorbed from the gastrointestinal tract and apparently undergoes extensive distribution to all tissues. Steady-state plasma concentrations may be reached in four days. About 30% is excreted renally; the rest is metabolized hepatically. Its long duration of action is related to a slow elimination half-life. In the few controlled clinical trials of guanfacine versus placebo, systolic and diastolic blood pressures were reduced in patients treated with guanfacine; daily dosages of guanfacine 1, 2, and 3 mg (as the hydrochloride salt) were comparable in efficacy. Several large open trials of guanfacine showed blood pressure reductions of about 16% after one year; some patients received other antihypertensive therapy concomitantly. Guanfacine and clonidine appear to have comparable effects in reducing both systolic and diastolic blood pressure when given as monotherapy and as step-2 therapy; data on the comparative blood-pressure-lowering effects of guanfacine and methyldopa are less consistent. Guanfacine's adverse reactions include dry mouth, sedation, and constipation. Adverse effects and reaction to sudden withdrawal of the drug may be less severe with guanfacine than with clonidine. A daily dose of guanfacine 1 mg (as the hydrochloride salt) at bedtime is recommended; 2 or 3 mg, or divided doses, may be given if needed. Once-daily administration and fewer adverse effects may give guanfacine some advantage over other centrally acting antihypertensive agents. Further study is needed to determine whether it will be adequate as first-line therapy.
Antihypertensive Agents↗
Binding characteristics of [3H]guanfacine to rat brain alpha-adrenoceptors. Comparison with [3H]clonidine.
The tritium-labeled alpha-adrenoceptor agonist and antihypertensive drug guanfacine, N-amidino-2-(2,6-dichlorophenyl)-acetamide (sp. act. 24.2 Ci/mmole) was employed for a direct identification and characterization of alpha-adrenoceptors in rat brain membranes. Its usefulness as a radioligand was studied in comparison with [3H]clonidine (sp. act. 26.7 Ci/mmole). The nonspecific binding of [3H]guanfacine to rat cerebral membranes was considerably more pronounced than that observed for [3H]clonidine. The specific binding of [3H]guanfacine (0.1 - 20 nM) and [3H]clonidine (0.1 - 20 nM) as defined as the excess over blanks containing (-)-norepinephrine (10 microM) was saturable. Scatchard analyses of these binding data indicated single populations of binding sites for both ligands. KC values of 3.9 ([3H]guanfacine) and 3.7 nM ([3H]clonidine) were calculated. Maximal number of specific binding sites amounted to 220 and 195 fmole/mg protein for [3H]guanfacine and [3H]guanfacine and [3H]clonidine, respectively. In case unlabeled guanfacine (1 microM) was used to characterize the specific bonding of [3H] guanfacine, KD value and maximal number of binding sites were about twice as high as determined in the presence of excess (-)-norepinephrine. The rate of association of both radioligands was rapid. Binding reached equilibrium by about 10-15 min of incubation. Half-maximal binding was attained at approximately 1-2 min. The rates of dissociation were biphasic. A rapid and a slow component were identified. The specific binding sites of [3H] guanfacine in rat brain possess the general characteristics of alpha 2-adrenoceptors. Selective antagonists of alpha 2-adrenoceptors, like yohimbine and rauwolscine strongly interfered with this binding. However, preferential blocking agents of alpha 1-adrenoceptors, such as prazosin and corynanthine, were weak competitors. The relative potency of agonists and antagonists in displacing [3H]guanfacine was identical to their effectiveness in competing for [3H]clonidine specific binding sites. It is concluded that [3H]guanfacine labels the same alpha 2-adrenoceptor population in rat brain as [3H]clonidine. However, [3H]guanfacine seems not as suitable as [3H]clonidine for routine use in the direct identification of alpha 2-adrenoceptors in view of its relatively high nonspecific binding.
Animals↗
[The potential antinarcotic effects of guanfacine].
alpha 2-Agonist clonidine has been used for several years in the detoxification of opiate-addicts since it reduces withdrawal symptoms in man although craving for narcotic is not well suppressed. In the present work the potential "anticraving" properties of another alpha 2-agonist guanfacine were studied in rats trained to self-administer morphine. In the special series of experiments the influence of guanfacine on behavioral manifestation of morphine withdrawal in rats was studied. Analgesic action of guanfacine was evaluated by tail-flick procedure. It was shown that guanfacine (2-4 mg/kg, i.p.) essentially inhibited the morphine intravenous self-administration in a dose-dependent manner. These findings can be interpreted as reduction of morphine's positive reinforcing properties by guanfacine and point out on the possibility to prevent morphine abuse by guanfacine. Analgesic effect of guanfacine in tail-flick test was revealed in doses of 1-8 mg/kg, i.p. (50-100% increase in latency of nociceptive reaction, p < 0.05, Student's t-test). In the other experiments the morphine dependence was induced by i.p. injections of this drug during 5 day period with gradually elevated doses from 5 up to 25 mg/kg. Morphine discontinuation and injection of naloxone (0.5 mg/kg, i.p.) on day 6 induced the behavioral symptoms of abstinence ("wet dog shakes" and jumping). Guanfacine (4 mg/kg, i.p., immediately after naloxone) significantly increased the number of jumps and locomotions (p < 0.05), while increase in "wet dog shakes" was not statistically significant. The potentiation of morphine-withdrawal jumping by guanfacine was antagonized by iohimbine and prazosine in doses of 1 mg/kg, i.p. In the same conditions both prazosine and iohimbine removed "wet dog shakes." The results suggest that the potentiation effect of guanfacine on morphine-withdrawal jumping in rats can be mediated through alpha 1- and alpha 2-adrenoreceptors. Nonspecific interaction between prazosine and mentioned effect of guanfacine (which can be resulted from potentiation of blood pressure fall and of motor deficit) cannot be excluded.
Adrenergic alpha-Antagonists↗
Antihypertensive efficacy of guanfacine and prazosin in patients with mild to moderate essential hypertension.
Guanfacine, an alpha 2 adrenoceptor agonist, was compared with prazosin hydrochloride for the treatment of patients with mild to moderate essential hypertension in an 8-week, double-blind, randomized, parallel evaluation to determine efficacy and safety. The study consisted of a 2-week screening/weaning period (phase I), a 3-week treatment period with chlorthalidone 25 mg every morning (phase II), and an 8-week double-blind treatment period with diuretic plus prazosin or guanfacine (phase III). Those who had an average seated diastolic blood pressure (BP) of 95 to 114 mm Hg at the end of the phase II period were eligible to enter the phase III period and were randomly assigned to chlorthalidone plus either guanfacine, 1 mg every night, or prazosin, 1 mg three times a day. Of the 102 patients who were randomly assigned to guanfacine or prazosin, 80% completed the entire study. Guanfacine and prazosin appeared to be equally effective and reduced seated as well as standing diastolic and systolic BP. The mean seated systolic and diastolic BP were reduced 11/9 mm Hg by guanfacine and 11/10 mm Hg by prazosin. The mean reduction in seated pulse was 3 beats/minute for guanfacine and no change with prazosin. Similar changes occurred in the standing position. Very few adverse effects were reported during the study. Adverse effects with an incidence of 5% or greater for either drug group were dizziness (6% guanfacine, 8% prazosin), xerostomia (6% guanfacine, 2% prazosin), and somnolence (0% guanfacine, 6% prazosin). Three patients (6%) in the prazosin group experienced symptoms of orthostasis requiring premature discontinuation of the drug and termination from the study.
Adult↗
The efficacy of guanfacine in reducing perioperative hemodynamic changes and volatile anesthetic requirement.
STUDY OBJECTIVE: To evaluate the efficacy of guanfacine, an alpha 2-adrenergic agonist, for attenuating hemodynamic changes associated with tracheal intubation or extubation, providing intraoperative hemodynamic stability, and reducing inhalation anesthetic requirement in patients undergoing gynecologic surgery. DESIGN: Randomized, double-blind, placebo-controlled study. SETTING: Inpatient gynecology at a university hospital. PATIENTS: 45 women (ASA I) undergoing elective abdominal hysterectomy. INTERVENTIONS: Guanfacine and placebo supplementation. Oral guanfacine at 0.5 or 1 mg or a placebo (control) 3 hours before induction of anesthesia. Anesthesia was induced with thiamylal 5 mg/kg and vecuronium 0.2 mg/kg, and maintained with isoflurane and 50% nitrous oxide (N2O) in oxygen. The inspired isoflurane concentration was maintained at 1% during the first 5 minutes following induction of anesthesia and titrated to the concentration required to maintain hemodynamic stability [defined as +/- 10% of systolic blood pressure (SBP)]. The end-tidal concentration of isoflurane was monitored throughout anesthesia. On completion of surgery, N2O and isoflurane were discontinued. Following confirmation of recovery from anesthesia and muscle relaxation, the endotracheal tube was removed. MEASUREMENTS AND MAIN RESULTS: Patients in the control group showed significant increases in SBP and diastolic blood pressure (DBP) and heart rate (HR) associated with tracheal intubation 50 +/- 5, 57 +/- 6.3, and 45 +/- 4.6 (%, mean +/- SEM, p < 0.05 for any variables), respectively. Plasma norepinephrine and epinephrine concentrations increased to 382 +/- 40 pg/ml and 49 +/- 4.2 pg/ml, respectively (p < 0.05 compared with basal values). These changes were attenuated in patients receiving 1 mg of guanfacine (29 +/- 4.2, 33 +/- 4.5, 25 +/- 3.2, 210 +/- 32, and 22 +/- 3.5, respectively (p < 0.05 for any variables compared with placebo group). Higher inspired concentrations of isoflurane (%) were required in the control and 0.5 mg guanfacine-treated groups (1.2 +/- 0.05 and 1.0 +/- 0.04, respectively) than in the 1 mg guanfacine-treated group (0.62 +/- 0.03) for hemodynamic stability (p < 0.05). Coefficient of variation in HR changes during surgery was 17.2, 13.9, and 8.8 in the placebo, guanfacine 0.5 mg, and guanfacine 1 mg treated groups, respectively. Compared with placebo, guanfacine 1 mg reduced the maximum changes (mean +/- SEM) in SBP (7 +/- 1.2 vs. 18 +/- 2.2) and in HR (23 +/- 2.1 vs. 44 +/- 3.6) occurring during tracheal extubation. The incidence of perioperative complications was similar among the three groups. CONCLUSION: Guanfacine 1 mg administered orally proved to be an effective premedicant for providing intraoperative hemodynamic stability, attenuating the increase in BP and HR associated with tracheal intubation and extubation, and reducing anesthetic requirements without increasing the incidence of perioperative complications.
Adult↗
A placebo-controlled study of guanfacine in the treatment of children with tic disorders and attention deficit hyperactivity disorder.
OBJECTIVE: This study evaluated the efficacy and safety of guanfacine in treating children with tic disorders and attention deficit hyperactivity disorder (ADHD). METHOD: Subjects from a specialty tic disorders clinic were randomly assigned to receive 8 weeks of treatment with guanfacine or placebo under double-blind conditions. Follow-up visits occurred every 2 weeks for safety monitoring and dose adjustment. RESULTS: Thirty-four medication-free subjects (31 boys and three girls with a mean age of 10.4 years) with ADHD, combined type, and a tic disorder participated. After 8 weeks of treatment, guanfacine was associated with a mean improvement of 37% in the total score on the teacher-rated ADHD Rating Scale, compared to 8% improvement for placebo. Nine of 17 subjects who received guanfacine were blindly rated on the Clinical Global Improvement scale as either much improved or very much improved, compared with none of 17 subjects who received placebo. The mean score on the parent-rated hyperactivity index improved by 27% in the guanfacine group and 21% in the placebo group, not a significant difference. On the Continuous Performance Test, commission errors decreased by 22% and omission errors by 17% in the guanfacine group, compared with increases of 29% in commission errors and of 31% in omission errors in the placebo group. Tic severity decreased by 31% in the guanfacine group, compared to 0% in the placebo group. One guanfacine subject with sedation withdrew at week 4. Guanfacine was associated with insignificant decreases in blood pressure and pulse. CONCLUSIONS: Guanfacine appears to be a safe and effective treatment for children with tic disorders and ADHD.
Adolescent↗
Comparison of effects of guanfacine and clonidine on blood pressure, heart rate, urinary catecholamines, and cyclic nucleotides during and after administration to patients with mild to moderate hypertension.
In a random trial, the effects of treatment and withdrawal of guanfacine were compared with those of clonidine in 20 uncomplicated hypertensive patients. Elevated blood pressure returned to normal or responded well in all the patients given either guanfacine once daily or clonidine thrice daily. The pulse rate was reduced comparably by both treatments after 12 weeks, but the effect of guanfacine developed more gradually. Both guanfacine and clonidine significantly inhibited urinary noradrenaline, dopamine, and cyclic nucleotide excretion, while urinary adrenaline levels were unaffected. Side effects occurred earlier during treatment with clonidine. After sudden withdrawal, all the parameters tended to increase gradually in the guanfacine group, reaching base line by days 4-6. In the clonidine group the increase was more rapid, with pretreatment values reached within the 2nd day, and sometimes these values were surpassed. After withdrawal of clonidine all the patients had one or more side effects, most of them occurring within 48 h, while only 60% of the patients in the guanfacine group reported the appearance of unwanted symptoms, on days 3-6. It is concluded that there are close similarities between the effects of guanfacine and clonidine on the parameters evaluated, except for dopamine excretion, which was significantly less affected by guanfacine. Marked differences were found after abrupt withdrawal, with guanfacine less likely to produce the "discontinuation syndrome," probably due to its long half-life.
Adult↗
Central effects of guanfacine and clonidine during wakefulness and sleep in healthy subjects.
1. Three double-blind studies in young normotensive male volunteers were carried out: a study in ten awake subjects, comparing guanfacine 2.0 and 4.0 mg with clonidie 0.15 and 0.30 mg and placebo; and two polygraphic sleep studies each with six subjects, comparing guanfacine 1.0 and 2.0 mg with placebo, and clonidine 0.15 and 0.30 mg with placebo, respectively. 2. In awake subjects, both drugs reduced systolic blood pressure without significantly altering diastolic blood pressure, pulse rate and objective performance parameters. 'Side-effects' such as tiredness, decreased inclination to work, and dryness of the mouth were somewhat more frequent after the higher clonidine dose than after both doses of guanfacine, and peaked 2 h after clonidine but only 4-6 h after guanfacine. 3. Clonidine 0.15 and 0.30 mg given in the evening was followed by a substantial and dose-dependent reduction in rapid eye movement (REM) sleep. Guanfacine 1.0 mg did not alter REM sleep and 2.0 mg of guanfacine had less effect than both doses of clonidine in this respect. Clonidine's effect on REM sleep began after about 2 h, whereas guanfacine's action on REM sleep began 5 h after the dose. 4. Guanfacine and clonidine possess a qualitatively similar pattern of activity with regard to the parameters studied; but the central effects are less pronounced and occur later after guanfacine than after clonidine in equiactive doses.
Adult↗
[Effects of guanfacine on the levels of cyclic nucleotides in anesthetized rat brain regions].
Effects of an antihypertensive drug, guanfacine, on brain regional cyclic AMP and cyclic GMP levels were studied in anesthetized rats. Cyclic nucleotides were analyzed in seven brain regions. Guanfacine decreased blood pressure and heart rate 20 min after administration. Yohimbine inhibited these hemodynamic effects of guanfacine. Guanfacine reduced cyclic AMP levels in the hypothalamus. The reducing effect of guanfacine on cyclic AMP was antagonized by yohimbine in the hypothalamus. Guanfacine lowered cyclic GMP in the cerebellum, medulla oblongata and hypothalamus. Yohimbine inhibited the effect of guanfacine on cyclic GMP in the cerebellum, medulla oblongata and hypothalamus. Prazosin showed no effect on guanfacine induced change of cyclic nucleotides in any brain region. From these results, it is concluded that guanfacine decreased cyclic AMP and cyclic GMP in the hypothalamus. In addition, it is suggested that alpha-2 adrenoceptors mainly modulate these changes of cyclic nucleotides.
Animals↗
The effects of clonidine, guanfacine and phenylephrine on the excitatory and inhibitory responses of the rat anococcygeus muscle.
The effects of clonidine, guanfacine and phenylephrine on twitch responses and the basal tone of the rat anococcygeus muscle were investigated. Clonidine (10(-9)-3 x 10(-8) M) and guanfacine (10(-9)-10(-7) M) inhibited the twitch responses with the same potency, whereas phenylephrine (10(-9)-10(-7) M) was found ineffective. The inhibitory effect of clonidine and guanfacine was antagonized by yohimbine. Higher concentrations of clonidine and guanfacine increased the muscle tone and elicited inhibitory responses during field stimulation. Phenylephrine at concentrations greater than 10(-7) M also increased the muscle tone but induced biphasic responses. Clonidine (10(-7)-3 x 10(-5) M), guanfacine (3 x 10(-7)-3 x 10(-5) M) and phenylephrine (3 x 10(-7)-10(-5) M) caused concentration-dependent increases in the basal tone. The order of potency of these agonists in increasing the basal tone was clonidine > guanfacine > phenylephrine. Both yohimbine (10(-8)-10(-5) M) and prazosin (10(-9)-10(-7) M) antagonized these tonic contractions. Prazosin was found to be 39-, 122- and 83-fold more potent than yohimbine in antagonizing clonidine, guanfacine and phenylephrine-induced tonic contractions, respectively. Clonidine and guanfacine inhibited twitch responses through stimulation of presynaptic alpha-2 adrenoceptors. Postsynaptic alpha-1 adrenoceptors seem responsible for the contractile effects of clonidine, guanfacine and phenylephrine in the rat anococcygeus muscle.
Animals↗
The alpha-2 adrenergic agonist guanfacine improves memory in aged monkeys without sedative or hypotensive side effects: evidence for alpha-2 receptor subtypes.
The present study attempted to identify an alpha-2 agonist that could improve working memory in aged nonhuman primates without the marked hypotensive and sedative side effects produced by clonidine. Toward this end, the hypotensive, sedative, and memory-altering properties of the alpha-2 adrenergic agonists, B-HT920 and guanfacine, were compared with clonidine's effects in 9 aged rhesus monkeys. Memory capacity was assessed by a variable delay, spatial delayed response paradigm that requires the animal to remember information over short temporal intervals and to update this information on every trial. B-HT920 was found to produce a dose-response profile qualitatively similar to, but weaker than, clonidine: low doses impaired memory and began to lower blood pressure and produce sedation, while high doses improved memory. In contrast, guanfacine produced a dose-response profile opposite to that seen with clonidine: low doses improved memory without inducing hypotension or sedation, while the memory-impairing, hypotensive, and sedating properties of the drug were observed at higher doses. The potency of the 3 agonists to lower blood pressure was clonidine = B-HT920 greater than guanfacine; sedation was affected in the order clonidine greater than B-HT920 greater than guanfacine; for memory impairment, as measured by performance on the delayed response task, the rank order potency was clonidine greater than B-HT920 greater than guanfacine, while for memory improvement it was guanfacine greater than clonidine greater than B-HT920. These differences in rank order potency are consistent with the recent proposal of alpha-2 receptor subtypes, a rauwolscine-sensitive site (Rs) that binds clonidine greater than B-HT920 greater than guanfacine and a rauwolscine-insensitive site (Ri) that binds guanfacine greater than clonidine greater than B-HT920 (Boyajian and Leslie, 1987). The data suggest that the hypotensive, sedating, and memory-impairing effects of alpha-2 agonists may be due to actions at one subtype of receptor (Rs), while the memory-enhancing effects of these drugs may result from actions at another alpha-2 receptor subtype, the Ri site. The ability of low doses of guanfacine to improve memory without inducing hypotension or sedation indicates that this agonist may be an excellent candidate for treating memory disorders in man.
Adrenergic alpha-Agonists↗
Clonidine and guanfacine--comparison of their effects on haemodynamics in hypertension.
The pharmacology of central alpha-adrenoceptor-stimulating agents is discussed, with particular reference to clonidine (Catapres; Boehringer Ingelheim) and guanfacine (Estulic; Sandoz), and their haemodynamic effects are compared and contrasted. The main differences between the effects of clonidine and guanfacine on hypertension are: guanfacine activates presynaptic alpha-adrenoceptors 10 times more selectively than clonidine; guanfacine has an alpha 2/alpha 1-selectivity ration 25 times higher than clonidine; clonidine decreases cardiac output and guanfacine decreases peripheral resistance, clonidine has no effect on stroke volume but guanfacine increases it; and when the clonidine withdrawal syndrome in the spontaneously hypertensive rat is compared with cessation of guanfacine treatment at an equipotent antihypertensive dose, the withdrawal syndrome after guanfacine appears later and is much less severe. Guanfacine may be preferable to clonidine as a central alpha-adrenoceptor stimulant in the treatment of hypertension.
Blood Pressure↗
The alpha-2a noradrenergic agonist, guanfacine, improves delayed response performance in young adult rhesus monkeys.
In aged monkeys with naturally occurring catecholamine depletion, alpha-2 adrenergic agonists such as guanfacine have repeatedly been shown to improve dorsolateral prefrontal cortical function, as assessed by the spatial delayed response task. Both low (0.0001-0.001 mg/kg) and high (0.5 mg/kg) but not intermediate (0.01-0.05 mg/kg) doses of guanfacine improve spatial working memory performance in aged animals. However, it is not known whether guanfacine would similarly improve performance in young animals. In the present study, the effects of guanfacine on delayed response performance were characterized in seven young adult rhesus monkeys. Low doses of guanfacine (0.0001-0.01 mg/kg) had no effect on task performance, while high doses of guanfacine (0.1-0.7 mg/kg) significantly improved task performance. The highest doses produced mild sedation that was independent of drug effects on delayed response. The most effective dose of guanfacine was challenged with the alpha-2 antagonist idazoxan (0.1 mg/kg). This dose of idazoxan had no effect on task performance when given alone. Consistent with an alpha-2 mechanism, idazoxan significantly decreased delayed response performance in guanfacine-treated animals. These results support the hypothesis that delayed response performance in young intact animals can be improved through actions at alpha-2 adrenergic receptors.
Adrenergic alpha-2 Receptor Agonists↗
Animal pharmacology of guanfacine.
The pharmacologic data obtained from animal experiments with guanfacine, a novel, centrally acting antihypertensive agent, are reviewed. When given orally, guanfacine lowers systemic blood pressure in conscious DOCA-NaCl-hypertensive rats, Grollman rats and spontaneously hypertensive rats in a dose-dependent manner. It is also effective in renal hypertensive cats. Guanfacine reduces blood pressure in cats, rabbits and rats after injection into the lateral cerebral ventricle and in dogs after infusion into the vertebral artery at intravenously ineffective doses. Vagally mediated reflex bradycardia in dogs is enhanced. The preganglionic splanchnic (sympathetic) nerve activity is reduced in cats. In rats, guanfacine reduces the noradrenaline turnover in the brain stem. All these findings indicate a central site of action. Peripheral alpha-adrenoceptor stimulant properties of guanfacine have been demonstrated in various studies. In addition to postsynaptic stimulant effects, presynaptic guanfacine-induced inhibition of sympathetic heart nerve stimulation is antagonized by rauwolscine but not by prazosin, indicating a highly preferential alpha 2-agonistic presynaptic action of the drug. In receptor binding studies using rat cortex membranes and human platelets, guanfacine exhibited a high selectivity for alpha 2 adrenoceptors. Guanfacine has the advantage over other centrally acting antihypertensives of being less sedative and causing no rebound hypertension after discontinuation of treatment. The latter is mainly due to its pharmaco-kinetic properties.
Animals↗
Peripheral alpha 2 adrenoceptor stimulation contributes to the sympatholytic effect of guanfacine in humans.
Guanfacine 3 mg was infused into six volunteers over 1 h on two occasions to investigate whether its sympatholytic effect is centrally or peripherally mediated. On one occasion, the central effects of guanfacine were blocked by prior administration of idazoxan 0.2 mg/kg i.v. (45 min preguanfacine); central alpha 2-blockade was confirmed by inhibition of the guanfacine-induced rise in plasma growth hormone. Rapid disappearance of idazoxan from the circulation prevented antagonism of peripheral alpha 2 receptor effects of guanfacine (confirmed by suppression of plasma insulin by guanfacine on both occasions). Idazoxan elevated plasma noradrenaline concentration by 0.26 +/- 0.018 ng/ml; however, guanfacine caused a similar (approximately 30%) reduction in plasma noradrenaline after both idazoxan and vehicle. Idazoxan elevated systolic and diastolic blood pressure, but no change was observed after guanfacine on either occasion. Thus, the reduction in plasma noradrenaline caused by guanfacine appears to be peripherally mediated but is not due to baroreceptor activation. This is consistent with stimulation of presynaptic alpha 2 receptors.
Adult↗
[3H]-guanfacine: a radioligand that selectively labels high affinity alpha2-adrenoceptor sites in homogenates of rat brain.
[3H]-guanfacine (N-amidino-2-(2,6-dichloro 3[3H] phenyl) acetamide hydrochloride; 24.2 Ci/mmol) has been used as a radioligand in homogenates of rat cerebral cortex. Specific binding of [3H]-guanfacine was linear with respect to tissue concentration (2.5-15 mg/ml), saturable and not markedly affected in the pH range 6.5-8.0. Analysis of the saturation of [3H]-guanfacine binding using an iterative least squares fitting procedure gave best fits to a single site model. [3H]-guanfacine binding was of high affinity (Kd 1.77 +/- 0.24 nM; n = 8) to a population of non interacting sites (nH 0.99 +/- 0.02; n = 8) with a density of 118.2 +/- 8.4 fmol/mg protein (n = 8). Highest levels of binding were achieved in cerebral cortex followed by thalamus greater than hypothalamus greater than medulla/pons greater than spinal cord greater than striatum greater than cerebellum. Binding was stereoselective with regard to the (-)-isomer of noradrenaline and the order of potency for displacement of [3H]-guanfacine by agonists was naphazoline greater than clonidine greater than (-)-adrenaline greater than (-)-alpha methylnoradrenaline greater than (-)-noradrenaline greater than (+/-)-alpha-methylnoradrenaline greater than (+)-noradrenaline greater than methoxamine greater than (+)-adrenaline greater than phenylephrine and by antagonists was phentolamine greater than dihydroergocryptine greater than piperoxane greater than yohimbine greater than prazosin greater than labetalol greater than indoramin suggested binding to alpha 2-adrenoceptors. The monovalent cations Na+ and K+ and also guanosine 5'-triphosphate (GTP) produced concentration-dependent inhibition whereas the divalent cations Ca2+, Mg2+, and Mn2+ first enhanced, then inhibited [3H]-guanfacine binding. Na+ (150 mM) or GTP (100 microM) produced marked reductions and Mn2+ (5 mM) marked increases in the number of receptor sites labelled by [3H]-guanfacine. 9 It is concluded that [3H]-guanfacine preferentially labels a high affinity state of the alpha 2- adrenoceptor in homogenates of rat cerebral cortex.
Adrenergic alpha-Agonists↗
Effects of the alpha 2-adrenoceptor agonist guanfacine on growth and thermogenesis in mice.
Guanfacine is an alpha 2-adrenoceptor agonist with antithermogenic properties. A single treatment of guanfacine caused a dose-related reduction in metabolic rate. The maximum reduction was 40%, and a dose of .5 mg/kg was close to that required to produce half this effect. It was determined whether the antithermogenic action of guanfacine would result in increased growth rate in mice. In animals treated once daily for 10 d (0, .125, .5, or 2 mg/kg), the drug caused dose-related reductions in feed intake, weight gain, and feed conversion efficiency. In a further experiment, mice were fed a restricted quantity of feed and treated for 14 d with guanfacine (.5 mg/kg twice daily). Because of repeated dosing, the antithermogenic effect of the drug was attenuated, so that metabolic rate was not lower in treated mice at the end of the experiment. Control and treated mice ate all the feed offered, but the guanfacine-treated group gained 2.9 g less weight (P < .01) than the controls. Half this difference in BW was accounted for by body water (P < .1), whereas body energy content was also reduced by the drug (P < .05). In a final experiment we sought possible sources of energy loss. Mice were treated with guanfacine (.5 mg/kg) three times over 24 h. Severe glucosuria was observed in the guanfacine-treated mice, with a tendency also toward increased output of fecal energy. We have confirmed that guanfacine has a powerful, if short-term, antithermogenic action. However, in mice, other effects of the drug on energy metabolism result in weight loss rather than growth stimulation.
Animals↗