注意性状,使用特点和疗效特点综合了注射剂剂型特点和给药途径的特点,可以看出不同剂型和用法可以产生不同的临床效果 口服给药的吸收速度与其脂溶性程度成正比注射给药的吸收速度则与其水溶性程度成正比90%以上与糖皮质激素结合球蛋白 和血浆白蛋白结合而无生物活性仅10%的游离部分具有生物活性在体内的分布无选择性,但炎性反应部位血流量及血管通透性增加,其药物浓 度可高于其他部位药物主要在肝脏灭活,淋巴细胞有使糖皮质激素氧化或还原的能力可的松在人体内需转化为氢化可的松才能产生生物活性 地塞米松本身即具有生物活性各种肾上腺糖皮质激素类药物的体内半衰期不同,可依据其半衰期长短而选择不同药物药物以代谢终产物形式由 肾脏排泄,但肾功能不全时不引起血浆中活性激素水平升高肾上腺皮质激素类药物的种类通过对肾上腺皮质激素的结构改造,而获得人工合成 的肾上腺糖皮质激素类或盐皮质激素类药物。肾上腺糖皮质激素类以氢化可的松为代表,主要调节糖,蛋白质和脂肪代谢,并具有抗炎、免疫抑制 等药理作用;肾上腺盐皮质激素类如去氧皮质酮和氟氢可的松则主要影响水、盐代谢。临床医师应根据不同疾病,按临床适应证,正确选 择肾上腺皮质激素类药物对糖皮质激素的分类常仅按照半衰期分为长效、中效、短效激素(抗炎强度基本与半衰期正 相关)鉴于免疫抑制也是选用糖皮质激素的重要出发点之一,Langhoff等又将泼尼松、地米与氢考等激素一起定义为中效抑制激素,而 将甲泼尼龙和氟氢可的松一起定义为强效免疫抑制激素经气道吸入及鼻腔给药的糖皮质激素常用药物、制剂及特点吸入给药方式评价 优点治疗范围局限在目标器官内,局部抗炎作用强将药物直接输送到患病部位,直接作用于呼吸道病变部位药物浓度高药物起效迅速 全身不良反应减少或减轻局部用药较全身用药,药物剂量显著降低HPA轴抑制作用显著降低通过消化道和呼吸道进入血液药物量小,大 部分被肝脏灭活缺点给药装置种类繁多对操作技能及患者培训要求较高,患者通常缺乏装置使用的知识吸入型糖皮质激素筛选和研制方向 局部抗炎活性越强越好亲脂性要高,与皮质激素受体亲和力要高到达靶细胞药物要多,停留时间要长全身作用越少越好-药物代谢动力学 性质首过代谢要强,吸收要少,生物利用度低,代谢物活性要小半衰期要短,具有很快的全身清除率倍氯米松布地奈德氟替卡松相对 亲脂性79432398031622肺生物利用度20%39%30%全身生物利用度15-20%10%<2%代谢 首过效应首过效应首过效应局部抗炎活性vs全身作用的比例第1个批准用于婴儿哮喘的药物和皮质激素雾化剂型;可用于治疗小 儿毛细支气管炎和急性喉炎。肺内沉积率高。治疗急性喉炎比甲泼尼龙、地塞米松静脉注射见效快,可缩短治疗时间。布地奈德雾化吸入剂 吸入型糖皮质激素不良反应全身不良反应吸入给药具有较高的呼吸道内活性,局部用药的全身不良反应与全身用药相比少而轻80%-90 %沉积在口腔内其中40%-50%进入消化道吸收入血,通过肝脏首过效应而使全身生物利用度明显降低。10%-20%吸入呼吸道,其 中4%呼出体外,其余沉积在下呼吸道,有一部分被吸收入血。所以,按正确的使用方法,吸过后及时漱口,真正被吸收入血的药量很小。发生 全身不良反应的危险因素增加严重哮喘患者吸入激素的治疗剂量提高干粉吸入剂储药量增加咽喉部刺激咽部不适,口干,咳嗽,嘶哑,口 咽部霉菌感染吸入性糖皮质激素类药物使用注意事项吸入品种的选择不能随意用全身用糖皮质激素替代地塞米松雾化吸入疗法:全身吸 收广泛,HPA轴抑制泼尼松雾化吸入疗法:水溶性强,局部疗效弱氢化可的松雾化吸入疗法:水溶性强,局部疗效弱不同类激素在使用中不 能随意替换全身用糖皮质激素类药物体内相互作用参见说明书和药学参考书主要考虑以下相关因素:如不良反应的叠加致溃疡药物:非 甾体解热镇痛药致感染药物:免疫抑制剂,疫苗致高血糖药物:噻嗪类利尿药:致精神症状药物:三环类抗抑郁药致水肿药物:蛋白质同 化激素酶代谢影响苯巴比妥、苯妥英、利福平等肝药酶诱导剂可加快皮质激素代谢,故同用时需适当增加剂量其他……糖皮质激素类药 物老年患者用药警惕高血压警惕糖尿病警惕更年期后女性骨质疏松加重糖皮质激素类药物儿童用药全身用药,须十分慎重,可抑制患儿 生长和发育,长期服用发生骨质疏松症、股骨头缺血性坏死、青光眼、白内障的危险性增加采用短效或中效制剂,避免使用长效制剂(如地塞米松 )口服中效制剂隔日疗法可减轻对生长的抑制作用。须密切观察不良反应。对于有肾上腺皮质功能减退患儿的治疗,激素用量应根据体表面 积而定,如果按体重计算则易发生过量,尤其是婴幼儿和矮小或肥胖的患儿。局部用药吸入型糖皮质激素布地奈德批准用于儿童正确使用 吸入装置,保证剂量准确吸入后漱口并吐出全身用糖皮质激素类药物妊娠期用药药物名称人类数据FDA危险分级澳大利亚危险分 级(氢化)可的松有致畸危险可使用D(1-3月)C轻微致畸和毒性作用,但用药的益处远大于危险性,应权衡利弊A泼 尼松(龙)有致畸危险可使用D(1-3月)C广泛使用,有轻微致畸作用A地塞米松有致畸危险可使用D(1-3 月)C孕妇益处远大于胎儿危险,目前尚无资料证明存在危险性A甲泼尼龙无资料A全身用糖皮质激素类药物妊娠期用药现有资料 显示,激素类药物在妊娠最初3个月时用药的安全性存在争论,临床研究结果有矛盾有荟萃分析显示全身用药可导致少量但与用药明显相关的口腔 裂发生虽然存在可疑致畸危险性,但应考虑孕妇疾病状态,权衡孕妇和胎儿利弊用药正常人群口腔裂的发生率低:1/1000,发生率略 有增加,对整体畸形发生率影响很小妊娠12周后上颚发育结束,之后用药是安全的全身用糖皮质激素类药物妊娠期用药氢化可的松透过胎 盘比例小:10%-15%(85%经胎盘代谢失活为可的松)治疗孕妇疾患泼尼松龙经胎盘代谢失活为泼尼松,比例不详,但有报道可同 时治疗孕妇和胎儿疾患地塞米松透过胎盘比例大:46%(54%经胎盘代谢失活)治疗胎儿疾患全身用糖皮质激素类药物哺乳期用药 糖皮质激素类药物可由乳汁痕量分泌,乳汁浓度是血浆浓度的5%-25%,经乳汁摄入的药量<0.1%的母体剂量,不足婴儿内源性 激素分泌量的10%。 有可能对婴儿造成不良影响,应权衡利弊,尽量避免使用。短效激素:内源性短效激素在母乳中有微量分泌,人工合 成短效激素无相关数据。中效激素:在母乳中有微量分泌。母亲服用泼尼松≤20mg/日,甲泼尼龙≤8mg/日,乳汁中含量可忽略不计。 如剂量超出,可于服药3-4小时后哺乳,以减少婴儿摄入量。长效激素:未见在哺乳期使用的报道,因此没有相关数据,但推测地塞米松分子 量低,完全可分泌进入乳汁,应避免长期使用,或用药期间停止哺乳。局部用糖皮质激素类药物妊娠期用药吸入型糖皮质激素(特 别是布地奈德)妊娠期间长期应用相对安全,未发现与致畸有相关性。谢谢天然的,人工合成的,内源性激素结构修饰的 目的9氟代-16a-甲基:地塞米松9氟代-16B-甲基:倍他米松疗效和不良反应 盐皮质激素作用常用糖皮质激素类药物制剂及特点北京协和医院药剂科李大魁王强全身给药口服给药静脉给药肌 内给药局部给药吸入给药经口吸入鼻腔喷雾关节内给药眼内局部给药滴眼剂眼部注射滴耳给药皮肤外用给药皮损内注射给药 硬膜外给药直肠给药糖皮质激素给药途径内源性可的松Cortisone氢化可的松Hydr ocortisone外源性泼尼松Prednisone泼尼松龙Prednisolone甲泼尼龙Methylpredni solone倍他米松Betamethasone地塞米松Dexamethasone全身用糖皮质激素常用药物内源性糖皮质 激素可的松C11位羟化糖皮质激素活性内源性糖皮质激素(与内源性糖皮质激素具有等效作用的药物)有哪些?其中具有生理活性的是? 其中没有生理活性,是无活性代谢物的是?两者之间的关系是什么?发生代谢转换的部位是?氢化可的松可的松氢化可的松可的松 在代谢中相互转化肝脏氢化可的松vs可的松关联与差异肝功能障碍患者可的松不能有效代谢成为活性产物氢化可的松急性或严 重应激状态使用氢化可的松无需代谢的活性成分,直接发挥作用人工合成糖皮质激素1929年发现可的松在治疗类风湿关节炎的治疗作 用1948年,1951年可的松和氢化可的松用于治疗类风湿关节炎正作用副作用糖皮质激素活性盐皮质激素活性抑制类风关所 需剂量正常代谢功能扩大内源性糖皮质激素外源性糖皮质激素糖皮质激素活性?4盐皮质激素活性?0.8C1=C2双键结构 无需肝脏代谢活化亲脂性增加糖皮质活性20盐皮质活性0糖皮质活性盐皮质活性亲脂性增加 糖皮质活性↗5盐皮质活性↘0.5药理学作用改变药代动力学特征改变与糖皮质激素受体亲和作用盐皮质激素作用没有增强略有下 降生物半衰期抗炎作用血浆半衰期延长代谢降低化学结构变化水钠潴留蛋白结合降低游离增加抗炎作用增强作用时间延长C 1,2位不饱和双键环A几何形态改变泼尼松龙泼尼松抗炎作用强弱和作用时间长短的药物化学基础其中具有生理活性的是?其中 没有生理活性,是无活性代谢物的是?两者之间的关系?发生代谢转换的部位是?关联与差异泼尼松龙泼尼松在代谢中相互转化肝脏 泼尼松龙vs泼尼松肝功能障碍患者:直接使用活性成分泼尼松龙泼尼松不能有效代谢成为活性产物。药理学作用 改变药代动力学特征改变与糖皮质激素受体亲和作用盐皮质激素作用更大幅度继续下降组织分布生物半衰期抗炎作用组织穿透性 更好代谢降低化学结构变化水钠潴留分布体积更大抗炎作用增强作用时间延长C6位-甲基取代C1,2位不饱和双键甲泼尼 龙脂溶性增加生物半衰期延长蛋白结合降低游离增加药理学作用改变药代动力学特征改变与糖皮质激素受体亲和作用盐皮质激素 作用明显下降组织分布生物半衰期抗炎作用组织穿透性加强代谢降低化学结构变化水钠潴留分布体积变大抗炎作用增强作用 时间延长C9位-氟代基团C16位-甲基取代C1,2位双键地塞米松脂溶性增加抗炎活性增加受体亲和力增加蛋白结合 降低游离增加生物半衰期延长药物名称抗炎强度水钠潴留强度等效剂量(mg)短效糖皮质激素(t1/2<12h)可 的松0.80.825氢化可的松1120中效糖皮质激素(t1/2=12-36h)泼尼松40.85泼尼松 龙40.85甲泼尼龙50.54长效糖皮质激素(t1/2>36h)地塞米松20-3000.75倍他 米松25-3000.6糖皮质激素糖盐代谢作用激素名称血浆半衰期(h)生物半衰期(h)HPA轴抑制时间(天)短 效可的松0.58-121.25-1.50氢化可的松1.68-121.25-1.50中效泼尼松 2.6-318-361.25-1.50泼尼松龙2-418-361.25-1.50甲泼尼龙 2-318-361.25-1.50长效地塞米松3-636-542.75 倍他米松3-636-543.25糖皮质激素半衰期(血浆和生物)皮质激素激素结合 蛋白白蛋白可的松90(激素结合蛋白饱和后,与白蛋白结合)氢化可的松90(激素结合蛋白饱和后,与白蛋白结合)泼尼松70 泼尼松龙70-90(与激素结合蛋白结合力强,可与内源性激素竞争结合,饱和后与白蛋白结合)甲泼尼龙<174倍他米松< 164地塞米松<177糖皮质激素蛋白结合作用不同糖皮质激素抗炎强度与免疫抑制强度相关性的研究L anghoff等人的研究指出,甲泼尼龙免疫抑制强度优于其他同类药物ErikLanghoffetal.Int.J.Im munopharmac,Vol9,No.4,469-473,1987甲泼尼龙>地塞米松>泼尼松龙>氢化可的松>可的松 112.20.610生理作用氢化可的松和可的松与内源性 糖皮质激素具有等效糖盐代谢作用长期或终生服用生理替代剂量原发性、继发性(垂体性)肾上腺皮质功能减退症肾上腺酶系缺乏所致的 肾上腺增生疾病特点用药特点急性肾上腺皮质功能减退慢性患者发生严重应激状况静脉滴注氢化可的松危象时,静脉给药迅速发挥作 用无需肝药酶活化,直接发挥药理作用中枢神经系统抑制肝功能不全口服:氢化可的松静脉:氢化可的松琥珀酸钠不能使用氢化可的 松注射液含50%乙醇相同的抗炎作用服用等效剂量糖皮质激素药理作用药物治疗相关影响因素有效性安全性具有较短的生物半衰 期没有盐皮质激素作用对HPA轴抑制作用小具有较强的抗炎活性治疗指数高起效快药效平稳肝功能不全是否适用激素名称抗炎 活性HPA轴抑制作用肝功能不全中效泼尼松中等(4)较弱可长期使用×泼尼松龙中等(4)较弱可长期使用 √甲泼尼龙中等(5)较弱可长期使用√长效地塞米松强效(20-30)最强不能长期使用√倍他米松强效(25 -30)最强不能长期使用√总结中效激素用于抗炎治疗,HPA轴抑制作用相对较弱甲泼尼龙:糖/盐作用比较好,长期服用 疗效稳定,适用于肝功能不全患者。注射剂可用于静脉,做冲击治疗。泼尼松(龙):糖/盐作用比次之,可长期服用,泼尼松龙适用于肝功能不 全患者,不宜使用泼尼松。长效激素生物半衰期长,HPA轴抑制作用长而强,不宜长期使用抗炎治疗指数高,用药剂量小适合短期使用 可用于其他糖皮质激素反应不佳或无效的场合全身用糖皮质激素常用药物、制剂及特点药品名称剂型剂型性状醋 酸可的松醋酸酯片剂注射液乳白色微细颗粒混悬液灭菌混悬液醋酸氢化可的松醋酸酯片剂注射液乳白色微细颗粒混悬液灭菌 混悬液氢化可的松片剂注射液无色澄清液体灭菌稀乙醇溶液氢化可的松琥珀酸钠琥珀酸钠注射用白色疏松块状物无菌冻干 品醋酸泼尼松醋酸酯片剂泼尼松龙片剂醋酸泼尼松龙醋酸酯片剂注射液 乳白色微细颗粒混悬液灭菌混悬液甲基泼尼松龙琥珀酸钠片剂注射液白色疏松块状物无菌冻干品倍他米松片剂倍 他米松磷酸钠磷酸钠注射液无色澄清液体灭菌水溶液地塞米松片剂地塞米松磷酸钠磷酸钠注射液无色澄 清液体灭菌水溶液醋酸地塞米松醋酸酯片剂注射液乳白色微细颗粒混悬液灭菌混悬液糖皮质激素类药物注射剂的分类溶液型注射 剂or注射用无菌粉末(无色澄清液体)可静脉或肌内注射起效迅速药效最快,常作急救混悬型注射剂(乳白色微细颗粒混悬液) 严禁静脉注射混悬液或乳浊液引起毛细血管栓塞一般仅供肌内注射吸收缓慢,药物作用时间延长。延长作用时间和给药间隔,减少给药次数 ,但不能代替口服治疗关节内注射不作预防或慢性病维持用药,只作为急症或恶化情况下的短期用药高效速效长效给药途径治疗效果 溶液型混悬型静脉给药肌内给药冻干粉针关节内给药药物剂型药物剂型、给药途径、治疗效果注射剂相关其它问题:溶媒和附加 剂溶媒-乙醇乙醇浓度≥10%时肌注有疼痛感静注时应防止溶血的发生(乙醇易透过人红细胞膜)。乙醇浓度=60%时(体外试验表 明)红细胞立即凝聚生成深红色束状沉淀,乙醇做注射用溶媒时浓度可高达50%浓度不易过高,使用前应充分稀释。可静点,不能静注。 氢化可的松注射液含乙醇50%,使用前必须充分稀释,加25倍生理盐水或5%葡萄糖注射液500毫升稀释。只能静脉滴注注射剂相关其它 问题:溶媒和附加剂附加剂局部止痛剂苯甲醇0.9%苯甲醇作为注射剂溶媒可以耐受1%有溶血现象2%苯甲醇溶媒可引起注射部位的 硬结。甲泼尼龙说明书:本品使用苯甲醇作为溶媒,禁止用于儿童肌肉注射曲安奈德说明书:本品含苯甲醇,儿童禁用。注射剂相关其它问题 :体外配伍氢化可的松琥珀酸钠多柔比星多西环素麻黄碱麦角胺肝素肝素钠肼屈嗪伊达比星卡那霉素硫酸镁甲氧西林 甲氨蝶呤甲泼尼龙甲硝唑+克霉唑+氯己定萘夫西林氢化可的松琥珀酸钠氨茶碱异戊巴比妥氨苄西林维生素C硫酸博来霉 素羧苄西林头孢噻吩氯霉素多粘菌素E维生素B12阿糖胞苷达卡巴嗪地西泮茶苯海明苯海拉明多沙普仑氢化可的松琥珀 酸钠萘夫西林土霉素青霉素戊巴比妥苯巴比妥苯妥英普鲁卡因乙二磺酸甲哌氯丙嗪丙嗪异丙嗪沙格司亭司可巴比妥四 环素万古霉素维生素BC复方注射剂相关其它问题:体外配伍氢化可的松头孢孟多头孢唑林头孢西丁甲基多巴拉氧头孢新生 霉素异丙嗪氢化可的松磷酸钠沙格司亭多沙普仑米托蒽醌氢化可的松琥珀酸钠5%葡萄糖+乳酸林格注射液5%葡萄糖+林 格注射液甲泼尼龙氨茶碱葡萄糖酸钙头孢噻吩阿糖胞苷肝素肝素钠氢化可的松琥珀酸钠间羟胺青霉素G钠氯化钾异丙嗪 沙格司亭Tigercycline维生素BC复合物甲泼尼龙琥珀酸钠别嘌醇钠氨茶碱安吖啶葡萄糖酸钙头孢噻吩阿糖胞 苷多沙普仑非诺多泮非格司亭格隆溴铵常规胰岛素间羟胺萘夫西林昂丹司琼紫杉醇青霉素丙泊酚四环素长春瑞滨注射 剂相关其它问题:体外配伍泼尼松龙葡庚糖酸钙葡萄糖酸钙茶苯海明间羟胺甲氨蝶呤多粘菌素B丙氯拉嗪丙嗪异丙嗪泼尼松 龙磷酸钠间羟胺地塞米松阿米卡星盐酸氯丙嗪盐酸柔红霉素苯海拉明多沙普仑多柔比星格隆溴铵氢吗啡酮劳拉西泮间 羟胺昂丹司琼丙氯拉嗪万古霉素地塞米松磷酸钠盐酸苯海拉明多沙普仑非诺多泮硝酸镓伊达比星劳拉西泮甲氧氯普胺昂丹 司琼盐酸昂丹司琼注射剂相关其它问题:体外配伍影响药物静脉配伍的因素有很多,主要有以下几方面药物本身的因素包括:主药的剂型、 规格、浓度、体积、处方中所含的其它成分或添加剂,如缓冲液系统、防腐剂、稳定剂,稀释液的pH值、渗透压、溶液离子强度等;药物存放条 件及外界环境对药物配伍的影响:温度(室温或冷冻或光照条件)、混合液的pH值、浓度,配制后存放的时间、药物的吸附和滤过特性;注射或输 液容器的性质等。由于上述诸多可变因素对药物配伍变化的影响,因此要想对其做出绝对的结论是困难也是不可能的。氢化可的松注射液 注射用氢化可的松琥珀酸盐制剂醇溶性制剂含乙醇50%(药典标示47%-55%乙醇)水溶性制剂规格2ml:10mg5ml :25mg20ml:100mg50mg/支(按氢化可的松计算)100mg/支(按氢化可的松计算)氢化可的松琥珀酸钠135m g含游离型氢化可的松100mg给药途径只能静脉滴注,肌注有疼痛感可静脉,肌肉及关节腔和软组织给药给药方式临用前必须充分稀 释用前加25倍氯化钠注射液或5%葡萄糖注射液500毫升稀释后静脉滴注(说明书)静脉滴注一次100mg用前可用少量溶剂稀释 给药速度慢,注意溶血,乙醇刺激性给药速度快,可直接入壶,静注药物作用特点液量大,药量小,单位时间内入药量小,起效慢液量 小,药量大,单位时间内入药量大,起效快适应证特点肾上腺皮质功能减退及垂体功能减退症,也用于过敏性和炎症性疾病,抢救危重 中毒性感染(说明书)急症,大剂量治疗严重肾上腺皮质功能减退及垂体前叶功能减退危象,严重支气管哮喘等过敏反应,哮喘持续状态,休克 等(说明书)半衰期100分钟(说明书)78-114分钟(说明书)价格全身用糖皮质激素类药物口服制剂种类及特征国内多为普 通片剂,种类较少可的松,氢化可的松,泼尼松,泼尼松龙,甲泼尼龙,地塞米松,倍他米松吸收好,肝脏首过效应小,生物利用度在70- 80%药物脂溶性高,吸收好,肝脏首过效应小,生物利用度高。甲泼尼龙与泼尼松龙相比,脂溶性增加,代谢降低,使其分布容积更大,具 有更好的组织穿透性。CycleIII/01氢化可的松OCH3OHCH3OHCOCH2OH5656M ethylprednisolone:improvedmolecularstructure:Let’sreturnto ourlessononpharmacology.Alterationsinmolecularstructureha veyieldedpreparationswithusefuldifferencesinpotency,miner alocorticoidactivity,andpharmacokineticprofiles.Thegoalin synthesizingaglucocorticoidistoproduceamoleculewithanti- inflammatoryeffectswithouttheaccompanyingunwantedeffectson proteinandcarbohydratemetabolism.Asdiscussed,thegenerals tructureofacorticosteroid(C21)isderivedfromthebasicC17 moleculeandcontainsaseriesofgroupsthatareessentialfori tsbiologicalactivity:-oxygenatC3andC20-doublebondb etweenC4andC5-hydroxylgroupatC11Changesinthesepositi onsleadtoalossofbiologicalactivity.Substitutionsinother sitesmaymodifythebiologicalactivity,impartingeitheranti- inflammatoryormineralocorticoidactivity.Chapter12Mechanis mThedoublebond1-2(prednisone,prednisolone)increasesthean ti-inflammatoryactivitycomparedwithamineralocorticoid.Meth ylationatC6(methylprednisolone)increasesanti-inflammatoryac tivityandimprovespulmonarypenetration.AnoxygenatomatC11 isessentialforanti-inflammatoryactivitybutisnotessential formineralocorticoidactivity.5656Methylprednisolone:im provedmolecularstructure:Let’sreturntoourlessononpharmac ology.Alterationsinmolecularstructurehaveyieldedpreparatio nswithusefuldifferencesinpotency,mineralocorticoidactivity ,andpharmacokineticprofiles.Thegoalinsynthesizingaglucoc orticoidistoproduceamoleculewithanti-inflammatoryeffects withouttheaccompanyingunwantedeffectsonproteinandcarbohyd ratemetabolism.Asdiscussed,thegeneralstructureofacortico steroid(C21)isderivedfromthebasicC17moleculeandcontains aseriesofgroupsthatareessentialforitsbiologicalactivit y:-oxygenatC3andC20-doublebondbetweenC4andC5-h ydroxylgroupatC11Changesinthesepositionsleadtoalossof biologicalactivity.Substitutionsinothersitesmaymodifythe biologicalactivity,impartingeitheranti-inflammatoryorminer alocorticoidactivity.Chapter12MechanismThedoublebond1-2 (prednisone,prednisolone)increasestheanti-inflammatoryactiv itycomparedwithamineralocorticoid.MethylationatC6(methyl prednisolone)increasesanti-inflammatoryactivityandimprovesp ulmonarypenetration.AnoxygenatomatC11isessentialforanti -inflammatoryactivitybutisnotessentialformineralocorticoid activity.CycleIII/01可的松OOOHCOCH2OH=CH3CH35656Met hylprednisolone:improvedmolecularstructure:Let’sreturntoou rlessononpharmacology.Alterationsinmolecularstructurehave yieldedpreparationswithusefuldifferencesinpotency,mineral ocorticoidactivity,andpharmacokineticprofiles.Thegoalinsy nthesizingaglucocorticoidistoproduceamoleculewithanti-in flammatoryeffectswithouttheaccompanyingunwantedeffectsonp roteinandcarbohydratemetabolism.Asdiscussed,thegeneralstr uctureofacorticosteroid(C21)isderivedfromthebasicC17mo leculeandcontainsaseriesofgroupsthatareessentialforits biologicalactivity:-oxygenatC3andC20-doublebondbet weenC4andC5-hydroxylgroupatC11Changesintheseposition sleadtoalossofbiologicalactivity.Substitutionsinothers itesmaymodifythebiologicalactivity,impartingeitheranti-in flammatoryormineralocorticoidactivity.Chapter12Mechanism Thedoublebond1-2(prednisone,prednisolone)increasestheanti -inflammatoryactivitycomparedwithamineralocorticoid.Methyl ationatC6(methylprednisolone)increasesanti-inflammatoryacti vityandimprovespulmonarypenetration.AnoxygenatomatC11is essentialforanti-inflammatoryactivitybutisnotessentialfo rmineralocorticoidactivity.5656Methylprednisolone:impr ovedmolecularstructure:Let’sreturntoourlessononpharmacol ogy.Alterationsinmolecularstructurehaveyieldedpreparations withusefuldifferencesinpotency,mineralocorticoidactivity, andpharmacokineticprofiles.Thegoalinsynthesizingaglucocor ticoidistoproduceamoleculewithanti-inflammatoryeffectswi thouttheaccompanyingunwantedeffectsonproteinandcarbohydra temetabolism.Asdiscussed,thegeneralstructureofacorticost eroid(C21)isderivedfromthebasicC17moleculeandcontainsa seriesofgroupsthatareessentialforitsbiologicalactivity: -oxygenatC3andC20-doublebondbetweenC4andC5-hyd roxylgroupatC11Changesinthesepositionsleadtoalossofb iologicalactivity.Substitutionsinothersitesmaymodifytheb iologicalactivity,impartingeitheranti-inflammatoryormineral ocorticoidactivity.Chapter12MechanismThedoublebond1-2( prednisone,prednisolone)increasestheanti-inflammatoryactivit ycomparedwithamineralocorticoid.MethylationatC6(methylpr ednisolone)increasesanti-inflammatoryactivityandimprovespul monarypenetration.AnoxygenatomatC11isessentialforanti-i nflammatoryactivitybutisnotessentialformineralocorticoida ctivity.CycleIII/01泼尼松(强的松)OOOHCOCH2OH=5656Methylpr ednisolone:improvedmolecularstructure:Let’sreturntoourles sononpharmacology.Alterationsinmolecularstructurehaveyiel dedpreparationswithusefuldifferencesinpotency,mineralocort icoidactivity,andpharmacokineticprofiles.Thegoalinsynthes izingaglucocorticoidistoproduceamoleculewithanti-inflamm atoryeffectswithouttheaccompanyingunwantedeffectsonprotei nandcarbohydratemetabolism.Asdiscussed,thegeneralstructur eofacorticosteroid(C21)isderivedfromthebasicC17molecul eandcontainsaseriesofgroupsthatareessentialforitsbiol ogicalactivity:-oxygenatC3andC20-doublebondbetween C4andC5-hydroxylgroupatC11Changesinthesepositionslea dtoalossofbiologicalactivity.Substitutionsinothersites maymodifythebiologicalactivity,impartingeitheranti-inflamm atoryormineralocorticoidactivity.Chapter12MechanismThed oublebond1-2(prednisone,prednisolone)increasestheanti-infl ammatoryactivitycomparedwithamineralocorticoid.Methylation atC6(methylprednisolone)increasesanti-inflammatoryactivity andimprovespulmonarypenetration.AnoxygenatomatC11isesse ntialforanti-inflammatoryactivitybutisnotessentialformin eralocorticoidactivity.5656Methylprednisolone:improved molecularstructure:Let’sreturntoourlessononpharmacology. Alterationsinmolecularstructurehaveyieldedpreparationswith usefuldifferencesinpotency,mineralocorticoidactivity,andp harmacokineticprofiles.Thegoalinsynthesizingaglucocorticoi distoproduceamoleculewithanti-inflammatoryeffectswithout theaccompanyingunwantedeffectsonproteinandcarbohydrateme tabolism.Asdiscussed,thegeneralstructureofacorticosteroid (C21)isderivedfromthebasicC17moleculeandcontainsaseri esofgroupsthatareessentialforitsbiologicalactivity:- oxygenatC3andC20-doublebondbetweenC4andC5-hydroxyl groupatC11Changesinthesepositionsleadtoalossofbiolog icalactivity.Substitutionsinothersitesmaymodifythebiolog icalactivity,impartingeitheranti-inflammatoryormineralocort icoidactivity.Chapter12MechanismThedoublebond1-2(predn isone,prednisolone)increasestheanti-inflammatoryactivitycom paredwithamineralocorticoid.MethylationatC6(methylprednis olone)increasesanti-inflammatoryactivityandimprovespulmonar ypenetration.AnoxygenatomatC11isessentialforanti-inflam matoryactivitybutisnotessentialformineralocorticoidactivi ty.CycleIII/01泼尼松龙(强的松龙)OCH3OHCH3OHCOCH2OH5656Meth ylprednisolone:improvedmolecularstructure:Let’sreturntoour lessononpharmacology.Alterationsinmolecularstructurehave yieldedpreparationswithusefuldifferencesinpotency,mineralo corticoidactivity,andpharmacokineticprofiles.Thegoalinsyn thesizingaglucocorticoidistoproduceamoleculewithanti-inf lammatoryeffectswithouttheaccompanyingunwantedeffectsonpr oteinandcarbohydratemetabolism.Asdiscussed,thegeneralstru ctureofacorticosteroid(C21)isderivedfromthebasicC17mol eculeandcontainsaseriesofgroupsthatareessentialforits biologicalactivity:-oxygenatC3andC20-doublebondbetw eenC4andC5-hydroxylgroupatC11Changesinthesepositions leadtoalossofbiologicalactivity.Substitutionsinothersi tesmaymodifythebiologicalactivity,impartingeitheranti-inf lammatoryormineralocorticoidactivity.Chapter12MechanismT hedoublebond1-2(prednisone,prednisolone)increasestheanti- inflammatoryactivitycomparedwithamineralocorticoid.Methyla tionatC6(methylprednisolone)increasesanti-inflammatoryactiv ityandimprovespulmonarypenetration.AnoxygenatomatC11is essentialforanti-inflammatoryactivitybutisnotessentialfor mineralocorticoidactivity.5656Methylprednisolone:impro vedmolecularstructure:Let’sreturntoourlessononpharmacolo gy.Alterationsinmolecularstructurehaveyieldedpreparations withusefuldifferencesinpotency,mineralocorticoidactivity,a ndpharmacokineticprofiles.Thegoalinsynthesizingaglucocort icoidistoproduceamoleculewithanti-inflammatoryeffectswit houttheaccompanyingunwantedeffectsonproteinandcarbohydrat emetabolism.Asdiscussed,thegeneralstructureofacorticoste roid(C21)isderivedfromthebasicC17moleculeandcontainsa seriesofgroupsthatareessentialforitsbiologicalactivity: -oxygenatC3andC20-doublebondbetweenC4andC5-hydr oxylgroupatC11Changesinthesepositionsleadtoalossofbi ologicalactivity.Substitutionsinothersitesmaymodifythebi ologicalactivity,impartingeitheranti-inflammatoryormineralo corticoidactivity.Chapter12MechanismThedoublebond1-2(p rednisone,prednisolone)increasestheanti-inflammatoryactivity comparedwithamineralocorticoid.MethylationatC6(methylpre dnisolone)increasesanti-inflammatoryactivityandimprovespulm onarypenetration.AnoxygenatomatC11isessentialforanti-in flammatoryactivitybutisnotessentialformineralocorticoidac tivity.CycleIII/01甲泼尼龙(甲强龙)OCH3CH3OHCH3OHCOCH2OH双 键C1=C2C6甲基取代C11羟基5656Methylprednisolone:improvedmo lecularstructure:Let’sreturntoourlessononpharmacology.Al terationsinmolecularstructurehaveyieldedpreparationswithu sefuldifferencesinpotency,mineralocorticoidactivity,andpha rmacokineticprofiles.Thegoalinsynthesizingaglucocorticoid istoproduceamoleculewithanti-inflammatoryeffectswithoutt heaccompanyingunwantedeffectsonproteinandcarbohydratemeta bolism.Asdiscussed,thegeneralstructureofacorticosteroid( C21)isderivedfromthebasicC17moleculeandcontainsaseries ofgroupsthatareessentialforitsbiologicalactivity:-ox ygenatC3andC20-doublebondbetweenC4andC5-hydroxylg roupatC11Changesinthesepositionsleadtoalossofbiologic alactivity.Substitutionsinothersitesmaymodifythebiologic alactivity,impartingeitheranti-inflammatoryormineralocortic oidactivity.Chapter12MechanismThedoublebond1-2(prednis one,prednisolone)increasestheanti-inflammatoryactivitycompa redwithamineralocorticoid.MethylationatC6(methylprednisol one)increasesanti-inflammatoryactivityandimprovespulmonary penetration.AnoxygenatomatC11isessentialforanti-inflamma toryactivitybutisnotessentialformineralocorticoidactivity .5656Methylprednisolone:improvedmolecularstructure:Le t’sreturntoourlessononpharmacology.Alterationsinmolecula rstructurehaveyieldedpreparationswithusefuldifferencesin potency,mineralocorticoidactivity,andpharmacokineticprofiles .Thegoalinsynthesizingaglucocorticoidistoproduceamolec ulewithanti-inflammatoryeffectswithouttheaccompanyingunwan tedeffectsonproteinandcarbohydratemetabolism.Asdiscussed, thegeneralstructureofacorticosteroid(C21)isderivedfrom thebasicC17moleculeandcontainsaseriesofgroupsthataree ssentialforitsbiologicalactivity:-oxygenatC3andC20- doublebondbetweenC4andC5-hydroxylgroupatC11Changesi nthesepositionsleadtoalossofbiologicalactivity.Substitu tionsinothersitesmaymodifythebiologicalactivity,impartin geitheranti-inflammatoryormineralocorticoidactivity.Chapt er12MechanismThedoublebond1-2(prednisone,prednisolone)in creasestheanti-inflammatoryactivitycomparedwithamineraloco rticoid.MethylationatC6(methylprednisolone)increasesanti-i nflammatoryactivityandimprovespulmonarypenetration.Anoxyge natomatC11isessentialforanti-inflammatoryactivitybutis notessentialformineralocorticoidactivity.CycleIII/01OCH3 OHCH3OHCOCH2OHFCH3地塞米松or倍他米松双键C1=C2C16甲基C9氟代 5656Methylprednisolone:improvedmolecularstructure:Let’sret urntoourlessononpharmacology.Alterationsinmolecularstruc turehaveyieldedpreparationswithusefuldifferencesinpotency ,mineralocorticoidactivity,andpharmacokineticprofiles.Theg oalinsynthesizingaglucocorticoidistoproduceamoleculewit hanti-inflammatoryeffectswithouttheaccompanyingunwantedeff ectsonproteinandcarbohydratemetabolism.Asdiscussed,thege neralstructureofacorticosteroid(C21)isderivedfromthebas icC17moleculeandcontainsaseriesofgroupsthatareessentia lforitsbiologicalactivity:-oxygenatC3andC20-double bondbetweenC4andC5-hydroxylgroupatC11Changesinthese positionsleadtoalossofbiologicalactivity.Substitutionsi nothersitesmaymodifythebiologicalactivity,impartingeithe ranti-inflammatoryormineralocorticoidactivity.Chapter12MechanismThedoublebond1-2(prednisone,prednisolone)increasestheanti-inflammatoryactivitycomparedwithamineralocorticoid.MethylationatC6(methylprednisolone)increasesanti-inflammatoryactivityandimprovespulmonarypenetration.AnoxygenatomatC11isessentialforanti-inflammatoryactivitybutisnotessentialformineralocorticoidactivity.5656Methylprednisolone:improvedmolecularstructure:Let’sreturntoourlessononpharmacology.Alterationsinmolecularstructurehaveyieldedpreparationswithusefuldifferencesinpotency,mineralocorticoidactivity,andpharmacokineticprofiles.Thegoalinsynthesizingaglucocorticoidistoproduceamoleculewithanti-inflammatoryeffectswithouttheaccompanyingunwantedeffectsonproteinandcarbohydratemetabolism.Asdiscussed,thegeneralstructureofacorticosteroid(C21)isderivedfromthebasicC17moleculeandcontainsaseriesofgroupsthatareessentialforitsbiologicalactivity:-oxygenatC3andC20-doublebondbetweenC4andC5-hydroxylgroupatC11Changesinthesepositionsleadtoalossofbiologicalactivity.Substitutionsinothersitesmaymodifythebiologicalactivity,impartingeitheranti-inflammatoryormineralocorticoidactivity.Chapter12MechanismThedoublebond1-2(prednisone,prednisolone)increasestheanti-inflammatoryactivitycomparedwithamineralocorticoid.MethylationatC6(methylprednisolone)increasesanti-inflammatoryactivityandimprovespulmonarypenetration.AnoxygenatomatC11isessentialforanti-inflammatoryactivitybutisnotessentialformineralocorticoidactivity. 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