Source: Web Search Revision Year: 1997
Wytensin 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.
In human studies, about 75% of an orally administered dose of Wytensin 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 Wytensin is about 6 hours. The site or sites of metabolism of Wytensin have not been determined. The effect of meals on the absorption of Wytensin has not been studied.
The onset of the antihypertensive action of Wytensin 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 Wytensin 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. Wytensin 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, Wytensin, 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. Wytensin 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 Wytensin. 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 Wytensin lost one to four pounds of body weight. The mechanism of this weight loss has not been established. Tolerance to the antihypertensive effect of Wytensin has not been observed.
During long-term administration of Wytensin, 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 Wytensin. No changes in serum electrolytes, uric acid, blood urea nitrogen, calcium, or glucose have been observed.
Wytensin and hydrochlorothiazide have been shown to have at least partially additive effects in patients not responding adequately to either drug alone.
Two-year studies were conducted with oral Wytensin administered in the diet to mice and rats. No evidence of carcinogenic potential was seen in mice given doses of up to 11.5 mg/kg/day (41.4 mg/m²/day) or in rats given doses of up to 9.5 mg/kg/day (83.8 mg/m²/day). On a body-weight basis, these doses are 9X and 7X, respectively, the maximum recommended human daily dose (MRHDD) of 64 mg (based on a 50 kg individual). On a body-surface-area basis, these doses are 1X (mice) and 2X (rats) the MRHDD.
In the Salmonella microsome mutagenicity (Ames) test system, Wytensin at 200 to 500 mcg per plate or at 30 to 50 mcg/mL in suspension gave dose-related increases in the number of mutants in one (TA 1537) of five Salmonella typhimurium strains with or without inclusion of rat liver microsomes. No mutagenic activity was seen at doses up to those which inhibit growth in the eukaryotic microorganism, Schizosaccharomyces pombe, or in Chinese hamster ovary cells at doses up to those which were lethal to the cells in culture. In another eukaryotic system, Saccharomyces cerevisiae, Wytensin produced no activity in an assay measuring induction of repairable DNA damage.
Reproductive studies showed a decreased pregnancy rate in rats administered high oral doses (9.6 mg/kg) of Wytensin, suggesting an impairment of fertility. The fertility of treated males (9.6 mg/kg) may also have been affected, as suggested by the decreased pregnancy rate of their mates, even though the females received Wytensin only during the last third of pregnancy.
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