Toxicology and Therapeutic Drug Monitoring: Comprehensive Study Notes

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Learning Objectives

  • Introduce therapeutic drug monitoring (TDM).
  • Review terms and definitions – pharmacokinetic parameters.
  • Understand the drugs that should be monitored.
  • Review techniques used for TDM.
  • Poisoning, drug metabolism and screening drugs/poisons.
  • Reasons for screening.
  • Quality control and sample considerations.

Toxicology: Definitions and Origins

  • Toxicology is the oldest branch of science.
  • Study of adverse effects of chemicals, drugs, substances or poisons on living organisms and the ecosystem.
  • Drugs/poisons are substances that alter normal physiological function and can pose a risk to life.
  • Key factors influencing toxicology outcomes: genes, age, amount and duration of exposure, dose, and susceptibility to a substance (e.g., pregnancy, infancy, adolescence).

Exposure: Origins and Nature

  • Living organisms are exposed to chemicals knowingly and unknowingly (e.g., natural compounds in food).
  • Chemicals can be natural, biological, or synthetic in origin.
    • Natural (food, metals, minerals).
    • Biological (toxins from bacteria).
    • Synthetic (manufactured chemically).

Exposure Routes and Effects

  • Exposure route determines dose and absorption; tissue-specific toxic response is possible.
  • Toxic effects may be local or systemic.
  • Rapid/toxic effects are greatest when exposure is directly into the bloodstream.
  • Routes include:
    • Dermal (skin)
    • Inhalation (lungs)
    • Oral/Ingestion (gastrointestinal tract)
    • Injection: intravenous, intraperitoneal, intramuscular

Exposure Sources

  • Deliberate or accidental exposure.
  • Environmental sources (occupational, dietary).
  • Therapeutic exposure.
  • Severity can be Acute, Subacute, or Chronic.

Therapeutic Drug Monitoring (TDM): Purpose

  • TDM provides information that may modify treatment.
  • Aids clinician in choosing drug dosage.
  • Aims to provide optimum treatment for the patient.
  • Helps avoid iatrogenic toxicity.
  • A note references a video from the Gastrointestinal Society/Canadian Society of Intestinal Research: link provided in class materials (for example, https://www.youtube.com/watch?v=csKhLXaD_JM).

Therapeutic Drug Monitoring: Approaches

  • a priori TDM: based on pharmacogenetic, demographic and clinical information alone.
  • a posteriori TDM: based on measurement of drug/metabolite concentrations in blood or markers of clinical effect.
  • Measuring drug metabolites helps relate plasma concentration to clinical effect.
  • Processes involved in drug handling are illustrated in the literature (e.g., Ahmed, 2016).

Pharmacokinetics, Pharmacodynamics, and Pharmacogenetics

  • Pharmacokinetics (PK): movement of drugs within the body (Absorption, Distribution, Metabolism, Excretion – ADME).
  • Pharmacodynamics (PD): effects of drugs in the body and their mechanisms of action; interactions with target sites/receptors (lock-and-key, bioavailability) and biochemical/physiological consequences.
  • Pharmacogenetics: how genes affect drug response; variability in enzymes (e.g., cytochrome P450) leads to differences in metabolism.
  • Enzymes responsible for metabolism (e.g., CYP450 family) show wide inter-individual variation in expression and activity.
  • Mutations in CYP genes can lead to inborn errors of metabolism and clinically relevant diseases (Nebert & Russell, 2002).

Pharmacokinetics: Key Concepts

  • Adherence (compliance): patient takes the drug as prescribed to exert the clinical effect.
  • Absorption (bioavailability): fraction of absorbed dose reaching systemic circulation; varies by individual, drug, and dosage form; incomplete bioavailability can occur for IM or SC administration.
  • Distribution: spread of drugs and metabolites throughout the body; depends on fat/water solubility and binding to plasma proteins and tissues.
  • Protein binding: affects distribution and free drug concentration; acidic drugs bind to albumin; basic drugs bind to α1-acid glycoprotein and other globulins.
  • Free concentration should be measured (instead of total concentration) by TDM when there is significant protein binding.
  • Metabolism and excretion: drug concentration declines due to hepatic metabolism and/or renal excretion; clearance describes the volume of blood cleared of drug per unit time.
  • Clearance (CL): theoretical volume of blood that can be completely cleared of drug per unit time (e.g., creatinine clearance).
  • Factors affecting clearance: body weight, body surface area, renal function, hepatic function, cardiac output, plasma protein binding, alcohol, tobacco, and pharmacogenetic factors.
  • Half-life (t1/2): depends on volume of distribution and clearance; determines time to steady state.
  • High-volume distribution indicates extensive tissue binding; low lipid solubility drugs bind strongly to plasma proteins and have limited distribution; high lipid solubility drugs with low protein binding distribute widely.
  • The free concentration of a drug is clinically important, particularly for drugs with significant protein binding.
  • Theoretical relationships (for reference):
    • t{1/2} = rac{0.693 imes Vd}{CL}
    • CL = rac{Dose}{AUC} (for IV dosing) or CL=kimesV<em>dCL = k imes V<em>d, where k = rac{CL}{Vd}
    • V_d = rac{A}{C} (where A = total amount in the body, C = plasma concentration)

When to Use Therapeutic Drug Monitoring

  • For most drugs, dosage can be varied according to clinical response; TDM is not always necessary.
  • TDM is particularly useful when levels would indicate under-treatment or toxicity if not monitored.
  • Examples where TDM may be unnecessary: diseases/conditions monitored by other biomarkers (e.g., insulin by glucose; warfarin by INR).
  • TDM may be unhelpful when drug effects can be assessed reliably by other means or when there is poor correlation between dose and effect.
  • Narrow therapeutic window increases the value of TDM (e.g., digoxin in renal failure raises toxicity risk).

Therapeutic Window and Clinical Markers

  • Therapeutic window: concentration range between therapeutic and toxic effects; when narrow, TDM is more valuable.
  • Absence of good clinical markers or poor pharmacodynamic variability can hinder TDM usefulness.
  • Good correlation between plasma drug concentration and clinical effect indicates lower pharmacodynamic variability and usefulness of TDM.

Drugs Typically Monitored in TDM

  • Aminoglycoside antibiotics (e.g., gentamicin, tobramycin)
  • Carbamazepine (anti-epileptic)
  • Ciclosporin (immunosuppressant)
  • Digoxin (cardiac glycoside)
  • Lithium
  • Methotrexate