临床药理学教学课件之治疗药物监测和个体化治疗英文教学课件

1、Chapter 4. Therapeutic Drug Monitoring and Individualized drug therapy第1页，共52页。 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页，共52页。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页，共52页。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页，共52页。（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页，共52页。Nameconcentration rangeNameconcentration rangeDigitoxigenin monodigitoxoside 洋地黄毒甙1430 g/LProcainamid

9、e普鲁卡因胺48 mg/LDigoxin 地 高 辛0.92 g/Lpropranolol普萘洛尔2050 g/LPHENYTOIN SODIUM苯妥英钠1020 mg/Ldiazepam安 定0.52.5 g/LPrimidone扑 米 酮1020 mg/LGlutethimide格鲁米特0.2 mg/Lphenobarbital苯巴比妥1020 mg/Lmeprobamate methanol solution甲丙氨酯10 mg/Lcarbamazepine卡马西平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磺胺异噁唑90100 mg/LTheophylline茶 碱615 mg/Lsalicylic acid 水杨酸盐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页，共52页。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页，共52页。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页，共52页。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页，共52页。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页，共52页。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页，共52页。（一）血药浓度与药效呈直接关系图41. 药理效应强度和血药浓度的线性关系12第12页，共52页。（二）药效滞后于血药浓度图42. 药理效应血药浓度滞后环13第13页，共52页。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页，共52页。3 patient compliance4 route of administration5 drug interactions: Clarithromycin 克拉霉素is inhibitor of P-glycoprotein and CYP3A4, midazolam咪达唑仑 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 镇静和催眠 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页，共52页。 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页，共52页。 Effective Blood Drug Concentration Rang第17页，共52页。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页，共52页

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页，共52页。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氨基糖苷类, samples are obtained for measurement of peak and trough concentrations. To guide chronic therapy (e.g. with anticonvulsants抗惊厥药), sufficient time must elapse after starting treatment or changing dose for the steady state to have been achiev

31、ed, before sampling.第20页，共52页。Drugs which may usefully be monitored in this way include digoxin, lithium, aminoglycosides, several anticonvulsants, methotrexate, 氨甲喋呤theophylline, 茶碱several anti-dysrhythmic drugs (including amiodarone胺碘酮) and ciclosporin. 环孢素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页，共52页。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页，共52页。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页，共52页。Chromatographic method 色谱法can be used to complete the

38、 analysis of the concentration of 90% drugs 高效液相色谱法（High Performance Liquid Chromatography HPLC） liquid chromatograph-mass spectrometer 液相色谱仪-质谱仪, LC-MS/MS, 气相色谱-质谱联用仪（GC-MS:Gas Chromatography-Mass Spectrometer）.Immunological methods are mainly used for protein and peptide drugs.Radioimmunoassay (RI

39、A)放射免疫测定分析,Enzyme immunoassay (EMIT)酶免疫分析,enzyme-linked immunosorbent assay(ELISA)酶联免疫吸附试验, Methods Chemiluminescent microparticle immunoassay ( CMIA)微粒子化学发光免疫分析方法. Fluorescence polarization immunoassay (FPIA)荧光偏振免疫分析.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页，共52页。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页，共52页。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页，共52页。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页，共52页。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.氨茶碱、氨基糖苷类、抗癫痫药物，如氨甲喋呤。The effective concentration range of digoxin: 0.5 2.0ng/ml.第28页，共52页。 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页，共52页。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，普萘洛尔，乙酰水杨酸（阿司匹林），香豆素第30页，共52页。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页，共52页。The common clinical drugs that require monitoring第32页，共52页。Clinical significance of TDM and individual drug delivery cases1.指导临床合理用药（如对治疗指数低、安全范围窄的药物）第33页，共52页。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页，共52页。

55、1.指导临床合理用药（如对治疗指数低、安全范围窄的药物）1.To guide rational drug use in clinical（Medicine with low therapeutic index and narrow safety range）第35页，共52页。1.To guide rational drug use in clinical（Medicine with low therapeutic index and narrow safety range）第36页，共52页。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.指导临床合理用药（治疗指数低、安全范围窄的药物）1.To guide ratio

58、nal drug use in clinical（Medicine with low therapeutic index and narrow safety range）第37页，共52页。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页，共52页。Example 2 pa