43．高特灵
出处：按学科分类—医药、卫生 军事医学科学出版社《临床常用进口药物手册》第224页（21970字）
【中文释文】：
(盐酸四喃唑嗪)
〔概述〕
高特灵(盐酸四喃唑嗪)，为一种选择性α1肾上腺受体阻滞药，是喹唑啉的衍生物，其化学名为：1-(4-amino-6，7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)acrbonyl]，piperazine，monohydrochloride，dihydrate．
盐酸四喃唑嗪为白色状物，易溶于水和等渗盐水。分子量459．93。
高特灵片(盐酸四喃唑嗪片)为口服片剂具含有1mg、2mg及5mg三种规格。
〔临床药理学〕
药效学：
四喃唑嗪减低动物的外周血管总阻力，使血压下降。产生舒张血管降低血压的作用主要是通过阻滞α1肾上腺受体。口服后15min内，血压逐渐降低。
无论卧位或立位，人的收缩血压和舒张血压均降低。降压作用对舒张压更为显着。通常并不伴随反射性心动过速。服药后数小时血药浓度达高峰期，血压降低最明显，并呈现一定程度的体位反应(直立体位降压较明显)，药效持续至24h，同时，服药后头几小时内直立位心率可增快6～10次／min。
研究显示，α1肾上腺素受体阻滞剂对膀胱排出道慢性梗阻，例如良性前列腺肥大(BPH)的病人的尿流动力学也有所改善。
BPH产生临床症状的主要原因是肥大的前列腺的存在以及前列腺及膀胱出口平滑肌紧张度增加，而后者受α1肾上腺素受体的控制。
体外试验显示，在人前列腺组织中，四喃唑嗪拮抗苯福林导致的痉挛。临床试验亦已显示四喃唑嗪改善BPH病人的尿流动力和临床症状。
四喃唑嗪治疗过程中有体重上升的趋向。服药的男女病人平均体重增加0．93和1．20公斤。安慰剂对照组体重减轻0．11和0．65公斤。两组有明显的统计学差异。
临床对照研究中，以四喃唑嗪治疗的病人血脂全貌均有改进。与服安慰剂病人相比，单独服四喃唑嗪的病人总胆固醇、结合的低密度及极低密度脂蛋白分数稍有降低，但有统计学显着性。对比基线，这些病人的高密度脂蛋白和HDL-胆固醇／LDL-胆固醇比率明显升高，甘油三脂明显降低。然而，与安慰剂组相比，这些改变并不明显。
服高特灵6个月或以上的长期临床监测并未发现因本品所引起的实验室改变，包括血糖、尿酸、肌酐、血液尿素氮、肝功能和电解质。服用四喃唑嗪后临床实验室数据分析表明，血细胞比容、血红蛋白、白细胞、总蛋白及白蛋白均有下降，这可能由于血液稀释所致。服用其它α1阻滞剂也曾观察到与血液稀释有关的血细胞比容及总蛋白含量减少。
〔药代动力学〕
由于药物的溶解度好，人服用高特灵基本全部吸收。食物对四喃唑嗪的生物利用度几乎没有影响。四喃唑嗪的肝首过代谢很少，几乎全部以原形进入循环。服药后约1h血药浓度达到峰值，然后逐渐下降，半衰期约为12h。药物与血浆蛋白高度结合，结合力超过临床上的药物浓度。药物原形自尿中排出约占口服剂量的10%，大便排出约占20%。其余的以代谢产物排除。自尿排出约为40%，自粪便排出约为60%。药物在动物体内的处理性质上和人相近。四喃唑嗪的药代动力学显示与肾功能无关，故勿需对肾功能损害病人作剂量调整。
〔适应证〕
高特灵(盐酸四喃唑嗪)适合于治疗高血压。可以单独应用，也可与其他抗高血压药物同用。
下述情况高特灵也可单用治疗良性前列腺肥大(BPH)：
无前列腺切除手术指征者；
不能接受外科治疗者；
择期手术在等待期间(如轮候手术)者；
病人不愿手术者。
〔禁忌证〕
临床研究和文献均未提示使用高特灵的禁忌证。
〔警语〕
晕厥和“首剂”反应：
像所有其他α1肾上腺受体阻滞剂一样，高特灵能引致明显的低血压，尤其是体位性低血压，以及服首剂及首几剂之后发生晕厥。假如在服用数剂之后突然停药，亦可发生晕厥。其他α1肾上腺阻滞剂亦有报告在剂量增加过快或突然改用其他药物而发生晕厥。据认为晕厥是由于严重的体位性低血压所致，虽然有些晕厥是因发生心率超过120～160次／min的阵发性室上性心动过速所致。
为了减少发生晕厥及严重的体位性低血压，高特灵治疗必须从1mg／d的低剂量开始，并在临睡前服用。开始治疗时不宜用2mg和5mg。增加剂量应该缓慢，请注意根据“用法与剂量”项内推荐的方法，逐步缓慢增加剂量，加用其他抗高血压药物亦须谨慎。在增加剂量期间应该告戒病人什么是可能导致晕厥的情况并嘱他们避免之。
在2000例的多剂量临床试用中，晕厥发生率约为1%，没有1例是严重的或较长时间的，亦不一定发生于首剂给药。在治疗BPH病例里，晕厥发生率在0．5%以下。
一旦发生晕厥，立刻应把病人置于平卧位，如有必要给于支持治疗。已证实服用四喃唑嗪后短时间内直立位的降压反应是比较明显的，即使是缓慢增量情况下。
〔注意事项〕
1．一般性事项 直立性低血压的最严重症状是晕厥(见警告)，而其他低血压的症状，例如头昏、头晕和心悸也较常见。对那些有潜在体位性问题职业的病人治疗时应特别注意。
应告诫病人，特别是在开始治疗期间，有发生直立性症状及晕厥的可能性，因此，服首剂后及增加剂量后12h内，或停止服本药时避免驾车或做有危险的工作。在增加药量期间，病人应避免去那些一旦发生晕厥会导致伤害的环境。告诉病人如发现低血压的症状必须立即坐下或躺下，尤其在坐位或心悸时应该报告医生以便重新考虑剂量。
还需告诉驾车或开重型机器的病人，服用高特灵后偶有瞌睡或嗜睡，要加倍小心。
2．药物相互作用 给高血压病人作临床对比试验证明，本品与利尿剂以及数种β肾上腺受体阻滞剂并无不良的相互作用。
高特灵与下列药物联合使用每种最少做50例以上的非配伍药物的观察，均未发现不良的相互作用，这些药包括：镇痛／消炎药(如扑热息痛、阿斯匹林，可待因，布洛芬，消炎痛等)；抗生素(如红霉素、甲氧苄氨嘧啶(TMP)、新诺明等)；抗胆碱／拟交感神经药(如苯福林，去甲麻黄碱，假麻黄碱)；抗痛风药物(如别嘌呤醇)；抗组织胺药物(如扑尔敏)；心血管药物(如氨酰心安，氢氯噻嗪，甲氯噻，心得安)；皮质类固醇；胃肠药物(如抗酸药物)；降糖药物；安定镇静药(如安定)。未有文献介绍有关在良性前列腺肥大病人使用高特灵的同时用其他药物的经验。因而尚未能认证药物相互作用。
3．致癌，致突变，对生育的影响 体外体内检查评价(包括Ames试验，体内细胞遗传试验，小鼠显性致死试验，中国仓鼠染色体畸变试验和V79正向突变测定)均无发现潜在致突变作用。
小白鼠的致癌测定中一系列试验未发现致突变性；未发现任何细胞类型的致瘤性；大鼠和小鼠两种属均未发现总肿瘤发生率增加。
4．妊娠 对妊娠妇女尚无足够及良好对照研究，高特灵对妊娠的安全性也未确定。妊娠期不推荐使用高特灵，除非估计对母子的益处大于害处。
5．乳母 四喃唑嗪是否进母乳排出不清楚，由于很多药物自乳中排出，如给乳母用药应特别小心。
6．儿科 本品对儿科病的药效和安全性尚未确定。
〔副作用〕
高血压。在14组有安慰剂对照的试验中，以日服1剂，剂量1～40mg单独用药或与其他药物同用，副作用的发生率如下，下表概括了那些用于高血压病人方面的副反应，其发生率至少为5%，发生率至少为2%而同时大于对照组者。
与安慰剂比较，有统计学意义的副反应常为无力、视力模糊、头晕、鼻塞、恶心、下肢水肿、心悸和嗜睡(P＜0．05)，对照研究显示单独用药与使用其他药物的副反应率相似。
表15 高特灵和安慰剂副反应的比较
＃包括软弱、疲倦、劳累、倦怠
§统计学上显着，在P=0．05
副作用通常轻度至中度，但偶然严重需中止治疗。
〔过量〕
如果服用过量的高特灵(盐酸四喃唑嗪)引起低血压，最重要的是对心血管的支持治疗。把病人置于平卧位往往能恢复正常血压及使心律回复正常。如果这方法未能改善，则首先使用血容量扩张剂以治疗休克。如有必要随后可用血管加压药物，并应监测及支持肾功能。实验室数据指出高特灵高度与蛋白给合，故此血液透析治疗并无作用。
〔用法与剂量〕
高特灵的剂量和剂量之间的间隔时间(12h或24h)应该根据病人的具体血压反应。下述为一般给药方法：
1．开始剂量 所有病人初始每晚临睡前服1mg。不应超过这个剂量。这种给药方法可以使潜在的严重低血压减到最低限度。
2．随后剂量
(1)高血压：剂量应逐渐增加直至达到理想的血压。通常的推荐剂量为每日1次每次1～5mg，然而某些病例可高达20mg／d剂量。如超过20mg则血压不呈现进一步的下降，临床上未有超过40mg的经验。血压监测应在每个剂量间隔的终末时测量，以确定在整个间隔期内的血压控制情况。服药后2～3h测1次血压，以观察最大和最小的血压下降反应是否相同，而且可以评估那些过度的血压下降引起的症状诸如头晕心悸等。假如在24h实际血压回升，可以考虑增加剂量或改为每日2次。假如停药数天或更久，重新开始治疗者，亦必须从小剂量开始渐增剂量。在临床试用期间，除了起始剂量于临睡前服用外，其他剂量在清晨给药。
(2)良性前列腺肥大(BPH)：剂量缓慢增加至达到BPH的理想临床疗效。通常推荐用量在5～10mg范围内，每天1次。最后一剂服药后约24h测量尿流率显示，药物对BPH的疗效持续到两剂间隔之末。如果停用四喃唑嗪数天或更久，再用药时应该由小量开始，用渐增法调整剂量。
〔与其他药物同用〕
当高特灵与其他抗高血压药物并用(例如钙离子拮抗剂)时必须小心防止明显的低血压。当加用利尿剂或其他抗高血压药物时，应减低高特灵的剂量并须重新确定最佳剂量。
〔包装〕
1mg，白色片，铝箔包装，每盒28片。
2mg，橙色片，铝箔包装，每盒28片。
5mg，棕黄色色片，铝箔包装，每盒28片。
〔生产厂家〕
美国雅培制药厂
【外文释文】：
(terazosin hydrochloride)
Description
Hytrin(terazosin hydrochloride)，an alpha-1-selective adrenoceptor blocking agent，is a quinazoline derivative represented by the following chemical name and structural formula：：1-(4-amino-6，7-dimethoxy-2-quinazolinyl)-4-[(tetrahydro-2-furanyl)acrbonyl]，piperazine，monohydrochloride，dihydrate．
The impirical formula is C19H25N5O4HCL．2H2O．
Terazosin hydrochloride is a white crystaline substance，freely soluble in water and isotonic saline and has a molecular weight of 459．93．Hytrin tablets(terazosin hydrochloride tablets)for oral ingestion are supplied in three dosage strengths containing terazosin hydrochloride equivalent to 1 mg，2mg or 5mg．
Clinical 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 tachycadia．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 hypertrophy(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 preliminary clincal 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 placebocontrolled monotherapy trials，male and female patients receiving teazosin 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．
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 loner)administration of hytrin 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 hytrin tablets is essentially completely absorbed in man．Food had little or no effect on the bioavailability of terazosin administered in a capsule formulation．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 orally administered dose is excreted as parent drug in the urine and approximately 20% is excreted in the feces．The remainder is eliminated as meta bolites．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．
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．
Indications
Hytrin(terazosin hydrochloride)used alone or in combination with other antihypertensive agents is indicated for the treatment of hypertension．
Hytrin used alone is also indicated for the symptomatic and pathophysiologic treatment of benign prostatic hypertrophy(BPH)when：
·prostatectomy is not indicated
·patient is not fit for surgery
·slective surgery must be postponed(e．g．，waiting list)
·patient refuses surgical treatment(see also Drug Interactions Section)
Contraindications
Clinical studies and available literature do not suggest any contraindication to the use of hytrin．
Warnings
Syncope and“First dose”effect：
Terazosin，like other alpha-adrenergic blocking agents，can cause marked hypotension，especially postural hypotension，and syncope in association with the first dose or first few doses of therapy．A similar effect can be anticipated if therapy is interrupted for more than a few doses．Syncope has also been reported with other alpha-adrenergic-blocking agents in association with rapid dosage increases or the introduction of another antihypertensive drug．Syncope is believed to be due to an excessive postural hypotensive effect，although occasionally the syncopal episode has been preceded by a bout of severe supraventricular tachycardia with heart rates of 120-160 beats per minute．
To decrease the likelihood of syncope or excessive hypotension，treatment should always be initiated with a 1 mg dose of terazosin，given at bedtime．The 2 mg and 5mg tablets are not indicated as initial therapy．Dosage should then be increased slowly，according to recommendations in the Dosage and Administration section and additional antihypertensive agents should be added with caution．The patient should be cautioned to avoid situations where injury could result should syncope occur during initiation of therapy．
In multiple dose clinical trals involoving 2000 patients syncope was reported in about 1%of patients，in no case severe or prolonged，and was not necessarily associated with early doses．
If syncope occurs，the patient should be placed in a recumbent position and treated supportively as necessary．There is evidence that the orthostatic effect of terazosin is greater，even in chronic use，shortly after dosing．
Precautions
General：
1．Orthostatic Hypotension
While syncope is the most severe orthostatic effect of terazosin(see Warnings)，other symptoms of lowered blood pressure，such as dizziness，lightheadedness and palpitations，are more common．Patients with occupations in which such events represent potential problems should be treated with particular caution．
2．Information for Patients
Patients should be made aware of the possibility of syncopal and orthostatic symptoms，especially at the initation of therapy and to avoid driving or hazardous tasks for 12 hours after the first dose，after a dosage increase and after interruption of therapy when treatment is resumed．They should be cautioned to avoid situations when injury could result should syncope occur during initiation of terazosin therapy．They should also be advised of the need to sit or lie down when symptoms of lowered blood pressure occur，although these symptoms are not always orthostatic，and to be careful when rising from a sitting or lying position．If dizziness，lightheadedness，or palpitations are bothersome they should be reported to the physician，so that dose adjustment can be considered．
Patients should also be told that drowsiness or somnolence can occur with terazosin，requiring caution in people who must drive or operate heavy machinery．
3．Drug Interactions
During controlled trials in hypertension，terazosin has been added to diuretics，and several beta-adrenergic blockers，no unexpected interactions were observed．Terazosin has also been used in patients on a variety of concomitant therapies；while these were not formal interaction studies，no interactions were observed．Terazosin has been used concormitantly in at least 50 patients on the following drugs or drug classes：1)analgestic／anti-inflammatory(e．g．acetaminophen，aspirin，codeine，ibuprofen，indomethacin)；2)antibiotics(e．g．erythromycin，trimethoprin and sulfamethoxazole)；3)anticholinergic／sympathomimetics(e．g．phenylephrine hydrochloride，phenylpropanolaminel hydrochloride，phenylpropano hydrochloride)；4)antigout(e．g．allopurinol)；5)antihistamines(e．g．chlorpheniramine)；6)cardiovascular agents(e．g．atenolol，hydrochlorothiazide，methyclothiaside，propranolol)；7)corticosteroids；8)gastrointestinal agents(e．g．antacids)；9)hypoglycemics；10)sedatives and tranquilizers(e．g．diazepam)．
No experience has been reported on the concomitant use of hytrin with other drugs for the treatment of benign prostatic hypertrophy and therefore，drug interactions have not been identified．
4．Carcinogenesis，Mutagenesis，Impairment of Fertility
Hytrin was devoid of mutgenic 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)．
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．
5．Pregnancy
There are no adequate and well controlled studies in pregnant women and the safety of terazosin in pregnancy has not been established．Hytrin is not recommended during pregnancy unless the potential benefit justifies the potential risk to the mother and fetus．
6．Nursing Mothers
It is not know whether terazosin is excreted in breast milk．Because many drugs are excreted in breast milk，caution should be exercised when terazosin is adminis tered to a nursing woman．
7．Pediatric use
Safety and effectiveness in children have not been determined．
Adverse reactions
Hypertension：The prevalence rates presented below are based on adverse experiences(events)combined from fourteen placebo-controlled stuedies involving once-a-day administration of terazosin as monotherapy or in cobination with other antihypertensive agents，at doses ranging from 1 to 40 mg．Table 1 summarizes those adverse experiences reported for hypertension patients in these studies where the prevalence rate for the terazosin group was at least 5%，where the prevalence rate for the terazosin group was at least 2% and was greater than the prevalence rate for the placebo group，or where the reaction is of particular interest．
Asthenia，blurred vision，dizziness，nasal congestion，nusea，peripheral edema，palpitations and somnolence were the only symptoms that were significantly(P less than 0．05)more common in patients receiving terazosin than in patients receiving placebo．Similar adverse reaction rates were observed in placebo controlled monotherapy trials．
Table 15 Adverse reactions during placebo-controlled studles in hypertension
↑Includes weakness，tiredness，lassitude，and fatigue．
·Statistically significant at P=0．05 level．
The adverse reactions were usually mild or moderate in intensity but sometimes were serious enough to interrupt treatment．
Overdosage
Should overdosage of hytrin lead to hypotension，support of the cardiovascular system is of first importance．Restoration of blood pressure and normalization of heart rate may be accomplished by keeping the patient in the supine position．If this measure is inadequate，shock should first be treated with volume expanders．If necessary，vasopressors should then be used and renal function should be monitored and supported as needed．Laboratory data indicate that hytrin is highly protein bound；therefore，dialysis may not be benefit．
Dosage and administration
The dose of hytrin should be adjusted according to the patient’s individual blood pressure response．The following is a guide to its administration：
Initial dose：
The recommended staring dose for all patients is 1 mg at bedtime．This dose should not be exceeded．This initial dosing regimen should be strictly observed to minimize the potential for severe hypotensive effects．
Subsequent doses
Hypertension：
The dose may be slowly increased to achieve the desired blood pressure response．The usual recommended dose range is 1mg to 5mg administered once a day；however，some patients may benefit from doses as high as 20 mg per day．Doses over 20 mg do not appear to provide further blood pressure effect and doses over 40 mg have not been studied．Blood pressure should be monitored at the end of the dosing interval to be sure control is maintained throughout the interval．It may also be helpful to measure blood pressure 2-3 hours after dosing to see if the maximum and minimum responses are similar，and to evaluate symptoms such as dizziness or palpitations which can result from excessive hypotensive response．If response is substantially diminished at 24 hours an increased dose or use of a twice daily regimen can be considered．If terazosin administration is discontinued for several days or longer，therapy should be reinstituted using the initial dosing regimen．In clinical trials，except for the inital dose，the dose was given in the morning．
Benign prostatic hypertrophy
The dose may be slowly increased to achieve the desired clinical response in BPH patients．The usual recommended dose range is 5-10 mg administered once a day．Urine flow rate measured approximately 24 hours after the last dose has shown that the benefical effect in BPH persists for the recommended dosing interval．If terazosin administration is discontinued for several days or longer，therapy should be reinstituted using the initial dosing regimen，
Use with other drugs
Caution should be observed when terazosin is administered concomitantly with other antihypertensive agents(e．g．calcium antagonists)to avoid the possibility of significant hypotension．When adding a diuretic or other antihypertensive agent，dosage reduction and retitration may be necessary．
How supplied
Hytrin tablets(terazosin hydrochloride tablets)are available in three dosage strengths：
1 mg white 140 tablets／box，
28 tablets／box，
2 mg orange 140 tablets／box，
28 tablets／box，
5 mg tan 140 tablets／box，
28 tablets／box，
Manufacturer
Abbott Laboratories Ltd．U．S．A．