PHARMACOLOGY WELCOME PHARMACOLOGY Tel 88383146 Email zhangxmsdu edu

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PHARMACOLOGY § WELCOME !

PHARMACOLOGY § WELCOME !

药 理 学 PHARMACOLOGY 张岫美 山东大学医学院 药理学研究所 Tel: 88383146 Email: zhangxm@sdu. edu. cn

药 理 学 PHARMACOLOGY 张岫美 山东大学医学院 药理学研究所 Tel: 88383146 Email: zhangxm@sdu. edu. cn

CHAPTER 2 PHARMACOKINETICS 药物代谢动力学 Pharmacokinetics 药代动力学 The Processes of Drug in the Body 体内过程

CHAPTER 2 PHARMACOKINETICS 药物代谢动力学 Pharmacokinetics 药代动力学 The Processes of Drug in the Body 体内过程

PHARMACOKINETICS To reveal the principles of dynamic changes of drug in the body, mainly

PHARMACOKINETICS To reveal the principles of dynamic changes of drug in the body, mainly explained the changes of blood concentration of drug with time in the body.

The Processes of Drug in the Body receptor B tissue free F bound circula

The Processes of Drug in the Body receptor B tissue free F bound circula absorp excret Free drug Bound drug metabolites

The Drug Processes in the Body The Classifications Absorption吸收 Distribution分布 Metabolism代谢 Excretion排泄 Disposition处置: 转运与转化

The Drug Processes in the Body The Classifications Absorption吸收 Distribution分布 Metabolism代谢 Excretion排泄 Disposition处置: 转运与转化 Elimination消除: 代谢与排泄

SECTION 1 Transportation of Drug Molecules 1. Modes of transportation转运方式 (1) Filtration滤过 (2) Simple

SECTION 1 Transportation of Drug Molecules 1. Modes of transportation转运方式 (1) Filtration滤过 (2) Simple diffusion简单扩散 (down hill) Passive transport被动转运 No need for energy, carrier. No saturation limited. No competitive inhibition.

Passive Transport by Factors Affected by properties, areas of membrane, concentration between memb. ,

Passive Transport by Factors Affected by properties, areas of membrane, concentration between memb. , and properties of drug: molecular size, lipid solubility, polarity. Ion trapping离子障

Transports of weak acidic and weak basic drug by Handerson-Hasselbalch Equation Weak acidic drug

Transports of weak acidic and weak basic drug by Handerson-Hasselbalch Equation Weak acidic drug weak basic drug HA ≒ H+ + ABH+ ≒ H+ + B Ka = H+ A- / HA Ka = H+ B / BH+ p. Ka = A- / HA p. Ka = H+ B / BH+ p. Ka = p. H - log A- / HA p. Ka=p. H-log B / BH+ p. H–p. Ka=log A- / HA p. K –p. H=log BH+ / B when p. H = p. Ka, A- = HA B = BH+

Transports of weak acidic and weak basic drug by Handerson-Hasselbalch Equation p. H–p. Ka=log

Transports of weak acidic and weak basic drug by Handerson-Hasselbalch Equation p. H–p. Ka=log A- / HA p. K – p. H=log BH+ / B [HA]/[A-] = 10 pka-p. H BH+ / B = 10 pka-p. H [A-]/[HA] = 10 p. H-pka

(3) Carrier transport 载体转运 Need carrier Selectivity Saturation limited Competitive inhibition

(3) Carrier transport 载体转运 Need carrier Selectivity Saturation limited Competitive inhibition

a. Active Transport 主动转运 (up hill) Need energy, carrier Has saturation limited With competitive

a. Active Transport 主动转运 (up hill) Need energy, carrier Has saturation limited With competitive inhibition b. Facilitated diffusion易化扩散 No energy need, with carrier, belong to passive transport.

SECTION 2 The Drug Processes in the Body 1. Absorption吸收 The movement of a

SECTION 2 The Drug Processes in the Body 1. Absorption吸收 The movement of a drug from its site of administration into the blood circulation. The pathways of absorption Gastroentestinal pathway

Gastroentestinal pathway (1)Oral administration口服给药 (per os) Advantages Safety, convenience and economy. It is most

Gastroentestinal pathway (1)Oral administration口服给药 (per os) Advantages Safety, convenience and economy. It is most frequently used route in clinic. Disadvantages Absorption and onset low, some drugs have first-pass elimination.

First-pass elimination首关消除 Drugs are absorbed by the gastrointestinal tract, first enter the liver via

First-pass elimination首关消除 Drugs are absorbed by the gastrointestinal tract, first enter the liver via portal vein along with blood flow and then enter into the systemic circulation. Some drugs are metabolized in the gastrointestinal tract and liver before entering the systemic circulation. The process, called first-pass elimination, this process decreases actual quantity of drug entering the systemic circulation.

Bioavailability生物利用度 (F): The fraction of unchanged drug reaching systemic circulation following administration by any

Bioavailability生物利用度 (F): The fraction of unchanged drug reaching systemic circulation following administration by any route. F = A/D x 100%

The Pathways of Absorption (2)Inhalation吸入给药 (3)Topical uses Sublingual舌下含服 Transdermal经皮给药 Per rectum直肠给药 Adoption of sublingual

The Pathways of Absorption (2)Inhalation吸入给药 (3)Topical uses Sublingual舌下含服 Transdermal经皮给药 Per rectum直肠给药 Adoption of sublingual and rectal administration without passing the portal vein can avoid the first pass elimination of the liver.

(4)Injection administration注射给药 Injection also is one of the most common clinical routes of administration,

(4)Injection administration注射给药 Injection also is one of the most common clinical routes of administration, through which drugs directly reach the systemic blood circulation without the process of absorption after intravenous administration. Following intramuscular and subcutaneous injection, drugs entering into the blood circulation via capillary vessels.

Injection administration注射给药 Intravenous injection静脉注射(iv) Intravenous infusion静脉滴注(ivd) Intramuscular injection肌内注射 (im) Subcutaneous injection皮下注射(sc) Intra-arterial injection动脉注射 (ia)

Injection administration注射给药 Intravenous injection静脉注射(iv) Intravenous infusion静脉滴注(ivd) Intramuscular injection肌内注射 (im) Subcutaneous injection皮下注射(sc) Intra-arterial injection动脉注射 (ia)

The rate of absorption by different routes iv (ia) inhalation sublingual per rectum im

The rate of absorption by different routes iv (ia) inhalation sublingual per rectum im sc per os transdermal

2. Distribution Conception The process by which a drug leaves the blood circulation to

2. Distribution Conception The process by which a drug leaves the blood circulation to enter the extracellular fluids and the tissues of the body.

Factors Affecting Drug Distribution a. Plasma protein binding血浆蛋白结合 Acidic drug-albumin, basic drugalbumin, lipoptrotein, and

Factors Affecting Drug Distribution a. Plasma protein binding血浆蛋白结合 Acidic drug-albumin, basic drugalbumin, lipoptrotein, and 1 acidic glycoprotein. D ≒ D + P ≒ DP Free drug bound drug

Plasma Protein Binding Rate(PPBR) The fraction of drug binding to plasma protein to amount

Plasma Protein Binding Rate(PPBR) The fraction of drug binding to plasma protein to amount of drug in the body: The extent of combination of drugs with plasma protein differs, which is usually expressed by the ratio of the concentration of bound drug over total drug in the body, i. e. , PPBR.

Plasma Protein Binding Reversibility Inactivation Molecule bigger Unmetabolized No transmembrane Capacity-limited protein binding Replacement

Plasma Protein Binding Reversibility Inactivation Molecule bigger Unmetabolized No transmembrane Capacity-limited protein binding Replacement

Plasma Protein Binding Replacement Anticoagulant warfarin with PPBR of 99%, an anti-inflammatory agent, phenylbutazone

Plasma Protein Binding Replacement Anticoagulant warfarin with PPBR of 99%, an anti-inflammatory agent, phenylbutazone with PPBR of 98%, when the two drugs are used at the same time, the replacement may occur, and eventually bleeding tendency due to the high free warfarin.

b. Organ blood flow The more blood flow of tissue and organ, the more

b. Organ blood flow The more blood flow of tissue and organ, the more drugs go to these tissues or organs. Such as liver, brain, kidney and lung.

Organ blood flow Some higher lipid-solubility drug first go to the abundant blood flow

Organ blood flow Some higher lipid-solubility drug first go to the abundant blood flow tissue or organ and then go to the much poor blood flow tissue or organ, such as thiopental first go to brain, and then go to muscle or other lipid tissue to form new equilibrium called redistribution.

c. Binding to tissue cells Some tissue or organs have affinity to some drugs,

c. Binding to tissue cells Some tissue or organs have affinity to some drugs, then the concentration of these drug are higher in these tissue or organ than others. Such as iodide in thyroid gland, tetracycline in bone tissue, chloroquine concentrated in liver and red blood cells.

d. The properties of drug and physical p. H The p. H of body

d. The properties of drug and physical p. H The p. H of body fluid may influence the extent of dissociation of drugs and thus affect the distribution and transport of drugs in the body.

The properties of drug and physical p. H The p. H of cellular fluid

The properties of drug and physical p. H The p. H of cellular fluid is 7. 0 and that of extracellular fluid is 7. 4 under physiological circumstances, so the concentration of weak acidic drugs in extracellular fluid is higher than that in cellular fluid.

The properties of drug and physical p. H Reducing the p. H of the

The properties of drug and physical p. H Reducing the p. H of the blood can transfer weak acidic drugs into cells, while decreasing the p. H of the blood can cause right-about transfer of acidic drugs. The situation for weak basic drugs is opposite.

The properties of drug and physical p. H Pentobarbital is a weak acidic drug,

The properties of drug and physical p. H Pentobarbital is a weak acidic drug, when it is used overdose and intoxication, the sodium bicarbonate may used to base the blood and urine to increase the excretion of pentobarbital and to anti-toxicant.

e. Cell membrane barriers Blood-brain barrier血脑屏障 (BBB): Blood-brain cells Blood-cerebrospinal fluid (CSF) CSF-brain Placental

e. Cell membrane barriers Blood-brain barrier血脑屏障 (BBB): Blood-brain cells Blood-cerebrospinal fluid (CSF) CSF-brain Placental barrier胎盘屏障: Fetus and maternal tissue胎盘绒毛-子宫血窦 Blood-eye barrier血眼屏障

3. Metabolism (Biotransformation) Concept The process in which drugs result in chemical changes, that

3. Metabolism (Biotransformation) Concept The process in which drugs result in chemical changes, that may lead to the termination or alternation of biological activity. it is also called biotransformation of drug in the body. The metabolism and excretion of drugs are generally called elimination.

Roles of drug metabolism Action of drug metabolism the polarity of drugs increases after

Roles of drug metabolism Action of drug metabolism the polarity of drugs increases after metabolism in the body, which is helpful to the excretion of drugs. However, the alternation of pharmacological activities after metabolism of drugs are complex. Most of metabolic products are often inactivated, some is active, some is toxic.

Roles of drug metabolism For instance, procainamide is metabolized to acetyl procaninamide in the

Roles of drug metabolism For instance, procainamide is metabolized to acetyl procaninamide in the body both of which have antiarrhythmic activity, and the activities are similar with the only change of pharmacokinetic behavior.

Roles of drug metabolism If a drug without any pharmacological activities is metabolized to

Roles of drug metabolism If a drug without any pharmacological activities is metabolized to be active, the maternal drug is called pro-drug, such as cyclophosphamide which is metabolized to be aldophosphamide in liver.

The sites of drug metabolism Most drugs are metabolized in liver. So liver is

The sites of drug metabolism Most drugs are metabolized in liver. So liver is the most important organ for drug metabolism.

Metabolism Action of drug metabolism: help to excretion or inactivation, active, toxicity. Pro-drug.

Metabolism Action of drug metabolism: help to excretion or inactivation, active, toxicity. Pro-drug.

Metabolism (Biotransformation) Steps of drug metabolism a. phase 1: oxygenation, reduction, hydrolysis b. phase

Metabolism (Biotransformation) Steps of drug metabolism a. phase 1: oxygenation, reduction, hydrolysis b. phase 2: conjugation (glucuronic acid, glycine or sulfate, acetylation and methylation)

Biotransformation The enzymes of drug metabolism Cytochrome P 450 monooxidase system, Hepatic microsomal mixed

Biotransformation The enzymes of drug metabolism Cytochrome P 450 monooxidase system, Hepatic microsomal mixed function oxidase system, hepatic microsomal enzymes(肝药酶): P 450

P 450 Cytochrome P 450 (CYP 450)is superfamily of aheme-thiolate proteins(亚铁血红素-硫醇盐蛋白), it metabolize the

P 450 Cytochrome P 450 (CYP 450)is superfamily of aheme-thiolate proteins(亚铁血红素-硫醇盐蛋白), it metabolize the endogenous and exogenous substances including drugs, and environmental chemicals.

The properties of cytochrome P 450 with low selectivity to its substrates, and it

The properties of cytochrome P 450 with low selectivity to its substrates, and it can metabolize various drugs with different chemical structures. Variability with the nutrition, pathological state. Activity changed by other factors

Cytochrome P 450 (P 450) Enzyme induction Enzyme inhibition Enzyme inducer: phenobarbital, rifampin, carbamazepine,

Cytochrome P 450 (P 450) Enzyme induction Enzyme inhibition Enzyme inducer: phenobarbital, rifampin, carbamazepine, phenytoin sodium, dexamethasone Enzyme inhibitor: chloramphenicol ketoconazole, citemidine

Enzyme inducers and its affected drugs inducers affected drugs barbiturates, chloramphenicol chlorpromazine, cortisone, dicumarol,

Enzyme inducers and its affected drugs inducers affected drugs barbiturates, chloramphenicol chlorpromazine, cortisone, dicumarol, digoxin, phenytoin griseofulvin warfarin phenylbutazone cortisone, digoxin phenytoin cortison, dexamethason rifampin dicumarol, digoxin, cortison oral contraceptives

Enzyme inhibitors and its affected drugs inhibitors affected drugs chloramphenicol dicumarol isoniazid diazepam cimetidin

Enzyme inhibitors and its affected drugs inhibitors affected drugs chloramphenicol dicumarol isoniazid diazepam cimetidin warfarin dicumarol phenytoin phenylbutazone phenytoin

Metabolism § Non-microsomal enzymes

Metabolism § Non-microsomal enzymes

4. Excretion of Drug The process in which of their prototype and their metabolites

4. Excretion of Drug The process in which of their prototype and their metabolites transferred from the internal to the external environment of body. The pathways of excretion includes: renal peptic, respiratory and milk excretion.

The pathways of excretion a. Kidney肾脏 Glomerular filtration Active tubular secretion: Probenecid丙磺舒 – penicillin青霉素

The pathways of excretion a. Kidney肾脏 Glomerular filtration Active tubular secretion: Probenecid丙磺舒 – penicillin青霉素 Passive tubular reabsorption phenobarbital – sodium bicarbonate

b. Peptic excretion-bile excretion Some drugs can be excreted from bile into duodenum by

b. Peptic excretion-bile excretion Some drugs can be excreted from bile into duodenum by means of simple diffusion or active transport, and then excreted along with excrement. Drugs excreted into duodenum by bile can be partially reabsorbed in the intestine, which forms enterohepatic circulation. Digitoxin 26%, t 1/2 7 days, digoxin 7%, t 1/2 36 hours,blocked by cholestyamine.

Excretion of drug c. Other routes Respiratory tract: ethanol Milk: low p. H, morphine

Excretion of drug c. Other routes Respiratory tract: ethanol Milk: low p. H, morphine Sweat Salivary

Section 3 Compartment Models One-compartment open model 一室开放模型 Two-compartment open model 二室开放模型 Central compartment中央室:

Section 3 Compartment Models One-compartment open model 一室开放模型 Two-compartment open model 二室开放模型 Central compartment中央室: plasma, liver, heart, brain, lung. Peripheral compartment周边室: bone, adipose tissue, muscle.

SECTION 4 The Elimination Kinetics of Drug The elimination of drug means the duration

SECTION 4 The Elimination Kinetics of Drug The elimination of drug means the duration of drug concentration reduction in plasma due to distribution, metabolism and excretion.

The Elimination Kinetics of Drug Kinetic Types d. C/dt = -k. Cn C: drug

The Elimination Kinetics of Drug Kinetic Types d. C/dt = -k. Cn C: drug concentration, t: time K: constant n = 0, zero-order kinetics n = 1, first-order kinetics

1. First-order Elimination Kinetics 一级消除动力学 The character of first-order kinetics is that the rate

1. First-order Elimination Kinetics 一级消除动力学 The character of first-order kinetics is that the rate of elimination is directly proportional to the drug dose (linear relationship), here the half-life time keeps constant and has nothing to do with the amount of drug in the body. Most drug are eliminated with this kind of kinetics in their metabolism capacity.

First-order Elimination Kinetics 一级消除动力学 dc/dt = -ke. C 1 = -ke. C Ct =

First-order Elimination Kinetics 一级消除动力学 dc/dt = -ke. C 1 = -ke. C Ct = C 0 e-ket log. Ct = log. C 0 – ke/2. 303 x t t = log. C 0/Ct x 2. 303/ke when Ct = 1/2 C 0, t is half life(t 1/2), t 1/2 = log 2 x 2. 303/ke = 0. 301 x 2. 303/ke = 0. 693/ke

2. Zero-order Elimination Kinetics 零级消除动力学 The character of zero-order kinetics is that the rate

2. Zero-order Elimination Kinetics 零级消除动力学 The character of zero-order kinetics is that the rate of elimination is constant, i. e. , independent of drug doses, and that the halflife time is positively relates to the drug doses. When the concentration of drug exceeds the capacity of the metabolism of the body, the drug is eliminated with zero-order kinetics. And then turn to the first-order kinetics elimination.

Zero-order Elimination Kinetics 零级消除动力学 When n = 0 -d. C/dt = KC 0 =

Zero-order Elimination Kinetics 零级消除动力学 When n = 0 -d. C/dt = KC 0 = -K C t = C 0 – Kt C 0 is initial drug concentration, Ct is drug concentration at t time 1/2 C 0 = C 0 - Kt 1/2 = 0. 5 x C 0/K

SECTION 5 The Drug Concentration –Time in the Body 1. AUC of drug concentration-time

SECTION 5 The Drug Concentration –Time in the Body 1. AUC of drug concentration-time in single dose (1)The time-concentration curve of drug Time–concentration relationship 时量关系 Time–response relationship 时效关系

Time–Concentration (effect) Curve 时–量(效)曲线

Time–Concentration (effect) Curve 时–量(效)曲线

Three periods in the curve Latent period潜伏期: the period from administration to the time

Three periods in the curve Latent period潜伏期: the period from administration to the time when the drug concentration in plasma reached the minimum effective plasma concentration. The length of this period depends on the rate of absorption and distribution of the drug.

Peak Concentration(峰浓度,Cmax) Peak Time(达峰时间, tmax, tpeak)

Peak Concentration(峰浓度,Cmax) Peak Time(达峰时间, tmax, tpeak)

Peak concentration(Cmax) Peak concentration(Cmax ) The highest concentration of the drug achieved in the

Peak concentration(Cmax) Peak concentration(Cmax ) The highest concentration of the drug achieved in the plasma following extravascular administration. Peak time (tmax, tpeak) The time of the peak concentration is the period of time required to achieve the peak concentration of drug.

Elimination half-life time消除半衰期(t 1/2) Minimum effective concentration最低有效浓度 (MEC)

Elimination half-life time消除半衰期(t 1/2) Minimum effective concentration最低有效浓度 (MEC)

Elimination half-life time(t 1/2) Minimum effective concentration (MEC) Elimination half-life time(t 1/2): The time

Elimination half-life time(t 1/2) Minimum effective concentration (MEC) Elimination half-life time(t 1/2): The time required for any given drug concentration in plasma to decrease by half. Minimum effective concentration (MEC) The concentration inducing the minimal effect.

Effective period: duration of MEC效应持续时间

Effective period: duration of MEC效应持续时间

Persistent period (duration of MEC) Referring to period during which the drug concentration in

Persistent period (duration of MEC) Referring to period during which the drug concentration in the plasma exceeds the minimum effective plasma concentration. The length is mainly determined by the rate of absorption and elimination of drug.

Residual period残效期 The drug concentration in the plasma in residual period is below the

Residual period残效期 The drug concentration in the plasma in residual period is below the minimum effective plasma concentration. So residual period is defined as the period from the minimum effective plasma concentration point to the time when the drug is completely eliminated from the body. The length of the period depends on the rate of elimination of drug.

Area Under the Curve (曲线下面积,AUC) AUC = C 0/ke (g. h. L-1)

Area Under the Curve (曲线下面积,AUC) AUC = C 0/ke (g. h. L-1)

Area Under the Curve (AUC) AUC indicates the area under the timeconcentration curve which

Area Under the Curve (AUC) AUC indicates the area under the timeconcentration curve which can be calculated by trapezoid area method. AUC = C 0/ke (g. h. L-1) AUC is an important index to appraise the extent of absorption of drugs and is usually applied in the quality evaluation of preparation.

Minimum toxic concentration最低中毒浓度(MTC)

Minimum toxic concentration最低中毒浓度(MTC)

Minimum toxic concentration (MTC) The concentration of drug inducing the minimal toxic effect. MTC

Minimum toxic concentration (MTC) The concentration of drug inducing the minimal toxic effect. MTC represents the toxicity of a drug, the higher the MTC, the lower the toxicity of the drug.

2. Css in Multiple-dose

2. Css in Multiple-dose

Css in Multiple-dose (1)Steady state concentration Css(稳态浓度) Css is defined as a time of

Css in Multiple-dose (1)Steady state concentration Css(稳态浓度) Css is defined as a time of not net change in the amount of drug when rate of input equals rate of output. Css = R x t 1/2/Vd x 0. 693 R: rate of intravenous infusion

Css in Multiple-dose (2)the maximum steady state concentration,Css-max (峰浓度)and the minimum steady state concentration,

Css in Multiple-dose (2)the maximum steady state concentration,Css-max (峰浓度)and the minimum steady state concentration, Css-min(谷浓度, trough concentration) Css-max = A/Vd x (1/1 - e-kt) Css-min = A/Vd x (1/1 - e-kt) x e-kt = C(ss)max x e-kt

Multiple-dose Kinetics

Multiple-dose Kinetics

Multiple-dose Kinetics 2. The average concentration of Css (平均峰浓度, Css) Css = A/Vd x

Multiple-dose Kinetics 2. The average concentration of Css (平均峰浓度, Css) Css = A/Vd x K x = A/CL x

The Average Concentration of Css When in steady state, RA = RE = Css

The Average Concentration of Css When in steady state, RA = RE = Css x CL= Css x Vd x Ke RA: absorption rate RE: elimination rate Therefore, Css = RA/CL = RA/Vd x Ke = RA/Vd x 0. 693/t 1/2= RA x 1. 44 x t 1/2/Vd

Section 6 Pharmacokinetic Parameters 1. Half life半衰期, t 1/2 The time required for any

Section 6 Pharmacokinetic Parameters 1. Half life半衰期, t 1/2 The time required for any given drug concentration in plasma to decrease by half. 血浆药物浓度下降一半所需要的时间。 t 1/2 = 0. 693/ke = 0. 693 x Vd/CL

Significance of Half-life Using a single dose, during 5 t 1/2 is to 3.

Significance of Half-life Using a single dose, during 5 t 1/2 is to 3. 13% of total drug in the body; Using multiple doses, during 5 t 1/2 reach to 96. 9% of steady state concentration (Css).

Time–Concentration (effect) Curve

Time–Concentration (effect) Curve

Multiple-dose Kinetics

Multiple-dose Kinetics

Parameters of Kinetics 2. Clearance(CL, 清除率,L/h ): The volume of body fluid containing a

Parameters of Kinetics 2. Clearance(CL, 清除率,L/h ): The volume of body fluid containing a drug that can be eliminated by the body in unit time. 单位时间内有多少毫升血浆中所含 的药物被机体清除。 CL = rate of elmination(RE)/Cp = Vd x ke (L. h-1)

Parameters of kinetics 3. Apparent volume of distribution (表观分布容 积, Vd) Vd means that

Parameters of kinetics 3. Apparent volume of distribution (表观分布容 积, Vd) Vd means that the ratio of in vivo drug quantity verses concentration in plasma when the drug reaches the dynamic equilibrium in the body. Vd = A/C 0 = A/AUC x Ke(L)

Apparent volume of distribution For instance, if the Vd of a drug is about

Apparent volume of distribution For instance, if the Vd of a drug is about 3 -5 L, this drug may mainly distribute in the blood. If the Vd of a drug is about 10 -20 L, the drug chiefly distributing in plasma and extacellular fluid. And if a drug has the Vd of 40 L, the drug could distribute in extra-cellular and intracellular fluids, indicating its widespread distribution in whole body.

Importances of Vd Vd: 5 L(plasma), 10~20 L(systemic fluid), > 40 L(tissue and organs),

Importances of Vd Vd: 5 L(plasma), 10~20 L(systemic fluid), > 40 L(tissue and organs), >100 L(concentrate in some organ or large area of tissue) a 70 kg male, blood volume is 5. 5 L, plasma 3 L , extracellular fluid is 12 L, total body fluids about 42 L, Vd of aspirin is 11 L, diazepam 80 L, morphine 230 L.

Pharmacokinetic Parameters 4. Bioavailability生物利用度 (F) Concept: The fraction of unchanged drug reaching systemic circulation

Pharmacokinetic Parameters 4. Bioavailability生物利用度 (F) Concept: The fraction of unchanged drug reaching systemic circulation following administration by any route. 经任何给药途径给予一定剂量的药物后到达 全身血循环内药物的百分率。

Bioavailabilty Oral bioavailability F = A/D x 100% F absolute = AUC(oral)/AUC(iv) x 100%

Bioavailabilty Oral bioavailability F = A/D x 100% F absolute = AUC(oral)/AUC(iv) x 100% F relative = AUCtest/AUCstandard x 100% Bioequivalence生物等效性

Parameters of Kinetics 5. Elimination rate constant (消除速率常数,Ke) Ke = 0. 693/t 1/2(h-1) The

Parameters of Kinetics 5. Elimination rate constant (消除速率常数,Ke) Ke = 0. 693/t 1/2(h-1) The percentage elimination of drug in a moment. 体内药物瞬间消除的百分率。

Parameters of Kinetics 6. Rate of elimination(清除速率,RE) Drug amount eliminated by body within unit

Parameters of Kinetics 6. Rate of elimination(清除速率,RE) Drug amount eliminated by body within unit time. 单位时间内被机体消除的 药量。 RE = CL x Cp

Section 7 Design and Optimization of Dosage Regimens 1. The maintenance dose维持剂量, Am Am

Section 7 Design and Optimization of Dosage Regimens 1. The maintenance dose维持剂量, Am Am = CL x TC x x F TC: target concentration : dose internal F: bioavailabilty if TC = Css, Am = Css x K x Or = (MTC-MEC) x Vd

Multiple-dose kinetics 2. The loading dose负荷量, Dl Dl = Css x Vd = RA/Ke

Multiple-dose kinetics 2. The loading dose负荷量, Dl Dl = Css x Vd = RA/Ke = 1. 44 t 1/2 RA When is t 1/2 , Dl = Dm/1 -e-0. 693 = D/0. 5 = 2 Dm 3. Amount of drug in the body 药物在体内的总量 A A = C x Vd

How cute it is ?

How cute it is ?

CHAPTER 4 FACTORS AFFECTING DRUG EFFECTS AND PRINCIPALS FOR RATIONAL DRUG USE

CHAPTER 4 FACTORS AFFECTING DRUG EFFECTS AND PRINCIPALS FOR RATIONAL DRUG USE

SECTION 1 Factors From the Drug 1. Preparations and administration route Pharmaceutical equivalance Bioequivalance

SECTION 1 Factors From the Drug 1. Preparations and administration route Pharmaceutical equivalance Bioequivalance slow release formulation缓释制剂 controlled release formulation控释制剂

Factors From the Drug extended release formulation 延迟释放剂 sustained release formulation 持续释放剂 transdermal patch透皮贴剂

Factors From the Drug extended release formulation 延迟释放剂 sustained release formulation 持续释放剂 transdermal patch透皮贴剂 2. Administration Methods pathway

Administration methods iv inhalation sublingual per rectum im sc per os transdermal

Administration methods iv inhalation sublingual per rectum im sc per os transdermal

Drug interaction The results of drug combination use Synergism协同 Addition相加: 1 + 1 =

Drug interaction The results of drug combination use Synergism协同 Addition相加: 1 + 1 = 2 Potentiation增强: 1 + 1 > 2 Antagonism拮抗 Subtraction(相减): 1 + 1 < 1 Counteraction(抵消): 1 + 1 = 0

Drug interaction a. Pharmacokinetics Absorption Plasma protein binding Biotransformation Hepatomicrosomal drug metabolism enzymes: Induction

Drug interaction a. Pharmacokinetics Absorption Plasma protein binding Biotransformation Hepatomicrosomal drug metabolism enzymes: Induction and inhibition Excretion: kidney

Drug interaction b. Pharmacodynamics Physical antagonism and synergism Receptor synergism and antagonism Interfering with

Drug interaction b. Pharmacodynamics Physical antagonism and synergism Receptor synergism and antagonism Interfering with transport of neurotransmitters

SECTION 2 Factors From the Body 1. Age Children Elderly 2. Sex 3. Genetic

SECTION 2 Factors From the Body 1. Age Children Elderly 2. Sex 3. Genetic Factors Genetic pharmacology (pharmacogenetics)

Genetic Pharmacology Extensive(rapid)metabolizer(EM) Poor(slow)metabolizer(PM) Isoniazid 6 -p-glucose-dehydroxygenase (G 6 PD) difficiency: primaquine Acetylcholinesterase inactivated:

Genetic Pharmacology Extensive(rapid)metabolizer(EM) Poor(slow)metabolizer(PM) Isoniazid 6 -p-glucose-dehydroxygenase (G 6 PD) difficiency: primaquine Acetylcholinesterase inactivated: succinylcholine

Factors From the Body 4. Idiosyncrasy 6 -p-glucose-dehydroxygenase (G 6 PD) difficiency: primaquine(伯氨喹) Acetylcholinesterase

Factors From the Body 4. Idiosyncrasy 6 -p-glucose-dehydroxygenase (G 6 PD) difficiency: primaquine(伯氨喹) Acetylcholinesterase inactivated: Succinylcholine(琥珀胆碱)

Factors From the Body 5. Pathological States Heart, Liver, kidney, gastro-intestinal, nutrition, acidic-basic disorder.

Factors From the Body 5. Pathological States Heart, Liver, kidney, gastro-intestinal, nutrition, acidic-basic disorder. 6. Psychological Factors Placebo and placebo effects

Factors From the Body 7. The Changes of Organism to Drug Reaction in Long

Factors From the Body 7. The Changes of Organism to Drug Reaction in Long term Use (1) Tolerance and drug resistance Tachyphylaxis: ephedrine Cross tolerance Drug resistance

Dependence Euphoria: rush and high Addiction Drug abuse Narcotics(麻醉药品): morphine, cocaine Anaesthetics(麻醉药)

Dependence Euphoria: rush and high Addiction Drug abuse Narcotics(麻醉药品): morphine, cocaine Anaesthetics(麻醉药)

Papaver somniferum Is it a beautiful flower or a poison ?

Papaver somniferum Is it a beautiful flower or a poison ?

Beautiful flower

Beautiful flower

morphine

morphine

Some International Airport Say If you carry heroine, we shall hang you !

Some International Airport Say If you carry heroine, we shall hang you !

Life is Most Important ! The World is so beautiful, Please love yourself, love

Life is Most Important ! The World is so beautiful, Please love yourself, love your family and the society. Never to touch the drugs !

Withdrawal symptoms/syndrome Antihypertensive drugs βadrenoceptor antagonists used in the treatment of angina.

Withdrawal symptoms/syndrome Antihypertensive drugs βadrenoceptor antagonists used in the treatment of angina.

SECTION 3 The Principals For Drug Rational Use 1. Exact Diagnosis 2. Choosing Drug

SECTION 3 The Principals For Drug Rational Use 1. Exact Diagnosis 2. Choosing Drug According to Pharmacological theory 3. Understanding Factors Affecting Drug Action - individualization 4. Both Etiological and Symptomatic Treatments are Important 5. High Responsibility for Patients

Thank You !

Thank You !

How cute it is ?

How cute it is ?