71．利其丁
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402页（18932字）
【中文释文】：
(酚妥拉明)α-受体阻滞药
〔组分〕
安瓿剂型的含水注射溶液
活性物质：2-([N-(m-羟苯基)-p-甲苯氨基]-甲基)-2-咪唑啉甲烷磺酸酯(甲磺酸酚妥拉明)
1ml安瓿：
活性物质：甲磺酸酚妥拉明10mg；
赋形剂：葡萄糖35mg，加水至1ml；
抗氧化剂：偏亚硫酸氢钠(E223)0．5mg。
5ml安瓿：
活性物质：甲磺酸酚妥拉明50mg；
赋形剂：葡萄糖175mg，加水至5ml；
抗氧化剂：偏亚硫酸氢钠(E223)2．5mg。
〔性能与疗效〕
利其丁的活性组分——酚妥拉明是一种具有竞争性的非选择性α1和α2受体阻滞药，其作用持续较短，通过阻断突触后血管中α1和α2受体，因而引起血管扩张和血压降低，它亦能对去甲肾上腺素和肾上腺素引起的血管收缩反应产生拮抗作用。由于突触前α2受体的阻断作用导致增加神经元的去甲肾上腺素的释放，这可说明利其丁对增强心肌收缩力和速率有良好效应的原因。
病人经静脉注射利其丁后，由于动脉以及静脉血管床的血管舒张，使全身动脉平均值和全身血管阻力平均值得到暂时的下降。受利其丁的这些影响，压力感受器系统和自主神经系统，触发伴随而来的反射性心动过速。
〔药代动力学〕
1．吸收 静脉输注10mg14C的酚妥拉明，输注时间为45min。输后30min，总放射性峰值血浓度(0．11μg／ml)及原形药物量的峰浓度(0．09μg／ml)均在输注后30min达到。
2．分布 当浓度范围为0．02～109μg／ml时，酚妥拉明与人血清蛋白结合率为54%。
3．代谢 人体经过静脉输注酚妥拉明后，能产生广泛的代谢变化。平均13%以原形物从尿液中排出。主要的代谢物是羧基-苯衍生物，它占剂量的17%。静脉注射给药时，这两种物质的结合物是次要的代射物。口服酚妥拉明受代谢的影响较静脉注射为大。
4．排泄 静脉输注10mg甲磺酸酚妥拉明后的头24h内，尿中的排泄物和代谢物占剂量的70%，粪中占3%。在3d的观察期结束时，尚未完成排泄平衡，此时排泄量只占剂量的79%。酚妥拉明很快由血中排出，它不遵循一级动力学规律：经2～4h后，其浓度已降低到其峰值的约15%。有关数据不能用于计算排泄半衰期。
〔适应证〕
控制嗜铬细胞瘤病人可能出现的高血压危象，例如在外科手术前的准备和手术中。
对疑似嗜铬细胞瘤的病例，在无其它现成测试条件下，可用作诊断性测试。
预防在静脉或静脉旁输注去甲肾上腺素后偶然出现的皮肤坏死和腐肉。
〔剂量与使用〕
控制嗜铬细胞瘤所引起的高血压危象。
在外科手术前，或在麻醉、插管期间，或外科切除肿瘤期间，为了控制高血压危象，需静脉注射2～5mg利其丁，若有需要则重复注射。在此同时须监视血压变化。
在疑有嗜铬细胞瘤的利其丁测试
此测试对检测持久性高血压病人的嗜铬细胞瘤有最大的可靠性，而对只有阵发性高血压病人的可靠性较低。这种测试，对没有嗜铬细胞瘤的高血压病人，可能产生假阳性反应。
〔测试准备〕
除了被确认为是必需的药品，例如洋地黄和胰岛素外，在测试前至少在24h内禁止使用镇静剂、止痛剂和所有其它的药物。最好在测试前48～72h就停止使用这些药物。禁用抗高血压药物，直至血压恢复到未治疗时的高血压水平。对于正常血压的病人，不能进行该种测试。
〔通过静脉途径进行利其丁测试〕
1．程序 在测试过程中，病人保持静止仰卧，最好在安静的暗房之内，至少在30min内每隔10min读取一次血压读数，等血压稳定后再注入利其丁。
对成年病人的剂量是5mg。
注射器针头插入血管，但不立即注药，直到对静脉穿刺的升压反应表现平静为止。
迅速注入利其丁。在头3min内每隔30s记录1次血压，在其后的7min内每隔60s记录1次血压。
2．说明 当心收缩压降低超过46．5Pa，心舒张压降低33．2Pa时，将呈现阳性反应，暗示存在嗜铬细胞瘤。典型的阳性反应是心收缩压降低79．7Pa，心舒张压降低33．2Pa。通常在注射后的2min内将出现最大的作用。一般在15～30min或更短时间内恢复到注射前的血压水平。
如果血压降到危险的水平，则须按“用药过量”对病人进行处理。当注射利其丁后，心收缩压降低少于46．5Pa，心舒张压降低少于33．2Pa，或血压升高，或不发生变化则表示阴性反应，对该种测试的阴性反应，也不能排除诊断为嗜铬细胞瘤，特别是具有阵发性高血压的病人，因为他们曾经常地显示假阴性反应。
〔通过肌肉注射进行利其丁测试〕
对成年人的肌肉注射剂量为5mg。在注射的30～45min内，每隔5min记录1次血压，当注射后的20min内，心收缩压的降低至少为46．5Pa、心舒张压的降低为33．2Pa，显示阳性反应。对于假阴性的结果，肌肉注射比静脉注射要多。
预防在静脉或静脉旁注射去甲肾上腺素后出现的皮肤坏死和腐肉。
在12h内，将利其丁(10ml盐水中含有5～10mg)注入去甲肾上腺素外溢处。
〔禁忌证〕
已知对酚妥拉明和有关化合物过敏。已知对亚硫酸酯过敏。血压过低、心肌梗塞、有心肌梗塞病史、冠状功能不全、心绞痛或其它显着的心脏冠状动脉疾患。
〔预防〕
应监护病人血压变化，这不但保证选择适用病例使用利其丁治疗，而且可以决定适合的剂量和注射治疗时限。
已报道，使用利其丁后曾发生心肌梗塞、脑血管痉挛和脑血管闭塞，通常这些疾患都与明显的血压过低有关。
利其丁安瓿中存在的亚硫酸酯，在个别例子中，特别是哮喘病人可能导致急性气喘、休克或失去知觉等形式的过敏性反应。
在对高血压病人的普检中，基于准确和安全理由，现在多选用儿茶酚胺的尿液化验或其它生化检验代替利其丁和其它药理学检验。因此，利其丁测试法，只有在无其它测试提供下才使用。
使用利其丁可能出现心动过速及心律失常现象。
由于利其丁对胃肠道(包括胃分泌)有刺激作用。因此胃炎和胃溃疡病人须慎用利其丁。
由于没有用利其丁治疗肾损害病人的动力学资料。因此该类病人要慎用利其丁。
利其丁可能引起中枢神经某些症状的出现(参见副作用)，而这些症状可能损害病人的反应能力。因此，要对从事需快速反应活动的病人，例如驾车者和操作机器者提出告诫。
〔妊娠与哺乳〕
一般来说，在妊娠(妊娠类型C)头3个月不能使用该药。在整个妊娠期间应认真考虑使用该药的利弊。
有关妊娠妇女使用酚妥拉明的情况，尚无资料介绍。
除非使用利其丁治疗是必需外，妊娠期间应不使用该药。
酚妥拉明是否进入乳汁之资料尚未确立。为安全起见，在哺乳期间建议不使用酚妥拉明。
〔副作用〕
已观察到有以下副作用：
1．心血管系统
经常出现：直体位低血压和心动过速。
偶然出现：急性或延长性低血压。心肌梗塞、脑血管痉挛，在这些情况下可能出现脑血管闭塞。
极稀少出现：绞痛。
2．中枢神经系统
偶然出现：头晕和衰弱。
3．胃肠道
偶然出现：恶心、呕吐和腹泻。
4．其它方面
偶然出现：鼻塞和红晕。
极少出现：胸腔痛。
5．相互作用
利其丁可能增加其它抗高血压药的降血压作用。神经松弛剂(主要镇静剂)可能增加α-受体阻滞药的降血压作用。
6．用药过量
征兆和症状。
使用利其丁过量的临床症状，主要是动脉血压过低、反射性心动过速、心脏兴奋、心律失常，全身静脉容量增大和可能出现休克。这些症状可能伴随头痛、过度兴奋、视觉障碍、出汗、胃的能动性增大、呕吐、腹泻和低血糖。
7．处理
血压过低、周围血管扩张过大：以滴注方式投用经小心调整剂量的生理拮抗剂去甲肾上腺素。此时利其丁的作用会在短时间内消失。因此须相应调整去甲肾上腺素的剂量。当使用升压剂时，由于可能出现心律失常，所以要监视心电图。同时，也应采取其它的措施，例如使病人的脚部抬高，使用血浆扩容剂。此时不宜使用肾上腺素，因为在此情况下，使用肾上腺素可能使血压进一步降低。
(1)心脏兴奋度和高血压危象 使用β-受体阻滞药，例如β1-选择性阻滞药美托洛尔，进行缓慢的静脉注射。
(2)心律失调 对心律失常的本质进行调节性治疗。
〔3)低血糖 静脉注射葡萄糖。直到低血糖指标合适为止。
〔配伍禁忌〕
碱性溶液。
〔贮存〕
隔热、避光保存。
药品应小心存放，防止儿童误取。
在包装盒上印刷的“Exp”下注明了使用期，过期药品不能使用。
〔包装盒〕
5支安瓿，每支10mg
5支安瓿，每支50mg
〔生产厂家〕
瑞士巴塞尔汽巴一嘉基公司
(附本品别名：瑞士停，立其丁，苄胺唑啉，酚胺唑啉，甲烷磺酸酚妥拉明，酚妥拉明甲磺酸盐)
【外文释文】：
Alpha-receptor blocker
Composition
Aqueous injectable solution in ampoules
Active substance：2-([N-(m-Hydroxyphenyl)-p-toluidino]-methyl)-2-imidazoline methane sulphonate(phentolamine methane sulphonate)．
Ampoules of 1 ml：
Active substance：phentolamine methane sulphonate 10 mg
Excipients：glucose 35 mg，water up to 1 ml
Anti-oxidant：sodium metabisulphite(E 223)0．5mg
Ampoules of 5ml：
Active substance：phentolamine methane sulphonate 50mg
Excipients：glucose 175mg，water up to 5ml
Anti-oxidant：sodium metabisulphite(E 223)2．5mg
Properties／Effects
Phentolamine，the active substance of Regitine，is a competitive non-selective a1-and a2-receptor blocker with a relatively short duration of action．It causes vasodilatation and a fall in blood pressure resulting from the blockade of post-synaptic vascular a1-and α2-receptors．It also antagonizes the vasoconstrictor response to noradrenaline and adrenaline infusions．Enhanced neuronal release of noradrenaline due to pre-synaptic α2-blockade may contribute to the positive inotropic and chronotropic effects of Regitine on cardiac muscle．
In man intravenous administration of Regitine produces transient declines in mean systemic vascular resistance and mean systemic arterial pressure as a result of vasodilatation in the arterial as well as in the venous vascular bed．These effects of Regitine are accompanied by refex tachycardia，triggered by the baroceptor system and the autonomc nervous system．
Pharmacokinetics
Absorption
During intravenous infusion of 10 mg14C-labelled phentolamine methane sulphonate over a period of 45 minutes，both the peak blood concentrations of total radioactivity(0．11μg／ml)and of unchanged drug(0．09μg／ml)are attained at 30 minutes．
Distribution
Phentolamine becomes bound to an extent of 54%to proteins of human serum in the concentration range of 0．02-109μg／ml．
Metabolism
Phentolamine is extensively metabolized in man after intravenous infusion；on the average，about 13%of the dose administered can be recovered in the urine in the form of unchanged drug．A prominent metabolite is the carboxy-phenyl derivative，which accounts for 17% of the dose．Conjugates of these two substances are of minor importance after intravenous administration．Phentolamine becomes metabolized on a larger scale after oral than after intravenous dosing of the drug．
Elimination
After intravenous infusion of 10mg phentolamine methane sulphonate，urinary excretionof the drug and its metabolites accounts for 70%of the dose with in the first 24 hours；another 3%is found in the faeces．At the end of an observation period of 3 days，the excretory balance is not complete，the quantity excreted amounting to 79%of the dose．Elimination of phentolamine from the blood is rapid and dose not follow first-order kinetics；already after 2-4 hours the concentration drops to about 15%of its peak value．The data do not allow calculation of an elimination half-life．
Indications／Scope of use
Management of hypertensive crisis which may occur in patients with phaeochromocytoma，e．g．during pre-operative preparation and surgical intervention．
Diagnosis of phaeochromocytoma by the Regitine test if other specific tests are not available．
Prevention of skin necrosis and sloughing after accidental intravenous or paravenous administration of noradrenaline．
Dosage／Use
Management of hypertensive crisis due to phaeochromocytoma
For the management of hypertensive crisis that occur before surgery or during induction of anaesthesia，intubation or surgical removal of the tumour，2-5mg Regitine is injected intravenously，and the injection repeated if necessary，while at the same time monitoring the blood pressure response．
Regitine test in cases of suspected phaeochromocytoma．The test is most reliable in detecting phaeochromocytoma in patients with sustained hypertension and least reliable in those with only paroxysmal hypertension，The test may yield false-positive results in hypertensive patients without phaeochromocytoma．
Preparation for the test：
Sedatives，analgesics，and all other medications except those that might be deemed essential(such as digitalis and insulin)are withheld for at least 24 hours，and preferably 48-72 hours，prior to the test．Antihypertensive drugs are withdrawn until the blood pressure returns to its untreated，hypertensive level．This test is not performed on normotensive patients．
Regitine test by the intravenous route
Procedure：
The patient is kept at rest in the supine position throughout the test，preferably in a quiet，darkened room．Injection of Regitine is delayed until the blood pressure becomes stabilized，as evidenced by blood pressure readings taken every 10 minutes for at least 30 minutes．
The dose in 5 mg for adults．
The syringe needle is inserted into the vein，but the injection is not administered untilthe pressor response to venepuncture has subsided．
Regitine is injected rapidly．The blood pressure is recorded immediately after the injection，at 30-second intervals for the first 3 minutes，and at 60-second intervals for the next 7 minutes．
Interpretation：
A positive response，suggestive of phaeochromocytoma，is indicated when the blood pressure falls by more than 35 mm Hg systolic and 25 mm Hg diastolic．A typical positive response is a reduction in pressure of 60 mm Hg systolic and 25 mg Hg diastolic．The maximal effect usually becomes evident within 2 minutes after the injection．A return to preinjection pressure commonly occurs within 15-30 minutes but may occur more rapidly．
If the blood pressure decreases to a dangerous level，the patient should be treated as outlined under“Overdosage”．A negative response is indicated when the blood pressure is elevated，unchanged，or reduced by less than 35 mm Hg systolic and 25 mm Hg diastolic after the injection of Regitine．A negative response to this test does not exclude a diagnosis of phaeochromocytoma，especially in patients with paroxysmal hypertension，who frequently show a false-negative response．
Regitine test by the intramuscular route
The dose for adults is 5 mg intramuscularly．The blood pressure is recorded every 5 minutes for 30-45 minutes following the injection．A positive response is indicated when the blood pressure is reduced by at least 35 mm Hg systolic and 25 mm Hg diastolic within 20 minutes after the injection．False-negative results are far more common by the intramuscular than by the intravenous route．
Prevention of skin necrosis and sloughing after intravenous or paravenous administration of noradrenaline Regitine(5-10 mg in 10ml saline)is injected within 12 hours into the area in which extravasation of noradrenaline has occurred．
Restrictions on use
Contra-indications
Known hypersensitivity to phentolamine and related compounds，known hypersensitivity to sulphites，hypotension，myocardial infarction，Instory of myocardial infarction，coronary insufficiency，angina pectoris，or other evidence of coronary artery disease．
Precautions
Monitoring of the blood pressure is of decisive importance for appropriate selection of patient，dosage，and duration of therapy．
Occurrences of myocardial infarction，cerebrovascular spasm，and cerebrovascular occlusion have been reported following administration of Regitine，usually in association with marked hypotensive episodes．
The presence of a suphite in the arnpoules of Regitine can，especially in asthmatic patients，lead in isolated cases to hypersensitivity reactions，which may take the form of an acute asthma attack，shock，or clouding of consciousness．As screening tests in patients with hypertension，the generally available urinary assay of catecholamines or other biochemical assays have now largely replaced the Regitine and other pharmacological tests for reasons of accuracy and safety，the Regitine test is therefore not the procedure of choice and should be used only when these other specific tests are not available．
Tachycardia and cardiac arrhythmias may occur with the use of Regitine．
Owing to its stimulant effect on the gastro-intestinal tract，including gastric secretion，Regitine should be employed with caution in patients with gastritis and peptic ulcer．Since no kinetic data are available on treatment with Regitine in patients with renal impairment，the drug should be used cautiously in such patients．
Regitine may cause central nervous symptoms(see’Unwanted effects”)which might impair the patients reactions．Patients must therefore be warned against engaging in activities that require quick reactions，such as driving motor vehicles and operating machines．
Pregnancy／Lactation
(Pregnancy Category C)
As a general rule no drugs should be taken during the first 3 months of pregnancy，and the benefits and risks if taking drugs should be carefully considered throughout the whole of pregnancy．
No experience with phentolamine in pregnant women is available．
The drug should be employed during pregnancy only if its use is considered essential．
It is not known whether phentolamine passes into the breast milk．For safety reasons it is not recommended that Regitine be used during lactation．
Unwanted effeets
The following unwanted effects have been observed：
Cardiovascular system
Frequently：Orthostatic hypotension and tachycardia．
Occasionally：Acute or prolonged hypotension，myocardial infarction，cerebrovascular spasm，and cerebrovascular occlusion may occur under these circumstances．
Rarely：Anginal pain．
Central nervous system
Occasionally：Dizziness and weakness．
Gastro-intestinal tract
Occasionally：Nausea，vomiting，and diarrhoea．
Miscellaneous
Occasionally：Nasal stuffiness and flushing．
Rarely：Chest pain．
Interactions
Regitine may increase the hypotensive effect of other antihypertensive agents．Neuroleptic drugs(major tranquillisers)may enhance the hypotensive effect of alpha-receptor blockerS．
Overdosage
Signs and symptoms
The main clinical manifestations of overdosage with Regitine are arterial hypotension，reflex tachycardia，cardiac stimulation，arrhythmia，increase in systemic venous capacity，and possibly shock．These effects may be accompanied by headache，hyperexcitability，disturbances of vision，sweating，increased gastric motility，vomiting，diarrhoea，and hypoglycaemia．
Management
Hypotension，excessive peripheral vasodilatation：noradrenaline，which can be regarded as the physiological antagonist，should be given in a carefully titrated dosage by continuous intravenous infusion．The effect of Regitine may wear off in a short time，and administration of noradrenaline may have to be adjusted accordingly．When a pressor agent is used，the ECG should be monitored，because major arrhythmias may occur．At the same time other measures should be taken，e．g．keeping the patient’s legs raised and administering a plasma expander．Adrenaline should not be employed，since in such a situation it may cause a further fall in blood pressure．
Excessive cardiac stimulation and hypertensive crisis：administer a beta-blocker，e．g．the β1-selective metoprolol(Lopresor)，by slow intravenous injection．
Disturbances of cardiac rhythm：
Adjust treatment to the nature of the arrhythmia．
Hypoglycaemia：
Intravenous administration of glucose until the hypoglycaemia has been corrected．
other information
Incompatibilities
Alkaline solutions．
Storage
Protect from light and heat．
Medicines should be kept out of the reach of children．
The product should be used only up to the date indicated by“EXP”on the pack．
Packs
5 ampoules of 10rng
5 ampoules of 50mg
Manufacturer
Ciba-Geigy AG，Basle，Switzerland