统计工作要求.doc

*风湿免疫常用治疗药物ThecommomtreatmentdrugsinRheumatology北京积水潭医院药剂科*主要内容 定义： 激素/NSAIDs 起效较慢，缓解和阻止关节炎和结缔组织病进展，又称缓解病情抗风湿药（DMARDs） 分类： MTX 柳氮磺吡啶 来氟米特 羟氯喹 沙利度胺 雷公藤 白芍总苷MTX* 药理作用：抑制二氢叶酸还原酶，使嘌呤合成受抑 用法用量：7.5-20mg/周，口服为主 不良反应：胃肠道反应，骨髓抑制，肝、肾功能损害，肺间质纤维化 特点: 最经济、有效、相对安全的DMARDS药物 RA首选，4-6周起效，疗程半年 生物利用度60%，80%通过肾脏排泄，肾功能受损者慎用 每1个月查1次血常规和肝肾功能，剂量稳定后每1-3月检查上述指标1次 妊娠和哺乳期的妇女禁用MTX，受孕前3个月停止使用MTX抑制白细胞趋化，抗炎疗效存在剂量依赖性，可根据患者临床反应和耐受性可每2-4周增加5mg，直至20-30mg/周。停药后多能恢复无论男女一旦确诊，就应该考虑MTX，除非有禁忌。控制病情后，逐渐撤药，最后再撤MTX。好比行船时起锚。每月不到5块钱。抗癌标签不敢用，治疗肿瘤剂量是1-3g，大剂量MTX化疗骨肉瘤时用到8-12g，RA用量只有10-15mg/周*来氟米特 药理作用：新型抗代谢免疫抑制剂，抑制二氢乳清酸脱氢酶活性，使嘧啶合成受抑。 用法用量：10-20mg/d 不良反应：腹泻、腹痛，皮疹，可逆脱发，肝损害，骨髓抑制 特点：1.RA治疗一线用药，单药治疗效果等同于MTX，耐受性好于MTX。2.T1/2为15-18d，治疗剂量1月后起效，3个月达稳态血药浓度。3.血浆白蛋白结合率99%，肝肠循环广泛,约2年血药浓度检测不到。4.动物实验致畸作用，妊娠和准备妊娠妇女禁用。对狼疮性肾炎有较好的疗效，可用于不能耐受环磷酰胺（CTX）治疗的患者联用可提高缓解率，单用用于对MTX不能耐受或疗效不佳者。肝损害：ALT2倍，2-3倍观察，继续升高或持续，停药，3倍以上停药。恢复后一般可以再次使用，多数人不会再次升高。白细胞降低：3000以上，继续用药；2000-3000，观察；低于2000，中断服药。中性粒计数不应低于1.5*109半衰期长，中途停药达不到目的,推荐快速消除：口服考来稀胺，每次8g，Tid，连服11天,至少2周后确定来氟米特血药浓度低于0.02mg/L雷公藤 药理作用：抑制淋巴细胞和单核细胞、抑制免疫球蛋白合成及抗炎作用 用法用量：每次20mg，每日3次；维持量10mg/次，每日3次 不良反应：性腺毒性，外周血白细胞减少、色素沉着、指甲变薄软、肝损害、胃肠道反应 特点：1.抗炎止痛及免疫抑制双重作用,起效快、疗效肯定,有效率80%-90%2.能使部分患者RF滴度下降甚至转阴3.对生殖系统影响大,禁用于年轻女性或有生育计划的男性我国首创抗风湿药物,许多人持反对意见，但目前多数医师认为只要掌握适应症，选择老年人或短期应用，是很好的选择柳氮磺吡啶 药理作用：抑制血栓素合成酶、脂氧酶和蛋白水解酶活性，抑制白细胞运动，抑制IL-1、IL-6和TNF等促炎因子产生 用法用量：0.25-0.5g/d，每日2次，治疗剂量2g/d 不良反应：过敏反应，肝、肾功能损害，胃肠道反应 特点： 外周型血清阴性脊柱关节病首选，4-8周起效 D类妊娠用药，可通过胎盘 代谢产物磺胺吡啶影响男性生殖能力，停药3个月以上 磺胺过敏者禁用为减小胃肠道刺激，常从小剂量开始，每周增加0.5g直至1-2个月起效，在此期间，可以配合NSAIDS使用，直到柳氮发挥作用。多饮水，尿液发黄，必要时可碱化尿液作用温和，常作为RA的联合用药。有效率40%，对中轴关节作用好，MTX对外周关节作用好，所以RA用MTX，强柱用柳氮不影响女性生殖力，妊娠期使用不会增加畸形、流产及早产等发生风险。对妊娠期或准备怀孕的女性较其他慢作用药更为安全。用量不应超过2g/d，整个妊娠期需服用足量叶酸羟氯喹 药理作用：抑制淋巴细胞转化、中性粒细胞趋化以及吞噬细胞和浆细胞的活化，减少PG合成 用法用量：每次0.2g，每日2次 不良反应：视物盲点、视野缺损、视网膜病变、眼底改变 特点：1.作用最弱，最易耐受，副作用较少，3-6个月起效2.对血管炎性皮疹、尤其对SLE的面部皮疹疗效好3.用前常规检查眼底，以后每6-12月进行眼底检查，尤其服用超过6年者，发现异常立即停药4.C类妊娠用药，可通过胎盘。妊娠期使用羟氯喹是安全的，对SLE患者妊娠期疾病的复发亦有很好的疗效。5.羟氯喹很少经母乳排泄，不足以对婴儿造成影响。羟氯喹的疗效是氯喹的2/3，毒性是氯喹的1/2长期用药；视网膜病变为其严重不良反应，用前常规检查眼底以排除已经存在的眼底病变，常与其他DMARDS药物合用**可编辑沙利度胺 药理作用：稳定肝脏溶酶体膜，拮抗致炎因子生成，刺激抗炎因子产生 用法用量：起始剂量50mg/d、治疗剂量50-200mg/d 不良反应：头晕、嗜睡、恶心、皮疹和便秘 特点：1.皮肤型狼疮、狼疮难治性皮损、盘状狼疮效果好，对RA、AS、BD也有疗效2.SLE、RA、AS、结节红斑和脂膜炎二线治疗3.周围性神经炎是最主要的剂量限制毒性4.临床上从小剂量开始使用，每晚25-50mg，最大剂量不超过400mg/d5.X类妊娠用药，致畸，妊娠妇女禁用大多可耐受、停药后消退神经炎：14完全恢复，1/4好转或部分恢复，1/4停药4-5年仍不能恢复手足麻木，麻刺感，烧灼样痛，应停药剂量限制毒性：40-50g白芍总苷 药理作用：明显的抗炎和免疫调节作用 用法用量：0.6g/d，分2-3次服用 特点：改善RA患者病情、减轻症状和体征并能调节患者的免疫功能 不良反应：大便性状改变、次数增多以及轻度腹痛、纳差，多可自行缓解激素 短效激素（可的松、氢化可的松） 内源性激素补充替代治疗 应激情况 氢化可的松直接发挥药理作用 中效激素（泼尼松、泼尼松龙、甲泼尼龙） 抗炎、抗过敏、免疫抑制 肝功不全可以使用泼尼松龙和甲泼尼龙 对HPA轴影响小，水钠潴留轻，可以长期使用 长效激素（地塞米松、倍他米松） 其他糖皮质激素反应不佳或无效的场合 作用强大，半衰期长，肝功不全可以使用 HPA轴抑制作用长而强，适合短期使用内源性激素人工合成激素C1=C2双键结构抗炎活性增强水钠潴留作用减弱无需肝脏代谢活化亲脂性增加，作用增强水钠潴留作用减弱抗炎作用更强，几无水钠潴留HPA轴抑制、肌肉毒性增强亲脂性增加，作用增强水钠潴留作用减弱泼尼松（强的松）OOOHCOCH2OH=CycleIII/015656Methylprednisolone:improvedmolecularstructure:Let’sreturntoourlessononpharmacology.Alterationsinmolecularstructurehaveyieldedpreparationswithusefuldifferencesinpotency,mineralocorticoidactivity,andpharmacokineticprofiles.Thegoalinsynthesizingaglucocorticoidistoproduceamoleculewithanti-inflammatoryeffectswithouttheaccompanyingunwantedeffectsonproteinandcarbohydratemetabolism.Asdiscussed,thegeneralstructureofacorticosteroid(C21)isderivedfromthebasicC17moleculeandcontainsaseriesofgroupsthatareessentialforitsbiologicalactivity:-oxygenatC3andC20-doublebondbetweenC4andC5-hydroxylgroupatC11Changesinthesepositionsleadtoalossofbiologicalactivity.Substitutionsinothersitesmaymodifythebiologicalactivity,impartingeitheranti-inflammatoryormineralocorticoidactivity.Chapter12Mechanism Thedoublebond1-2(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.Chapter12Mechanism Thedoublebond1-2(prednisone,prednisolone)increasestheanti-inflammatoryactivitycomparedwithamineralocorticoid. MethylationatC6(methylprednisolone)increasesanti-inflammatoryactivityandimprovespulmonarypenetration. AnoxygenatomatC11isessentialforanti-inflammatoryactivitybutisnotessentialformineralocorticoidactivity.甲泼尼龙（甲强龙）OCH3CH3OHCH3OHCOCH2OH双键C1=C2C6甲基取代C11羟基CycleIII/015656Methylprednisolone:improvedmolecularstructure:Let’sreturntoourlessononpharmacology.Alterationsinmolecularstructurehaveyieldedpreparationswithusefuldifferencesinpotency,mineralocorticoidactivity,andpharmacokineticprofiles.Thegoalinsynthesizingaglucocorticoidistoproduceamoleculewithanti-inflammatoryeffectswithouttheaccompanyingunwantedeffectsonproteinandcarbohydratemetabolism.Asdiscussed,thegeneralstructureofacorticosteroid(C21)isderivedfromthebasicC17moleculeandcontainsaseriesofgroupsthatareessentialforitsbiologicalactivity:-oxygenatC3andC20-doublebondbetweenC4andC5-hydroxylgroupatC11Changesinthesepositionsleadtoalossofbiologicalactivity.Substitutionsinothersitesmaymodifythebiologicalactivity,impartingeitheranti-inflammatoryormineralocorticoidactivity.Chapter12Mechanism Thedoublebond1-2(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.Chapter12Mechanism Thedoublebond1-2(prednisone,prednisolone)increasestheanti-inflammatoryactivitycomparedwithamineralocorticoid. MethylationatC6(methylprednisolone)increasesanti-inflammatoryactivityandimprovespulmonarypenetration. AnoxygenatomatC11isessentialforanti-inflammatoryactivitybutisnotessentialformineralocorticoidactivity.OCH3OHCH3OHCOCH2OHFCH3地塞米松or倍他米松双键C1=C2C16甲基C9氟代CycleIII/015656Methylprednisolone:improvedmolecularstructure:Let’sreturntoourlessononpharmacology.Alterationsinmolecularstructurehaveyieldedpreparationswithusefuldifferencesinpotency,mineralocorticoidactivity,andpharmacokineticprofiles.Thegoalinsynthesizingaglucocorticoidistoproduceamoleculewithanti-inflammatoryeffectswithouttheaccompanyingunwantedeffectsonproteinandcarbohydratemetabolism.Asdiscussed,thegeneralstructureofacorticosteroid(C21)isderivedfromthebasicC17moleculeandcontainsaseriesofgroupsthatareessentialforitsbiologicalactivity:-oxygenatC3andC20-doublebondbetweenC4andC5-hydroxylgroupatC11Changesinthesepositionsleadtoalossofbiologicalactivity.Substitutionsinothersitesmaymodifythebiologicalactivity,impartingeitheranti-inflammatoryormineralocorticoidactivity.Chapter12Mechanism Thedoublebond1-2(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.Chapter12Mechanism Thedoublebond1-2(prednisone,prednisolone)increasestheanti-inflammatoryactivitycomparedwithamineralocorticoid. MethylationatC6(methylprednisolone)increasesanti-inflammatoryactivityandimprovespulmonarypenetration. AnoxygenatomatC11isessentialforanti-inflammatoryactivitybutisnotessentialformineralocorticoidactivity.可的松OOOHCOCH2OH=CH3CH3CycleIII/015656Methylprednisolone:improvedmolecularstructure:Let’sreturntoourlessononpharmacology.Alterationsinmolecularstructurehaveyieldedpreparationswithusefuldifferencesinpotency,mineralocorticoidactivity,andpharmacokineticprofiles.Thegoalinsynthesizingaglucocorticoidistoproduceamoleculewithanti-inflammatoryeffectswithouttheaccompanyingunwantedeffectsonproteinandcarbohydratemetabolism.Asdiscussed,thegeneralstructureofacorticosteroid(C21)isderivedfromthebasicC17moleculeandcontainsaseriesofgroupsthatareessentialforitsbiologicalactivity:-oxygenatC3andC20-doublebondbetweenC4andC5-hydroxylgroupatC11Changesinthesepositionsleadtoalossofbiologicalactivity.Substitutionsinothersitesmaymodifythebiologicalactivity,impartingeitheranti-inflammatoryormineralocorticoidactivity.Chapter12Mechanism Thedoublebond1-2(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.Chapter12Mechanism Thedoublebond1-2(prednisone,prednisolone)increasestheanti-inflammatoryactivitycomparedwithamineralocorticoid. MethylationatC6(methylprednisolone)increasesanti-inflammatoryactivityandimprovespulmonarypenetration. AnoxygenatomatC11isessentialforanti-inflammatoryactivitybutisnotessentialformineralocorticoidactivity.氢化可的松OCH3OHCH3OHCOCH2OHCycleIII/015656Methylprednisolone:improvedmolecularstructure:Let’sreturntoourlessononpharmacology.Alterationsinmolecularstructurehaveyieldedpreparationswithusefuldifferencesinpotency,mineralocorticoidactivity,andpharmacokineticprofiles.Thegoalinsynthesizingaglucocorticoidistoproduceamoleculewithanti-inflammatoryeffectswithouttheaccompanyingunwantedeffectsonproteinandcarbohydratemetabolism.Asdiscussed,thegeneralstructureofacorticosteroid(C21)isderivedfromthebasicC17moleculeandcontainsaseriesofgroupsthatareessentialforitsbiologicalactivity:-oxygenatC3andC20-doublebondbetweenC4andC5-hydroxylgroupatC11Changesinthesepositionsleadtoalossofbiologicalactivity.Substitutionsinothersitesmaymodifythebiologicalactivity,impartingeitheranti-inflammatoryormineralocorticoidactivity.Chapter12Mechanism Thedoublebond1-2(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.Chapter12Mechanism Thedoublebond1-2(prednisone,prednisolone)increasestheanti-inflammatoryactivitycomparedwithamineralocorticoid. MethylationatC6(methylprednisolone)increasesanti-inflammatoryactivityandimprovespulmonarypenetration. AnoxygenatomatC11isessentialforanti-inflammatoryactivitybutisnotessentialformineralocorticoidactivity.糖皮质激素半衰期 根据生物半衰期划分为短效、中效、长效 激素名称 血浆半衰期(h) 生物半衰期(h) HPA轴抑制作用 HPA轴抑制时间(天) 短效 可的松 0.5 8-12 1 1.25-1.50 氢化可的松 1.6 8-12 4 1.25-1.50 中效 泼尼松 2.6-3 18-36 4 1.25-1.50 泼尼松龙 2-4 18-36 5 1.25-1.50 甲泼尼龙 2-3 18-36 5 1.25-1.50 长效 地塞米松 3-6 36-54 50 2.75 倍他米松 3-6 36-54 50 3.25糖皮质激素蛋白结合作用 药物名称 抗炎强度 等效剂量(mg) 水钠潴留强度 能否长期应用 肝功能不全 激素结合蛋白（CBG） 白蛋白 短效糖皮质激素(t1/2<12h) 可的松 0.8 25 0.8 能 × 90 氢化可的松 1 20 1 能 √ 90 中效糖皮质激素(t1/2=12-36h) 泼尼松 4 5 0.8 能 × 70 泼尼松龙 4 5 0.8 能 √ 70-90 甲泼尼龙 5 4 0.8 能 √ ＜1 74 长效糖皮质激素(t1/2>36h) 地塞米松 20-30 0.75 0 否 √ ＜1 64 倍他米松 20-30 0.6 0 否 √ ＜1 77**可编辑抑制白细胞趋化，抗炎疗效存在剂量依赖性，可根据患者临床反应和耐受性可每2-4周增加5mg，直至20-30mg/周。停药后多能恢复无论男女一旦确诊，就应该考虑MTX，除非有禁忌。控制病情后，逐渐撤药，最后再撤MTX。好比行船时起锚。每月不到5块钱。抗癌标签不敢用，治疗肿瘤剂量是1-3g，大剂量MTX化疗骨肉瘤时用到8-12g，RA用量只有10-15mg/周*对狼疮性肾炎有较好的疗效，可用于不能耐受环磷酰胺（CTX）治疗的患者联用可提高缓解率，单用用于对MTX不能耐受或疗效不佳者。肝损害：ALT2倍，2-3倍观察，继续升高或持续，停药，3倍以上停药。恢复后一般可以再次使用，多数人不会再次升高。白细胞降低：3000以上，继续用药；2000-3000，观察；低于2000，中断服药。中性粒计数不应低于1.5*109半衰期长，中途停药达不到目的,推荐快速消除方案：口服考来稀胺，每次8g，Tid，连服11天,至少2周后确定来氟米特血药浓度低于0.02mg/L我国首创抗风湿药物,许多人持反对意见，但目前多数医师认为只要掌握适应症，选择老年人或短期应用，是很好的选择为减小胃肠道刺激，常从小剂量开始，每周增加0.5g直至1-2个月起效，在此期间，可以配合NSAIDS使用，直到柳氮发挥作用。多饮水，尿液发黄，必要时可碱化尿液作用温和，常作为RA的联合用药。有效率40%，对中轴关节作用好，MTX对外周关节作用好，所以RA用MTX，强柱用柳氮不影响女性生殖力，妊娠期使用不会增加畸形、流产及早产等发生风险。对妊娠期或准备怀孕的女性较其他慢作用药更为安全。用量不应超过2g/d，整个妊娠期需服用足量叶酸羟氯喹的疗效是氯喹的2/3，毒性是氯喹的1/2长期用药；视网膜病变为其严重不良反应，用前常规检查眼底以排除已经存在的眼底病变，常与其他DMARDS药物合用大多可耐受、停药后消退神经炎：14完全恢复，1/4好转或部分恢复，1/4停药4-5年仍不能恢复手足麻木，麻刺感，烧灼样痛，应停药剂量限制毒性：40-50g