pharmacology1

1、1pharmacology药理学药理学chapter 1introduction2what is pharmacology?drug药物pharmacology is the study ofinteractions between drugs and the bodybody身体3what is pharmacology?drug药物pharmacology is the study ofinteractions between drugs and the bodybody身体pharmacodynamics 药物效应动力学is the study of what the drug does

2、 to the body4what is pharmacology?drug药物pharmacology is the study ofinteractions between drugs and the bodybody身体pharmacodynamics 药物效应动力学is the study of what the drug does to the bodyabsorption, distribution, eliminationare what the body does to the drugpharmacokinetics 药物代谢动力学studies the concentrat

3、ions (浓度) over time5action on the bodydrug药物药物6action on the bodydrug药物药物poison毒物毒物7action on the bodydrug药物药物poison毒物毒物indication 适应征unwanted effectscontra-indication8action on the bodydrug药物药物dose剂量剂量poison毒物毒物indication 适应征adverse reactioncontra-indication9action on the bodydrug药物dose剂量剂量poison毒物

4、indication 适应征适应征adverse reactioncontra-indicationclinical pharmacology toxicology 临床药理学临床药理学 毒物学毒物学10highlights of thehistory of pharmacologythe egyptian ebers papyrus from the 16th century bc is the oldest complete medical document still in existence. it is mainly a collection of prescriptions (处方

5、处方) for various symptoms (症状症状).神农本草经神农本草经 (shennongs classic of herbal medicine) is considered to be the earliest chinese pharmacological work, a compilation of all medicinal knowledge accumulated around the first century bc.tang dynastys 新修本草新修本草 (revised canon of materia medica) is the first offi

6、cial pharmacopoeia (药典药典) in the world, dating from 659.ming dynastys 李时珍李时珍 writes the 本草纲目本草纲目 (compendium of materia medica) in 1596. it is the classical reference of traditional chinese medicine, or tcm. it consists of 52 volumes detailing more than 1800 drugs. it is a must-have for tcm scholars

7、 today.11german chemist f. w. sertrner (1783-1841) is the first to isolate morphine (分离提纯吗啡分离提纯吗啡) from the poppy. experimentation on dogs proves its analgesic action. isolation (分离分离) of compoundsgerman microbiologist p. ehrlich tests hundreds of chemical substances on syphilis. the 606th substance

8、 tested, an arsenic compound, proves effective. screening (筛选出筛选出) of compoundspharmacology becomes an independant discipline when r. buchheim (1820-1879) sets up the first laboratory of pharmacology in germany, writes the first pharmacology textbook, and becomes the first professor of pharmacology.

9、 in 1869, buchheims student o. schmiedeberg (1838-1921) shows that muscarine produces the same effect on the heart as electrical stimulation of the vagus nerve. study of drug targets (药物的作用部位药物的作用部位)in 1940 in britain, florey, on the basis of flemings work in 1928, isolates penicillin (分离出青霉素分离出青霉素)

10、 from a culture of blue mold, and initiates the clinical use of antibiotics (抗生素抗生素).modern clinical pharmacology12more recent research developmentsbetter understanding of molecular mechanisms of drug actions and the root causes of diseasesidentification of new drug targetsnew techniques of chemical

11、 synthesis and high-throughput screening13development of new drugspreclinical tests on isolated tissues and animalsclinical tests:phase 1: test of activity and toxicity on a few healthy humansphase 2: test on a few patients, and dosage studyphase 3: double-blind testing on a large number of patients

12、phase 4: post-marketing surveillance14gene therapy15chapter 2 pharmacokineticspart 1absorption 吸收吸收distribution 分布分布elimination 消除消除( (including including of )of )of drugs16absorption 吸收excretion 排泄distribution 分布metabolism 代谢plasma 血浆17passage of a drug through a membrane (跨膜转运)the cell (细胞细胞) is c

13、ontained within a membranea membrane is made of two lipidic (油脂油脂) filmsproteins (蛋白质蛋白质) float on the membrane, or across the membranethe membrane is lipophilic (疏水的疏水的) in its middle layer18(1) simple diffusion(简单扩散)、passive diffusion (被动被动扩散扩散)：the most common passage of drug from a higher concen

14、tration (浓度浓度)to a lower concentration(2) transport by a carrier (主动主动转运转运)can also go from a lower concentration to a higher concentration(3) diffusion through a channel (易化扩散易化扩散)from a higher concentrationto a lower concentration191. absorption 吸收oral administration drugs are mainly absorbed by t

15、he intestine (肠肠) because of its surface of absorption (200m2)a the emptying of the stomach (胃胃) is the factor limiting the ratefood slows the emptying of the stomacha drugs diffusing slowly are taken with fooda other drugs are taken on an empty stomach for faster onsetsome drugs are taken on an emp

16、ty stomach to avoid interaction with food (ex: tetracycline, levothyroxine, etc.)20first-pass elimination (首过消除首过消除)general: parenteral transcutaneous sublingualblood from the intestine flows into the portal vein (门静脉门静脉) then through the liver (肝肝), where much metabolism takes placethe most serious

17、 drug interactions involve drugs with a high first-pass metabolism (ex: cimetidine taken with acenocoumarol)local: rectal pulmonary topical: skin, mucosa, eyeother modes of administration:21first-pass elimination2223parenteral administration (肠胃外)iv intravenousfastreliableeven for big or labile mole

18、culesim intramuscular and sc subcutaneousmore convenientslower (especially in case of non watery vehicles)242. distribution 分布blood flow1. brain 脑脑, liver 肝脏肝脏, kidneys 肾脏肾脏: high flow2. muscles 肌肌3. adipose tissues 脂肪组织脂肪组织: low flowcapillary 毛细管毛细管 permeabilityliver: loose junctions between cellsb

19、rain: tight junctions between cells. it is the blood-brain barrierg what should be the characteristics of a sedative drug?25the blood-brain barrierjunctions between cells lining the blood vessels in the brain are tightly knit, so that drugs have to cross membranes to reach the brain26binding to prot

20、eins 蛋白质many drugs bind to plasma proteins (albumin, a1-glycoprotein,.) which may constitute a reservoir for those drugsclass 1: drugs in concentrations lower than saturation 饱和饱和 (=most drugs)bound drug free drugclass 2: drugs in concentrations above saturationfree drug bound drugpossible drug inte

21、raction:a class 1 drug displaced by a class 2 drugexample: tolbutamide displaced by a sulfonamide antimicrobial27class 1 drugclass 2 drugdrug interaction!28 drugmetabolite(s) 代谢物代谢物metabolism 代谢代谢(liver 肝脏肝脏,)excretion 排泄排泄 (urine 小便小便, bile 胆汁胆汁,)3. elimination 消除293.1 metabolism 代谢 occurs mainly i

22、n the liver 肝脏肝脏, also in the intestine 肠is performed by enzymes 酶酶(ex: p450 monooxygenase system)produces metabolites 代谢物代谢物 that:are generaly more water-solublemay be inactive (most often)may be active (ex: diazepam 地西泮 g nordazepam)may be toxic (ex: paracetamol 对乙酰氨基酚g acetyl-benzo-quinoneimine)3

23、031phase ifunctionalizationoxidation 氧化 addition of 0: rh g roh, etc.reduction 还原 removal of ch2o or nh2hydrolysis 水解 r1-coo-r2 g r1-cooh + r2-ohphase iiconjugationif metabolites from phase i not yet excreted; may occur in the same hepatocyteglucuronidation葡萄糖醛酸化, sulfatation硫酸化, acetylation乙酰化,most

24、 drugs are metabolized through several pathways32cyp450 monooxygenase system 细胞色素p450单氧化酶系统 va superfamily of heme-thiolate protein 亚铁血红素-硫醇盐蛋白vbe involved in the metabolism of a plethora of chemically diverse, endogenous and exogenous cpmpouds, including drugs.33the oxidation of a drug by the p450

25、monooxygenase system. electrons are supplied by nadph (nicotinamide adenine dinucleotide)34substrates of human cypscyp 1a2verapamil, imipramine, amitryptiline,caffeine (arylamine n-oxidation) .cyp 2a6nicotine, coumarin cyp 2c9diclofenac, naproxen, piroxicam, warfarincyp 2c19diazepam, omeprazole, pro

26、panololcyp 2d6amitryptiline, captopril, codeine, mianserin, chlorpromazine . cyp 2e1dapsone, ethanol, halothane, paracetamolcyp 2b6cyclophosphamidcyp 3a4testosterone, alprazolam, cisapride, terfenadine, .cyps substrate35some drugs are enzyme-inducers (k metabolism)cyp 1a2omeprazole, insulin, aromati

27、c hydrocarbons (cigarette smoking, charbroiled meat)cyp 2c9rifampicin, secobarbital,cyp 2c19carbamazepine, prednisonecyp 2d6dexamethasoncyp 2e1ethanol, isoniazidcyp 3a4glucocorticoide, phenobarbitone, rifampicin, nevirapine, sulfadimindine, nevirapine, sulfinpyrazone, troglitazonecyps inducer36some

28、drugs are enzyme-inhibitors (m metabolism), drug interaction!ex, phenobarbital 苯巴比妥 inhibiting the metabolism of dicoumarol 双香豆素cypsinhibitorcyp1a2furafylline, fluvoxamine, cimetidine, ciprofloxacinecyp2a6methoxsalen, pilocapine, chloramphenicol, amiodarone, omeprazole,.cyp2c9sulfaphenazole, fluoxet

29、ine, fluvastatin, sertraline,.cyp2c19teniposide, fluconazolecyp2d6quinidine, fluoxetine, paroxetine, haloperidol, ritonavir,.cyp2e1diethyldithiocarbamate, disulfiram, cimetidine,.cyp3a4troleandomycin,ketoconazole,gestodene373.2. excretion1.renal (肾肾)1) filtration: of all molecules mr 50002) re-absor

30、ption: weak acids will be reabsorbed more if the urine is more acidic, etc. (ex: aspirin)3) lipophilic drugs are passivelly reabsorbed active 4) secretion of some drugs in the proximal tubule, such as the penicillins, furosemide, thiazides, etc.2.biliary and fecal excretionthere exists an entero-hep

31、atic (intestine-liver) cycle for some drugs3.other routes: sweat, saliva, tears3839part 2pharmacokinetics药物动力学药物动力学the study of drug concentrations over time40(1) one-compartment model 一室模型absorptioneliminationkcompartment房室房室1. the compartment model 房室模型41absorptioneliminationkcompartment 1compartm

32、ent 2more slowly equilibrating tissuesex: adipocytes, etc.(2) two-compartment model 二室模型422. kinetics of elimination 消除动力学433.1. first-order (一级) eliminationrate of eliminationconcentration= constantdc/dt=-kec44dc/dt=-keclgct=lgc0 ket/2.303453.2. zero-order (零级) eliminationmetabolization by saturate

33、d enzymes and/or elimination by a saturated active transportapplies to many drugs at high concentration, and some others, such as aspirin or phenytoindc/dt=-k0ct=c0k0t463. relationship between plasma concentration and time473.1 single-administrationvauc: area under curve 曲线下面积vcmax：peak concertratio

34、n 峰浓度vtmax：peak time 达峰时间48css: steady-state concentration稳态浓度concentrations add up while the elimination rate increases, until a steady state is reachedthe mean steady-state concentration obeys the same rules as when the drug is infused continually3.2 repeated administration494. important parameter

35、s of pharmacokinetics4.1 the plasma half-life t1/2 消除半衰期t is the time taken for any plasma concentration to decrease by 50%50515253544.1.1 t1/2 of first-order eliminationln cp = ln cp(o) k tt = t1/2 gg cp = cp(o)/2 ln (cp(o)/2) = ln cp(o) k t1/2ln (1/2) = ln 1 k t1/2kln 1 ln (1/2)t1/2 = 0.693=k常数，不受

36、药物初始浓度和给药剂量的影响554.1.2 t1/2 of zero-order eliminationcp = cp(o) k0 tt = t1/2 gg cp = cp(o)/2 cp(o)/2 = cp(o) k0 t1/2k00.5 cp(o)t1/2 = 与血浆药物初始浓度成正比564.2 drug clearance, cl 清除率cl = could be described as “the volume of plasma cleared of drug per unit time”. (usually in ml/min)clearance =elimination rateplasma concentration= dose/auchepatic clearance, renal clearance and total body clearance：cl total = cl hepatic + cl renal + cl pulmonary + cl others57