Evidence based medicine and tdm

Evidence based medicine and Therapeutic drug monitoring

1. Evidence Based Medicine & Therapeutic drug monitoring Dr Naser Tadvi

2. Competency PH1.2 Describe the basis of Evidence based medicine and therapeutic drug monitoring

3. Objectives Identify reliable sources for research evidence Understand research study designs and the hierarchy for research evidence Ascertain strength of evidence of treatments Understand the purpose of TDM Explain the methods in TDM Enlist the drugs requiring TDM

4. Reliable sources for research evidence Credible sources Published within last 10 years Written by respected authors Belong to educational or governmental institutions Non credible sources Older than last 10 years Written by someone without proper credentials Published on commercial websites

5. Definition of Evidence based medicine Evidence-based medicine is the science of integrating the best available evidence from clinical research with Physician`s clinical expertise and patient’s unique values and preferences Patient Values Clinical Expertise Best research evidence EBM Straus SE, Richardson WS, Glasziou P, Haynes RB. Evidence-based medicine: how to practice and teach EBM 3d ed. London: Churchill Livingstone, 2005

6. Purpose of evidence based medicine Assess the evidence and the risks and benefits of ordering diagnostic tests and treatment To predict if treatment will do more harm than good Encourages dialogue between patient & doctor, so patients can share in decision making and make their preferences and values known

7. Steps in Evidence Based Research Heneghan C, Badenoch D. Evidence-based medicine toolkit. 2d ed. Malden, MA: Blackwell, 2007

8. Step 1 Asking answerable questions – focused, searchable, clinical PICO Patient, Problem, Population (subjects) Intervention or therapy Comparison, Control Outcome (results)

9. Elements while asking question

10. Can You Identify PICO? In children under 5 years age, is intravenous diazepam equally effective as compared to per rectal diazepam for treatment of status epilepticus/ convulsions In children under 5 years age (P) , is intravenous diazepam (I) equally effective as compared to per rectal diazepam(C) for treatment of status epilepticus/ convulsions (O)

11. Step 2 Finding the best evidence with which to answer the question through structured searches and understanding the literature

12. Types of studies

13. So What Is PubMed?

14. Accessing PubMed Directly at: http://pubmed.gov Or, National Library of Medicine’s homepage: http://www.nlm.nih.gov

15. Types of studies

16. Grades of strength of evidence Grade 1 Systemic reviews/ Meta-analysis More reliable, may form basis of clinical decisions Grade II Well powered randomized controlled trial/ more than one trial Reliable but may be supported or refuted by similar studies Grade III Open label trials/ pilot studies/ observational (Cohort and case-control studies Less reliable, need more rigorous testing , may indicate further investigation Grade IV Case reports/ Clinical Expericence Least reliable: may serve as pointers to initiate formal studies

17. Step 3 Appraisal of evidence Verifying whether the results are valid What are the results Are the results suited to your patient

18. Step 4 Best documented critically appraised research evidence is already with us Patient values to be considered while applying evidence are Economical status of patient No contraindication for drug to be applied Dosage form preferred Integrate the evidence with clinical expertise and patient preferences Evidence is applied on the patient

19. Benefits of evidence-based medicine Minimize the errors in patient care Reduces the cost of treatment to patient Optimizes the quality patient care Skills learned in practicing evidence based medicine are same as ones needed to be life long learner, self directed learner Habit of accessing literature on a daily basis best guarantor of ensuring advancement of knowledge and keeping abreast of scientific progress

20. Therapeutic drug monitoring Dr. Naser Ashraf Tadvi

21. What is therapeutic drug monitoring (Definition) Therapeutic Drug Monitoring is measurement of the plasma concentration level of a drug and the coordination of this serum level with a serum therapeutic range.

22. Why should drug level be monitored ? Some drugs have a narrow therapeutic range, In concentrations above the upper limit of the range, the drug can be toxic In concentrations below the lower limit of the range, the drug can be ineffective. Not all patients have the same response at similar doses TDM can guide the clinician to provide effective and safe drug therapy in the individual patient using serum drug concentration .

23. Therapeutic range/ therapeutic window The therapeutic range/ therapeutic window is the concentration range of drug in plasma where the drug has been shown to be efficacious without causing toxic effects in most people.

24. Where to find information regarding therapeutic range Recommended therapeutic ranges can generally be found in the product inserts for drugs that require monitoring. They are also available in books such as the Physicians Desk Reference, and articles in the primary medical journals.

25. Digoxin Plasma concentration –response relationship 0.5µcg/L: No therapeutic effect 0.7 µcg/L: some ↑ in force of contraction of heart 0.8- 2 µcg/L: Optimum therapeutic range 2 -2.5 µcg/L: ↑ risk of toxicity although tolerated in some patients ˃ 2.5 µcg/L: Gastrointestinal, cardiovascular and CNS toxicity

26. Theophylline Plasma concentration response relationship ˂ 5mg/L: No bronchodilation 5-10 mg/L: Some bronchodilation and possible anti-inflammatory action 10-20 mg/L: optimum bronchodilation , minimum side effects 20-30 mg/L: increased incidence of nausea, vomiting and cardiac arrhythmias ˃ 30 mg/L: cardiac arrhythmias & Seizures

27. Lithium Plasma concentration response relationship ˂ 0.4 mmol /L: Little therapeutic effect 0.4 to 1 mmol /L: Optimum range for prophylaxis of mania 0.8 to 1.2 mmol /L: Optimum range for acute mania 1.2 to 1.5 mmol /L: Causes possible renal impairment 1.5 to 3 mmol /L: Renal impairment, weakness, drowsiness, thirst and diarrhoea 3 to 5 mmol /L: Confusion, spasticity, convulsions, coma and death

28. Phenytoin ˂ 0.5 mg/L: No therapeutic effect 5 to 10 mg/L: Some anti- convulsant action 10 to 20 mg/L: optimum concentration for anticonvulsant effect 20-30 mg/L: Nystagmus , blurred vision ˃30 mg/L: Ataxia, drowsiness, coma

29. Do all drugs require TDM No

30. Indications of TDM Drugs with narrow Therapeutic index Lithium, digoxin, phenytoin, aminoglycosides etc Drugs showing large interindividual variation To ascertain compliance For drugs whose toxicity is increased in presence of renal failure In patients who do not respond to therapy without any known reason

31. Drugs not suitable for TDM Drugs that are used for treating diseases of which their clinical end points e.g., BP Drugs whose serum concentrations do not correlate with therapeutic or toxic effects. Drugs having wide therapeutic index Hit and run drugs: omeprazole, MAO inhibitors

32. Clinical significance /Uses of TDM Maximizes efficacy Avoids toxicity Identif ies therapeutic failure Non compliance, subtherapeutic dose Facilitat es adjustment of dosage New dose = Old dose X Desired C ss /Old C ss 5. Facilitates the therapeutic effect of drug by achieving target drug concentration 6. Identify poisoning, drug toxicity and drug abuse

33. Examples of drugs requiring TDM Digoxin: 0.8 -2 µ cg/L Theophylline:10-20 mg/L Gentamicin: 2-12 mg/L Lithium: 0.8-1.2 mmol /L Phenytoin: 10-20 mg/L Carbamazepine: 4-12 mg/L Ciclosporin : 100-200 ng/Ml Vancomycin Procainamide

34. The management of therapy using plasma concentration

35. REQUEST FORM OF TDM Patient Name............................................. Date............................................... HN........................................................ Age.................................. Sex................................. Wt...................................... Ht......................................................... Ward.............................................Ordered by....................................................... Phone No.......................................... DRUG LEVEL REQUESTED.................................................................................................................................................. REASON FOR REQUEST : ( ) Suspected toxicity ( ) Compliance ( ) Therapeutic confirmation ( ) Absence of therapeutic response Please indicate when level is needed : ( ) within 24 h ( ) within 1-2 h ( ) stat ( ) others........................ TIME AND DATE OF LAST DOSE : Date.................... Route : IV, IM, SC, PO, Others........................... Time.................... Dose.......................... Freq.................................. THIS DRUG LEVEL IS FOR : SAMPLING TIME : ( ) Trough or predose level Date....................... Time......................... ( ) Peak level Date....................... Time........................ DOES THE PATIENT HAVE ORGAN-SYSTEM DAMAGE ? ( ) Renal ( ) Hepatic ( ) Cardiac ( ) GI ( ) Endocrine ( ) Others........................…. OTHER DRUG(S) PATIENT IS TAKING :.........................................................................................................…….. DRUG LEVEL & USUAL THERAPEUTIC RANGE............................................................................................……. INTERPRETATION...............................................................................................................................................…... .............................................................................................................................................................................……. Date.......................... Technologist................................. Time............................…………..

36. Can drug concentration in other fluids of body be measured Yes Urine: benzodiazepines Sweat: cocaine & heroin Saliva: marijuana, cocaine, alcohol Breath: alcohol

37. Therapeutic index (TI) It is index of safety of drug TI= Median lethal dose (LD 50 ) Median effective dose (ED 50 ) Wider the value of therapeutic index safer is the drug Example penicillin has a high therapeutic index Digoxin, lithium, phenytoin have low TI

38. Summary TDM is monitoring of plasma concentration of drug for individualization of dose in patients Mainly indicated for drugs having narrow therapeutic index, or to check compliance and titration of dose Most common drugs to undergo TDM are anticonvulsants, lithium, digoxin, gentamicin