临床药理学部分.doc

临床药理学药物分类a. 普通对乙酰氨基酚是是一种止痛、解热剂，已被临床证明它能够有效的治疗临时轻微的疼痛有关的普通感冒、头痛、牙痛、肌肉痛、背痛、小关节疼痛、痛经、降烧。在婴儿、儿童和成人群体中，对乙酰氨基酚是一种有效的解热剂。b. 药物类别对乙酰氨基酚是一种中枢作用的镇痛、解热剂。c. 作用机理止痛尽管确切的地点和镇痛作用的机理不是很明确，对乙酰氨基酚似乎通过痛阈产生镇痛作用2-4。潜在机制可能涉及多种神经递质受体包括 N-甲基-D-天冬氨酸盐 和物质磷5，调节一氧化氮的抑制途径。解热调查表明了, 内原性致热物是在脑脊髓液中的白细胞引起前列腺素E(PGE)产生的。发烧时导致前列腺素作用于下丘脑时热损失减少,热能量的增加。对乙酰氨基酚已被证实在大脑调节高温中心具有抑制内生热活动的作用，并具有在中枢神经系统释放前列腺素的形成的作用。6-9对乙酰氨基酚的退热疗效不是抑制花生四烯酸的代谢机制。10对乙酰氨基酚不依靠于精氨酸抗利尿激素V-1受体的活化作用去诱发大鼠退热，这是由于使用吲哚美辛处理的大鼠已被大家关注。11,12未被对乙酰氨基酚麻痹的病患猫、兔子和狗在发烧和前列腺素活动下降的试验中的观察证实了：对乙酰氨基酚的治疗使用抑制了大脑前列腺素合成酶的合成。13,14d. 药代动力学数据吸收常规释放口服对乙酰氨基酚主要是在小肠内能够通过胃肠道迅速、几乎可以完全吸收。该吸收过程采取被动转运的方式进行的。相对生物利用度为85%。图1显示24位禁食的受试者接受1000毫克液体或囊片的对乙酰氨基酚的平均药代动力学分布。独立研究：对乙酰氨基酚在摄食10到90分钟内的血浆浓度范围是从8到32g/mL。对乙酰氨基酚在摄食六小时后的血浆浓度范围从1到4g/mL。缓慢释放每个扩展释放的对乙酰氨基酚双分子层，一个是650毫克囊片中含有325毫克的立即释放对乙酰氨基酚制剂,另一个是在母体结构中325毫克的对乙酰氨基酚能够用于缓慢释放。体外的数据表明:这两种扩展释放650毫克的囊片（共含1300毫克的对乙酰氨基酚）在服药3至5个小时内释放药物量分别为88%和 95%。16 在服用单剂量的2片650-mg的缓释胶囊，吸收0.5至3小时内的平均最大血浆浓度范围是从6.9至14.1g/mL。图1. 服用一种TYLENOL对乙酰氨基酚成人液体止痛药或者是两个TYLENOL对乙酰氨基酚加强剂囊片的24位男性受试者在口服给药1000毫克剂量的对乙酰氨基酚后的平均血浆浓度。图 2. 服用两种TYLENOL对乙酰氨基酚关节炎扩展救济囊片或者是四种TYLENOL对乙酰氨基酚常规加强剂囊片（两种囊片在服用0至4小时内）的24位男性受试者在口服给药1300毫克剂量的对乙酰氨基酚后的平均血浆浓度。图2显示24位禁食的受试者接受两片共1300毫克剂量的缓释胶囊或四片普通囊片（0至4小时内服两片胶囊）的对乙酰氨基酚的平均药代动力学分布。分布对乙酰氨基酚似乎广泛分布在人体内除了脂肪以外的大部分体液中。对乙酰氨基酚的表观容积分布情况是0.95 L/kg.17 一个相对小比例(10%至25%)的对乙酰氨基酚和血浆蛋白相关，并且超剂量时会轻微地增加血浆浓度18,19。即使在相对较高的浓度下，硫酸盐与酸雄烷代谢物不与血浆蛋白结合。脊髓液低蛋白结合率和低分子量允许对乙酰氨基酚通过血脑屏障。在服用2至3小时后，对乙酰氨基酚在脑脊液中的浓度会达到峰值。21,22胎盘屏障尿液样品的分析说明了非结合的对乙酰氨基酚通过胎盘传递。23 给母亲服用治疗剂量的对乙酰氨基酚，在摄取30分钟就可以通过胎盘传递到胎儿的血液循环中，尽管产妇及脐血间的血浆浓度的差异没有显著的统计过。24在胎儿体内，对乙酰氨基酚是与硫酸盐结合才有效代谢。25母乳母体摄入推荐剂量的对乙酰氨基酚镇痛剂并不会影响到婴儿的健康。婴儿从母乳中摄取到的剂量为母体摄入剂量的0.1% 至 1.85%。26-28 这些研究已证实了，尽管对乙酰氨基酚在母乳中达到了峰值，但是婴儿所摄入的量还是少于母亲摄入剂量的2%。因此，母体摄入推荐剂量的对乙酰氨基酚时，不会中断用母乳喂养婴儿。新陈代谢对乙酰氨基酚在肝脏内的主要代谢是一阶动力学,包括三个主要独立的途径:a) 与葡糖苷酸接合b) 与硫酸盐结合c) 通过细胞色素氧化,P450-依附物,多功能氧化酶途径形成活性中间代谢物，此物可以与谷胱甘肽共轭，并可以进一步形成半胱氨酸和硫醚（醇）氨酸共轭代谢物。29主要的细胞色素P450同工酶似乎参与了CYP2E1的形成，加入CYP1A2和CYP3A4将作为其他的途径。30-32另外也有两条途径参与对乙酰氨基酚的代谢:33a) 通过羟基化形成3-羟基-对乙酰氨基酚。b) 通过甲氧基化形成3-甲基-对乙酰氨基酚。这些代谢物进一步与葡糖苷酸或者硫酸盐共轭。在成年人中，大多数的对乙酰氨基酚与葡萄糖醛酸共轭,在较小程度上,与硫酸盐共轭。这些葡糖苷酸-，硫酸盐-，和失去生物活性的谷胱甘肽衍生物。8共轭硫酸盐在早产儿、新生儿、婴儿中占据主导地位。23,34排泄对乙酰氨基酚的生物半衰期在正常成年人常用剂量范围内约为2至3小时。21,35在儿童身上会较短，在新生儿和肝硬化患者身上会较长些。18缓释胶囊产品的消除半衰期大约是3个小时。根据合并收据，对乙酰氨基酚在脑脊液中的消除半衰期为3.2小时。21对乙酰氨基酚主要是通过与葡糖苷酸或硫酸盐共轭结合方式从体内排出。以下几页将显示了：表1正常人使用治疗剂量（10 mg/kg或1000-mg剂量）代谢产物中的平均范围值36-40不到9%的对乙酰氨基酚是通过原尿液分泌的。37表1. 尿液中对乙酰氨基酚代谢产物对乙酰氨基酚 代谢产物平均百分比葡糖苷酸46.8 - 62.2硫酸盐25.4 - 35.9Mercapturate2.7 - 5.0共轭的半胱氨酸2.1 - 3.0游离的对乙酰氨基酚3.4 - 8.7表 2. 成人用TYLENOL对乙酰氨基酚制剂制剂用量成人单剂量频率aRegular Strength TYLENOL 片剂/胶囊325 mg650 mg每4至6小时bExtra Strength TYLENOL 片剂/胶囊/胶丸剂/Geltabs500 mg1000 mg每4至6小时c,dAdult Liquid500 mg/15 mL1000 mg每4至6小时d,eTYLENOL Arthritis Extended Relief Caplets650 mg1300 mg每8小时hd,fa 每24-小时周期内部超过4000 mg。b 每天不超过12片。 c 每天不超过8片。 d 不能用于12岁以下的儿童。 e 每天不超过8大匙。 f 每天不超过6片胶囊。 表3. 儿科用TYLENOL对乙酰氨基酚制剂制剂用量aInfantsTYLENOL Concentrated Drops80 mg/0.8 mLChildrens TYLENOL Elixir160 mg/5 mLChildrens TYLENOL Suspension Liquid160 mg/5 mLChildrens TYLENOL Chewable Tablets80 mgJunior Strength TYLENOL Chewable Tablets160 mgJunior Strength TYLENOL Caplets160 mga 剂量时根据年龄和体重规定(大约为10-15 mg/kg/剂; 在24小时内不超过5剂).其他小的代谢产物各占4%或更少治疗剂量,包括与3-甲氧基-对乙酰氨基酚、3-羟基-对乙酰氨基酚、3-甲基-对乙酰氨基酚共轭的硫酸盐与葡糖苷酸。39,41-43不同种族人群也出现了细微的差异(eg,亚洲, 西班牙)。36,44-46 参考文献：2. 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