Guanabenz

Guanabenz is an orally active central alpha-2 adrenergic agonist. Its antihypertensive action appears to be mediated via stimulation of central alpha adrenergic receptors, resulting in a decrease of sympathetic outflow from the brain at the bulbar level to the peripheral circulatory system.

The onset of the antihypertensive action of guanabenz begins within 60 minutes after a single oral dose and reaches a peak effect within two to four hours. The effect of an acute single dose is reduced appreciably six to eight hours after administration, and blood pressure approaches baseline values within 12 hours of administration.

The acute antihypertensive effect of guanabenz occurs without major changes in peripheral resistance, but its chronic effect appears to be a decrease in peripheral resistance. A decrease in blood pressure is seen in both the supine and standing positions without alterations of normal postural mechanisms, so that postural hypotension has not been observed. Guanabenz decreases pulse rate by about 5 beats per minute. Cardiac output and left ventricular ejection fraction are unchanged during long-term therapy.

In clinical trials, guanabenz, given orally to hypertensive patients, effectively controlled blood pressure without any significant effect on glomerular filtration rate, renal blood flow, body fluid volume or body weight. Guanabenz given parenterally to dogs has produced a natriuresis. Similarly, hypertensive subjects, 24 hours after salt loading, have shown a decrease in blood pressure and a natriuresis (5% to 240% increase in sodium excretion) following a single oral dose of guanabenz. After seven consecutive days of administration and effective blood-pressure control, no significant change on glomerular filtration rate, renal blood flow, or body weight was observed. However, in clinical trials of six to thirty months duration, hypertensive patients with effective blood-pressure control by guanabenz lost one to four pounds of body weight. The mechanism of this weight loss has not been established. Tolerance to the antihypertensive effect of guanabenz has not been observed.

During long-term administration of guanabenz, there is a small decrease in serum cholesterol and total triglycerides without any change in the high-density lipoprotein fraction. Plasma norepinephrine, serum dopamine beta-hydroxylase, and plasma renin activity are decreased during chronic administration of guanabenz. No changes in serum electrolytes, uric acid, blood urea nitrogen, calcium, or glucose have been observed.

Guanabenz and hydrochlorothiazide have been shown to have at least partially additive effects in patients not responding adequately to either drug alone.

In human studies, about 75% of an orally administered dose of guanabenz is absorbed and metabolized with less than 1% of unchanged drug recovered from the urine. Peak plasma concentrations of unchanged drug occur between two and five hours after a single oral dose. The average half-life for guanabenz is about 6 hours. The site or sites of metabolism of guanabenz have not been determined. The effect of meals on the absorption of guanabenz has not been studied.