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功矿郎
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1 人体功能基础第二节药物的体内过程 Absorption, Distribution, Metabolism and Excretion 基础医学院

2 Process of Drug in the Body 药物过给药部进入直至排出机体的过程包括药物的吸收 (absorption) absorption) 分布 (distribution) distribution) 代谢 (metabolism) 和排泄 (excretion) excretion) 即 ADME 代谢和排泄都是药物在体内渐消失的过程统消除 (elimination) elimination)

3 吸收 Absorption n 药物自给药部进入血液循的过程

4 同给药途径的吸收速度排序腹腔注射吸入吸入舌直肠直肠肌注肌注皮口服口服皮肤同给药途径的吸收程度排序吸入舌舌直肠直肠肌注肌注皮皮口服口服皮肤

5 (1) 口服给药 (Oral ingestion) 吸收部要在小肠停留时间长毛吸收面大毛血管壁道大血流丰富 ph5-8 对药物解离影响小

6 Clinical sketch A man with angina has not understood instruction on the use of glyceryl trinitrate tablets. He swallows them instead of putting them under his tongue. There is no therapeutic benefit. 硝酸甘油 Comment: this drug is subject to extensive first-pass metabolism.

7 首关消除 (First pass eliminaiton) 药物在肠道吸收后通过门进入肝脏部分药物在通过肠膜及肝脏时被代谢使进入体循的药少的象

8 舌直肠很大程度避免一定程度避免

9 2 注射给药静注射 iv 静滴注 iv in drop 肌内注射 im 被动扩散滤过皮注射 sc 吸收快而全

10 Clinical sketch A patient with extensive burns is given intramuscular opiate for the pain. His blood pressure is very low. Adequate pain relief is not achieved for over half an hour. 阿片 Comment: muscle blood flow is reduced by shock, and the rate of drug absorption can be affected.

11 3 呼吸道吸入给药 (Inhalation) 气体和挥发性药物或极微粉吸收迅速 4 部用药

12 分布 Distribution 药物吸收后通过血液循到达机体各部和组的过程影响因素血浆蛋合率器官血流药物组亲和力体液的 ph 和药物的解离度体内屏障

13 血浆蛋合率 n 血中蛋合的药物总药的分数 n D 结结结结结结 D+P 结结结结结 DP 结可逆性动态衡 n 合型药物能进行跨膜转运因而也被代谢和排泄暂时失去药理活性药物储 n 特异性竞争合置换象 n 血浆蛋过少或质蛋合率易中毒

15 Drug interaction of plasma protein binding 99.9% bound Drug A: 1000 molecules + Drug B with 94% bound 90.0% bound 1 molecules free 100 molecules free 100-fold increase in free pharmacologically active concentration at site of action. Effective TOXIC

16 Clinical sketch A man takes phenytoin for his epilepsy. Unknown to him, his plasma albumin falls markedly over the next few weeks, without the dose of phenytoin being changed. He develops marked ataxia. 苯妥英共济失调癫痫

17 Clinical sketch Comment:the clinical relevance of plasma protein binding is often much less clear cut than in this example. Here, the patient s ataxia has resulted from an increases in the free concentration of phenytoin.

18 组的亲和力大多数药物在体内的分布是均匀的呈一定的器官选择性药物的一种储存象可逆的组合药物的良有关 TetracyclineStains on Teeth

19 器官血流再分布药物再分布 redistribution 血管心肝脑脂肪药物先分布于血流大的组器官随后向他组器官转移的这种象

20 HA A A A HA A H+ PH 7.0 PH 7.4 H+ HA H+ HA H+ H+ H+ H+ A H+

21 弱酸性药物中毒时碱化血液弱酸性药从脑血再肾排出弱碱性药物中毒时则相

22 思考 n 注射吗啡过中毒给患者洗胃有无意义?

23 特殊胞屏障某些器官组特殊解剖构限制药物转运而形成特殊的屏障 n 血脑屏障 (blood blood-brain brain barrier) n 血眼屏障 (blood-ocular ocular barrier) n 胎盘屏障 (placental barrier)

24 Clinical sketch A patient with meningitis is treated with gentamicin. The organism is very sensitive to the antibiotic in vitro, but the patient shows no improvement. 庆大霉素脑膜炎 Comments:this would be very unacceptable clinical practice and the patient may well die. Gentamicin does not readily cross the blood-brain barrier.

25 血脑屏障 n 在组学由血 - 脑血 - 脑液及脑液 - 脑种屏障组成 n 高脂溶性药物可通过脂质膜转运进入中枢神系统 n 在脑膜炎或脑炎时对药物通性可增

26 血眼屏障循血液眼球内组液之间的屏 u 障包括血水屏障血视网膜屏障等 u 构使全身给药时药物在眼球内难以达 u 到有效浓度大部分眼病的有效药物治疗是部 u 给药

27 胎盘屏障 n 胎儿胎盘毛妇子宫血窦间的屏障 n 有药物均能从妇体内通过胎盘进入胎儿体内只是程度快慢差异 n 妊娠期避免用药, 尤对胎儿有影响的药物, 以策安全

28 3. 代谢生物转化 ) Metabolism, Biotransformation 药物作外源性物质在体内发生化学构的改生物转化或药物代谢要器官肝脏

29 代谢骤和方式 Phase I 氧化原水解引入或脱去基团 (-OH -CH 3 -NH 2 -SH) Phase II 内源性葡萄糖苷酸硫酸醋酸药物或 I 期反应代谢物结合药物药物无活性活性或结合结合结合排泄药物亲脂亲水

31 药物代谢酶系专一性酶是指催化作用选择性很强活性很高的酶非专一性酶要指肝胞的微粒体混合能氧化酶系统 ( hepatic microsomal mixedfunction oxidase system 也肝药酶 )

32 肝药酶即肝微粒体胞色素 P-450 酶系统由 70 余种同酶构成是一类非专一性酶要存在于肝胞内质网中参数种药物的生物转化

33 药物氧化代谢 (Oxidation) 胞色素 P450 单氧化酶系 CYP1B1 CYP2A6 CYP1A1/2 CYP2B6 CYP2C8 Non-CYP enzymes CYP2C9 CYP2C19 CYP3A4/5/7 CYP2E1 CYP 2D6

34 要特点 n 生物转化的要酶 n 选择性活性有限 n 异性较大个体差异大 n 易药物诱导或抑制药物相互作用

35 Clinical sketch A man with moderately severe alcoholic liver disease needs flecainide for a cardiac arrhythmia. The clinical team consults Appendix of the BNF and is advised to give reduced doses. 氟 Comments:flecainide accumulates in patients with chronic liver disease.

36 酶的诱导能够增强 CYP 酶活性的药物酶诱导剂 (enzyme inducer) 可产生两种临床后果使治疗效果增强或弱 Parent drug Active Inactive (prodrug) Metabolites Inactive Active Pharmacological activity Decreased Increased

37 Clinical sketch A young woman on the contraceptive pills is found to have tuberculosis. She is started on treatment and suffers contraceptive failure soon after. 核病利福避的 Comments:it would be unacceptable practice to fail to warn the woman that rifampicin (which induces the liver drugmetabolising enzyme CYP450) is very likely to cause failure of contraception.

38 酶的抑制能够弱 CYP 酶活性的药物酶抑制剂 (enzyme inhibiter) 可产生两种临床后果使治疗效果增强或弱 Parent drug Active Inactive (Prodrug) Metabolites Inactive Active Pharmacological activity Increased Decreased

39 Omeprazole + Warfarin Serious bleeding reactions + Nifedipine Hypotension

40 4. 排泄 Excretion) 排泄途径 : 肾脏 ( 要 ) 消化道肺皮肤唾液乳汁等

41 1. 肾脏排泄 Renalexcretionexcretion Net renal excretion= (Glomerular filtration + tubular secretion) - tubular reabsorption Glomerular filtration Active tubular secretion Passive tubular reabsorption

42 影响因素肾小球滤过肾血流肾血流降肾小球滤过少血浆蛋合率血浆蛋合率高肾小球滤过少

43 肾小管重吸收改液 ph 值可以明显改弱酸性或弱碱性药物的解离度从而调节药物重吸收程度 Passive reabsorption Passive Reabsorption of lipidsoluble, unionized drug Ionized or polar metabolite

44 Passive Tubular Reabsorption Weak acids can be eliminated by alkalinization of the urine. (with NaHCO 3 ). Elimination of weak bases may be increased by acidification of the urine. (with NH 4 Cl). basic acid acidic base

45 肾小管动分泌肾小管动分泌的药物如果将由同一载体转运药物合用时可发生竞争性抑制 (competitive inhibition) 象丙磺舒 + 青霉素 penicillin penicillin penicillin penicillinprobenecid probenecid OATs OATs OATs OATs OATs OATs

46 消化道排泄胆汁排泄 (Biliary excretion) & 肝肠循环 (Enterohepatic recycling) Liver Bile duct Gut Portal vein Feces excretion

47 肝肠循 hepato-enteral enteral circulation 有的药物在肝胞内葡萄糖醛酸合后分泌到胆汁中胆汁排泄到小肠后被肠道菌水解成游离药物又被肠粘膜皮胞重吸收由肝门静重新进入全身循的这种象肝肠循使药物在体内停留时间延长

48 Clinical sketch A young woman on a low-dose combined oral contraceptive pill went on holiday to St Petersburg with her boyfriend. She had read that many people catch gastroenteritis in this destination and sought advice from her doctor. He prescribed doxycyline and advised her to take this throughout her 3- weeks stay. Upon her return, she became concerned that she may be pregnant and did a pregnancy test: it was positive. 胃肠炎多西素

49 Clinical sketch Oral contraceptive steroids are given in very low dose to avoid adverse effect. Reliance is placed on enterohepatic circulation. The tetracyclines, by killing gut bacteria, interrupt this circulation and may cause drug failure. 四素

50 要肠道排泄被吸收的口服药物随胆汁排泄到肠道的药物由肠粘膜动分泌排入肠道的药物

51 肺排泄 n 是某些挥发性药物的要排泄途径 n 影响因素药物的血中溶解度肺血流呼吸速率

52 他途径排泄许多药物可通过唾液乳汁汗液泪液排泄临床意义在临床就可测定唾液中的药浓度来进行血药浓度监测弱碱性药物在乳汁中可达较高浓度通过哺乳进入婴儿体内产生药效或良

53 第节室模型 Compartment Model n 是药动学研究中按药物在体内转运速率的差异以实验理论相合设置的数学模型是一种抽象地抽象地假设机体是一个分 u 体器官或组只按药物转运速率划分同室的系统

54 open one compartment model open two compartment model central compartment D 0 D 0 central compartment k 1 2 k 2 1 peripheral compartment ke ke logc logc -ke/ α / β /2.303 t t 一室模型和二室模型

55 一室模型 one compartment model n 假定身体由一个室组成给药后药物立即均匀地分布于整个室并以一定的速率从该室消除 n 单次静注给药时时 ( 对数浓度 ) 曲线呈单指数消除

56 二室模型 two compartment model n 假定身体由两个室组成即中央室 ( 血流丰富的器官如心肝肾 ) 和周边室 ( 血流少的器官如骨脂肪 ) n 单次静注给药时时 ( 对数浓度 ) 曲线呈指数衰即分分布相和消除相

57 第四节第二章体内药物的药 - 时间关系 Time course of drug concentration

58 一单次给药单次静脉注射 Plasma aspirin concentration (mg/l) 0 Cmax 单次口服 Tmax Time (min)

59 Plasma concentration 峰浓度 Cmax 一次给药后的最高浓度时吸收和消除达平衡 AUC Area under curve 达峰时间 Tmax 曲线下面积 AUC 单位 :ng h/ml 反映药物体内总量给药后达峰浓度的时间, 多 hrs hrs

60 第五节药物消除动力学 Elimination Kinetics 第二章

61 体内药物浓度因断消除而随时间 u 断化体内某一部的药物少速度 dc/dt u 该部药 C 的关系符合 dc/dt=-kc N N 0 一级消除动力学 (Firstorder elimination kinetics ) n = 1 dc/dt = -kc 零级消除动力学 (Zero order elimination kinetics) n = 0 dc/dt = -k

62 first-order kinetics 药代动力学特征 u 药物的消除速率当时的药或浓度一次方成恒消除 u C-t 图指数衰曲线 lgc-t 图直线 n 同一药物 t 1/2 恒定剂无关 t 1/2 =0.693/k) n 大多数药物按消除

63 first-order kinetics C logc t t Concentration-time curve and logarithm concentration-time curve of the first-order kinetics.

64 zero-order order kinetics 药代动力学特征 u 药物的消除速率当时的药或浓度无关恒消除 u C-t 图直线 lgc-t 图指数衰曲线 n t 1/2 初始的药或浓度有关并之成 t 1/2 =C 0 /2k 0 ), 剂依赖半衰期 n 发生于体内药相对过高时

65 zero-order order kinetics C logc t t Concentration-time curve and logarithm concentration-time curve of the zero-order kinetics.

66 非线性消除米曼氏速率少部分药物小剂时以一级速率消除而在大剂时以零级速率消除述这类药物的消除速率需要将两种速率类型合起来通常以米 - 曼氏方程式述即 Michaelis-MentenMenten 方程式

67 第六节第二章药物代谢动力学重要参数 Important Parameters in Pharmacokinetics

68 半衰期 (half-life life t 1/2 1/2 ) n 血浆中药物浓度降一半需的时间 n 按一级速率消除的药物 t 1/2 一恒定值 n 按一级速率消除一级速率消除的药物单次给药后 4~5 个 t 1/2 体内药基消除完间隔一个 t 1/2 药一次则给药 4~5 个 t 1/2 后体内药物累可达到稳态浓度水 n 会因龄合并用药疾病等因素而改 1/2 用

69 稳态血药浓度 (Steady-state concentration) 多次给药旨在稳态血药浓度达有效浓度范围 : MTC>C ss >MEC 需 4-5 half-life Css-max < MTC Css-min > MEC

70 稳态血药浓度属于一级动力学消除的药物在恒恒速重复多次给药 4~5 个 t 1/2 后给药消除达到动态衡体内药物的总再增而达到稳定状态曲线趋向稳时的血药浓度稳态血药浓度 (steady state concentration Css) Css) 也坪值 (plateau) plateau)

71 稳态浓度的意义 n 高给药总成 n 波动幅度给药间隔成 n 达到稳态浓度的时间 t 1/2 成

72 问题某病人病情危急需立即达到稳态浓度以制或某药半衰期较长应如何给药大剂量缩短给药间隔时间它方法

73 大剂量 Time MTC MEC Plasma Drug Concentration

74 缩短给药间隔时间 Time MTC MEC Plasma Drug Concentration

76 负荷 Loading dose 了使血药浓度迅速达到需要的水在常规给药前用的一次剂

77 二清除率 Clearance CL 单位时间内机体清除药物的速率单位时间内多少容积血浆中的药物被清除反映肝肾能单位 :L/h 或 ml/min CL=CL 肾脏 CL 肝脏 CL 它计算公式 : CL=(-dC/dt)/t=kVd

78 三表观分布容积 Volume of distribution 设想药物均匀分布于各种组体液且浓度血液中相同在种假设条件下药物分布所需容积给药剂量或体内药物总量血药物浓度之比数学概念并代表体的生理空间 Vd=D/C

79 Vd 的临床应用意义 l 测药物在体内的分布范围 Digoxin:0.5mg 0.78 ng/ml Vd = 645 L 要分布于肌肉包括心肌浓度血浓 30 倍和脂肪组 l 计算用药剂量 :D=Vd C

80 Total body water 60% 42 L Extracellular 25% 17 L Intracellular (35%) 25 L plasma volume (5%) 3 L interstitial volume (20%) 14 L Water composition in 70 Kg Body Weight

81 Vd, L in a 70 kg normal person % Body Weight Extent of Distribution 5 7 Only in plasma In extracellular fluids In total body fluids. >40 >56 In deep tissues; bound to peripheral tissues

82 四生物利用度 Bioavailability 药物到达全身血循环内的相对量和速度 1. 吸收相对量 l 绝对生物利用度 : AUC 血管外 F = 100% AUC 静注 l 相对生物利用度 : F = (AUC 受试制剂 AUC 标准制剂 ) 100% 2. 吸收速度 : 比较 T max

83 生物利用度的速度 C maxa increase risk of toxicity MEC for adverse response plasma drug conc centration C maxb MEC for C desired response maxc C B A T maxa T maxb T maxc time

84 Chemical equivalence CE Drug products contain the same active compound in the same amount Bioequivalence BE Bioequivalence occurs when drugs with equal F have the same drug concentration versus time relationship (i.e. similar rate and extent of drug absorption).

内容 : 药物分子的跨膜转运药物的体内过程房室模型药物消除动力学体内药物的药量 - 时间关系药动学参数药物的剂量设计和优化

内容 : 药物分子的跨膜转运药物的体内过程房室模型药物消除动力学体内药物的药量 - 时间关系药动学参数药物的剂量设计和优化第二章药物代谢动力学 (pharmacokinetic s) 主讲 : 李进霞内容 : 药物分子的跨膜转运药物的体内过程房室模型药物消除动力学体内药物的药量 - 时间关系药动学参数药物的剂量设计和优化药动学定义研究机体对药物的作用处理过