《药理学》课程教学课件（PPT讲稿）Section 1 Basic Principles of Pharmacology

Section 1.Basic Principles of Pharmacology Chapter 1 Introduction 【Definition of Pharmacology】 Relationship between drug and body 【Contents of Pharmacology】 1.Pharmacodynamics drug台body 2.Pharmacokinemics 【Drugs and toxins】 【Diseases from drugs.】 【Relative subjects】 Clinical Pharmacology Drug therapeutics Toxicology

Section 1. Basic Principles of Pharmacology Chapter 1 Introduction 【Definition of Pharmacology】 Relationship between drug and body 【Contents of Pharmacology】 1. Pharmacodynamics drug  body 2. Pharmacokinemics 【Drugs and toxins】 【Diseases from drugs】 【Relative subjects】 Clinical Pharmacology Drug therapeutics Toxicology

Chapter 2 Pharmacodymamics 【Characteristics of drug effects】 Modulate the original function of body: Excitation or Inhibition 【Selectivity of drug effects】 For any drug:comparable;depending on properties of drug,dose,and routes 【Consequences of drug actions】 1.Therapeutic effect Purposes inc.etiological and symptomatic 2.Untoward reaction 1)Side reaction 2)Toxic reaction inc.acute,chronic,and unusual toxicities(carcinogenesis, teratogenesis,mutagenesis,reproductive toxicity,etc) 3)After effect(residual effect) 4)Allergic reaction and idiosyncratic reaction 5)Dependence of drugs 【Dose-effect relationship】 1.Graded dose-response relationship

Chapter 2 Pharmacodymamics 【Characteristics of drug effects】 Modulate the original function of body: Excitation or Inhibition 【Selectivity of drug effects】 For any drug: comparable; depending on properties of drug, dose, and routes 【Consequences of drug actions】 1. Therapeutic effect Purposes inc. etiological and symptomatic 2. Untoward reaction 1) Side reaction 2) Toxic reaction inc. acute, chronic, and unusual toxicities (carcinogenesis, teratogenesis, mutagenesis, reproductive toxicity, etc) 3) After effect (residual effect) 4) Allergic reaction and idiosyncratic reaction 5) Dependence of drugs 【Dose-effect relationship】 1. Graded dose-response relationship

1)The chart of graded dose-effect relationship: 2)Relative parameters: EC50 and KD Potency Efficiency(Efficacy,Intrinsic activity) 2.Quantal dose-response relationship “All or No”response 1)The chart of quantal dose-effect relationship: 2)Relative parameters: Median effective dose(ED50) Median lethal dose(LD50) Therapeutic index(TD) 【Mechanism of drug action】 1.Receptor Properties of receptor:(1)stereo-specificity;(2)high effectiveness;(3) saturability;(4)reversibility;(5)versatility;(6)modification

1) The chart of graded dose-effect relationship: 2) Relative parameters: EC50 and KD Potency Efficiency (Efficacy, Intrinsic activity) 2. Quantal dose-response relationship “All or No” response 1) The chart of quantal dose-effect relationship: 2) Relative parameters: Median effective dose (ED50) Median lethal dose (LD50) Therapeutic index (TI) 【Mechanism of drug action】 1. Receptor Properties of receptor: (1) stereo-specificity; (2) high effectiveness; (3) saturability; (4) reversibility; (5) versatility; (6) modification

2.Ligand Binding with special receptor;Standard:high affinity to receptor 1)Full agonist 2)Partial agonist 3)Antagonist 4)Partialinverse agonist 5)Full inverse agonist 3.Evaluation parameters of affinity 1)PD2 2)pA2 4.Drug-Receptor Theory 1)Occupation theory ClarkA.J.(1933) V L R=LR- E V2 Vi=k1-[L][R],v2=k-[LR],k2/k=KD=[L].[RV/[LR],[LR]=[L].[RJ/KD

2. Ligand Binding with special receptor; Standard: high affinity to receptor 1) Full agonist 2) Partial agonist 3) Antagonist 4) Partial inverse agonist 5) Full inverse agonist 3. Evaluation parameters of affinity 1) PD2 2) pA2 4. Drug-Receptor Theory 1) Occupation theory Clark A.J. (1933) V1 L + R = LR - E V2 v1=k1 .[L][R], v2=k2 .[LR], k2 /k1=KD= [L].[R]/[LR], [LR] = [L].[R]/KD

Effect/Emax=[LRJ/[RTl [LR]/[R]+[[LR]=([L].[R]/KD)/([R]+[L].[R]/KD) =([L].[RJ/KD)/([R].KD+[L].[RJ/KD) Effect/Emax=[L]/(KD+[L]) When effect=.Emax,ie [LR]=1/2.[R],[L]=KD 2)Two-state theory (allosteric theory) G 5.The interaction of drugs on the receptor levels 1)Competitive antagonism(agonist-competitive antagonist) I 2)Non-competitive antagonism(agonist-non-competitive antagonist) 3)Competitive dualism(agonist-partial agonist)

Effect/Emax = [LR]/[RT ] = [LR]/[R]+[[LR] = ([L].[R]/KD)/([R]+[L].[R]/KD) = ([L].[R]/KD)/{([R].KD+[L].[R])/KD} Effect/Emax= [L]/(KD+[L]) When effect = ½.Emax, ie [LR]=1/2.[ RT ] , [L]=KD 2) Two-state theory (allosteric theory) 5. The interaction of drugs on the receptor levels 1) Competitive antagonism(agonist – competitive antagonist) 2) Non-competitive antagonism (agonist – non-competitive antagonist) 3) Competitive dualism(agonist – partial agonist)

Chapter 3 Pharmacokinetics 1.Drug transport across the biomembranes 1)Drug transport styles (1)Passive membrane transport Sort:filtration and simple diffusion;the later is very important. Feature:No energy is needed;No carrriers are needed;No saturability; The factors that influence on the drug simple diffusion: A.aspect of drug:lipophilicity,ionization level,pKa,molecular size and shape;B. aspect of transport circumustances:areas,pH,blood flow) HA(weak acid) B(weak base) HA台H++A BH+台B+H Ka=[HA]/[H+][A-] Ka=BH/BH剀 log Ka=-l0g([H+][A-]/[HA]) log Ka=-log([B][H+]/[BH+]) =-log[H+]-log([A-]/[HA]) =-log[H+]-log([B]/[BH+]) pKa=pH-log([A-]/[HA]) pKa=pH+log(BH中/[B) pH -pKa=log([A-]/[HA]) pKa-pH=log([BH+]/[BD)

Chapter 3 Pharmacokinetics 1. Drug transport across the biomembranes 1) Drug transport styles (1) Passive membrane transport Sort: filtration and simple diffusion; the later is very important. Feature: No energy is needed; No carrriers are needed; No saturability; The factors that influence on the drug simple diffusion: A. aspect of drug: lipophilicity, ionization level , pKa, molecular size and shape; B. aspect of transport circumustances: areas, pH, blood flow) HA (weak acid) B (weak base) HA  H+ + A− BH+  B + H+ Ka = [HA] / [H+ ][A− ] Ka = [BH+ ] / [B][H+ ] log Ka = − log([H+ ][A− ]/ [HA]) log Ka = −log([B][H+ ]/ [BH+ ]) = −log[H+ ] − log([A− ] / [HA]) = −log[H+ ] − log([B] / [BH+ ]) pKa = pH − log([A− ]/ [HA]) pKa = pH + log([BH+ ] / [B]) pH − pKa = log([A− ] / [HA]) pKa − pH = log([BH+ ] / [B])

(2)Carrier-mediated membrane transport Sort:active transport(feature:just opposite to passive transport) facilitate transport(feature:No energy is needed) 2.Drug absorption 1)Definition 2)Factors ofinfluence (1)The factors that influence drug transport (2)The factors from drug preparations 3)Evaluation parameters (1)First pass effect (2)Bioavailability F=(amount of absorption/administration dose)x 100% F=[AUC(extravascular)/AUC(intravenous)]x 100%.absolute bioavailability F=[AUC(sample)/AUC(standard)]x 100%.relative bioavailability

(2) Carrier-mediated membrane transport Sort: active transport(feature: just opposite to passive transport) facilitate transport(feature: No energy is needed) 2. Drug absorption 1) Definition 2) Factors of influence (1) The factors that influence drug transport (2) The factors from drug preparations 3) Evaluation parameters (1) First pass effect (2) Bioavailability F = (amount of absorption/administration dose)  100% F = [AUC(extravascular)/AUC(intravenous)]  100% . absolute bioavailability F = [AUC(sample)/AUC(standard)]  100% . relative bioavailability

3.Drug distribution 1)Definition 2)Factors ofinfluence (1)Factors that influence drug transport (2)Affinities and binding of drug to plasma proteins and special tissues or organs (3)The barriers of organs(such as blood-brain barrier,blood-eye barrier,and placenta barrier) 3)Parameters of evaluation Apparent volume of distribution(Vd) Vd total amount of drug in body/concentration of drug in plasma 4.Biotransformation 1)Definition 2)Phases of biotransformation including phase I and phase II 3)Main responsible enzymes-Cytochrome P-450 monoxygenase system,also called as hepatic microsomal drug enzymes 4)Properties of the enzymes:(1)low specificity,(2)large individual difference,(3) saturability,(4)variable activity of enzumes Inducer:phenobarbital,phenytoin,rifampin,. Inhibitor:cimetidine,isoniazid,chloromycetin

3. Drug distribution 1) Definition 2) Factors of influence (1) Factors that influence drug transport (2) Affinities and binding of drug to plasma proteins and special tissues or organs (3) The barriers of organs ( such as blood-brain barrier, blood-eye barrier, and placenta barrier) 3) Parameters of evaluation Apparent volume of distribution (Vd) Vd = total amount of drug in body/concentration of drug in plasma 4. Biotransformation 1) Definition 2) Phases of biotransformation including phase I and phase II 3) Main responsible enzymes — Cytochrome P-450 monoxygenase system, also called as hepatic microsomal drug enzymes 4) Properties of the enzymes: (1) low specificity, (2) large individual difference, (3) saturability, (4) variable activity of enzumes Inducer: phenobarbital, phenytoin, rifampin, . Inhibitor: cimetidine, isoniazid, chloromycetin,

5.Drug excretion 1)Definition 2)Routes of excretion (1)Kindeys includingglomerular filtration,tubular active transport,and tubular passive re-absorption. (2)Milk (3)Bile enterohepatic recycle ☒ 6.Pharmacokinetics of drug elimination 1)Concentration-time curve of drug (1)Cmax (2)Tpeak (3)AUC (4)TC 2)Essential conceptions (1)Compartment (2)Compartment models (3)Serum elimination half-life(t12) (4)Steady state concentration(Css)consisting of Css peak and Css valley

5. Drug excretion 1) Definition 2) Routes of excretion (1) Kindeys including glomerular filtration, tubular active transport, and tubular passive re-absorption. (2) Milk (3) Bile enterohepatic recycle 6. Pharmacokinetics of drug elimination 1) Concentration-time curve of drug (1) Cmax (2) Tpeak (3) AUC (4) TC 2) Essential conceptions (1) Compartment (2) Compartment models (3) Serum elimination half-life (t1/2) (4) Steady state concentration (Css) consisting of Css peak and Css valley

3)The elimination of first-order kinetics (1)Feature:The drug concentrations in plasma follow a exponential pattern of decline(constantratio elimination).The elimination half-life is a constant. t2=0.693/ (2)Clinical uses: Estimate the time that is needed for drug to be eliminated thoroughly from body. Estimate the time that is needed for drug to reach the Css after a certain amount of drug is given at regular time intervals. If a certain amount of drug is given orally at regular time intervals,it is very convenient to arrive at Css by doubling first dose. If drug is given iv gtt,5 fold of ti time is needed to arrive at Css without Css peak and valley. decreasing dose,shortening time interval,but keeping the total dose(that is given at same time intervals)not changed will diminish the difference between Css peak and Css valley. 4)Zero-order kinetics Feature:constant amount elimination;elimination half-life is not constant

3) The elimination of first-order kinetics (1) Feature: The drug concentrations in plasma follow a exponential pattern of decline (constant ratio elimination). The elimination half-life is a constant. t1/2 = 0.693/k (2) Clinical uses: Estimate the time that is needed for drug to be eliminated thoroughly from body. Estimate the time that is needed for drug to reach the Css after a certain amount of drug is given at regular time intervals. If a certain amount of drug is given orally at regular time intervals, it is very convenient to arrive at Css by doubling first dose. If drug is given iv gtt, 5 fold of t1/2 time is needed to arrive at Css without Css peak and valley. decreasing dose, shortening time interval, but keeping the total dose (that is given at same time intervals) not changed will diminish the difference between Css peak and Css valley. 4) Zero-order kinetics Feature: constant amount elimination; elimination half-life is not constant