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.     

Transdermal clonidine. A preliminary review of its pharmacodynamic properties and therapeutic efficacy

The clonidine transdermal therapeutic system (TTS) is a cutaneous delivery device which provides therapeutically effective doses of clonidine at a constant rate over 7 days. In clinical trials it reduces blood pressure in patients with mild to moderate hypertension as effectively as oral clonidine but with greater stability of blood pressure control. Most patients find the transdermal system more convenient than oral treatments, and compliance may be improved. The side effects known to occur with orally administered clonidine, dry mouth and sedation in particular, are also produced with transdermal administration, but possibly at a lower incidence than during oral treatment. A proportion of patients experience adverse skin reactions with the transdermal system. At this stage of its development, transdermal clonidine has not been adequately compared with other 'standard' antihypertensive treatments such as diuretics or beta-adrenoceptor blocking drugs. However, despite the lack of such comparative studies, transdermal clonidine represents a worthwhile new approach to antihypertensive therapy, particularly in terms of patient convenience.     

Withdrawal of guanfacine after long-term treatment in essential hypertension

Summary 1. Guanfacine (2–6 mg/day) a centrally acting antihypertensive drug, was effective in controlling blood pressure in 5 essential hypertensives and lowered plasma noradrenaline and urinary catecholamine excretion. 2. Withdrawal of guanfacine by blind substitution of identical placebo tablets under observation in hospital led to a gradual recovery of blood pressure over 2–4 days. 3. Salivary flow, which was reduced on guanfacine, returned to pretreatment levels by 2 days after withdrawal and significantly exceeded control for the next two days. 4. Urinary catecholamine excretion returned to pretreatment levels by 3 days but did not exceed control levels during the period of study. 5. Plasma noradrenaline returned gradually to pretreatment levels, and by day 4 significantly exceeded them. 6. No patient experienced symptoms suggesting catecholamine excess although four out of five reported a headache from the second day onwards. 7. Guanfacine, a centrally acting drug which pharmacologically resembles clonidine, has a slow offset of hypotensive effect over 2–3 days. Symptoms or biochemical evidence of catecholamine excess were not encountered within 48 h of withdrawal, possibly reflecting the longer duration of action and plasma half-life of guanfacine.     

Centrally Acting Imidazoline I1-Receptor Agonists

Centrally acting imidazoline I₁-receptor agonists such as moxonidine and rilmenidine induce peripheral sympathoinhibition via the stimulation of hypothetical I₁-receptors in the rostral ventrolateral medulla. Because of a rather weak affinity for α₂-adrenoceptors, the use of these agents is associated with a lower incidence of adverse reactions, such as sedation and dry mouth, compared with classic centrally acting α₂-adrenoceptor agonists (clonidine, guanfacine, methyldopa). The antihypertensive efficacy of moxonidine and rilmenidine is well documented, and they display a favorable hemodynamic profile. Their tolerability is better than that of the aforementioned centrally acting antihypertensive agents. However, long-term outcome data for moxonidine and rilmenidine are not available, and neither is a quantitative evaluation of their adverse effects. There exists some uncertainty with respect to the identity of the imidazoline I₁-receptor, which has so far not been cloned. Furthermore, it would be desirable to develop highly selective I₁-receptor agonists as successor drugs to moxonidine and rilmenidine. Although available data indicate that I₁-receptor agonists are effective in patients with hypertension, comparative data versus agents such as β-blockers, diuretics, calcium channel antagonists and ACE inhibitors are required to establish their position in the treatment of hypertension. Finally, I₁-receptor agonists have potential in the treatment of patients with CHF and those with the metabolic syndrome; syndrome X.     

Clinical pharmacology of centrally acting antihypertensive agents

The centrally acting agents are one of several differing classes of drugs now available for antihypertensive therapy. The availability of newer pharmacologic classes, including the beta-blockers, alpha-blockers. ACE inhibitors and calcium channel blockers, has resulted in a relative decline in the use of the centrally acting drugs. A major reason for this change in emphasis has been the perception by clinicians that the centrally acting agents, although effective, tend to produce symptomatic side effects that are difficult or unacceptable for patients. Some recent innovations in administering the centrally acting drugs appear to have addressed this problem. The pharmacokinetic characteristics of agents such as the transdermally administered clonidine or oral guanfacine appear to provide them with sustained efficacy without concomitant adverse effects. A further attribute of these drugs is their ability to decrease blood pressure without producing sodium retention. A growing awareness of the importance of treatment-induced metabolic effects has further served to reawaken interest in these agents. Specifically, they do not appear to produce alterations in glucose metabolism, and possibly may even have some slight beneficial effects on the blood lipid profile. Their ability to cause regression of left ventricular muscle hypertrophy, and possibly to enhance diastolic function, may add a further dimension of cardiovascular protection beyond their antihypertensive efficacy.     

Moxonidine. A review of its pharmacology, and therapeutic use in essential hypertension.

Interest in centrally acting antihypertensive agents has recently been renewed with the development of drugs that are associated with fewer central adverse effects (e.g. sedation, dry mouth) than the older drugs in this class. Moxonidine reduces sympathetic outflow and hence lowers blood pressure through stimulation of central imidazoline receptors. Blood pressure is decreased by 10 to 20% during moxonidine treatment, with about 70% of patients with mild to moderate hypertension achieving a diastolic pressure of < 90mm Hg. The relatively few published comparative studies demonstrate that moxonidine has efficacy comparable with that of clonidine, prazosin, atenolol, nifedipine, captopril and hydrochlorothiazide. It is at least as well tolerated as these agents in trials and, importantly, appears to cause less sedation and dry mouth than clonidine. Compliance may be aided by the once- or twice-daily administration schedule with moxonidine, and dosage adjustment is only necessary in patients with moderate renal impairment. While its published clinical data base needs further expanding, moxonidine thus appears to be a more attractive option than oral clonidine, and may be considered along with the other classes of drug used to treat patients with mild to moderate hypertension.     

Guanfacine and clonidine: antihypertensive and withdrawal characteristics after continuous infusion and its interruption in the spontaneously hypertensive and normotensive rat

Summary In conscious unrestrained spontaneously hypertensive and normotensive rats, prepared with permanently indwelling abdominal aortic catheters, the effects on blood pressure and heart rate of a 12-day continuous subcutaneous infusion of guanfacine (10 mg/kg/day) and clonidine (500 g/kg/day) and sudden interruption of these treatments were studied. Both drugs significantly and consistently reduced the mean arterial pressure and heart rate throughout the infusion period in the SH rats, but not in the normotensive animals. The magnitude of the effects of both drugs in the SH rat were similar. Following withdrawal of treatment with guanfacine, a discontinuation syndrome was evoked, much less severe than that observed after suspension of the infusion with clonidine. The withdrawal syndromes were characterized by an overshoot of heart rate and a period of blood pressure lability. In spite of the ineffectiveness of guanfacine and clonidine to reduce blood pressure and heart rate consistently in the normotensive rat, similar withdrawal patterns as those found in the SH rat were observed. These findings are in general agreement with the results previously found in clinical studies in hypertensive patients. The spontaneously hypertensive rat may prove a suitable animal model for pre-clinical studies of discontinuation symptoms after cessation of treatment with antihypertensive drugs.     

Antihypertensive drug withdrawal syndrome

After discontinuation of antihypertensive medications, patients may experience symptoms associated with catecholamine excess, with or without a rapid rise in blood pressure; this is referred to as antihypertensive drug withdrawal syndrome. Though most often associated with the discontinuation of clonidine, this syndrome has been reported to follow the withdrawal of many other antihypertensives. Proposed mechanisms for the syndrome, depending on the drug involved, include enhanced activity of (1) the sympathoadrenal system, (2) the renin-angiotensin-aldosterone system, and (3) the thyroid hormones. The typical patient at risk is a younger person with severe hypertension, who has been on multiple drugs in high doses for a long period. Guidelines are provided for minimizing the occurrence of the syndrome and for treating the reaction, should it occur.     

The pinna reflex and its inhibition by clonidine: relationship to sedation and quantitation of central alpha 2-antagonist potency

The relationship between sedation and pinna reflex inhibition has been measured for a range of centrally acting drugs. Ability to abolish the pinna reflex was not related to sedative activity as assessed by a behavioural method. Thus, at equisedative doses, diazepam, haloperidol, mianserin, prazosin and indoramin failed to abolish the pinna reflex while phenobarbitone and chlorpromazine caused partial- and clonidine complete-inhibition. At the ED50 for pinna reflex inhibition, guanabenz and guanfacine were significantly less sedative than clonidine. Mepyramine, yohimbine, RS-21361, idazoxan and phenylephrine produced little or no sedation and did not inhibit the reflex. When these agents (except for guanabenz and guanfacine) were tested for their ability to prevent clonidine-induced pinna reflex inhibition, all except the drugs with alpha 2-adrenoceptor antagonist activity were inactive. The potency order of the active agents was idazoxan greater than yohimbine greater than RS-21361 = mianserin. Antagonism of clonidine-induced pinna reflex inhibition may therefore prove to be a useful quantitative model for assessing the central potency of alpha 2-adrenoceptor antagonists.     

Regimen for the control of blood pressure and symptoms during clonidine withdrawal

Abrupt withdrawal of the centrally-acting antihypertensive agent, clonidine, is associated with a high incidence of rebound hypertension and tachycardia, with symptoms of sympathetic overactivity and increased catecholamine excretion. Gradual clonidine withdrawal has been recommended, but does not always avoid the reaction. A regimen is described comprising high doses of the alpha 1-adrenoceptor antagonist, prazosin, the cardioselective beta-blocker, atenolol, and chlordiazepoxide, specifically designed to counter both central and peripheral effects of sudden withdrawal of a central alpha 2-adrenoceptor agonist. This combination was completely successful in preventing the haemodynamic and symptomatic features of clonidine withdrawal in eight hypertensive patients.     

The effect of clonidine and guanfacine on blood pressure

Imidazoline derivatives, clonidine and guanfacine, were reviewed with respect to their effect on blood pressure. Excitation of the central alpha-adrenoceptors induced by clonidine or guanfacine produced a simultaneous decrease in peripheral sympathetic tone, hypotension and bradycardia. Both ponto-medullary regions and the hypothalamus are important action sites for these two drugs. With respect to the effects of clonidine or guanfacine on central alpha-adrenoceptors, two possibilities were investigated. First, we presumed that the excitation of central alpha-adrenoceptors induced by these two drugs appears to be located at postsynaptic sites. Thus, the alpha 2-subtype was considered. Secondarily, stimulation of the central presynaptic alpha 2 receptor produced by clonidine or guanfacine could not be excluded completely. It has been reported that after abrupt cessation of guanfacine, a withdrawal syndrome infrequently occurs which is moderate as compared with that caused by the abrupt cessation of clonidine. In comparison with clonidine, the characteristics of guanfacine pharmacokinetics, including its large volume of distribution, long biological half life and long duration of action, appear to be associated with the infrequent occurrence of withdrawal syndrome after guanfacine cessation.     

The effects of treatment and of withdrawal of treatment with guanfacine and clonidine on blood pressure and heart rate in normotensive and renal hypertensive rats

Disagreement in the literature about the occurrence of rebound hypertension (hypertensive overshoot) in animal models initiated this investigation. Oral doses of clonidine (0.03 mg kg^?1) or guanfacine (0.3 mg kg^?1) were administered twice daily during three weeks to groups of normotensive and renal hypertensive rats. Blood pressure and heart rate were measured immediately before and 3 h after the first daily dose, and compared with values obtained from placebo-treated control rats. Treatment with either drug induced large daily fluctuations rather than sustained falls in blood pressure. In the normotensive, but not in the hypertensive groups, the morning blood pressures measured before the first daily dose were significantly elevated over those of the control groups after 9 and 5 days of treatment with clonidine or guanfacine. This elevation persisted for 3 days after drug withdrawal. It is concluded that in the rat the duration of action of both drugs was short, so that twice daily administration of both drugs similarly produced large daily fluctuations rather than sustained falls in blood pressure. Blood pressure rises developed during treatment rather than after withdrawal in normotensive rats only. Therefore, this type of study does not relate well to the human situation and different experimental approaches to this problem are needed.     

The effects of treatment and of withdrawal of treatment with guanfacine and clonidine on blood pressure and heart rate in normotensive and renal hypertensive rats.

Disagreement in the literature about the occurrence of rebound hypertension (hypertensive overshoot) in animal models initiated this investigation. Oral doses of clonidine (0.03 mg kg-1) or guanfacine (0.3 mg kg-1) were administered twice daily during three weeks to groups of normotensive and renal hypertensive rats. Blood pressure and heart rate were measured immediately before and 3 h after the first daily dose, and compared with values obtained from placebo-treated control rats. Treatment with either drug induced large daily fluctuations rather than sustained falls in blood pressure. In the normotensive, but not in the hypertensive groups, the morning blood pressures measured before the first daily dose were significantly elevated over those of the control groups after 9 and 5 days of treatment with clonidine or guanfacine. This elevation persisted for 3 days after drug withdrawal. It is concluded that in the rat the duration of action of both drugs was short, so that twice daily administration of both drugs similarly produced large daily fluctuations rather than sustained falls in blood pressure. Blood pressure rises developed during treatment rather than after withdrawal in normotensive rats only. Therefore, this type of study does not relate well to the human situation and different experimental approaches to this problem are needed.     

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.     

Rilmenidine selectivity for imidazoline receptors in human brain

The selectivity of three centrally acting antihypertensive agents for the medullary imidazoline-preferring receptors (IPR) versus cortical alpha-adrenoceptors was investigated in human brain. [3H]Clonidine binding was studied in various membrane preparations. Competition experiments were performed. Cortical membrane preparations were used as they mainly contained classical alpha-adrenoceptors whereas medullary membrane preparations from the nucleus reticularis lateralis contained only IPR insensitive to catecholamines. Rilmenidine, a new antihypertensive agent, appeared 2.5 and 3.5 times more selective than clonidine and guanfacine, respectively, for medullary IPR sites than for cortical alpha-adrenoceptors, thus providing a possible explanation for the low sedative effects of this new molecule.     

I1 imidazoline agonists. General clinical pharmacology of imidazoline receptors: implications for the treatment of the elderly

In recent years evidence has accumulated for the existence of central imidazoline (I1) receptors that influence blood pressure. While there is some controversy, it has been suggested that clonidine exerts its blood pressure-lowering effect mainly by activation of imidazoline I1 receptors in the rostral ventrolateral medulla, while its sedative effect is mediated by activation of central alpha2-receptors. Moxonidine and rilmenidine are 2 imidazoline compounds with 30-fold greater specificity for I1 receptors than for alpha2-receptors. In comparison, clonidine displays a 4-fold specificity for I1 receptors compared with alpha2 receptors. Moxonidine and rilmenidine lower blood pressure by reducing peripheral resistance. They reduce circulating catecholamine levels and moxonidine reportedly reduces sympathetic nerve activity in patients with hypertension. Moxonidine and rilmenidine modestly reduce elevated blood glucose levels and moxonidine has been reported to reduce insulin resistance in hypertensive patients with raised insulin resistance. Small reductions in plasma levels of total cholesterol, low density lipoprotein-cholesterol and triglycerides have been reported with rilmenidine. Both moxonidine and rilmenidine are well absorbed after oral administration and are eliminated unchanged by the kidneys. The elimination half-life (t(1/2)) of rilmenidine and moxonidine is 8 and 2 hours, respectively, but trough/peak plasma concentration ratios indicate that moxonidine can be administered once daily, suggesting possible CNS retention. As would be expected, t(1/2) values are increased in patients with reduced renal function, and in elderly individuals. Both drugs have been compared with established antihypertensive drugs from all the major groups. Studies, almost all of which were of a double-blind, parallel-group design, indicate that blood pressure control with moxonidine or rilmenidine is similar to that with established drugs, i.e. alpha-blocking drugs, calcium antagonists, ACE inhibitors, beta-blocking drugs and diuretic agents. There have been few studies conducted solely in elderly patients. However, evidence clearly suggests that the antihypertensive effect of the imidazoline compounds is not reduced in elderly patients. The overall adverse effect profile of moxonidine and rilmenidine compares reasonably with established agents. In accord with the receptor-binding studies, drowsiness and dry mouth are observed less often with these drugs than with other centrally acting drugs, although the symptoms occur more often than with placebo. An overshoot of blood pressure was seen when treatment with clonidine, but not moxonidine, was abruptly discontinued in conscious, spontaneously hypertensive rats. Clinical evidence of withdrawal reaction with moxonidine or rilmenidine is scant but caution should be observed pending more formal studies.     

Precipitation by yohimbine of the withdrawal syndromes of clonidine, guanfacine, and methyldopa in the spontaneously hypertensive rat

In conscious spontaneously hypertensive (SH) rats, continuously infused with clonidine (500 micrograms/kg/day s.c.) for 12 days, yohimbine (3 or 10 mg/kg i.p.) dose dependently precipitated an overshoot of heart rate and other withdrawal symptoms, such as blood pressure upswings, diarrhea, ptosis, body shivering, jumping, and wet-dog shakes. Naloxone (3 or 30 mg/kg i.p.) or prazosin (1 mg/kg i.p.) did not evoke withdrawal signs in clonidine-treated SH rats. In SH rats treated for 12 days with guanfacine (10 mg/kg/day s.c.), the administration of yohimbine elicited a withdrawal pattern similar in severity and appearance to that observed in clonidine-treated rats. In methyldopa-treated (200 mg/kg/day) SH rats, the yohimbine-precipitated withdrawal symptoms were much less pronounced than those observed in the clonidine- and guanfacine-treated animals, despite the equipotency of the infusions in reducing mean arterial pressure. These results indicate that the clonidine-withdrawal syndrome can be precipitated by acute alpha 2-adrenoceptor blockade. The previously observed minor severity of the guanfacine-discontinuation syndrome in the rat should be attributed to the longer half-life of this drug as compared to clonidine. On the other hand, alpha-methylnoradrenaline much less intensively triggers the mechanisms underlying withdrawal symptoms than clonidine or guanfacine.     

Guanabenz. A review of its pharmacodynamic properties and therapeutic efficacy in hypertension

Guanabenz is an orally active central alpha 2-adrenoceptor agonist. Its antihypertensive action is thought to result from a decrease in sympathetic outflow from the brain to the peripheral circulatory system as a result of stimulation of central alpha 2-adrenoceptors. In mild to moderate hypertension it is as effective as methyldopa and clonidine in lowering blood pressure when used as the sole treatment. As with these drugs, guanabenz may be combined with a diuretic to increase its blood pressure-lowering effect. The overall incidence of side effects seen with guanabenz was at least as high as with methyldopa or clonidine, and side effects such as drowsiness or dry mouth have been bothersome enough to lead to discontinuation of guanabenz therapy in some patients. However, particularly troublesome effects such as sodium retention, depression or sexual dysfunction which may occur with methyldopa or clonidine have not been reported with guanabenz.     

Comparison of two alpha-noradrenergic agonists (clonidine and guanfacine) on norepinephrine turnover in the cortex of rats during morphine abstinence

The effects of the alpha-agonists clonidine and guanfacine on rat cortical norepinephrine turnover during morphine withdrawal were assessed. Cortical norepinephrine levels were measured, after administration of alpha-methyl-p-tyrosine, by fluorometric assay. Chronic treatment with morphine did not affect norepinephrine levels or norepinephrine turnover. In control animals, doses up to 200 micrograms/kg clonidine and 1060 micrograms/kg guanfacine did not affect norepinephrine steady state levels, but did reduce alpha-methyl-p-tyrosine-induced norepinephrine depletion. As little as 5 micrograms/kg clonidine reversed the accelerated turnover observed during naloxone precipitated morphine withdrawal; while for guanfacine, the minimum effective dose was 212 micrograms/kg. the ED50 for guanfacine's reversal of the withdrawal-induced acceleration of turnover was approximately 60 times that for clonidine.     

Comparison of guanabenz and clonidine in hypertensive patients

Summary

The antihypertensive and clinical effects of two centrally acting drugs, guanabenz and clonidine, were compared in a double-blind trial in 29 patients with established hypertension. After a 1-week baseline period and 2 weeks on placebo, patients received treatment with either guanabenz (mean dose 24?mg daily) or clonidine (mean dose 0.45?mg daily) alone for 8 weeks. Both drugs produced equivalent and highly significant (p < 0.001) reductions in systolic and diastolic blood pressures in the standing and supine positions. They also reduced significantly the standing and supine pulse rates. Normal orthostatic responses were maintained with both regimens. AN but 1 patient in each group reported side-effects during active treatment, the most frequent being dry mouth and sedation with each drug. No laboratory or ECG abnormalities related to treatment were observed.