Terazosin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in essential hypertension

Terazosin is a post-synaptic alpha 1-adrenoceptor antagonist with a similar pharmacodynamic profile to prazosin. It differs from prazosin in having a longer duration of action, with an elimination half-life some 2 to 3 times that of prazosin, allowing the convenience of once daily administration. Moreover, its absorption from the gastrointestinal tract is more complete and predictable than that of prazosin which may facilitate dose titration. Terazosin therapy results in a significant reduction in blood pressure in patients with mild to moderate essential hypertension, with little influence on heart rate. The drug is an effective antihypertensive when administered as monotherapy or in combination with a range of antihypertensive agents including beta-blockers, diuretics and combinations of the two. In the few patients with congestive heart failure studied, terazosin produced an increase in cardiac output with a reduction in ventricular filling pressure and systemic vascular resistance, but no studies have been performed to assess the therapeutic potential of terazosin in this indication. Reductions in total plasma cholesterol and low density plus very low density lipoprotein cholesterol fractions have been reported after terazosin therapy, while high density lipoprotein cholesterol concentrations have tended to increase. Should such beneficial changes be confirmed in long term clinical studies they would suggest a therapeutic advantage of terazosin over some other antihypertensive drugs, particularly diuretics, which have been reported to adversely affect the plasma lipid profile. The most common side effects associated with terazosin treatment are dizziness, headache, asthenia and nasal congestion, but these are usually mild and do not require treatment discontinuation. Terazosin is normally administered once daily, starting at a dose of 1 mg/day and gradually titrating upwards as the blood pressure stabilises at each new dose, until blood pressure is adequately controlled or to a maximum dose of 20mg daily. First-dose syncope occurs rarely after terazosin, and can largely be avoided by giving the first dose at bedtime. Thus, terazosin offers a useful alternative to the drugs currently available for the management of mild to moderate essential hypertension either as monotherapy or in combination with other antihypertensive drugs.     

Alpha-adrenoceptor blocking action of terazosin

alpha-Adrenoceptor blocking activities and vascular relaxation activities of terazosin, a new antihypertensive agent, were studied. Terazosin had no effect on Ba2+, serotonin, angiotensin II and Ca2+ induced contractions in the isolated rat aorta. Terazosin competitively inhibited norepinephrine (NE) and phenylephrine (PE) induced contractions of the isolated rat aorta, and their pA2 values were 9.28 and 8.74, respectively. The potency of terazosin in the NE induced contraction was about 0.11, 8 and 176 times more than prazosin, phentolamine and yohimbine, respectively. The potency of terazosin in the PE induced contraction was about 0.09, 6 and 60 times more than prazosin, phentolamine and yohimbine. Terazosin (i.v.) competitively inhibited the PE induced pressor response. The "pA2" values of postsynaptic alpha-adrenoceptor blocking activity was 5.22, and its potency was about 0.05, 5 and 62.5 times more than prazosin, phentolamine and yohimbine, respectively. Terazosin (0.3 mg/kg, i.v. or less) did not show any significant effect on clonidine induced bradycardia during electrical stimulation of cardiac sympathetic nerve, whereas prazosin (0.3 mg/kg), phentolamine (0.1 mg/kg) and yohimbine (0.1 mg/kg) antagonized the effect of clonidine by 37%, 80.6% and 63.3%, respectively. Terazosin, 0.3 and 1 mg/kg, p.o., antagonized the PE (3 micrograms/kg, i.v.) induced pressor response in conscious unrestrained rats. This effect lasted for 8 hr in the case of 0.3 mg/kg and lasted for 12 hr in the case of 1 mg/kg. Thus, it is strong suggested that the antihypertensive effect of terazosin is based on the postsynaptic alpha-adrenoceptor blocking action.     

Effect of age on pharmacokinetics of and blood pressure responses to prazosin and terazosin

Prazosin and terazosin are two alpha 1-adrenoceptor blocking agents, their principal difference being the longer half-life of terazosin. The present study was carried out to determine if elderly subjects are different from the young in their pharmacokinetic handling of these two drugs and if age influences the blood pressure response to each drug. Ten young healthy subjects (aged 19-30 years) and five older healthy subjects (aged 54-62 years) received 1 or 2 mg terazosin, 1 or 2 mg prazosin, or placebo 1 week apart according to a 5 X 5 Latin square design. Concentrations of prazosin and terazosin were measured using a high-performance liquid chromatographic procedure with a detection limit of approximately 0.25 ng/ml. Pharmacokinetic parameters of prazosin were virtually the same in both groups, whereas mean terazosin plasma concentrations were higher in the older group and pharmacokinetic analysis revealed higher peak plasma concentrations and a longer terminal elimination half-life. There was no evidence of increased sensitivity to the hypotensive action of the drug, as peak upright blood pressure falls were similar in the two groups. Symptoms of dizziness in the upright position were also less common. In view of their lack of sedative effects and minimal metabolic disturbances, further studies should be conducted to assess the suitability of these drugs as monotherapy for hypertension in elderly patients.     

Effects of terazosin in the treatment of benign prostatic hyperplasia. A pilot study

Several reports in the literature suggest that alpha-receptor blockade may have therapeutic value in treating the symptoms of patients with benign prostatic hyperplasia (BPH). Terazosin (Heitrin, Hytrin) is a long acting, highly selective alpha 1-adrenergic blocking agent structurally similar to prazosin. The present study, which also can be regarded as a pilot study, was undertaken as part of a multicenter study to evaluate the safety and efficacy of terazosin in the treatment of patients with BPH. This article presents the results with terazosin in the first 15 patients who completed a dose-ranging, non-comparative single-blind study. These preliminary results confirm that terazosin significantly improved peak as well as mean urine flow rates and significantly reduced residual volume and significantly improved obstructive symptoms in patients with benign prostatic hyperplasia (p less than 0.001). The results of this study support the conclusion that terazosin is beneficial for treatment of symptoms in patients with BPH.     

液质联用（LC-MS）法检测特拉唑嗪及应用

目的：建立液质联用（LC-MS）法测定人体血浆特拉唑嗪的浓度及应用。方法：岛津LC-MS2010液相色谱-质谱联用仪,色谱柱为Thermo Hypersil-Hypurity C18（150mm×2.1mm,5μm）;柱温：40℃;流动相为20mmmol/L乙酸铵溶液（pH4.3）∶甲醇∶乙腈=65∶20∶15;流速：0.25mL/min。采用电喷雾正离子模式离子化,用于定量分析的离子分别为m/z388（特拉唑嗪）、m/z384（哌唑嗪）。血浆样品采用3mol/L氢氧化钠碱化、二氯甲烷萃取后LC-MS测定。进样体积为5μL,样品室温度为5℃。结果：特拉唑嗪线性范围为0.25～50ng/mL,最小定量浓度为0.25ng/mL,提取回收率均〉70%,方法回收率为96.0%～97.6%,日间、日内RSD均〈15%。方法灵敏、稳定、特异性高,并已成功地应用到人体血浆特拉唑嗪药代动力学的研究。结论：该方法简便、准确、重复性好,可以准确地定量人体血浆特拉唑嗪的浓度,适于特拉唑嗪生物利用度和生物等效性的研究。     

Effects of terazosin on the blood pressure responses to tilting in conscious animals: comparison with prazosin

Inhibitory effects of terazosin on the compensatory blood pressure responses to tilting were studied in conscious rabbits and spontaneously hypertensive rats (SHR). In rabbits, doses which reduced the mean blood pressure by 15 mmHg were 330 micrograms/kg, i.v., for terazosin and 42 micrograms/kg, i.v., for prazosin, while those which depressed the blood pressure responses to tilting by 30 mmHg were 180 micrograms/kg, i.v., for terazosin and 54 micrograms/kg, i.v., for prazosin. In SHR, almost equal decreases in the mean blood pressure (about 30%) were observed by 1 mg/kg prazosin, p.o., 20 mg/kg hexamethonium, i.p., 3 mg/kg hydralazine, p.o., or 3 mg/kg nicardipine, p.o. In these conditions, prazosin and hexamethonium markedly depressed the blood pressure responses to tilting, whereas hydralazine and nicardipine showed little effect. The results with these antihypertensive drugs closely paralleled the established orthostatic profiles seen clinically. In this SHR tilting model, when the mean blood pressure was reduced by 15%, prazosin significantly depressed the tilting reflexes; however, terazosin produced no depression. Considering the dose ratio of terazosin to prazosin for antihypertensive effects and inhibitory effects on the tilting reflexes, the orthostatic liability of terazosin was about 3 times as low as that of prazosin. On the basis of these results, it is expected that terazosin causes less orthostatic hypotension than prazosin in clinical use.     

特拉唑嗪对原发性高血压病人的血压、血脂及糖代谢的影响

目的：观察特拉唑嗪对３８例（男性２２例，女性１６例；年龄５６±ｓ８ａ）原发性高血压Ｉ期病人血压、血脂及糖代谢的影响。方法：特拉唑嗪首剂于晚上睡前服１ｍｇ，以后根据血压情况逐渐增量，最大剂量为１０ｍｇ／ｄ，８ｗｋ为一个疗程。结果：特拉唑嗪治疗后，血压下降（Ｐ＜０．０１），糖负荷曲线略降低，胰岛素水平（Ｉｎｓ）及胰岛素抵抗（ＩＳＲ）降低（Ｐ＜０．０１），心率及血脂无改变（Ｐ＞０．０５）。结论：特拉唑嗪对原发性高血压Ｉ期者，在改善血压的同时，不影响脂代谢，对糖代谢、胰岛素及ＩＳＲ有益。     

特拉唑嗪及与双氯芬酸钠联合治疗CP/CPPS的研究

目的:比较单用特拉唑嗪与特拉唑嗪联合双氯芬酸钠治疗慢性前列腺炎/慢性骨盆疼痛综合征(CP/CPPS)的效果。方法:将106例CP/CPPS患者随机分为2组,A组予特拉唑嗪治疗(2 mg/d),B组予特拉唑嗪(2 mg/d)加双氯芬酸钠(25 mg/d)治疗。采用美国国立卫生研究所慢性前列腺炎症状评分(NIH-CPSI)、亚评分(疼痛及生活指数)及国际前列腺症状评分(IPSS)标准评价患者治疗8周后的效果。结果:2组治疗后的NIH-CPSI、亚评分及IPSS均明显减少,且2组之间评分无显著性差异。结论:特拉唑嗪单独治疗与联合双氯芬酸钠治疗CP/CPPS的效果相当。     

A pharmacoeconomic analysis of patients with symptoms of benign prostatic hyperplasia

A pharmacoeconomic analysis of therapies for patients with benign prostatic hyperplasia (BPH) was conducted. The therapies compared were androgenic hormone inhibition (finasteride) and alpha-blockade (doxazosin, prazosin and terazosin). This was a cost-effectiveness analysis from the perspective of the US military. The 36-month decision-tree model considered the aforementioned drugs as initial therapy for BPH following an unsuccessful period of watchful waiting. Therapy was continued toward a successful response. All patients who did not respond to therapy received secondary interventions, including transurethral resection of the prostate (TURP). The main outcome measures were clinical effectiveness and incurred costs. A Monte Carlo sensitivity analysis was performed on all cost-effectiveness ratios. The model and sensitivity analysis supported prazosin as the most cost effective alpha-blocker over finasteride: the mean difference was $US381.65 (1994 values) per successfully treated patient, with a range of $US57.83 to $US675.53, in favour of prazosin. If prazosin was used as initial drug therapy after watchful waiting for a man over 50 years of age with classical symptoms of prostatism and no other severe or confounding comorbid conditions, a cost of $US578.15 per treatment could be expected, with clinical effectiveness of 70.3%. Patients who cannot tolerate prazosin should be considered for terazosin therapy before moving on from alpha-blockers. Subsequent treatment with finasteride would cost $US1426.53, with an additional clinical effectiveness of 9.9%. For the small number of patients who fail both therapies, the cost effectiveness of a first TURP as 'third-line' intervention [$US4321.36 for an additional effectiveness of 8.62% and a repeat TURP as 'fourth-line' ($US7650.54 for 0.59%) interventional] was calculated in a similar manner. Costs were cumulative, and effectiveness was derived from the total number of patients who started prazosin therapy. Pharmacological therapy was more cost effective than surgical intervention, and alpha-blockers were more cost effective than finasteride. Among the alpha-blockers, prazosin was by far the most cost effective followed by terazosin, then doxazosin.     

Pharmacological blockade of brain alpha1-adrenoceptors as measured by ex vivo [3H]prazosin binding is correlated with behavioral immobility.

The present studies examined the relationship between the blockade of central alpha1-adrenoceptors, as measured by ex vivo binding of [3H]prazosin in the cerebral cortex and the inhibition of behavioral activation to a mildly novel environment (cage change). It was found that intraventricular (i.v.t.) terazosin, a saline-soluble alpha1-adrenoceptor antagonist, dose dependently inhibited both ex vivo cortical binding and behavioral activation and that there was a highly significant positive correlation between the two with a slope near unity. Prazosin, a nonsaline soluble antagonist which had to be given intraperitoneally (i.p.), was much less potent at blocking both behavioral activity and cortical ex vivo binding, although it blocked ex vivo binding in the lung, indicating that it was effective peripherally but did not readily enter the brain. Despite this, however, the inhibition of cortical binding and behavioral activation that i.p. prazosin did produce were highly correlated with each other and had a slope near unity as with terazosin, whereas the more potent inhibition of lung binding was less well correlated with behavioral inhibition and had a slope significantly less than one. These results confirm our earlier studies, which have shown that alpha1-adrenoceptor activity is essential for gross and fine motor behavior in the mouse and that prazosin, which is used extensively in behavioral research, has difficulty entering the mouse brain.     

Effects of intravenous and intracerebroventricular terazosin, prazosin and clonidine on spontaneous sympathetic outflow in rats

The hypotensive activity of terazosin has been attributed to inhibition of postsynaptic alpha-1 adrenoceptors. The present study examined the influence of terazosin on spontaneous sympathetic outflow in anesthetize and immobilized rats. The effects on blood pressure and heart rate were also evaluated. Intravenously (i.v.) injected terazosin 0.3 mg/kg and prazosin 0.1 mg/kg increased a sympathetic outflow by 15.4 and 21.6%, respectively. These drugs produced a significant and long-lasting fall in blood pressure with slight heart rate change. On the contrary, clonidine 0.1 mg/kg, i.v. significantly inhibited the sympathetic outflow by 69.2%. The intracerebroventricularly administered 10 micrograms/kg clonidine also showed the sympathoinhibitory effect. However 3 micrograms/kg, i.c.v. of terazosin and prazosin increased the sympathetic tone by 16 and 7.2%. During these periods, in both drugs slightly decreased the blood pressure. These changes in hemodynamic parameters and nerve activities were obtained at 2 approximately 3 min after the i.c.v. administration. The 10 micrograms/kg, i.c.v. of terazosin and prazosin significantly inhibited the pressor response by phenylephrine 1 micrograms/kg, i.v. These results indicate the peripheral effect of terazosin and prazosin through the penetration of the drugs from the brain. The results provide evidence that terazosin, like prazosin, dose not affect cardiovascular regulation by a central action.     

Clinical pharmacological studies with prazosin during pregnancy complicated by hypertension

The disposition and effect of orally administered prazosin have been studied in eight women with hypertension which was uncontrolled by beta-adrenoceptor blockade during the last trimester of pregnancy. Results were compared with healthy men of similar age. The median time to peak concentration was 165 min during pregnancy and 120 min in the men (P less than 0.04). Area under the concentration vs time curve was 3914 ng l-1 min in pregnancy and 2439 ng l-1 min in the men (P less than 0.06). Mean elimination half-life was 171 min in the pregnant women and 130 min in the men (P less than 0.01). Blood pressure was lowered by prazosin in both supine and standing positions. Blood pressure control remained satisfactory in six of the eight women and the median prolongation of pregnancy was 22 days. Neonatal outcome was satisfactory and all babies are developing normally. We conclude that prazosin is more slowly, but apparently more completely, absorbed during pregnancy and that its half-life is slightly prolonged. Prazosin appears to be both effective and safe when used during the last trimester to control blood pressure.     

Pharmacological characterization of the postsynaptic alpha-adrenoceptors in isolated canine mesenteric arteries and veins

Summary This investigation was undertaken to characterize the postsynaptic alpha-adrenoceptors in isolated canine mesenteric arterial and venous preparations. Contractile responses to cumulative additions of phenylephrine (selective alpha, -adrenoceptor agonist), UK-14,304 (selective alpha₂-adrenoceptor agonist), noradrenaline (non-selective alpha-adrenoceptor agonist), and dopamine (non-selective alpha-adrenoceptor agonist) were measured in the presence and absence of rauwolscine, a selective alpha₂-antagonist, and terazosin, a selective alpha₁-antagonist. Phenylephrine was a more potent agonist in the mesenteric artery than in the mesenteric vein; UK-14,304 exhibited the opposite profile of activity. Terazosin was a more potent antagonist than rauwolscine against each of the agonists, except dopamine, in the mesenteric artery but rauwolscine was more potent than terazosin in the vein. Terazosin and rauwolscine were equipotent in inhibiting the contractile responses to dopamine in the artery while rauwolscine was more potent than terazosin in the vein. The pA₂ values measured in both vessels failed, however, to demonstrate a high selectivity for either alpha-adrenoceptor antagonist. These results suggest that the alpha-adrenoceptors in the canine mesenteric artery and vein exhibit pharmacological characteristics typical of both alpha,- and alpha₂-adrenoceptor subtypes.This work was supported by NIH grants HL-00872 and GM-22220, and the Searle Clinical Pharmacology ProgramDr. Rajfer is the recipient of a Clinical Investigator Award (HL-00872) from the National Institutes of Health Send offprint requests to S. I. Rajfer at the above address     

二氢吡啶类钙通道拮抗剂的剂型研究进展

二氢吡啶类钙拮抗剂是目前临床应用最广泛的抗高血压药物之一,但该类药物大多存在水溶性差和半衰期短等缺点。为此,研究人员尝试通过制剂学手段对该类药物的水溶性及半衰期等参数进行改进,并获得了一定成果。介绍了国内外有关二氢吡啶类钙拮抗剂的药物剂型研究进展,旨在为该类溶解性不佳或半衰期较短的药物的制剂开发提供一定参考。     

Pharmacological blockade of brain α1-adrenoceptors as measured by ex vivo [H]prazosin binding is correlated with behavioral immobility

The present studies examined the relationship between the blockade of central α₁-adrenoceptors, as measured by ex vivo binding of [³H]prazosin in the cerebral cortex and the inhibition of behavioral activation to a mildly novel environment (cage change). It was found that intraventricular (i.v.t.) terazosin, a saline-soluble α₁-adrenoceptor antagonist, dose dependently inhibited both ex vivo cortical binding and behavioral activation and that there was a highly significant positive correlation between the two with a slope near unity. Prazosin, a nonsaline soluble antagonist which had to be given intraperitoneally (i.p.), was much less potent at blocking both behavioral activity and cortical ex vivo binding, although it blocked ex vivo binding in the lung, indicating that it was effective peripherally but did not readily enter the brain. Despite this, however, the inhibition of cortical binding and behavioral activation that i.p. prazosin did produce were highly correlated with each other and had a slope near unity as with terazosin, whereas the more potent inhibition of lung binding was less well correlated with behavioral inhibition and had a slope significantly less than one. These results confirm our earlier studies, which have shown that α₁-adrenoceptor activity is essential for gross and fine motor behavior in the mouse and that prazosin, which is used extensively in behavioral research, has difficulty entering the mouse brain.     

Indoramin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in hypertension and related vascular, cardiovascular and airway diseases

Indoramin is a postsynaptic selective alpha 1-adrenoceptor antagonist used in the treatment of hypertension. In contrast to some other alpha-blockers, animal studies suggest that its blood pressure lowering effect results from relaxation of peripheral arterioles as a consequence of blockade of postsynaptic alpha 1-adrenoceptors. Furthermore, unlike some other alpha-blockers, this lowering of blood pressure is rarely associated with reflex tachycardia or postural hypotension. Therapeutic trials have shown indoramin to be effective in lowering blood pressure in all grades of hypertension: mild and moderate hypertension when used alone, but generally in combination with a thiazide diuretic, and in moderate to moderately severe hypertension when used in combination with a beta-blocker and diuretic. In a few small comparative studies, no significant difference was found in the blood pressure lowering effects between indoramin and methyldopa, propranolol and prazosin. Side effects were similar for indoramin, propranolol and methyldopa; however in the 1 comparative study with prazosin, prazosin produced a lower incidence of sedation. Indeed, the most common side effect with indoramin therapy has been sedation of a mild to moderate and/or transient nature, reported in about 19% of cases. Other side effects which have sometimes led to a withdrawal of indoramin treatment have been dry mouth, dizziness, and in males, failure of ejaculation; however, side effects may be reduced by starting therapy with smaller doses and titrating more gradually.     

鞘内注射6-羟多巴胺、α_1受体拮抗剂对氯胺酮脊髓镇痛作用的影响

目的　在体探讨脊髓去甲肾上腺素 (NE)能神经元α1受体和氯胺酮 (Ket)脊髓镇痛的关系。方法　用热水甩尾法观察鞘内注射 (ith)氯胺酮 5 0、10 0、2 0 0 μg对小鼠甩尾潜伏期(TFL)的影响。并观察鞘内分别预先注射 6 羟多巴胺 (6 OH DA ,6 μg)、α1受体拮抗剂哌唑嗪 (Pra,5、15 μg)或特拉唑嗪(Ter,5、15 μg )对Ket(10 0 μg ,ith)脊髓镇痛的影响。 结果　Ket(5 0 μg ,ith)对小鼠TFL无影响 (P >0 0 5 ) ,而Ket(10 0、2 0 0μg ,ith)可剂量依赖性地延长小鼠TFL(P <0 0 5 )。鞘内单独注射 6 OHDA、Pra或Ter对小鼠的痛阈无影响 (P >0 0 5 )。ith 5 μgPra或Ter对Ket脊髓镇痛无影响 (P >0 0 5 ) ,而ith 6 OHDA、15 μgPra或Ter则可明显减弱Ket脊髓镇痛 (P <0 0 5 )。结论　脊髓是Ket的镇痛部位之一 ,Ket脊髓镇痛和脊髓NE神经元α1受体有关     

Doxazosin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in mild or moderate hypertension

Doxazosin is a long-acting selective alpha 1-adrenoceptor antagonist structurally related to prazosin. Like prazosin, doxazosin exerts its antihypertensive effect by reducing total peripheral resistance by selective postsynaptic alpha 1-blockade, without reducing cardiac output, and similarly, doxazosin appears to have a negligible effect on heart rate. Doxazosin differs from prazosin in that its long half-life enables once-a-day oral administration. Doxazosin significantly lowers both standing and supine blood pressure and appears to maintain this antihypertensive effect over a 24-hour dosing interval. Doxazosin 1 to 16 mg once daily has been found to be comparable in efficacy to atenolol 50 to 100 mg and prazosin 1 to 20 mg daily. Characteristic of alpha 1-adrenoceptor antagonists, doxazosin also has favourable effects on the plasma lipid profile in that it decreases total cholesterol and triglycerides, and increases high density lipoprotein (HDL) cholesterol as well as the HDL/total cholesterol ratio. Although further long term trials are needed to clarify the role of doxazosin in multidrug regimens in more severe hypertension, it appears to be a suitable drug for consideration as first-line therapy in mild to moderate essential hypertension.     

盐酸特拉唑嗪对细菌性前列腺炎模型大鼠血浆中左氧氟沙星浓度的影响

目的:研究盐酸特拉唑嗪对细菌性前列腺炎模型大鼠血浆中左氧氟沙星浓度的影响,并探讨二者协同作用机制。方法:取大鼠建立细菌性前列腺炎模型,随机分为实验组与对照组,每组60只,实验组大鼠灌服盐酸特拉唑嗪溶液(0.44mg·kg-1),对照组同时灌服溶媒,12h后重复1次并立即给2组大鼠静脉注射左氧氟沙星溶液(44mg·kg-1),分别于注射给药后1、3、7.5、15、30、60、120、240、480、720min断头取血,采用高效液相色谱法测定其中左氧氟沙星血药浓度。结果:与对照组比较,实验组大鼠血浆中左氧氟沙星浓度无显著性差异(P>0.05)。结论:盐酸特拉唑嗪对细菌性前列腺炎模型大鼠血浆中左氧氟沙星的浓度无明显影响,前者不是通过增加后者的血药浓度,而可能是通过增加后者在组织中的浓度来提高治疗前列腺炎的效果。