MLAB 2401: Clinical Chemistry Keri Brophy-Martinez

1. MLAB 2401: Clinical ChemistryKeri 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

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 .