Hytrin Mechanism of Action

Pharmacology: Pharmacodynamics: In animals, terazosin causes a decrease in blood pressure by decreasing total peripheral vascular resistance. The vasodilatory hypotensive action of terazosin appears to be produced mainly by blockade of alpha-1-adrenoceptors. Terazosin decreases blood pressure gradually within 15 minutes following oral administration.
In man, systolic and diastolic blood pressures are lowered in both the supine and standing positions. The effect is most pronounced on the diastolic blood pressure. These changes are usually not accompanied by reflex tachycardia. A greater blood pressure effect associated with peak plasma concentrations (first few hours after dosing) appears somewhat more position-dependent (greater in the erect position) than the effect of terazosin at 24 hours, and in the erect position there is also a 6-10 beat per minute increase in heart rate in the first few hours after dosing.
Studies suggest that alpha-1-adrenoceptor blockade is also useful in improving the urodynamics in patients with chronic bladder outlet obstruction, such as in benign prostatic hyperplasia (BPH). The symptoms of BPH are caused mainly by the presence of an enlarged prostate and by the increased smooth muscle tone of the bladder outlet and the prostate, which is regulated by alpha-1-adrenergic receptors.
In in vitro experiments, terazosin has been shown to antagonize phenylephrine-induced contractions in human prostatic tissue. In clinical trials terazosin has been shown to improve the urodynamics and symptomatology in patients with BPH.
There is a tendency for patients to gain weight during terazosin therapy. In placebo-controlled monotherapy trials, male and female patients receiving terazosin gained a mean of 0.8 and 1 kg (1.7 and 2.2 pounds) respectively, compared to losses of 0.1 and 0.5 kg (0.2 and 1.2 pounds) respectively, in the placebo group. Both differences were significant.
During controlled clinical studies, patients receiving terazosin had an improved lipid profile. Patients receiving terazosin monotherapy had a small but statistically significant decrease compared to placebo in total cholesterol and the combined low-density and very-low-density lipoprotein fractions. These patients had significant increases from baseline in high-density lipoproteins, the HDL/LDL cholesterol ratio, and significant decreases from baseline in triglycerides. However, these changes were not significant when compared to placebo.
Long-term (6 months or longer) administration of terazosin has produced no pattern of clinically significant changes attributable to the drug in the following clinical laboratory measurements: glucose, uric acid, creatinine, BUN, liver function tests, and electrolytes. Analysis of clinical laboratory data following administration of terazosin suggested the possibility of hemodilution based on decreases in hematocrit, hemoglobin, white blood cells, total protein, and albumin. Decreases in hematocrit and total protein have been observed with alpha-blockade and are attributed to hemodilution.
Pharmacokinetics: Relative to solution, terazosin hydrochloride administered as terazosin tablets is essentially completely absorbed in man. Terazosin has been shown to undergo minimal hepatic first-pass metabolism and nearly all of the circulating dose is in the form of parent drug. The plasma levels peak about one hour after dosing, and then decline with a half-life of approximately 12 hours. The drug is highly bound to plasma proteins and binding is constant over the clinically observed concentration range. Approximately 10% of an orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the faeces. The remainder is eliminated as metabolites. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the faeces. The disposition of the compound in animals is qualitatively similar to that in man.
The pharmacokinetics of terazosin appear to be independent of renal function. This would obviate the need to adjust dosing regimens for patients with impaired renal function.
Toxicology: Pre-Clinical Safety Data: Carcinogenesis, Mutagenesis and Impairment of Fertility: Terazosin was devoid of mutagenic potential when evaluated in vivo and in vitro (the Ames test, in vivo cytogenetics, the dominant lethal test in mice, in vivo Chinese hamster chromosome aberration test and V79 forward mutation assay).
Terazosin, administered in the feed to rats at doses of 8, 40, and 250 mg/kg/day for two years, was associated with a statistically significant increase in benign adrenal medullary tumors in male rats exposed to the 250 mg/kg dose. This dose is 695 times the maximum recommended human dose of 20 mg/55 kg patient. Female rats were unaffected. Terazosin was not oncogenic in mice when administered in feed for two years at a maximum tolerated dose of 32 mg/kg/day.
The absence of mutagenicity in a battery of tests, of tumorigenicity of any cell type in the mouse carcinogenicity assay, of increased total tumor incidence in either species, and of proliferative adrenal lesions in female rats, suggests a male rat species-specific event.
Numerous other diverse pharmaceutical and chemical compounds have also been associated with benign adrenal medullary tumors in male rats without supporting evidence for carcinogenicity in man.
The effect of terazosin on fertility was assessed in a standard fertility/reproductive performance study in which male and female rats were administered oral doses of 8, 30, and 120 mg/kg/day. Four of 20 male rats given 30 mg/kg and five of 19 male rats given 120 mg/kg failed to sire a litter. Testicular weights and morphology were unaffected by treatment. Vaginal smears at 30 and 120 mg/kg/day, however, appeared to contain less sperm than smears from control matings and good correlation was reported between sperm count and subsequent pregnancy.
Oral administration of terazosin for one or two years elicited a statistically significant increase in the incidence of testicular atrophy in rats exposed to 40 and 250 mg/kg/day, but not in rats exposed to 8 mg/kg/day (greater than 20 times the maximum recommended human dose). Testicular atrophy was also observed in dogs dosed with 300 mg/kg/day (greater than 800 times the maximum recommended human dose) for three months but not after one year when dosed with 20 mg/kg/day. This lesion has also been seen with prazosin, another selective-alpha-1 blocking agent. As human investigation has not been carried out, the relevance of this finding to man is not known.