臨床藥理學(xué)教學(xué)課件之治療藥物監(jiān)測和個體化治療英文教學(xué)課件

1、Chapter 4. Therapeutic Drug Monitoring and Individualized drug therapy第1頁，共52頁。 Learning Guide1 To master the definition of therapeutic drug monitoring (TDM), indications and clinical applications, routine monitoring of the effective blood drug concentration range and influencing factors, the proced

2、ur of TDM.2 To familiar with the quality control, analysis methods and application characteristics of TDM and clinical significance of determination of free drug concentration.3To learn how to design and adjust the dosing regimen according to pharmacokinetic parameters.第2頁，共52頁。Traditional treatment

3、 methods such as the average dose recommended in the reference manual, the results are that only some patients get effective treatment, others failed to achieve the desired effect, and some even appear toxic reaction. Obviously different patients need different doses of drugs.These differe are deriv

4、ed from the following factors:Individual differences (gender, age, genetics, etc.). Pharmaceutical dosage form, route of administration and bioavailability. Disease status. The combined use of drug induced interaction. Problems in drug clinical application3第3頁，共52頁。Only according to the specific cir

5、cumstances of each patient to develop individualized drug administration program, it is possible to make the drug treatment safe and effective.In the absence of therapeutic drug monitoring technology (TDM), it is difficult to achieve individual drug delivery. Because clinicians lack the objective in

6、dex of judging the drug in the body, it is impossible to find out what these factors are at play. Problems in drug clinical application4第4頁，共52頁。（Therapeutic Drug Monitoring, TDM) TDM to determine the parameters of a drug through the laboratory, and to make an appropriate explanation to affect the p

7、rocess of drug use behavior. TDM was guided by the principles of pharmacokinetics, and by means of modern advanced analytical techniques, to determine drug concentration in blood or other body fluids, in order to guidance and evaluation of drug therapy. To guide the treatment of drugs, TDM mainly re

8、fers to the design or adjustment to the drug program. Therefore, it is also called the clinical pharmacokinetic monitoring.（Clinical Pharmacokinetic Monitoring, CPM）。Section 1. Survey of TDM第5頁，共52頁。Nameconcentration rangeNameconcentration rangeDigitoxigenin monodigitoxoside 洋地黃毒甙1430 g/LProcainamid

9、e普魯卡因胺48 mg/LDigoxin 地 高 辛0.92 g/Lpropranolol普萘洛爾2050 g/LPHENYTOIN SODIUM苯妥英鈉1020 mg/Ldiazepam安 定0.52.5 g/LPrimidone撲 米 酮1020 mg/LGlutethimide格魯米特0.2 mg/Lphenobarbital苯巴比妥1020 mg/Lmeprobamate methanol solution甲丙氨酯10 mg/Lcarbamazepine卡馬西平38 mg/L Methaqualone甲 喹 酮5 mg/LEthosuximide乙 琥 胺3050 mg/LQuinid

10、ine奎 尼 丁25 mg/Llidocaine利多卡因1.54 mg/LSulfadiazine磺胺嘧啶80150 mg/LNortriptyline去甲替林50140 g/LSulfamethoxazole磺胺異噁唑90100 mg/LTheophylline茶 堿615 mg/Lsalicylic acid 水楊酸鹽150300 mg/LTolglybutamide甲苯磺丁脲5396 mg/LImipramine丙 咪 嗪50160 g/LSafe and effective serum drug concentration range of some drugs第6頁，共52頁。Dru

11、g response differs greatly between individuals. This variability results from two main sources:variation in absorption, distribution, metabolism or elimination (pharmacokinetic);variation at or beyond tissue receptors or othermacromolecular drug targets (pharmacodynamic).第7頁，共52頁。To determine the pl

12、asma concentration of drugs Pk parameters were calculated according to pharmacokinetics principle.To design the individuation project rational administration of drugsTherapeutic Drug Monitoring（TDM）Section 1. Survey of TDM第8頁，共52頁。Drugs can be combined with the receptor to form a reversible, resulti

13、ng in pharmacological effects (efficacy).The intensity and duration of the drug effect was proportional to the concentration of the drug in the receptor site.Blood drug concentration indirectly reflects the concentration of the drug in the receptor site, and it is difficult to directly determine the

14、 concentration of the drug in its receptor site.The drug effect was more directly related to the free concentration of the drug.The correlation between the efficacy and blood concentration is better than correlation between efficacy and dose. Correlation between pharmacological action and blood drug

15、 concentration.Section 1. Survey of TDM第9頁，共52頁。Most of the anti-tumor drugs were of different in pharmocokinetics, delayed drugs efficacy and complex characteristics of dose and effect relationship.The correlation between the efficacy and blood concentration is better than correlation between effic

16、acy and dose.Most TDM reflects the relationship between drug concentration and adverse drug reactions. Correlation between pharmacological action and blood drug concentration.Section 1. Survey of TDM第10頁，共52頁。The correlation between free drug concentration and pharmacological effect and adverse reac

17、tion was higher than that of the total drug concentration.When the protein binding rate was low, the concentration of free drug was high, and the effect of drugs was enhanced.The concentration of free drug, for example Phenytoin sodium,carbanazepine, and Valproic Acid, in foreign countries has been

18、determined.Active metabolite: The correlation between the concentration of active metabolite , drug enantiomers and the pharmacological effects was higher .For example, the active metabolite of risperidone was 9-OH.（50） Application of free drug and active metabolite determination in TDM.Section 1. S

19、urvey of TDMFree drug concentration:第11頁，共52頁。（一）血藥濃度與藥效呈直接關(guān)系圖41. 藥理效應(yīng)強度和血藥濃度的線性關(guān)系12第12頁，共52頁。（二）藥效滯后于血藥濃度圖42. 藥理效應(yīng)血藥濃度滯后環(huán)13第13頁，共52頁。1. Individual genetic differences: the genetic polymorphism of cytochrome P450 oxidase (CYPs), such as CYP3A4, CYP2C19, CYP2C9 and CYP2D6, etc. For example:As the gen

20、otype of CYP2C9 was *3/*3, the CYP2C9 activity could be significantly reduced, Which resulted in abnormal increase of serum concentration of phenytoin sodium, that was prone to poisoning, should be used reducting dose in clinical application. (T2 P51).2 physiological and pathological factors (1) spe

21、cial populations: children and the elderly (students summary) (2) gender: women are more sensitive (3) cardiovascular disease: As the drug metabolism in the liver is decreased, the drug concentration is increased in heart failure, (4) thyroid function: P450 activity increased in hyperthyroidism (5)

22、the change of protein binding rate: The main factors that influence the blood drug concentration and drug effect include Section 1. Survey of TDM第14頁，共52頁。3 patient compliance4 route of administration5 drug interactions: Clarithromycin 克拉霉素is inhibitor of P-glycoprotein and CYP3A4, midazolam咪達(dá)唑侖 is

23、substrate for P-glycoprotein and CYP3A4, Clinical clarithromycin and midazolam should not be taken at the same time, otherwise the midazolam intestinal absorption was increased, liver metabolism was reduced, the bioavailability was improved, and the sedative and hypnotic 鎮(zhèn)靜和催眠 effects were significa

24、ntly enhanced.(P53) The main factors that influence the blood drug concentration and drug effect include Section 1. Survey of TDM第15頁，共52頁。 Effective Blood Drug Concentration RangEffective blood drug concentration range usually refers to the concentration range between the minimum effective concentr

25、ation(MEC) and the minimum toxic concentration(MTC). This range is often used as the target value of individual drug delivery, in order to achieve the best efficacy and avoid toxic side effects.第16頁，共52頁。 Effective Blood Drug Concentration Rang第17頁，共52頁。The preferred TDM steady state trough concentr

26、ation(simultaneous determination of peak and trough concentration of vancomycin and aminoglycosides)Determination of free drug concentration is betterThe effective blood drug concentration range was also changed when the route of administration was changed.Effective blood drug concentration第18頁，共52頁

27、。 Usually during repeated dosing a sample is taken justbefore the next dose to assess the trough concentration, and a sample may also be taken at some specified time after dosing (depending on the drug) to determine the peak concentration.A retrospective survey conducted at the MassachusettsGeneral

28、Hospital showed that before the use of digoxinmonitoring, 13.9% of all patients receiving digoxin showed evidence of toxicity, and that this figure fell to 5.9% following the introduction of monitoring.Effective blood drug concentration第19頁，共52頁。Determining the plasma concentrations of drugs in orde

29、r to adjust therapy is referred to as therapeutic drug monitoring. It has distinct but limited applications.Therapeutic drug monitoring permits dose individualization and is useful when there is a clearrelationship between plasma concentration and pharmacodynamic effects.The timing of blood samples

30、in relation to dosing is crucial. For aminoglycosides氨基糖苷類, samples are obtained for measurement of peak and trough concentrations. To guide chronic therapy (e.g. with anticonvulsants抗驚厥藥), sufficient time must elapse after starting treatment or changing dose for the steady state to have been achiev

31、ed, before sampling.第20頁，共52頁。Drugs which may usefully be monitored in this way include digoxin, lithium, aminoglycosides, several anticonvulsants, methotrexate, 氨甲喋呤theophylline, 茶堿several anti-dysrhythmic drugs (including amiodarone胺碘酮) and ciclosporin. 環(huán)孢素Individualization of dosage using therape

32、utic drug monitoring permits the effectiveness of these drugs to be maximized, while minimizing their potential toxicity.第21頁，共52頁。1 The relationship between special disease and effective blood drug concentrationTable 4-4: The effective blood concentration of simmunosuppressive agents in the early s

33、tage is high, but that of the late stage is low.When the same drug treats different diseases, the effective blood drug concentration range(BDCR) is different, such as clozapine 氯氮平: the BDCR of treatment of schizophrenia is 300-600ug/L, that ofTreatment of negative symptoms of mental illness is 260-

34、390ug/Lthat of the treatment of depression is 200-280ug/L.2 The effect of genetic variation and drug: drug transporters and metabolic enzyme polymorphisms affects drug effect of wild type : FOXP3 gene AA was more easily rejectionthan mutant CC . Immunosuppressive agents need higher doses (such as cy

35、closporin A). Influencing factors of effective blood drug concentration include Section 1. Survey of TDM第22頁，共52頁。Target concentration intervention: the target concentration of drug therapy was obtained by predicting the individual dose of the drug.The target concentration (target concentration inte

36、rvention, TCI intervention TCI) using all information in physiology and pathology and disease (such as age, weight, liver and kidney function, genotype and drug interactions), combined with the pharmacokinetic and pharmacodynamic principle, factor analysis, explain the relationship between drug conc

37、entration and drug effect and related the effect of computing to target effect required dosage, play an important role in the development of individualized administration scheme. Target concentration intervention Section 1. Survey of TDM第23頁，共52頁。Chromatographic method 色譜法can be used to complete the

38、 analysis of the concentration of 90% drugs 高效液相色譜法（High Performance Liquid Chromatography HPLC） liquid chromatograph-mass spectrometer 液相色譜儀-質(zhì)譜儀, LC-MS/MS, 氣相色譜-質(zhì)譜聯(lián)用儀（GC-MS:Gas Chromatography-Mass Spectrometer）.Immunological methods are mainly used for protein and peptide drugs.Radioimmunoassay (RI

39、A)放射免疫測定分析,Enzyme immunoassay (EMIT)酶免疫分析,enzyme-linked immunosorbent assay(ELISA)酶聯(lián)免疫吸附試驗, Methods Chemiluminescent microparticle immunoassay ( CMIA)微粒子化學(xué)發(fā)光免疫分析方法. Fluorescence polarization immunoassay (FPIA)熒光偏振免疫分析.Microbiological methods are mainly used for the monitoring of antimicrobial agents

40、 The application of drug analysis technology in TDMSection 1. Survey of TDM第24頁，共52頁。1. There is a direct relationship between plasma concentration and pharmacological or toxic effect, i.e. a therapeutic range has been established. (Drugs that workvia active metabolites, and drugs with irreversible

41、actions,are unsuited to this approach. Tolerance also restricts theusefulness of plasma concentrations.)2. Effect cannot readily be assessed quantitatively by clinical observation.3. Inter-individual variability in plasma drug concentrations from the same dose is large (e.g. phenytoin).4. There is a

42、 low therapeutic index (e.g. if the ratio of toxic concentration/effective concentration is 2).5. Several drugs are being given concurrently and serious interactions are anticipated.6. Replacement treatment (for example, of thyroxine) is to be optimized.7. Apparent resistance to the action of a drug

43、 needs an explanation, when non-compliance is suspected. ROLE OF DRUG MONITORING IN THERAPEUTICSSection 1. Survey of TDM第25頁，共52頁。Medicine with low therapeutic index and narrow safety rangeDrug that is difficult to distinguish between therapeutic effect and toxic reactionPeople with liver, kidney an

44、d heart disease.Drugs for the elimination of non linear pharmacokinetics in vivo Section 2. Indications for TDM第26頁，共52頁。Blood drug concentration and genetic differences were of larger individual differences, such as the tricyclic antidepressant, etc.Need long-term clinical application of drugs, suc

45、h as anticonvulsants and antipsychotics.Combined medication, medical disputes and medical errors, etc.Section 2. Indications for TDM第27頁，共52頁。Medicine with low therapeutic index and narrow safety rangeTreatment index is a measure of drug safety, usually with a median lethal dose (LD50) and half effe

46、ctive dose (ED50) ratio to indicate.The medicine with low therapeutic index is the effective blood drug concentration range is narrow, treatment is very close to the amount of poisoning, easy to produce adverse reactions and poisoning, it should be the treatment of drug monitoring.Such as digoxin an

47、d quinidine, procainamide, aminophylline, aminoglycosides, antiepileptic drugs, such as methotrexate.氨茶堿、氨基糖苷類、抗癲癇藥物，如氨甲喋呤。The effective concentration range of digoxin: 0.5 2.0ng/ml.第28頁，共52頁。 Difficult to distinguish between therapeutic effects and toxic reactionsDigoxin has a therapeutic effect on

48、 supra-ventricular arrhythmia, but it can also cause the toxic effects of supraventricular arrhythmia.TDM is helpful to distinguish between the result of Inadequate use of drugs and excessive use of drugs.Difficulty to distinguish between spasm resulted from phenytoin sodium poisoning and epilepsy.

49、Which should be TDM。第29頁，共52頁。Elimination of drugs in vivo was carried out by nonlinear pharmacokineticsThe elimination half-life of the drug is prolonged with the increase of dose, and the elimination ability of the body is easy to be saturated with the dosage of the drug. When the saturation limit

50、 is limited, the dose is slightly increased, the blood drug concentration can be increased, and Drug is easy to accumulate in the body and the occurrence of poisoning.Such as phenytoin, propranolol,acetylsalicylic acid, coumarin etc.苯妥英，普萘洛爾，乙酰水楊酸（阿司匹林），香豆素第30頁，共52頁。concomitant medicationThe absorpt

51、ion, distribution, biological transformation and excretion of the drug can be changed by the interaction of the drug, which can be adjusted by TDM.If the combination of the use of digoxin and digoxin can increase the blood concentration of digoxin by 2.5 times, the dosage of digoxin should be reduce

52、d to avoid drug poisoning.第31頁，共52頁。The common clinical drugs that require monitoring第32頁，共52頁。Clinical significance of TDM and individual drug delivery cases1.指導(dǎo)臨床合理用藥（如對治療指數(shù)低、安全范圍窄的藥物）第33頁，共52頁。1.To guide rational drug use in clinical（Medicine with low therapeutic index and narrow safety range）Cas

53、e1. 3 elderly patients with coronary heart disease and heart failure, aged 65 years old, 68 years old and 68 years old, liver and kidney function were normal. All long-term oral maintenance dose digoxin 0.125mg. to reach steady state after respectively in 0.5, 1, 2, 3, 6, 8, and 12 24h blood samples

54、, serum digoxin concentrations were determined by fluorescence polarization immunoassay technology, the pharmacokinetics of package, the design and implementation of pharmacokinetic parameters calculation and medication scheme.Clinical significance of TDM and individual drug delivery cases第34頁，共52頁。

55、1.指導(dǎo)臨床合理用藥（如對治療指數(shù)低、安全范圍窄的藥物）1.To guide rational drug use in clinical（Medicine with low therapeutic index and narrow safety range）第35頁，共52頁。1.To guide rational drug use in clinical（Medicine with low therapeutic index and narrow safety range）第36頁，共52頁。In patients with A, after 0.0625 1/8h, the steady

56、state serum digoxin range was 0.97-1.39nmol/L, the fluctuation range of blood drug concentration was decreased, the safety and efficacy of the drug was increased, and the control of heart failure was good.The principle of reducing the concentration fluctuation range of the driving force can be made

57、by the interval of the drug. The serum digoxin trough concentration was increased and the peak concentration decreased, which increased the safety and efficacy of digoxin.Pharmacokinetics principle: in the case of the same dose, a small amount, several times1.指導(dǎo)臨床合理用藥（治療指數(shù)低、安全范圍窄的藥物）1.To guide ratio

58、nal drug use in clinical（Medicine with low therapeutic index and narrow safety range）第37頁，共52頁。Patients with B, the original dose of 0.125 1/D, heart failure can not be controlled, the elimination of the phase half-life of 25.4h, shorter. Therefore, the drug regimen was changed to 0.0625 1/8h, the s

59、teady-state serum digoxin range was 1.21-1.46nmol/L, the fluctuation range of blood drug concentration was decreased, and the control of heart failure was good.Patients with C, the original dose of 0.125 1/D, the symptoms of poisoning, the elimination of the phase half-life of 124h, longer. Therefor

60、e, the drug regimen was changed to 0.0625 1/D, the steady-state serum digoxin range was 1.27-1.54, the toxic symptoms were eliminated, and the control of heart failure was good.1.To guide rational drug use in clinical（Medicine with low therapeutic index and narrow safety range）第38頁，共52頁。Example 2 pa