, Volume 26, Issue 3, pp 212-229
Date: 15 Oct 2012

Guanabenz

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Summary

Synopsis: Guanabenz1 is an orally active central α2-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 α2-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.

Pharmacodynamic Properties: Guanabenz causes a decrease in blood pressure both in supine and standing positions without alterations of normal postural mechanisms. Animal studies have shown that intravenous guanabenz penetrates the central nervous system, and reduces blood pressure, heart rate, and spontaneous sympathetic discharge by an interaction with post-synaptic α-adrenoceptors, primarily at the bulbar level. Additionally, however, although not a classic adrenergic neuron-blocking drug, guanabenz does decrease the response to peripheral sympathetic nerve stimulation in animal preparations. This fact may explain the observation that in long term therapy its antihypertensive effect appears to be due to a decrease in peripheral resistance. In hypertensive patients, guanabenz brings about a decrease in heart rate, but no significant change in left ventricular stroke volume, cardiac output or ejection fraction. Effective control of blood pressure in patients was not associated with any changes in glomerular filtration rate, sodium balance, plasma renin activity, mean maximal urine osmolality, fluid intake, urine volume or serum sodium concentration. In several studies, patients on medium to long term therapy have experienced a decrease in bodyweight, but the mechanism of this weight loss has not been established. Small decreases in serum cholesterol levels have been recorded in patients on long term therapy.

Pharmacokinetics: Maximum concentrations of guanabenz in plasma (1.2 to 5.2 ng/ ml) were reached 2 to 5 hours after administration of capsules containing 16 or 32mg of 14C-labelled guanabenz. Unchanged drug accounted for less than 3% of the peak 14C concentration in plasma, indicating that most of the radioactivity was due to metabolites. The effect of food on absorption has not been studied. The drug is extensively metabolised and large amounts of metabolites are recovered in the urine in the first 24 hours. Guanabenz is 90% bound to human plasma proteins. Less than 1% of the dose is excreted as unchanged drug, the greatest proportion being in the form of the inactive metabolite (E)-p-hydroxyguanabenz. The site or sites of metabolism and the consequences of renal or hepatic insufficiency on the kinetics of guanabenz have yet to be determined.

Therapeutic Trials: Guanabenz has undergone trials both as the sole agent for initial antihypertensive therapy and in combination with a thiazide diuretic in previously treated patients with mild to moderate hypertension. In nearly all the studies the dosage has been titrated for each patient within the range of 8 to 64mg daily, the majority of patients being controlled on up to 32 mg/day. Non-comparative trials have suggested that guanabenz is an effective antihypertensive agent in about 70% of patients, this being confirmed in double-blind placebo-controlled trials. The drug has been consistently better than placebo in parallel group and crossover studies. Guanabenz (16 to 64mg) produced a similar response rate, but not quite as large a mean decrease in blood pressure as methyldopa (500 to 2000mg) in the few studies reported so far. Trials comparing guanabenz (8 to 64mg) and clonidine (0.2 to 0.9mg) suggest that they are almost equally effective, with similar decreases in blood pressure and response rates. In preliminary studies, guanabenz (4 to 64mg) has been found similar in efficacy to hydrochlorothiazide (25–100mg) in patients with mild to moderate hypertension. Treatment with guanabenz plus hydrochlorothiazide is more effective than that with either drug alone. However, side effects tend to be more frequent with the combination. In the only study comparing guanabenz with a β-adrenoceptor blocking drug, the antihypertensive effects of guanabenz (16mg) were similar to those of propranolol (120mg).

Side Effects: The most frequent side effects associated with guanabenz therapy are drowsiness, dry mouth, dizziness and weakness, and such effects may lead to discontinuation of therapy in some patients. Apart from a decrease in heart rate, cardiovascular effects have seldom occurred. Gastrointestinal symptoms and impotence have been rare. Postural hypotension has not proved to be a problem. No significant abnormalities of renal or liver function tests have been reported. A withdrawal syndrome compatible with sympathetic overactivity has been described, and this finding needs further investigation but no reports of rebound hypertension have been documented. In comparative studies, the overall incidence of side effects with guanabenz was at least as high as with drugs such as methyldopa or clonidine, although some of the particularly troublesome effects that may occur with these drugs (sodium retention, depression, sexual dysfunction) have not been reported at this stage of the drug’s development.

Dosage and Administration: Therapy should begin with 4mg twice a day whether guanabenz is prescribed alone or in combination with a thiazide diuretic. Increases can be made in increments of 4 to 8mg daily at 1- to 2-week intervals, depending on the patient’s response, up to a maximum of 64mg daily.

Various sections of the manuscript reviewed by: D.N. Bateman, Wolfson Unit of Clinical Pharmacology, University of Newcastle upon Tyne, England; P. Bolme, Karolinska Institutet, Department of Pediatrics, Huddinge Hospital, Huddinge, Sweden; M. Cressman, Department of Hypertension and Nephrology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA; R.W. Gifford, Department of Hypertension and Nephrology, The Cleveland Clinic Foundation, Cleveland, Ohio, USA; P. Hironven, Research Finnish Heart Association, Helsinki, Finland; B. Hollandy Hypertension Service, The University of Texas Medical Branch, Galveston, Texas, USA; F.G. McMahon, Tulane University School of Medicine, New Orleans, Louisiana, USA; J.A. Millar, Department of Pharmacology, University of Otago, New Zealand; Y. Misu, Department of Pharmacology, Yokohama City University School of Medicine, Yokohama, Japan; D.T. Nash, Clinical Professor of Medicine, Syracuse, New York, USA.
‘Wytensin’, ‘Rexitene’ (Wyeth).