, Volume 31, Issue 4, pp 301–336 | Cite as


A Review of Its Pharmacodynamic and Pharmacokinetic Properties, and Therapeutic Efficacy in the Treatment of Hypertension
  • Eugene M. Sorkin
  • Rennie C. Heel
Drug Evalution


Synopsis: Guanfacine,1 a phenylacetyl-guanidine derivative, is a centrally acting α-adrenoceptor agonist, with a mechanism of antihypertensive action similar to that of clonidine. It reduces blood pressure in patients with essential hypertension at least as effectively as clonidine or methyldopa. Like lower doses of clonidine, guanfacine can be given once daily due to its relatively long elimination half-life. Although dry mouth and sedation occur frequently with higher doses of guanfacine, their incidence is lower than with other centrally acting antihypertensives; in addition, other troublesome side effects such as orthostatic hypotension or sexual dysfunction also occur much less with guanfacine than with other centrally acting antihypertensive agents. While a withdrawal syndrome may occur on abruptly discontinuing guanfacine administration, the symptoms are generally mild, and the incidence of withdrawal symptoms appears lower than occurs with abrupt withdrawal of clonidine.

Thus, guanfacine is an effective and well tolerated alternative to other centrally acting antihypertensive drugs. Whether its final place in therapy will be as an alternative ‘second-line’ drug, or as initial monotherapy in patients with mild to moderate hypertension, remains to be clarified in comparative studies with diuretics, calcium antagonists, and β-adrenoceptor blocking drugs.

Pharmacodynamic Properties: Guanfacine is an α-adrenoceptor agonist which decreases central sympathetic tone. This has been substantiated in several animal models where intravertebral arterial and intracerebroventricular injection of guanfacine produced blood pressure reductions (not seen with intravenous administration) which were blocked by prior central injections of phentolamine. In addition, guanfacine causes a reduction of central sympathetic outflow and decreases the electrical activity of preganglionic sympathetic nerves, as well as reducing noradrenaline (norepinephrine) turnover in the brain.

The selectivity of guanfacine for α2-adrenoceptors has been verified by radioligand binding studies in which guanfacine was shown preferentially to bind cerebral cortex α2-adrenoceptor sites with essentially no activity on dopamine-, serotonin-, histamine H1-or β-adrenoreceptor sites. Guanfacine may be as much as 12 times more specific than clonidine for the α2 than the α1adrenoceptor.

Guanfacine also activates peripheral α-adrenoceptors, as transient increases in blood pressure produced by its intravenous administration in animal models of hypertension are not seen after intracisternal administration, and are prevented by the administration of phentolamine. Similarly, in man guanfacine has decreased blood pressure and plasma noradrenaline concentrations while causing subsequent increases in growth hormone concentrations, also indicating that guanfacine reduces sympathetic activity through both central and peripheral actions. Thus, the overall effect of guanfacine on mean arterial pressure is the summation of opposing pre- and postsynaptic peripheral and central effects, with the central effects rapidly predominating.

Guanfacine has been reported to decrease supine systolic and diastolic blood pressure in patients with mild to moderate essential hypertension by up to 24%, and standing systolic and diastolic blood pressures by up to 37%. Maximum blood pressure reduction occurs 8 to 12 hours after oral administration and this reduction is maintained for up to 36 hours after discontinuation of the drug. Although guanfacine is 5 to 20 times less potent than clonidine on a weight basis, comparable blood pressure lowering effects have been achieved when the 2 drugs were given in appropriate equipotent dosages. However, the onset of guanfacine action appears to be slower and its duration of action may tend to be longer than that of clonidine.

The primary effect of guanfacine on cardiovascular haemodynamics that contributes to its effectiveness as an antihypertensive agent is its ability to reduce systemic vascular resistance. Oral administration for up to 12 weeks has produced significant reductions of up to 20% and 15%, respectively, in rest and exercise systemic vascular resistance values. These reductions of left ventricular impedance (afterload) have resulted in concomitant improvements in left ventricular performance, which would be desirable in patients with incipient cardiac failure.

Dose-related reductions in plasma renin activity occur after administration of guanfacine, with plasma renin activity gradually returning to pretreatment levels within 4 days of guanfacine withdrawal. However, reductions in blood pressure produced by guanfacine are related neither to simultaneous reductions in plasma renin activity nor to pretreatment basal plasma renin activity levels.

Pharmacokinetic Properties: Orally administered guanfacine is rapidly and completely absorbed, with peak plasma concentrations occurring 1 to 4 hours after administration. Dose-related steady-state plasma concentrations are reached within 4 days of the initiation of guanfacine therapy. Guanfacine is widely distributed, with volumes of distribution ranging from 276 to 456L in healthy subjects and in hypertensive patients. Thus, low guanfacine plasma concentrations are achieved in spite of the high bioavailability of the drug. The total clearance of guanfacine from human plasma is between 11 and 22 L/h, and the drug is primarily metabolised by the liver; 24 to 37% is excreted unchanged by the kidneys. Neither maintenance doses nor dosage intervals of guanfacine need to be modified in patients with renal failure or in those undergoing intermittent haemodialysis.

Therapeutic Trials: Open studies of guanfacine in the treatment of mild-to-moderate hypertension have shown it to decrease blood pressure by 13 to 18% in most patients. However, two long term (3 and 5 years, respectively) studies reported that guanfacine decreased blood pressures by up to 19 to 29%. Guanfacine has been used as effective monotherapy in the treatment of patients with mild-to-moderate hypertension and in cases where previous antihypertensive therapy has been ineffective. During long term treatment with guanfacine there was no need for increased doses to maintain antihypertensive effectiveness in most patients. Indeed, the addition of diuretics or other anti-hypertensives to the guanfacine treatment regimen may prevent the apparent tolerance that has been reported in some patients and in fact allow the guanfacine dosage to be reduced. Normalisation of blood pressures has been shown to be greatest, with fewer associated side effects, when guanfacine has been given once daily; twice daily or 3 times daily dosages not only produced lower normalisation rates, but also increased the incidence of side effects.

Placebo-controlled studies have likewise shown guanfacine to produce significant blood pressure lowering effects, which were apparent within about 7 days after the initiation of therapy.

Although there have been few well-controlled clinical trials comparing the antihypertensive effectiveness of guanfacine and diuretics, either alone or in combination, considerable increases in antihypertensive efficacy have been reported when diuretics have been added to guanfacine therapy, and vice versa.

Several controlled clinical trials have shown that guanfacine produces antihypertensive effects comparable with those produced by clonidine and many investigators have reported that guanfacine and methyldopa also produce equivalent blood pressure lowereng effects. However, some studies have shown that guanfacine has been slightly more effective than methyldopa in decreasing blood pressure.

While there have been very few studies investigating the comparative and/or additive effects of guanfacine with other centrally acting antihypertensives, vasodilators or β-blockers, both guanfacine and guanabenz have been noted to produce equivalent blood pressure lowering effects. Furthermore, the addition of hydralazine or endralazine to treatment regimens of guanfacine has produced greater blood pressure reductions than guanfacine monotherapy, suggesting that guanfacine may also be used as an alternative to β-blockers to counteract increases in sympathetic nervous tone that are induced by arterial vasodilators. Both guanfacine and pindolol have been used in combination with diuretics and have resulted in equivalent blood pressure reductions, and the addition of propranolol to guanfacine/diuretic therapy has produced greater antihypertensive effects than the prior 2-drug combination. However, further studies comparing guanfacine with vasodilators and β-blockers are needed.

Side Effects: Side effects due to guanfacine are generally dependent on dose and dose frequency, and usually occur during the beginning of treatment with the drug, especially when large doses are given or when the dosage is increased or other drugs are added to the treatment regimen. As with other centrally acting antihypertensive drugs, the most common side effects of guanfacine are dry mouth and sedation, which have been reported to occur in 60% and 33% of patients, respectively, who have been treated over a period of 1 year. However, the incidence of such effects, and others such as headache, impotence and orthostatic hypotension, appears to be lower with guanfacine than with clonidine or guanethidine.

Withdrawal of Guanfacine: Severe rebound hypertension or marked withdrawal syndromes are rarely seen after discontinuation of guanfacine therapy. When a withdrawal syndrome associated with guanfacine use has been noted, its onset was slower, and symptoms less severe, than the syndrome following abrupt withdrawal of clonidine. Predisposing factors favouring the occurrence of a withdrawal syndrome include patients with histories of very high blood pressure, tachycardia, prior antihypertensive drug therapy, and those receiving divided doses of guanfacine exceeding 4mg per day.

Dosage and Administration: Oral antihypertensive therapy with guanfacine should be initiated with 0.5mg to 1.0mg per day, given once daily at bedtime. If necessary, dosage increases of 0.5mg or 1.0mg may be made after intervals of no less than 1 or 2 weeks. If the desired reduction in blood pressure is not achieved with 2 or 3mg daily given as a single dose, a diuretic may be added in the smallest recommended dose. Conversely, if guanfacine is to be added to the therapeutic regimen of a patient already receiving a diuretic, 1mg given once daily at bedtime will usually suffice in further decreasing blood pressure. Additional increases in guanfacine dosage up to a maximum of 2 to 3 mg/day may also be made in similar increments as described above.


Clinical Pharmacology Clonidine Essential Hypertension Plasma Renin Activity Methyldopa 
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© ADIS Press Limited 1986

Authors and Affiliations

  • Eugene M. Sorkin
    • 1
  • Rennie C. Heel
    • 1
  1. 1.ADIS Drug Information ServicesMairangi Bay, Auckland 10New Zealand

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