Introduction of BMS Section Ⅵ. Pharmacological Basis of Therapeutics 2010-2011学年冬学期 第七周 Introduction of BMS Section Ⅵ. Pharmacological Basis of Therapeutics 药物治疗学基础(治疗学的药理学基础) 浙江大学医学院 陈季强教授 Email: chenjq@zju.edu.cn

Contents Basic Concept of Pharmacology Chapter 1. Pharmacodynamics Section Ⅵ. Pharmacological Basis of Therapeutics Contents Basic Concept of Pharmacology Chapter 1. Pharmacodynamics Chapter 2. Pharmacokinetics Chapter 3. Factors influencing effect of drug Chapter 4. Anti-neoplastics

Contents Basic Concept of Pharmacology Chapter 1. Pharmacodynamics Section Ⅵ. Pharmacological Basis of Therapeutics Contents Basic Concept of Pharmacology Chapter 1. Pharmacodynamics Chapter 2. Pharmacokinetics Chapter 3. Factors influencing effect of drug Chapter 4. Anti-neoplastics

Chapter 2 Pharmacokinetics 影响药物分布 药物的理化性质； 局部的血流量； 体液的pH值； 生物屏障(血脑屏障、胎盘屏障)等。 Section Ⅵ. Pharmacological Basis of Therapeutics Chapter 2 Pharmacokinetics

Chapter 2. Pharmacokinetics Contents Part 1. Transport of drug across cell membrane(药物的跨膜转运) Part 2. Pharmacokinetics process(药物的体内过程) Part 3. The rate process of pharmaco-kinetics(药动学过程)

Part 1. Transport of drug across cell membrane Chapter 2. Pharmacokinetics Part 1. Transport of drug across cell membrane

Part 1. Transport of drug across cell membrane

Part 1. Transport of drug across cell membrane 1. Classification of pharmacokinetics process(药动学过程的分类): ①Absorption(吸收); ②Distribution(分布); ③Biotransformation(生物转化), or Metabolism(代谢); ④Excretion(排泄). ①, ②, and ④: Transport(转运); ③ and ④: Elimination(消除).

2. The patterns of drug transport across cell membrane(药物跨膜转运类型): Part 1. Transport of drug across cell membrane 2. The patterns of drug transport across cell membrane(药物跨膜转运类型): 通过脂质 通过水性 通过载体 扩散 通道扩散 转运 简单扩散 滤过 主动转运

Part 1. Transport of drug across cell membrane (1)Passive transport(被动转运): ▲Filtration(滤过) —— along pressure gradient. ▲Simple diffusion(简单扩散) —— along concentration gradient. Characteristics of simple diffusion: ●don’t consume energy(不耗能); ●need not carrier(不需要载体); ●no saturation(无饱和现象); ●no competitive inhibition(无竞争性抑制); ●to dynamic equilibrium finally(最终保持在动态稳定水平).

The factors affecting simple diffusion: Part 1. Transport of drug across cell membrane The factors affecting simple diffusion: ①difference of drug concentration; ②lipid solubility of the drug, which be decided by ionizability of drug. The ionizability of drug following by pKa of drug and pH of solution. ion trapping(离子障)

影响药物分布 药物的理化性质； 局部的血流量； 体液的pH值； 生物屏障(血脑屏障、胎盘屏障)等。 Part 1. Transport of drug across cell membrane Handerson-Hasselbach’ Formula Weak acid drug(弱酸性药物): HA H+ + A- [H+] [A–] Ka = [HA] [HA] [H+] = [A-] Ka log [HA] / [A-] = log [H+] – log Ka log [HA] / [A-] = pKa – pH When pH = pKa, [HA] = [A-] pH ＞pKa, [HA] ＜[A-] pH ＜pKa, [HA] ＞[A-]

影响药物分布 药物的理化性质； 局部的血流量； 体液的pH值； 生物屏障(血脑屏障、胎盘屏障)等。 Part 1. Transport of drug across cell membrane log [HA] / [A-] = pKa – pH Effect of pH on ionization of Salicyclic acid(水杨酸, pKa=3) pH log [HA] / [A-] [HA] / [A-] non-ionized(%) 1 3 – 1 = 2 100/1 99.0 2 3 – 2 = 1 10/1 90.0 3 3 – 3 = 0 1/1 50.0 4 3 – 4 = –1 1/10 10.0 5 3 – 5 = –2 1/100 1.0 6 3 – 6 = –3 1/1000 0.1

影响药物分布 药物的理化性质； 局部的血流量； 体液的pH值； 生物屏障(血脑屏障、胎盘屏障)等。 Part 1. Transport of drug across cell membrane Weak base drug(弱碱性药物): BH+ H+ + B [B] [H+] Ka = [BH+] [B] Ka = [BH+] [H+] log [B] / [BH+] = log Ka – log [H+] = pH – pKa When pH = pKa, [B] = [BH+] pH ＞pKa, [B] ＞[BH+] pH ＜pKa, [B] ＜[BH+]

Clinical significance(临床意义): Part 1. Transport of drug across cell membrane Clinical significance(临床意义): ▲ 口服药物, 在胃肠道吸收, 弱酸性药物在酸性环境的胃中容易吸收, 弱碱性药物在pH较高的肠道内容易被吸收. ▲▲改变尿液的酸碱度可以影响药物在肾小管的重吸收过程. 弱酸性药物在酸性尿液中容易重吸收, 因此减少了该药物在尿液中的排出, 而弱酸性药物在碱性尿液中则重吸收减少, 可增加该药物的排出量. 这一知识在临床上可以用于治疗某些药物中毒. 如催眠药苯巴比妥(酸性药物)过量中毒时, 用NaHCO3静脉滴注, 使尿液碱化, 可减少苯巴比妥的重吸收而加速其排泄.

(2)Active transport(主动转运) ——adverse concentration gradient tran-sport. Part 1. Transport of drug across cell membrane (2)Active transport(主动转运) ——adverse concentration gradient tran-sport. Characteristics of active transport: ● need carrier; ● energy consumption; ● saturability; ● competitive inhibition by congeners; ● active transport stop when no drug at one side of membrane.

Chapter 2. Pharmacokinetics Part 2. Pharmacokinetics process

Part 2. Pharmacokinetics process 1. Absorpation: (1)Enteral ingestion(胃肠道给药): ①Oral administration(per os, po) ▲Site of absorption ▲first-pass elimination(首过消除) ②sublingual(舌下含服) ③per rectum(直肠给药)

Part 2. Pharmacokinetics process (2)Parenteral administration: ①Intravenous(iv): no absorption. ②Intramuscular(i.m.), ③Subcutaneous(s.c.), ④Other administration: ▲inhalation(吸入): aerosol; nebula ▲transdermal administration(透皮给药)

Part 2. Pharmacokinetics process 2. Distribution: Factors affecting distribution: ①Regional blood flow, redistribution ②Physicochemical properties of drug: MW, LS, polarity,   ③Selectivity of drug distribution: e.g. iodine(碘)  thyroid(甲状腺) ④Biological barriers: Blood-brain barrier(血脑屏障) Placenta barrier(胎盘屏障) ⑤Plasma protein binding of drug

Plasma protein binding rate (PBR, 血浆蛋白结合率): Free type Binding type Part 2. Pharmacokinetics process Plasma protein binding rate (PBR, 血浆蛋白结合率): Free type Binding type Free type: ●Activity, ●Can be transported. Binding type: ●Reversible; ●Inactive temporarily; ●Cannot pass through cell membrane passively; ●Saturability and competition.

Part 2. Pharmacokinetics process 3. Biotransformation: (1)Phase of biotransformation: ●Phase Ⅰ: Oxidation, Reduction, Hydrolysis Most case: inactivation or detoxification Some case: activation  or toxicity  activation: cortisone  hydrocortisone phenacetin  acetaminophen (非那西丁) (对乙酰氨基酚) toxicity : para-phenetidin (对氨基苯乙醚)

Part 2. Pharmacokinetics process ●Phase Ⅱ: Conjugation with glucuronides, or glycine, or acetyl, or sulfate, et al. Result of conjugation:  Solubility of compounds  easy to excrete from kidney.

Part 2. Pharmacokinetics process (2)Hepatic microsomal enzymes(肝微粒体酶, hepatic drug-metabolizing enzymes, 肝药酶) Cytochrome P450 enzymes(细胞色素P450), including oxidases, reductases, hydrolases and conjugases. The characteristics of P450: ●low selectivity(选择性低); ●high variability(变异性大): 481 kinds; ●Enzyme induction(酶诱导) and Enzyme inhibition(酶抑制).

Part 2. Pharmacokinetics process Enzyme induction(酶诱导) & Enzyme inducer(酶诱导剂) Phenobarbital(苯巴比妥), Rifampin(利福平), et al. Enzyme inhibition(酶抑制) & Enzyme inhibitor(酶抑制剂) Chloramphenicol(氯霉素), Isoniazid(异烟肼), Cimetidine(西咪替丁), et al.

(3)Other drug metabolism enzyme: Part 2. Pharmacokinetics process (3)Other drug metabolism enzyme: ●Non-microsomal reductive enzymes (非微粒体还原酶, in hepatic cell), ●Esterase(酯酶, in plasma), ●Acetification enzyme(乙酰化酶, in cell liquid), et al.

影响药物分布 药物的理化性质； 局部的血流量； 体液的pH值； 生物屏障(血脑屏障、胎盘屏障)等。 Part 2. Pharmacokinetics process 4. Excretion: (1)Renal excretion: including ● glomerular filtration, ● tubular secretion, ● tubular reabsorption ▲ factors influencing renal excretion urinary flow, urinary pH. ▲

Part 2. Pharmacokinetics process (2)Biliary excretion: tetracycline(四环素), rifampin(利福平), erythromycin(红霉素) ★hepato-enteral circulation: digitoxin(洋地黄毒苷) (3)Other excretion routes: lung, saliva, milk, sweat, et al. ▲▲

Part 2. Pharmacokinetics process ▲▲▲

Chapter 2. Pharmacokinetics Let’s take a rest !

Contents Basic Concept of Pharmacology Chapter 1. Pharmacodynamics Section Ⅵ. Pharmacological Basis of Therapeutics Contents Basic Concept of Pharmacology Chapter 1. Pharmacodynamics Chapter 2. Pharmacokinetics Chapter 3. Factors influencing effect of drug Chapter 4. Anti-neoplastics

Part 3. The rate process of pharmacokinetics Chapter 2. Pharmacokinetics Part 3. The rate process of pharmacokinetics

Part 3. The rate process of pharmacokinetics Contents 1. Concentration-time relationship and concentration-time curve (药物浓度-时间关系和药物浓度-时间曲线) 2. Kinetics of drug elimination(药物消除动 力学 —— 速率类型) 3. Pharmacokinetics model(药动学模型) 4. Parameters of pharmacokinetics and their meanings(药动学参数及其意义) 5. multiple dosing(多次给药)

Part 3. The rate process of pharmacokinetics 1. Concentration-time relationship and concentration-time curve[药物浓度-时间关系和药物浓度-时间曲线(药时曲线, C-T曲线, 时量曲线)] Tmax: 达峰时间, Cmax: 高峰浓度, AUC: 曲线下面积(area under curve).

Part 3. The rate process of pharmacokinetics MTC Cmax MEC AUC t Tmax(Tpeak) 1. latent period (潜伏期); 2. persistent period (持续期); 3. residual period (残留期)

2. Kinetics of drug elimination(药物消除动力学 —— 速率类型) Part 3. The rate process of pharmacokinetics 2. Kinetics of drug elimination(药物消除动力学 —— 速率类型) dC = - keC n dt C : concentration; t : time; ke: constant of elimination rate. n=0: zero-order kinetics elimination. n=1: first-order kinetics elimination;

(1)Zero-order elimination: (零级动力学消除, 恒量消除) Part 3. The rate process of pharmacokinetics (1)Zero-order elimination: (零级动力学消除, 恒量消除) dC C = - k0C0 dt = - k0 dC = - k0 dt Ct = C0 – k0t 0 t ①Constant amount is eliminated at maximal capacity per unit time; ② C-t curve is a straight line, its slope is -k; ③ t½ is not constant.

(2)First-order kinetics elimination: (一级动力学消除, 恒比消除) Part 3. The rate process of pharmacokinetics (2)First-order kinetics elimination: (一级动力学消除, 恒比消除) dC = – keC1 dt = – Ke C dt = – Kedt C Ct = C0e-ket logCt = logC0 – ke/2.303  t

Part 3. The rate process of pharmacokinetics logCt = logC0 – ke/2.303  t logC C logC0 t slope = -ke/2.303 t

Part 3. The rate process of pharmacokinetics logCt = log C0 - ke/2.303  t t = 2.303 / ke (logC0 - logCt) if: Ct = ½ C0 : t½为半衰期 t½= 2.303 / ke • log 2 = 0.693 / ke ke = 0.693 / t½ ①Constant fraction is eliminated per unit time; ②log C-t curve is a straight line, the slope is -ke/2.303; ③t½(半衰期) is constant, = 0.693/ke; (be continued)

Part 3. The rate process of pharmacokinetics ④once input drug(A), after 5 t½, 96% of A is eliminated. t½ surplusage(%) elimination(%) 0 100.0 0 1 50.0 50.0 2 25.0 75.0 3 12.5 87.5 4 6.25 93.8 5 3.12 96.9 6 1.56 98.4

Part 3. The rate process of pharmacokinetics (3)Michaelis-Menten elimination: e.g.: Phenytoin, Salicyclic acid, et al. dC Vmax • C = – dt Km + C When C is very high, Km＜＜C: 零级动力学 dC Vmax • C = – = – Vmax = – K0 dt C When C is very low, Km＞＞C: 一级动力学 = – = – KeC dt Km

Part 3. The rate process of pharmacokinetics Michaelis-Menten elimination (也称为非线性消除)

Part 3. The rate process of pharmacokinetics 3. Pharmacokinetics model(药动学模型) —— Compartment model(房室模型) (1)one-compartment model: Drug absorption elimination

Part 3. The rate process of pharmacokinetics Log C one-compartment model (iv) 32 16 8 elimination curve 4 C = C0e-Ket 2 1 0 1 2 3 4 5 6 t½

Part 3. The rate process of pharmacokinetics (2)two-compartment model: Drug Central compartment elimination absorption Peripheral compartment

Part 3. The rate process of pharmacokinetics logC two-compartment model(i.v.) A distribution curve C = Ae-t + Be-t B elimination curve t

Part 3. The rate process of pharmacokinetics 4. Parameters of pharmacokinetics and their meanings: (1)Area under the conentration-time curve(AUC) (2)Bioavailability(F) (3)Apparent volume of distribution(Vd) (4)Half-life time(t½)

Part 3. The rate process of pharmacokinetics (1)Area under the conentration-time curve(AUC): AUC代表药物进入体循环的相对量, 可由梯形法则求得, AUC的单位用g/ml‧min 或 mg/L‧h表示. AUC

Part 3. The rate process of pharmacokinetics 影响药物分布 药物的理化性质； 局部的血流量； 体液的pH值； 生物屏障(血脑屏障、胎盘屏障)等。 Part 3. The rate process of pharmacokinetics (2)Bioavailability(生物利用度, F): Fraction of absorption(吸收分数) F = A / D ×100% F = AUC(po)/AUC(iv)×100% F = AUC(供试药)/AUC(对照药)×100% Affected factors:  Rate of absorption  First pass elimination(p.o.)

Part 3. The rate process of pharmacokinetics F(AUC)相等, 但Tmax与Cmax不等 某药剂量相等的三种制剂的生物利用度比较 F(AUC)相等, 但Tmax与Cmax不等

Part 3. The rate process of pharmacokinetics 影响药物分布 药物的理化性质； 局部的血流量； 体液的pH值； 生物屏障(血脑屏障、胎盘屏障)等。 Part 3. The rate process of pharmacokinetics (3)Apparent volume of distribution (表观分布容积, Vd): A(mg) Vd = (L or L/kg) C(mg/L) FD VdC Vd = ;  D = C F Vd ≈ 5L: 药物主要分布在血液中; Vd = 10～20L: 分布在全身体液中; Vd ＞ 40L: 主要分布在组织器官中; Vd ＞ 100L: 集中分布在某个器官内. Vd值越小, 排泄越快, 体内存留时间越短; Vd值越大, 排泄越慢, 体内存留时间越长.

Part 3. The rate process of pharmacokinetics (4)Half-life time(半衰期, t½): t½是血浆药物浓度或体内药量下降一半所需要的时间. First-order kinetics elimination: ● t½ is constant ● t½ = 0.693/ke

Part 3. The rate process of pharmacokinetics

Part 3. The rate process of pharmacokinetics 5. multiple dosing(多次给药): Steady state concentration(稳态浓度, Css, Plateau, 坪值) Cmax(峰浓度) log C Cmin(谷浓度) t

Part 3. The rate process of pharmacokinetics (1)Multiple dosing repeated iv injection: logC t

Part 3. The rate process of pharmacokinetics (2)Change dose and not change interval: logC t

Part 3. The rate process of pharmacokinetics (3)Change dose and interval: logC t ▲

Part 3. The rate process of pharmacokinetics (4)Loading dose (DL): logC 2D = loading dose 2D D t ▲▲

Part 3. The rate process of pharmacokinetics (5)Continuous iv injection at a constant rate: logC t ▲▲▲

Chapter 2. Pharmacokinetics Let’s take a rest !

Factors influencing drug effect Section Ⅵ. Pharmacological Basis of Therapeutics Chapter 3. Factors influencing drug effect Part 1. Drug factors Part 2. Patient factors Part 3. Principle of rational administration

Part 1. Drug factors Chapter 3. Factors influencing drug effect 1. Dosage form(剂型): (1)Injection: i.v., i.m., s.c. (2)Oral dosage form: Tablet; Powder; Capsule, Oral liquid. Bioequivalence(生物等效性) (3)Drug delivery system(DDS): Slow release form(缓释剂); Controlled release form(控释剂): Extended(延迟) release form; Sustained(持续) release form. Transdermal patch(透皮贴剂)

2. Methods of administration: Part 1. Drug factors 2. Methods of administration: (1)Dose(from small dose  large dose); (2)Administration routes: iv, im, sc, po, inhalation, pr, etc. Absorption rate and take effect time: iv > inhalation > im> sc > po > pr > transdermal. (3)Time of administration; (4)Interval of administration, t½; (5)Course of treatment.

3. Drug in combination & drug-drug interaction: Part 1. Drug factors 3. Drug in combination & drug-drug interaction: (1)Drug in combination: Aim of drug in combination: more effectively treat disease. (2)Drug-drug interaction(药物相互作用): ①Pharmaceutical interaction Physicochemical reaction —— incompatibility(配伍禁忌) ②Pharmacokinetics interaction ③Pharmacodynamics interaction

Part 1. Drug factors (3)Outcome of drug-drug interaction: Synergism(协同作用): drug effect . Addition(相加作用): 1+1＞1 Potentiation(增强作用): 1+1＞2 Antagonism(拮抗作用): drug effect . Subtraction(相减作用): 1+1＜1 Counteraction(抵消作用): 1+1=0

Part 1. Drug factors (4)Mechanism of drug-drug interaction: ①Pharmacodynamics: agonist & antagonist ②Pharmacokinetics: absorption; plasma protein binding rate (PPB); enzyme induction & enzyme inhibition; excretion.

Chapter 3. Factors influencing drug effect Part 2. Patient factors 1. Age factors: Children The aged 2. Sex factors: Male Female

Part 2. Patient factors 3. Genetic factors (1)Individual variation(个体差异): ●quantitative difference hyperreactivity; hyporeactivity ●qualitative difference anaphylaxis (allergy); idiosyncrasy (genetic factors): G-6-PD deficiency. (2)Pharmacogenetics(遗传药理学): polymorphism of oxidation(氧化多态性) polymorphism of acetylation(乙酰化多态性)

Part 2. Patient factors 4. Pathological factors 5. Psychic factors Process and kind of diseases, Drug-induced diseases. 5. Psychic factors Mental state, Placebo(安慰剂) effect. ▲

6. Administration for long time —— Drug-induced abnormal responses Part 2. Patient factors 6. Administration for long time —— Drug-induced abnormal responses (1)Tolerance(耐受性——机体) Tachyphylaxis, Bradyphylaxis Resistance(耐药性——病原生物, 肿瘤) (2)Dependence(依赖性) Habituation(习惯性), Addiction(成瘾), abstinence syndrome(戒断症状), (3)Withdrawal syndrome(撤药症状) Rebound phenomenon(反跳现象) ▲▲

Chapter 3. Factors influencing drug effect Part 3. Principle of rational administration 1. Clear diagnosis and expectant adminis-tration; 2. Administration according to the charac-teristics of drugs; 3. Dose individualism; 4. Symptomatic treatment + etiological treatment + supplement treatment; 5. Close observation and adjust adminis-tration promptly. ▲▲▲

Chapter 2. Pharmacokinetics Today’s class is over !