TDM(Therapeutic Drug Monitoring)

Therapeutic Drug Monitoring (TDM)

Introduction to TDM

  • TDM is an individualized system for the administration and management of drug therapy.
  • It involves analysis, assessment, and evaluation of circulating drug concentrations in serum, plasma, or whole blood.
  • Ensures maximal therapeutic benefit and minimal side effects.
  • Allows for the safe use of potentially toxic drugs.

Goal of TDM

  • Achieve the therapeutic range.
  • Ensure the drug is at the proper concentration at its site of action.
  • Maintain the optimum medication level in the bloodstream for treating clinical disorders.

Drug Absorption

  • Most drugs are absorbed through passive diffusion (no energy required).

Additional Goals of TDM

  • Determine proper timing and dose.
  • Determine patient compliance.
  • Monitor drug interactions.
  • Monitor drugs used for preventive effects.

Basic Principles of TDM

1. Steady State Drug Level
  • Characterized by peaks and troughs.
  • Rate of administration equals the rate of metabolism and excretion.
  • In single-dose administration, the rate of decline in concentration is expressed in terms of half-life.
2. Half-Life
  • The time required to reduce a drug level to half of its initial value.
3. Peak Concentration
  • The highest concentration of the drug obtained in the dosing interval.
4. Trough
  • The lowest concentration of the drug obtained in the dosing interval.
5. Therapeutic Range
  • The drug concentration in the blood can be subtherapeutic, therapeutic, or toxic.

Steps in Change of Drug Concentration Over Time

1. Liberation
  • The release of the active ingredients from the dosage form (tablet, capsule, suspension, etc.).
2. Absorption
  • The process by which the drug molecule is taken up into the systemic circulation.
  • The transport of the drug from the site of administration to the blood.
  • Pinocytosis: The cell takes in fluids along with dissolved small molecules, creating small pockets (pinosomes).
3. First-Pass Elimination or Metabolism
  • Following absorption, the drug traverses the hepatic system.
  • Some drugs undergo substantial metabolism or elimination in the liver.
4. Distribution (30 minutes to 2 hours)
  • The process where drug molecules confined to the blood migrate to various tissues.
  • Bioavailability: The amount of drug absorbed into the system and available for distribution.
5. Metabolism
  • The transformation of the parent drug molecules into metabolites.
  • Drugs become water-soluble to facilitate elimination.
6. Elimination or Excretion
  • The drug and its metabolites are excreted from the body via urine, feces, sweat, or saliva.

Pharmacokinetics vs. Pharmacodynamics

  • Pharmacokinetics: Mathematical expression of the relationship between drug dose and drug blood levels.
    • dosearrowbloodleveldose arrow blood level
  • Pharmacodynamics: Relationship between drug concentration at the target site and the tissue's response.
    • drugarrowtissueresponsedrug arrow tissue response

Kinetic Processes

1. First-Order Kinetics
  • Describes the absorption, distribution, and elimination of drugs.
  • The rate depends on the concentration of the drug.
2. Zero-Order Kinetics
  • The rate is independent of the drug concentration.
  • A constant amount of drug is eliminated per unit of time.
  • Depends on the liver's ability to metabolize the drug.

Laboratory Analysis Specimens

  • Serum, plasma, urine.
  • Whole blood for cyclosporine and tacrolimus because these immunosuppressive drugs have a high affinity for red cells.

Timing of Specimen Collection

  • The single most important factor in TDM.
  • Avoid collecting specimens using SSTs (serum separator tubes) because the gel can absorb certain drugs like phenytoin, phenobarbital, lidocaine, and quinidine, leading to falsely decreased results.
  • Ensure measurement is done after a steady state has been achieved.

Trough Concentration

  • The concentration of the drug in the blood immediately before the next dose is administered.
  • Collect the sample immediately or 30 minutes before the next dose.
  • As clearance rate increases, trough level decreases.

Peak Concentration

  • Typically done one hour after an orally administered dose, except for digoxin.
  • Digoxin (a cardioactive drug) should be checked eight hours after oral administration.
  • Used for investigating drug toxicity.
  • For IV drugs, collect after infusion is completed.
  • Increasing dose rate may result in levels in the toxic range.

Analysis and Methodologies for Laboratory Analysis

1. Colorimetry
  • For acetaminophen, use urine and boil to form p-aminophenol, which reacts with o-cresol to create an indophenol blue.
  • For salicylate, use Trinder assay, which reacts with ferric nitrate to create a colored complex compound.
2. Immunoassay
  • Uses antibodies specific to a particular drug.
  • Useful for rapid detection or screening using blood or urine samples.
  • Can be used to detect nanomolar ranges.
  • Examples: EMIT (enzyme-mediated multiplied immunoassay technique), FPIA (fluorescence polarization immunoassay).
3. Chromatography
  • The best specimen is urine.
  • Techniques:
    • Thin Layer Chromatography (TLC): Based on how far the drug travels and separates when stained.
    • High-Performance Liquid Chromatography (HPLC): Depends on the type of column used, the solvent, and the detector of the system. Used for tricyclic antidepressants and their metabolites.
    • Gas Chromatography-Mass Spectrometry (GCMS): The gold standard for laboratory analysis of drug intoxication, especially for volatile drugs.

Classification of Drugs (According to Action)

  • Cardioactive
  • Antibiotics
  • Antiepileptic
  • Psychoactive
  • Bronchodilator
  • Immunosuppressive
  • Antineoplastic
  • Anti-inflammatory
  • Neuroleptics

Cardioactive Drugs

  • Used to treat arrhythmias or congestive heart failure.
  • Classified into four categories:
    • Class I: Rapid sodium channel blockers (e.g., quinidine, procainamide, lidocaine).
    • Class II: Beta-receptor blockers (e.g., propranolol).
    • Class III: Potassium channel blockers (e.g., amiodarone).
    • Class IV: Calcium channel blockers (e.g., verapamil).
1. Digoxin
  • A cardiac glycoside used for treating congestive heart failure and arrhythmia.
  • Action: Inhibits the sodium-potassium ATPase, decreasing potassium and magnesium while increasing calcium levels.
  • Effective for treating cardiac arrhythmia or atrial arrhythmia and CHF.
  • Patients with hyperthyroidism are resistant to digoxin.
  • Peak serum level: 8 hours post-oral dose (exception to the 1-hour rule).
  • Half-life: 38 hours.
  • Therapeutic level: 0.5 to 2 ng/mL.
  • Toxic level: >2 ng/mL.
  • Toxic effects: Nausea, vomiting, visual disturbances, premature ventricular contraction, and atrioventricular node blockage.
2. Lidocaine (Lidocaine)
  • Used to correct ventricular arrhythmias and prevent ventricular fibrillation, especially in patients with acute myocardial infarction.
  • Administered via continuous IV infusion only (not orally, due to complete hepatic removal).
  • Also used as a slow local anesthetic.
  • Action: Binds to albumin and AAG (Alpha-1-acid glycoprotein).
  • Metabolite: MEGX (monoethylglycinexylidide).
  • Therapeutic level: 1.5 to 4 μg/mL.
  • CNS depression: 4 to 8 μg/mL.
  • Seizure: >8 μg/mL.
  • Toxic level: >4 μg/mL.
  • Toxic effects: Congestive heart failure and heart block.
3. Quinidine
  • A naturally occurring drug for the treatment of arrhythmia.
  • Route of administration: Oral.
  • Peak serum level: 2 hours after the dose (quinidine sulfate) or 4 hours after the dose (quinidine gluconate).
  • Therapeutic level: 2.3 to 5 μg/mL.
  • Toxic effects:
    • Cinchonism: Pathological condition caused by an overdose of quinine or its natural source (Cinchona bark), leading to neural, retinal, and auditory toxicity.
    • Blood dyscrasias.
    • Hepatitis.