Effect Of Terazosin Research Articles

THE MECHANISM OF ADVERSE EVENTS ASSOCIATED WITH TERAZOSIN: AN ANALYSIS OF THE VETERANS AFFAIRS COOPERATIVE STUDY

We determined the mechanism of adverse events associated with alpha1-blockers for treating benign prostatic hyperplasia (BPH). We randomized 1,229 men with clinical BPH at 31 Veterans Affairs medical centers into equal treatment groups, including those who received placebo, terazosin, finasteride, and combined terazosin and finasteride therapy, respectively. Adverse events were captured at all study visits during our 1-year study. Our current review of adverse events is limited to patients randomized to the placebo and terazosin groups. We compared the incidence of orthostatic blood pressure change, postural symptoms and orthostatic hypotension in men who were normotensive and hypertensive at baseline, respectively. We also determined the association of changes in systolic blood pressure with the incidence of treatment related adverse events. The treatment related rates of dizziness, asthenia, postural hypotension and syncope were 19%, 6%, 6% and 1%, respectively. Of these adverse events only postural hypotension was associated with orthostatic blood pressure changes. The incidence of asthenia, dizziness and postural hypotension was not significantly greater in patients with a systolic blood pressure decrease of 5 or greater and less than 5 mm. Hg, respectively. Dizziness and asthenia are not associated with changes in blood pressure, suggesting that these treatment related adverse events associated with alpha1-blockers are not related to vascular events. Designing a subtype selective alpha1 antagonist that has less effect on blood pressure may not result in marked improvement in tolerability over commercially available alpha1-blockers.

Pathophysiology of Autonomic Dysreflexia: Long-Term Treatment With Terazosin in Adult and Paediatric Spinal Cord Injury Patients Manifesting Recurrent Dysreflexic Episodes

Introduction Spinal cord injury (SCI) results in disruption of synaptic influences on the sympathetic preganglionic neurones. Remodelling of spinal cord circuits takes place in spinal neurones caudal to cord injury. There is an increased vascular alpha-adrenoceptor responsiveness, and peripheral afferent (bladder) stimulation in SCI subjects induces a marked noradrenaline spillover below the level of spinal lesion. These neurophysiological changes possibly contribute to the development of autonomic dysreflexia, a condition of sympathetic hyper-excitability that develops after cervical, or upper dorsal cord injury with resultant paroxysmal rise in arterial pressure, and provide the scientific basis for the use of terazosin, a once-a-day, selective alpha-one adrenergic blocking drug. Objectives The use of terazosin, a long-acting, alpha 1-selective blocking agent was investigated in SCI patients who developed recurrent symptoms of autonomic dysreflexia, eg headache, sweating flushing of the face together with an increase in the arterial pressure. Design An open, prospective study of the efficacy of terazosin in controlling recurrent autonomic dysreflexia in traumatic tetraplegic/paraplegic patients manifesting clinical features of dysreflexia in the absence of an acute precipitating cause such as a blocked catheter. Setting The initial assessment and treatment were carried out in the Spinal Injuries Centre. Subsequently, the patients were followed-up in the community. They were monitored by telephonic interviews, follow-up visits by the patients to the hospital, and home-visits by the staff of the spinal unit. Subjects Eighteen adults with tetraplegia (female: 1; male: 17), three children with ventilator-dependent tetraplegia and three adult male patients with paraplegia who exhibited recurrent features of autonomic dysreflexia in the absence of an acute predisposing factor for dysreflexia eg performance of an invasive procedure such as cystoscopy, digital evacuation of bowels, or acute urinary retention, were enrolled in this study. Intervention After discussion with the patients and their carers, terazosin was prescribed with a starting dose of 1 mg in an adult and 0.5 mg in a child administered nocte. The patients were observed for (1) drug-induced hypotension; (2) clinical symptoms due to side effects of terazosin; and (3) continued occurrence of dysreflexic symptoms. Step-wise increments of the dose of terazosin (1 mg in case of adults, and 0.5 mg in a child) was carried out at intervals of 3-4 days, if a patient continued to develop dysreflexia but did not manifest any serious side effect. Outcome measures Complete subsidence of dysreflexic symptoms, or development of an adverse event necessitating termination of the terazosin therapy was the clinical end point. Results The dysreflexic symptoms subsided completely with the terazosin therapy in all the patients. The twenty-one adult patients required a dose varying from 1-10 mg, whereas the paediatric patients required only 1-2 mg of terazosin. The side effects of postural hypotension and drowsiness were transient, and mild. One tetraplegic patient developed persistent dizziness and therefore, the drug therapy was discontinued. Conclusion In 21 adult and three paediatric spinal cord injury patients manifesting recurrent episodes of autonomic dysreflexia in the absence of an acute predisposing cause, the use of terazosin, a once-a-day, specific alpha-one blocker resulted in complete subsidence of the dysreflexic symptoms. However, one tetraplegic patient required termination of terazosin therapy because of persistent dizziness.

DIAGNOSING BLADDER OUTLET OBSTRUCTION IN WOMEN

There are no universally accepted urodynamic criteria for diagnosing female bladder outlet obstruction. When accepted criteria for men are applied to women, the diagnosis of obstruction may often be missed, which is most likely due to differences in voiding dynamics. We propose video urodynamic criteria for diagnosing obstruction in women, and describe the urodynamic findings in those with and without obstruction. We reviewed the charts of 331 women who underwent multichannel video urodynamics for nonneurogenic voiding dysfunction. Of these women 261 (mean age 55.8 years) had evaluable voiding pressure flow studies with simultaneous video fluoroscopy of the bladder outlet during voiding. At video urodynamics cases were classified as obstructed if there was radiographic evidence of obstruction between the bladder neck and distal urethra in the presence of a sustained detrusor contraction. Strict pressure flow criteria were not used. Maximum flow rate, detrusor pressure at maximum flow rate, post-void residual, bladder capacity and the incidence of detrusor instability were compared between obstructed and unobstructed cases. A total of 76 women met the criteria for obstruction (mean age 57.5 years), while 184 (mean age 55) did not. Causes of obstruction were dysfunctional voiding in 25 cases, cystocele in 21, primary bladder neck obstruction in 12, iatrogenic from incontinence surgery in 11, urethral stricture in 3, uterine prolapse in 2, urethral diverticulum in 1 and rectocele in 1. Obstructed cases had lower mean maximum flow rate (9 versus 20.2 ml. per second, p <0.0001), higher mean detrusor pressure at maximum flow rate (42.8 versus 22.1 cm. water, p <0.0001) and higher mean post-void residual (157 versus 33 ml., p <0.0001). There was no difference in bladder capacity (381 versus 347 ml.) or incidence of detrusor instability (45 versus 41%). Using the proposed video urodynamic criteria obstructed cases had significantly higher voiding pressures, lower flow rates and higher post-void residual than unobstructed cases, as expected. However, absolute values, especially for voiding pressure, are not as dramatic in women as in men. Pressure flow studies alone may fail to diagnose obstruction but simultaneous imaging of the bladder outlet during voiding greatly facilitates diagnosis.

Effect of terazosin on prostatism in men with normal and abnormal peak urinary flow rates

Objectives To determine if men with normal peak urinary flow rates (PFR) and prostatism respond to terazosin. Methods Forty-one men over the age of 50 years with an American Urological Association (AUA) symptom score greater than 8, postvoid residual urine volume (PVR) less than 300 mL, and no clinical or biochemical evidence of prostate cancer were treated with terazosin independent of the baseline PFR. The effect of terazosin on the AUA symptom score and PFR were compared for subjects with a PFR of 15 mL/s or less (group I) and those with a PFR greater than 15 mL/s (group II). Results The baseline age, AUA symptom score, prostate volume, and PVR were not significantly different between the two groups. The mean changes in AUA symptom score were −45.0% and −49.5% for groups I and II, respectively. The mean changes in PFR were 7.0% and −26.6% for groups I and II, respectively. Conclusions The effect of terazosin on AUA symptom score is independent of baseline PFR, indicating that the mechanism of action of terazosin is not exclusively mediated by reduction of bladder outlet obstruction. Randomized controlled studies are required to confirm this provocative observation.

Side effects of terazosin in the treatment of symptomatic benign prostatic hyperplasia.

In this report, we assess the safety of terazosin in the treatment of patients with symptomatic benign prostatic hyperplasia. We analyzed seven prospectively designed placebo-controlled trials involving 3,080 patients, 1,689 of whom received the study drug in doses ranging from 1 mg to 20 mg daily for a total of 1,282 patient-years of exposure. The most common side effects seen in treated patients were dizziness (10.7%), asthenia (7.5%), and peripheral edema (4.0%). These side effects were generally reported as mild and improved after cessation of therapy. The incidence of withdrawal from the study due to side effects was 14.5% in the treatment arm versus 11.4% in the placebo control arm. Also noted was a statistically significant decreased risk of urinary tract infection and myocardial infarction in the terazosin-treated group. This updated report confirms that terazosin can be administered safely to a population of men with symptomatic benign prostatic hyperplasia with minimal clinically significant side effects.

Autonomic dysreflexia in a rat model spinal cord injury and the effect of pharmacologic agents

The object of this study was to develop a spinal cord injury (SCI) rat model for autonomic dysreflexia (AD), assessing the effect of alpha-adrenergic and calcium channel blockade and to determine the relationship of detrusor-external sphincter dyssynergia (DESD) to the development of AD. A laminectomy was performed in male rats at the T4 or T10 level and a controlled 50 g cm blunt SCI was induced using an impounder. Four weeks after injury, changes in arterial blood pressure and heart rate were monitored while simultaneous cystometry (CMG) and pelvic floor electromography (EMG) were performed in vivo in sham (control) and spinal cord injured rats. The effects of terazosin (0.1 mg/kg), diltiazem (0.5 mg/kg), and oxybutynin chloride (0.1 mg/kg) on hemodynamic changes were assessed independently. Both T4 and T10 SCI rat displayed evidence of DESD (enhanced pelvic floor EMG activity at cystometric capacity) while control rats did not. Only T4 injured rats exhibited evidence of AD, with mean blood pressure elevations from 82.9 +/- 13.6 to 93.9 +/- 11.3 mm Hg (P < 0.01) and a mean heart rate decrease from 332.2 +/- 56.5 to 311.1 +/- 54.5 beats/min (P = 0.02) at cystometric capacity. The intravenous administration of terazosin or diltiazem abolished the AD response during CMG. The administration of oxybutynin exhibited the ability to increase bladder capacity and improve compliance in all 3 groups but did not blunt AD. The rat model of SCI effectively reproduced hemodynamic changes consistent with the AD complex in T4 level SCI but not T10 level SCI animals, despite incomplete lesions. Blockade with either an alpha-1 or a calcium channel antagonist effectively ablated the AD response to bladder distention. Anticholinergic agents had no effect on AD. DESD frequently accompanies autonomic dysreflexia, although the development of AD is not a prerequisite for DESD.

Effect of terazosin on urine storage and voiding in the aging male with prostatism.

Patients in a private practice, evaluated for prostatism due to benign prostatic hypertrophy were offered the options of medical treatment with the alpha blocker terazosin, surgical treatment, or continued observation. Nineteen men accepted terazosin treatment and are the subjects of the present series. They were treated over a mean period of 8 months, the longest treatment lasting over 22 months. Dosage was started at 1 mg/d and increased as tolerated to 2, 5, and 10 mg/d over the test period. Extensive testing including invasive urodynamics, multiple voiding diaries, and symptoms scores at each dosage level was carried out. We found that flow rates increased moderately from baseline in a dose dependent fashion. At the 10 mg/d dosage some patients achieved flow rates in the low normal range. Patients on treatment documented a decrease in the number of voidings per day, a decrease in nocturia, an increase in bladder capacity and the volume of each voiding. On the other hand, patients frequently did not appreciate changes in their voiding patterns, as reflected in their responses to the symptom questionnaires. We could not demonstrate significant changes in bladder pressures on cystometry either during filling or voiding. Our data suggested that terazosin may well have a direct effect on the fundus of the aging bladder to increase capacity, and, through the well-known relationship between voided volume and flow rate, increase urinary flow rate.

Comparison of the Effects of Terazosin and Enalapril on Laboratory Stress Testing Blood Pressure in Patients with Essential Hypertension

It is the current opinion that an ideal antihypertensive drug should reduce blood pressure (BP) not only at rest but also during stressful situations. The current study was aimed to compare the effects of the selective alpha 1-adrenergic blocker terazosin (5 mg once daily) and of the angiotensin-converting enzyme inhibitor enalapril (20 mg once daily) on cardiovascular response to a set of standardized laboratory stressors, such as mental arithmetic, handgrip test and cycle ergometry, in a group of 16 essential hypertensive patients. The study was a randomized, double-blind, cross-over trial preceded by a placebo run-in period. Terazosin and enalapril had a comparable effect on resting BP, reducing systolic (SBP) and diastolic (DBP) blood pressure from 159.5 +/- 13.9/101.6 +/- 8.8 mm Hg during placebo by 7.8%/6.7% and by 11.3%/10.2%, respectively. The "response" rate to the two treatments was approximately the same, being 69% and 75% after terazosin and enalapril, respectively. During mental arithmetic, from an average of 181.6 +/- 17.8/118.6 +/- 11.5 mm Hg during placebo, BP was reduced by 11.5%/7.9% after terazosin and by 13.6%/8.5% after enalapril; during handgrip test, BP decreased from 207.2 +/- 22.2/142.2 +/- 13.6 mm Hg by 7.3%/8.4% after terazosin and by 7.7%/7.1% after enalapril; finally, during cycle ergometry, terazosin and enalapril lowered BP by 5.4%/6.7% and 7%/3.1%, respectively, from a placebo value of 215.5 +/- 17.3/127.6 +/- 11.2. No significant difference in antihypertensive efficacy was observed between the two drugs, either at rest and during stress testing.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of terazosin on blood pressure and serum lipids in nild to moderate hypertension

Effect of terazosin on blood pressure and serum lipids in nild to moderate hypertension

Effect of terazosin on lower urinary tract function in the male decerebrate dog

The effect of terazosin on the lower urinary tract function was studied by combined recording of bladder and urethral pressures and external sphincter electromyogram in 8 male decerebrate dogs. Reflex micturitions were induced by bladder filling before and after terazosin. The statistical analysis was carried out on the urodynamic parameters. During the collecting phase, terazosin at doses of 10, 30 and 100 micrograms/kg produced a significant decrease in maximum urethral pressure in the dose dependent manner. Threshold pressure was significantly shown to decrease at doses of 30 and 100 micrograms/kg. In the urodynamic parameters of the emptying phase there was a significant decrease in maximum contraction pressure at 10 and 30 micrograms/kg, and in voided volume at 100 micrograms/kg. Terazosin seems to facilitate an initiation of the bladder contraction with a decrease in threshold pressure. In concludes that alpha 1 adrenergic activity seems to take an important role for the maintenance of the urethral pressure and to control the initiation of bladder contraction in modulation with threshold pressure.

Quantitative analyses of human prostatic .ALPHA.-adrenoceptors and effects of terazosin on the .ALPHA.-adrenoceptor activity.

The adrenergic alpha-1 and -2 adrenoceptors in human hypertrophied and non-hypertrophied prostatic adenomas were measured in the saturation experiment using 3H-prazosin and 3H-yohimbine. Not only alpha-1 adrenoceptor but also alpha-2 adrenoceptor were found to exist with great amount in prostatic adenomas. In the inhibition experiment selective alpha-1 antagonists, prazosin and terazosin inhibited the 3H-prazosin or 3H-yohimbine bindings to prostatic adenomas. The ability as alpha-1 antagonist is ten times greater in prazosin than in terazosin, but that as alpha-2 antagonist is greater in terazosin than in prazosin. These data suggest that terazosin may have other effects than the relaxation of prostatic smooth muscles in hypertrophied prostatic adenoma.

Hemodynamic and Endocrinological Effects of a New Selective 1-Blocking Agent, Terazosin, in Patients With Essential Hypertension Results of Long-Term Treatment

Thirteen patients with essential hypertension were treated with an alpha 1-adrenoceptor antagonist, terazosin (1 to 4 mg/day) for 12 months. To assess the mechanism of its antihypertensive effect, the hemodynamic and endocrinological responses to terazosin were determined before, 3, and 12 months after the administration of terazosin. Blood pressure significantly decreased within 2 weeks after the start of terazosin and its effect was sustained throughout the 12 month period. Pulse rate did not change except slight increase in the third month. The hemodynamic studies revealed that total peripheral resistance significantly decreased and cardiac output slightly increased, indicating that the antihypertensive effect of terazosin is mainly produced by its vasodilation. Blood volume and plasma volume did not change. Although plasma renin activity remained the same, plasma aldosterone significantly decreased in response to terazosin. Plasma noradrenaline increased in the third month, but returned to the baseline level in the twelfth month. Thus, terazosin monotherapy lowered blood pressure throughout one year without drug tolerance including volume expansion and/or accentuation of renin-angiotensin-aldosterone system or sympathetic function.

The effects of terazosin and methyclothiazide on blood pressure and serum lipids

This study compared the antihypertensive efficacy and the effects on serum lipids of terazosin, a new selective α 1-adrenergic antagonist, of methyclothiazide (MCTZ), and of the two drugs used as combination therapy. Adult patients with supine diastolic blood pressures ranging from 95 to 120 mm Hg were eligible to enter this double-blind, randomized, parallel-group study. Analyses of the blood pressure data from the 194 evaluable patients revealed that all three treatments produced significant ( p < 0.001) reductions in supine and standing systolic and diastolic blood pressures from baseline values. Moreover, combination therapy resulted in significantly greater mean blood pressure reductions than were observed with either drug used as monotherapy. In the group receiving terazosin monotherapy, the total serum cholesterol level, low-density lipoprotein plus very-low-density lipoprotein cholesterol fraction, and triglyceride level fell significantly (median changes of 3.7%, 5.0%, and 16.3%, respectively, p < 0.05). However, in the group receiving MCTZ monotherapy, the total serum cholesterol level, low-density lipoprotein plus very-low-density lipoprotein cholesterol fraction, and triglyceride level increased significantly (4.7%, 7.1%, and 12.5%, respectively, p < 0.001). In contrast, no significant changes from baseline values were observed for any lipid variable in the group receiving terazosin/MCTZ combination therapy. We conclude that terazosin is effective antihypertensive therapy that has a potentially beneficial effect on the serum lipid profile when used as monotherapy and that it counteracts the negative impact of MCTZ monotherapy on the serum lipid profile when used concurrently with this thiazide diuretic.

Pharmacology of terazosin

Terazosin is a quinazoline antihypertensive agent that is chemically similar to prazosin. The saturated furan ring of terazosin distinguishes these two compounds. Terazosin (0.1 to 3.0 mg/kg) lowered blood pressure without increasing heart rate when given orally to spontaneously hypertensive rats. No tolerance was observed during five days of repeated oral administration. Although equally efficacious in spontaneously hypertensive rats as its congener prazosin, terazosin exhibited a more gradual onset of action than prazosin, a more uniform and linear dose-response curve, and a less variable duration of action. When administered intravenously to dogs, terazosin lowered blood pressure primarily by decreasing peripheral vascular resistance. Pretreatment with phenoxybenzamine but not with atropine or propranolol resulted in a greatly reduced hypotensive response to terazosin, demonstrating that this effect of terazosin is mediated by a sympatholytic mechanism of the alpha type. The nature of the alpha-blocking properties of terazosin was evaluated in vitro using both radioligand binding studies and functional tests in rabbit aorta and pulmonary artery. These studies demonstrated that terazosin is highly selective for alpha 1 receptors. The affinity for alpha 1 receptors was approximately one-third that of prazosin. Like prazosin, terazosin displayed minimal interaction with alpha 2 receptors. Median lethal dose values in rats ranged from 0.255 to 0.270 g/kg for intravenous administration and from 5.5 to 6.0 g/kg, for oral administration. Oral administration of high doses of the compound to rats did not produce any gastrointestinal irritation and/or apparent abnormal behavioral effects. Comparison of the oral activity of terazosin in spontaneously hypertensive rats with the oral toxicity values in normal rats revealed a high efficacy/ safety ratio. Terazosin given intravenously to rats and mice was 2.6 to 5.0 times less toxic than prazosin. The absorption of terazosin appeared to be slower than that of prazosin in rats. However, from eight to 16 hours after dosing, terazosin concentrations in plasma exceeded those of prazosin, suggesting the possibility of once-daily dosing with terazosin. In addition, terazosin exhibited statistically significant cholesterol lowering effects in gerbils.