1. MLAB 2401: Clinical Chemistry Keri Brophy-Martinez Therapeutic Drug Monitoring

2. Therapeutic Drug Monitoring= TDM  Goal  Ensure that a given drug dosage produces  Maximal therapeutic benefit  Minimal toxic adverse effects  Must have an appropriate concentration at site of action that produces benefits  Standard dosages derived from healthy population  Only the free fraction of drugs can interact with site of action, resulting in a biologic response

3. Routes of Administration  Routes  Injections  Circulation= IV (intravenous)  Muscles=IM (intramuscular)  Skin= SC (subcutaneous)  Epidermal  Inhaled  Absorbed through skin  Rectal  Oral (most common)

4. Pharmacokinetics  Involves the dynamics associated with the movement of drugs across cell membranes  Includes biological events:  Absorption  Distribution  Metabolism/Biotransformation  Excretion  Relationship of drug concentration to time  Process assists in establishing or modifying a dosage regimen

5. Absorption  Rate at which drug leaves the site of administration and the extent to which this happens  Mechanism  Passive diffusion  Active transport

6. Absorption: Limiting Factors  Oral Administration  Absorption depends on..  Formulation of drug  liquid/pill  Intestinal motility  pH  Inflammation  Food  Presence of other drugs  Patient age  Pregnancy  Concurrent Pathologic Conditions

7. Distribution  Dependent on  Blood flow  Capillary permeability  pH gradients  Lipid solubility of the drug  Binding of drugs to proteins/Availability of free fractions  Free vs. bound drug  Tissue volume

8. Metabolism  Primarily occurs in the liver  Biotransformation of the parent drug molecule into one or more metabolites  Metabolites are:  water soluble  easily excreted by kidney or liver  Pharmacologically active or inactive

9. First-Pass Metabolism

10. Elimination  Elimination Routes  Hepatic metabolism  Renal filtration  Other: skin, lungs, mammary glands and salivary glands  Functional changes in organs can affect rate of elimination  i.e. : Hepatic disease with a loss of tissue result in slow rate of clearance with a longer half-life.  Elimination half-life  The time required to reduce the blood level concentration to one-half after equilibrium is obtained.

11. Pharmacokinetics  Most drugs given on a scheduled basis not as a single bolus or mass  Oscillation between a maximum(peak) and a minimum (trough)of serum concentration  Goal of dosage regimens  Achieve troughs in therapeutic range and peaks that are non-toxic

12. Sample Collection  Timing of TDM most important  Collaborate with nursing & phlebotomy staff for appropriate timing  Trough: right before next dose  Peak: one hour post administration of dose (Verify drug protocol)  Random  Specimen Type  Serum: no gel  Plasma: Heparinized  EDTA, Citrated, Oxalated not acceptable  Whole Blood  Saliva

13. Drug Groups  Cardioactive  Antibiotics  Antiepileptic  Psychotherapeutic  Antiasthmatic  Immunosuppressive  Antineoplastic  Antihypertensive

14. Drug Groups: Cardioactive  Digoxin  Used to treat CHF( congestive heart failure)  Peaks draw at 2 hours post dose  Inhibits sodium and potassium transport within the heart  Allows for better cardiac muscle contraction and rhythm  Lidocaine  Used to treat premature ventricular contractions  Affects the timing of cardiac contraction

15. Drug Groups: Cardioactive (2)  Quinidine  Used to treat cardiac arrhythmic problems  Inhibits sodium and potassium channels  Prevents arrhythmias, atrial flutter and fibrillation  Procainamide  Used to treat cardiac arrhythmic situations  Blocks sodium channels  Affects cardiac muscle contraction  Often measured with NAPA(N-Acetyl procainamide)

16. Drug Groups: Antibiotics  Aminoglycosides  Used to treat infections with gram-negative bacteria that are resistant to less toxic antibiotics  Inhibits protein synthesis of the micro-organism  Examples include: gentamycin, tobramycin, amikacin and kanamycin  Vancomycin  Used to treat infections with more-resistant gram-positive cocci and bacilli  Inhibits cell wall synthesis

17. Drug Groups: Antiepileptics “AEDs”  Most first and second generation AEDs used to treat seizure disorders and epilepsy Second Generation Felbamate Gabapentin Levetiracetam Oxcarbazpine Tigabine Topiramate Zonisamide First Generation Phenobarbital Barbiturate Primidone is a proform Phenytoin=Dilantin Valproic Acid= Depakene Carbamazepine=Tegretol

18. Drug Groups: Psychotherapeutic  Used to treat manic depression (bipolar disorder)  Lithium  Tricyclic Antidepressants “TCAs”  Clozapine

19. Drug Group: Antiasthmatic  Used to treat neonatal breathing disorders or respiratory disoders of adults or children, like asthma  Examples include theophylline and theobromine

20. Drug Group: Immunosuppressive  Monitoring of this group of drugs important to prevent organ rejection (host-versus-graft)  Used to treat autoimmune disease  Examples  Cyclosporine  Whole blood is the specimen of choice, since it sequesters in the RBC  Tacrolimus (Prograf)  Prevents rejection of liver and kidney transplants

21. Drug Group: Antineoplastics  Inhibit RNA or DNA synthesis of tumor cells, leading to cell death  Methotrexate  Inhibits DNA synthesis

22. Drug Group: Antihypertensive  Used in treatment of high blood pressure  Dilate blood vessels  Sodium nitroprusside  Used for short-term control of hypertension

23. Techniques for Measurement of TDM  Immunoassays  Gas chromatography  Liquid chromatography  Mass spectrometry

24. References  Arneson, W., & Brickell, J. (2007). Clinical Chemistry: A Laboratory Perspective. Philadelphia, PA: F.A. Davis Company.  Bishop, M., Fody, E., & Schoeff, l. (2010). Clinical Chemistry: Techniques, principles, Correlations. Baltimore: Wolters Kluwer Lippincott Williams & Wilkins.  Sunheimer, R., & Graves, L. (2010). Clinical Laboratory Chemistry. Upper Saddle River: Pearson.