Therapeutic Drug Monitoring MOD5

Therapeutic Drug Monitoring (TDM)

  • Definition: TDM is the measurement of drugs and/or their metabolites in the blood to ensure therapeutic benefits.

  • Therapeutic Range: The dose/concentration range where the drug produces the desired therapeutic effects.

  • Factors Affecting Drug Concentration:

    • Age

    • Sex

    • Genetics

    • Diet

    • Other medications

    • Disease states altering physiological conditions.

  • Importance of monitoring compliance and drug-drug interactions.

TDM Definitions

  • Pharmacokinetics: Study of drug movement in the body; establishes dose-effect relationships. Influences include:

    • Absorption

    • Distribution

    • Metabolism

    • Excretion

  • Half-life (t1/2): Time for serum concentration to decline by 50%.

  • Peak Concentration: Maximum drug concentration post-dosage.

  • Trough Concentration: Minimum drug concentration post-dosage.

  • Steady State: Condition where total drug amount remains unchanged over multiple dosing intervals; requires approximately 5-7 doses to achieve.

Routes of Administration

  • Bioavailability: Fraction of administered dose that reaches its action site.

  • Types of Administration:

    • Oral: Most common, least invasive.

    • Intravenous (IV): Direct delivery into circulatory system.

    • Intramuscular (IM): Injection into muscle tissue.

    • Subcutaneous (SC): Injection just under the skin.

    • Aerosolized: Inhaled via nebulizer.

    • Transdermal: Absorbed through the skin via patches.

    • Rectal: Uses suppositories, often for infants.

Drug Absorption & Distribution

  • Factors Influencing Absorption:

    • Dissociation from administered form

    • Solubility in gastrointestinal fluids

    • Diffusion across membranes (passive/active)

    • pH of drug affects absorption.

  • Volume of Distribution: (Volume of Distribution=Dose of drugConcentration of drug)(Volume \, of \, Distribution = \frac{Dose \, of \, drug}{Concentration \, of \, drug} )

  • Distribution Factors:

    • Blood flow, capillary permeability, surface area.

    • Drug-protein binding impacts bioavailability.

    • Albumin is a key transporter; its concentration affects drug activity.

Drug Metabolism

  • Absorption from intestines enters hepatic portal system; drugs undergo first-pass metabolism, reducing effective concentration.

  • First-Pass Effect: Drug metabolized before circulation.

  • Variations in Metabolism:

    • Genetics influence (e.g., CYP450 gene).

    • Pharmacogenomics may predict therapeutic responses or interactions.

Enzymatic Reactions in Metabolism

  • Biotransformation: Changes drugs into more polar metabolites for easier excretion.

  • Phases:

    • Phase I: Functionalization, producing reactive intermediates.

    • Phase II: Conjugation, forming inactive products.

  • Drug metabolism generally follows Michaelis-Menten kinetics; often first-order for low doses.

Drug Elimination

  • Excretion Organs: Kidneys primarily excrete drugs/metabolites via:

    • Glomerular filtration

    • Renal secretion.

  • Elimination rate correlates to GFR; reduced GFR increases half-life and plasma concentrations.

Specimen Collection in TDM

  • Correct timing of sample collection is critical; trough concentrations are taken before the next dose, and peak concentrations are one hour after dose.

  • Documenting collection times and last doses is crucial for accurate treatment.

  • Serum is the specimen of choice; avoid anticoagulants that interfere with testing.

Specific Drug Class Monitoring

  • Cardiac Glycosides (Digoxin): Treats CHF, enhances cardiac contractility.

  • Psychoactive Drugs:

    • TCAs (e.g., Imipramine, Amitriptyline) for depression.

    • Lithium for bipolar disorder.

  • Antibiotics:

    • Aminoglycosides (e.g., Gentamicin) for resistant infections; risk of nephrotoxicity.

    • Vancomycin for gram-positive infections; monitor for side effects.

  • Antiepileptic Drugs:

    • Theophylline, Phenobarbital, Phenytoin, etc., with varying effects and monitoring needs.

References

  • Bishop, M. L., et al. "Clinical chemistry: Principles, techniques, and correlations (9th ed.)" 2023.

  • Sunheimer, R. L., & Graves, L. "Clinical laboratory chemistry (2nd ed.)" 2018.