Therapeutic drug monitoring ppt

THERAPEUTIC DRUG MONITORING NOTES FOT Bpharm students

1. THERAPEUTIC DRUG MONITORING Dr. S P SRINIVAS NAYAK, Assistant Professor, SUCP

2. Therapeutic drug monitoring TDM refers to the measurement and interpretation of principally blood or plasma drug concentration measurements with the purpose of optimizing a patient’s drug therapy and clinical outcome while minimizing the risk of drug induced toxicity Dr. S P Srinivas nayak, Assistant professor 2

3. Therapeutic drug monitoring (TDM) refers to the measurement of drug concentrations in biological fluids with the purpose of optimising a patient’s drug therapy. During administration of a dosage regimen, the concentration should be maintained within the therapeutic window. TDM refers to the tool utilised to individualise dosage regimen by maintaining plasma or blood drug concentrations within the therapeutic range Dr. S P Srinivas nayak, Assistant professor 3

4. 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. Dr. S P Srinivas nayak, Assistant professor 4

5. Need for TDM 1. Drugs which have narrow therapeutic index 2. Drugs for which small changes in the concentration of the drug in plasma are likely to exhibit large changes in drug response (should exhibit non-linear kinetics) 3. Drugs which exhibit poor and erratic absorption 4. Drugs which exhibit relatively wider inter-individual variation in drug metabolism 5. Patient exhibiting the signs and symptoms of toxicity (Theophylline intake and persistent nausea) Dr. S P Srinivas nayak, Assistant professor 5

6. To minimize the risk of toxicity 7. To identify the poison and to determine the severity 8. Drugs where signs of over dosage or under dosage are difficult to distinguish. 9. Drugs which are administered in the presence of gastrointestinal, hepatic or renal disease 10.When patients are receiving multiple drug therapy Dr. S P Srinivas nayak, Assistant professor 6

7. DRUGS THAT ARE NOT SUITABLE FOR TDM Dr. S P Srinivas nayak, Assistant professor 7 Drugs having wide therapeutic index , NSAIDS Toxicity is not a realistic concern ( Penicillin ) E f f e c ts c an b e me a su r ed usin g functiona l l abo r at o r y t e s t s ( Anticoagulants ) , Oral Aantidiabetics , antiHypertensives etc Plasma co nc e n t r a tion no t p r edi c t ably r el a t ed t o e f f e cts ( Anticoagulants ) E f f e c t o f the r el a tion s hi p r e m ains und e fi n ed ( Antidepressants ) Hit and run drugs: Omeprazole, MAO inhibitors

8. NARROW THERAPEUTIC DRUGS   Bronchodilators: Theophylline Antibiotics – Aminoglycosides - Gentamicin, Amikacin – Others - Vancomycin Immunosuppressants : Cyclosporine Anticancers : Methotrexate Antiepileptics : Phenobarbital, Phenytoin, Valproate Cardiac Drugs : Digoxin, Procainamide, Lidocaine Psychoactive Drugs: Lithium Dr. S P Srinivas nayak, Assistant professor 8

9. DIGOXIN Cardiac glycoside Given IV or orally Plasma concentration-response relationship: DRUG LEVEL < 0.5 μ cg/L  No clinical effect DRUG LEVEL 0.7 μ cg/L  SOME PPOSITIVE IONOTROPIC EFFECT 0.8-2 μ cg/L  Optimum therapeutic range 2-2.5 μ cg/L  Increased risk of toxicity >2.5 μ cg/L  GI, CVS and CNS toxicity Dr. S P Srinivas nayak, Assistant professor 9

10. Factors affecting TDM   1. Patient demographics Age, sex and lean body weight are particularly important for renally cleared drugs as knowledge of these allows calculation of creatinine clearance. Dr. S P Srinivas nayak, Assistant professor 10

11. 2. Patient Compliance If the concentration of the drug is lower than expected, the possibility of non compliance should be considered before a dose increase is recommended. Dr. S P Srinivas nayak, Assistant professor 11

12. 3. Individuals capacity to absorb/distribute/metabolize/excrete the drug Absorption: The rate of absorption and extent of absorption are dependent on various factors such as: Drug formulation Manufacturer Route of administration Intra-individual variations Another aspect of absorption is bioavailability. This is the fraction of the administered dose that reaches the systemic circulation. Bioavailability is 100% for IV injection. Dr. S P Srinivas nayak, Assistant professor 12

13. Distribution: ( Vd ) = dose/plasma concentration The absolute bioavailability of a drug. For example if a drug has a half life of four hours, four hours after the initial dose, 50% of the drug will be removed. Eight hours after the initial dose, half of the remaining drug (25% of total) will be removed, for a total of 75% having been removed at that time, and so on. Half-life information is used to determine the correct drug dose required to attain the desired therapeutic range Dr. S P Srinivas nayak, Assistant professor 13

14. Metabolism: In addition, drug metabolites can be either protein bound (inactive) or free (active). The drug dosage will depend on how the drug metabolizes. Factors that impact drug metabolism includes genetics, environment, nutrition,drug interaction and age. Dr. S P Srinivas nayak, Assistant professor 14

15. Excretion: Drug excretion from the body occurs through the kidneys, or fluids excreted through the lungs, GI or skin. Renal dysfunction reduces drug clearance and may contribute to drug accumulation and increased risk of adverse drug effects. Dr. S P Srinivas nayak, Assistant professor 15

16. Some other causes: Age: In general, drugs metabolized more slowly in foetal , neonatal, and geriatric populations Physical properties of the drug (hydrophobicity, pKa , solubility)If the drug is administered in a fed or fasted state Gastric emptying rate Dr. S P Srinivas nayak, Assistant professor 16

17. Enzyme induction/inhibition by other drugs/foods:- Enzyme induction (increase rate of metabolism). e.g. Phenytoin, barbiturates, carbamazepine, glutethimide , primidone , rifampicin induces CYP1A2, CYP2C9, CYP2C19 and CYP3A4, , which is involved in a drug's metabolism may reduce the drug's activity Enzyme inhibition (decrease rate of metabolism), resulting in ↑ drug activity, e.g. Protease inhibitors, Nitrogen mustard, Mtx , Cidenafil Citrate. Dr. S P Srinivas nayak, Assistant professor 17

18. 5. Concomitant disease, Tropical disease and nutritional deficiencies This includes diseases highly prevalent in developing countries such as Infections, Diarrhoea, Worm infestations, Tuberculosis, Nutritional deficiencies, plus a Higher proportion of patients with diabetes and AIDS Dr. S P Srinivas nayak, Assistant professor 18

19.  6. Alternative system of medicine India is unique in having at least three systems of medicine coexisting with ‘western’ medicine ( Allopathy ); Ayurveda, Homeopathy and Unani . A patient with a history of generalized tonic- clonic (GTC) seizures, well controlled and with plasma phenytoin levels within the therapeutic range, presented with sudden loss of seizure control. Dr. S P Srinivas nayak, Assistant professor 19

20. 8. Alcohol & Tobacco use Chronic use of alcohol has been shown to cause non-specific hepatic microsomal enzyme induction, resulting in increased clearance and decreased serum concentrations of hepatically cleared drugs. Cigarette smoking increases the hepatic clearance of theophylline and patients who have recently stopped smoking may have unexpectedly high theophylline concentrations. Dr. S P Srinivas nayak, Assistant professor 20

21. 9. Medication or sampling errors: In cases where the TDM result is incompatible with drug administration records, the possibility of a medication or sampling error should be considered. For Example, the drug may have been given to the wrong patient, or blood may have been mistakenly drawn from a patient in a neighbouring bed. Dr. S P Srinivas nayak, Assistant professor 21

22. 10. Laboratory errors: If a laboratory error is suspected, the laboratory should be contacted and asked to repeat the assay. Alternatively, a new blood sample can be drawn and sent to a different laboratory for assay. Dr. S P Srinivas nayak, Assistant professor 22

23. 11. Cost effectiveness: Rapid and cost-effective measurement of most drugs for which TDM is indicated can be achieved using commercial kits run on automated analysers using a number of different methodologies including fluorescence polarisation immunoassay.  Dr. S P Srinivas nayak, Assistant professor 23

24. Testing Methodologies In HPLC liquid containing sample is injected at one end of the column. high pressure is used to overcome resistance to flow As liquid flows some molecule move faster than others due to diff in solubility. The exact time for each molecule to flow through the column is measured by detector. The retention time is calculated. An internal standard compound similar in structure to the specimen to be analyzed is also run through the column. By comparing retention time of sample and standard molecule can be identified. Concentration of drug can also be determine that peak produce during run. Dr. S P Srinivas nayak, Assistant professor 24

25. REQUEST FORM REQUEST FORM OF TDM Patient Name.............................Date..........Age...........Gender....... Wt................Ht..............Ward..............Ordered by...............Phone No.............. DRUG LEVEL REQUESTED.................................................... REASON FOR REQUEST : ( ) Suspected toxicity ( ) Compliance ( ) ( ) Absence of therapeutic response Please indicate when level is needed :( )within 24 h ( )within 1-2 h ( )others.... WHEN THE THERAPY STARTED….. TIME AND DATE OF LAST DOSE:..... Route : IV, IM, SC, PO, others.... Dosage form............ 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........................................... Technologist/Chemist................................. INTERPRETATION...............................................................................................................................................….... ....................................................……. Pharmacists/Pharmacokinetics/Pharmacologist Date.......................... Time............................……… Dr. S P Srinivas nayak, Assistant professor 25

26. Dr. S P Srinivas nayak, Assistant professor 26

27. INDIAN SENARIO OF TDM The current population of India is  1,384,715,664  as of Friday, November 6, 2020, based on Worldometer elaboration of the latest United Nations data. India 2020 population is estimated at 1,380,004,385 people at mid year according to UN data. India population is equivalent to  17.7%  of the total world population. India ranks number 2 in the list of countries (and dependencies) by population. Dr. S P Srinivas nayak, Assistant professor 27

28. In such a populated country it is very challenging for the health care providers to fulfill the services. Rural areas in India have a shortage of medical professionals. 74% of doctors are in urban areas that serve the other 28% of the population. This is a major issue for rural access to healthcare. In such a condition TDM will be somewhere unheared in India. Dr. S P Srinivas nayak, Assistant professor 28

29. CHALLENGES IN INDIA TO PERFORM TDM. LACK OF HEALTH CARE PROVIDERS Scientific accuracy of the drug assay OVER POPULATION POVERTY IN INDIA LACK OF FACILITIES AND EQUIPMENTS IN HOSPITALS EXPENSIVE TDM PROCESS NO RECRUITMENT OF TDM PROCESS TEAM IN INDIAN HOSPITALS. Dr. S P Srinivas nayak, Assistant professor 29

30. Clinical Challenges in Therapeutic Drug Monitoring Clinical Challenges in Therapeutic Drug Monitoring: Special Populations, Physiological Conditions and Pharmacogenomics focuses on critical issues in therapeutic drug monitoring including special requirements of therapeutic drug monitoring important to special populations (infants and children, pregnant women, elderly patients, and obese patients). Difficult to identify the special population in Indian populations. Dr. S P Srinivas nayak, Assistant professor 30

31. SOME DRUGS TO WHICH WE PERFORM TDM Antiepileptic drugs : Phenytoin , phenobarbitone , benzodiazepines, carbamazepine , valproic acid and ethosuximide Antimicrobial agents: Aminoglycoside Antineoplastics : Methotrexate , Busulfan , 6-Mercaptopurine Cardioactive Drugs : Amiodarone , digoxin , digitoxin , disopyramide , lignocaine,procainamide,propranolol and quinidine Immunosuppressants : Cyclosporine, Tacrolimus , Sirolimus Antidepressants : Lithium and tricyclic antidepressants Bronchodilators : Theophylline , Caffeine Dr. S P Srinivas nayak, Assistant professor 31

32. PHENYTOIN Phenytoin is one of the most commonly used antiepileptic drugs. It has a selective antiepileptic effect and does not produce significant drowsiness. MOA: Phenytoin acts by stabilizing the neuronal membrane and prevents spread of seizure discharges. The sodium channels exist in three forms: resting, activated and inactivated states. Phenytoin delays recovery of Na+ channels from inactivated state, thereby reduces the neuronal excitability. At high concentrations, phenytoin inhibits Ca2+ influx into the neuron, reduces glutamate levels and increases responses to GABA. Dr. S P Srinivas nayak, Assistant professor 32

33. PHARMACOKINETICS: Phenytoin is absorbed slowly through the GI tract, widely distributed and highly (about 90%) bound to plasma proteins. It is almost completely metabolized in liver by hydroxylation and glucuronide conjugation. Repeated administration of phenytoin causes enzyme induction and increases the rate of metabolism of co-administered drugs . Phenytoin exhibits dose-dependent elimination or saturation kinetics. The plasma t/2 of phenytoin increases from 24 h to 60 h . The plasma concentration increases disproportionately with slight increase in dose, resulting in toxicity. Hence, therapeutic monitoring of phenytoin is essential for adjustment of dosage. Dr. S P Srinivas nayak, Assistant professor 33

34. Phenytoin has dose-dependent toxicity. The adverse effects are: Hypertrophy and Hyperplasia of gums: Seen on chronic therapy and can be minimized by proper oral hygiene. Hypersensitivity reactions include skin rashes, neutropaenia and rarely Hepatic necrosis. Hirsutism : Due to increased androgen secretion. Hyperglycaemia : Due to decreased insulin release. Megaloblastic anaemia : Due to folate deficiency. Osteomalacia : Due to increased metabolism of vitamin D. Hypocalcaemia: Due to decreased absorption of Ca2+ from the gut. Foetal Hydantoin syndrome: Cleft lip, cleft palate, digital Hypoplasia , etc. due to the use of phenytoin during pregnancy. Dr. S P Srinivas nayak, Assistant professor 34

35. At high concentrations, phenytoin may cause the following side effects: CNS: Vestibulocerebellar syndrome—vertigo, ataxia, tremor, headache, nystagmus , psychological disturbances, etc. occur on chronic therapy. GIT: Nausea, vomiting and dyspepsia can be minimized by giving phenytoin after food. CVS: Hypotension and cardiac arrhythmias may occur on i.v . administration . Dr. S P Srinivas nayak, Assistant professor 35

36. Normal therapeutic ranges of phenytoin The therapeutic  ranges  for most adults have been established at 10.0-20.0 mcg/ mL for total  phenytoin  (bound plus unbound) and 1.0-2.0 mcg/ mL for free  phenytoin  (unbound only). Dr. S P Srinivas nayak, Assistant professor 36

37. AMINOGLYCOSIDES They include streptomycin, gentamicin, tobramycin, amikacin , kanamycin, sisomicin , neomycin, framycetin and netilmicin . Common properties of aminoglycosides They are highly polar compounds, hence, poorly absorbed from the GI tract. They are administered by parenteral route ( i.m ./ i.v. ) for systemic effect . They are mainly distributed into extracellular fluid and poorly penetrate into the CSF. They are not metabolized in the body. They are excreted unchanged in urine. They have bactericidal action against gram-negative aerobes and are more active at alkaline pH. They exhibit ototoxicity and nephrotoxicity. Transport of aminoglycosides into the bacterial cell requires oxygen; hence anaerobes are resistant to aminoglycosides. Dr. S P Srinivas nayak, Assistant professor 37

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39. THEOPHYLLIN Methylxanthines inhibit phosphodiesterases (PDEs), thereby prevent degradation of cAMP and cGMP . Causes bronchodilation , inhibiting release of histamines Theophyllins are well absorbed after oral and parenteral administration, food delays the rate of absorption of theophylline. They are well distributed all over the body; cross placental and blood–brain barriers. They get metabolized in liver and are excreted in urine. 1 . Theophylline: It is poorly water soluble, hence not suitable for injection. It is available for oral administration. 2 . Aminophylline: It is water soluble but highly irritant. It can be administered orally or slow intravenously. 3 . Etophylline : It is water soluble and can be given by oral, intramuscular ( i.m .) or intravenous ( i.v. ) routes. Dr. S P Srinivas nayak, Assistant professor 39

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41. THANK YOU..