Terazosin pharmacokinetics and molecular data

Pharmacokinetics
Benign prostatic hyperplasia Hypertension Absorption Plasma protein binding
 * Overview (BPH)
 * Placebo-controlled studies
 * Short-term study
 * Long-term study
 * Blood pressure effect
 * Animal studies
 * Clinical trials
 * Blood pressure responses
 * Peak response
 * Weight gain
 * Cholesterol
 * Hemodilution

Overview (BPH)
The symptoms associated with BPH are related to bladder outlet obstruction, which is comprised of two underlying components: a static component and a dynamic component. The static component is a consequence of an increase in prostate size. Over time, the prostate will continue to enlarge. However, clinical studies have demonstrated that the size of the prostate does not correlate with the severity of BPH symptoms or the degree of urinary obstruction. The dynamic component is a function of an increase in smooth muscle tone in the prostate and bladder neck, leading to constriction of the bladder outlet. Smooth muscle tone is mediated by sympathetic nervous stimulation of alpha-1 adrenoceptors, which are abundant in the prostate, prostatic capsule and bladder neck. The reduction in symptoms and improvement in urine flow rates following administration of Terazosin is related to relaxation of smooth muscle produced by blockade of alpha-1 adrenoceptors in the bladder neck and prostate. Because there are relatively few alpha-1 adrenoceptors in the bladder body, Terazosin is able to reduce the bladder outlet obstruction without affecting bladder contractility. Return to top

Placebo-controlled studies
Terazosin has been studied in 1222 men with symptomatic BPH. In three placebo-controlled studies, symptom evaluation and uroflowmetric measurements were performed approximately 24 hours following dosing. Symptoms were quantified using the Boyarsky Index. The questionnaire evaluated both obstructive (hesitancy, intermittency, terminal dribbling, impairment of size and force of stream, sensation of incomplete bladder emptying) and irritative (nocturia, daytime frequency, urgency, dysuria) symptoms by rating each of the 9 symptoms from 0 to 3, for a total score of 27 points. Results from these studies indicated that Terazosin statistically significantly improved symptoms and peak urine flow rates over placebo as follows:
 * In all three studies, both symptom scores and peak urine flow rates showed statistically significant improvement from baseline in patients treated with Terazosin from week 2 (or the first clinic visit) and throughout the study duration.
 * Analysis of the effect of Terazosin on individual urinary symptoms demonstrated that compared to placebo, Terazosin significantly improved the symptoms of hesitancy, intermittency, impairment in size and force of urinary stream, sensation of incomplete emptying, terminal dribbling, daytime frequency and nocturia.
 * Global assessments of overall urinary function and symptoms were also performed by investigators who were blinded to patient treatment assignment. In studies 1 and 3, patients treated with Terazosin had a significantly (p ≤ 0.001) greater overall improvement compared to placebo treated patients. Return to top

Short-term study
In a short term study, patients were randomized to either 2, 5 or 10 mg of Terazosin or placebo. Patients randomized to the 10 mg group achieved a statistically significant response in both symptoms and peak flow rate compared to placebo. Return to top

Long-term study
In a long-term, open-label, non-placebo controlled clinical trial, 181 men were followed for 2 years and 58 of these men were followed for 30 months. The effect of Terazosin on urinary symptom scores and peak flow rates was maintained throughout the study duration. In this long-term trial, both symptom scores and peak urinary flow rates showed statistically significant improvement suggesting a relaxation of smooth muscle cells. Return to top

Blood pressure effect
Although blockade of alpha-1 adrenoceptors also lowers blood pressure in hypertensive patients with increased peripheral vascular resistance, Terazosin treatment of normotensive men with BPH did not result in a clinically significant blood pressure lowering effec. Return to top

Animal studies
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. Return to top

Clinical trials
Patients in clinical trials of Terazosin were administered once daily (the great majority) and twice daily regimens with total doses usually in the range of 5 to 20 mg/day, and had mild (about 77%, diastolic pressure 95 to 105 mmHg) or moderate (23%, diastolic pressure 105 to 115 mmHg) hypertension. Because Terazosin, like all alpha antagonists, can cause unusually large falls in blood pressure after the first dose or first few doses, the initial dose was 1 mg in virtually all trials, with subsequent titration to a specified fixed dose or titration to some specified blood pressure end point (usually a supine diastolic pressure of 90 mmHg). Return to top

Blood pressure responses
Limited measurements of peak response (2 to 3 hours after dosing) during chronic Terazosin administration indicate that it is greater than about twice the trough (24 hour) response, suggesting some attenuation of response at 24 hours, presumably due to a fall in blood Terazosin concentrations at the end of the dose interval. This explanation is not established with certainty, however, and is not consistent with the similarity of blood pressure response to once daily and twice daily dosing and with the absence of an observed dose-response relationship over a range of 5 to 20 mg, i.e., if blood concentrations had fallen to the point of providing less than full effect at 24 hours, a shorter dosing interval or larger dose should have led to increased response. Further dose response and dose duration studies are being carried out. Blood pressure should be measured at the end of the dose interval; if response is not satisfactory, patients may be tried on a larger dose or twice daily dosing regimen. The latter should also be considered if possibly blood pressure-related side effects, such as dizziness, palpitations, or orthostatic complaints, are seen within a few hours after dosing. Return to top

Peak response
The 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 to 10 beat per minute increase in heart rate in the first few hours after dosing. During the first 3 hours after dosing 12.5% of patients had a systolic pressure fall of 30 mmHg or more from supine to standing, or standing systolic pressure below 90 mmHg with a fall of at least 20 mmHg, compared to 4% of a placebo group. Return to top

Weight gain
There was 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 1.7 and 2.2 pounds respectively, compared to losses of 0.2 and 1.2 pounds respectively in the placebo group. Both differences were statistically significant. Return to top

Cholesterol
During controlled clinical trials, patients receiving Terazosin monotherapy had a small but statistically significant decrease (a 3% fall) compared to placebo in total cholesterol and the combined low-density and very-low-density lipoprotein fractions. No significant changes were observed in high-density lipoprotein fraction and triglycerides compared to placebo. Return to top

Hemodilution
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. Return to top

Absorption
Terazosin hydrochloride administered as a capsule is essentially completely absorbed in man. Administration of capsules immediately after meals had a minimal effect on the extent of absorption. The time to reach peak plasma concentration however, was delayed by about 40 minutes. 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. In a study that evaluated the effect of age on Terazosin pharmacokinetics, the mean plasma half-lives were 14 and 11.4 hours for the age group ≥ 70 years and the age group of 20 to 39 years, respectively. After oral administration the plasma clearance was decreased by 31.7% in patients 70 years of age or older compared to that in patients 20 to 39 years of age. Return to top

Plasma protein binding
The drug is 90 to 94% 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 feces. The remainder is eliminated as metabolites. Impaired renal function had no significant effect on the elimination of Terazosin, and dosage adjustment of Terazosin to compensate for the drug removal during hemodialysis (approximately 10%) does not appear to be necessary. Overall, approximately 40% of the administered dose is excreted in the urine and approximately 60% in the feces. The disposition of the compound in animals is qualitatively similar to that in man. Return to top