Lecture Notes on Drug Clearance

Definition of Clearance

• Clearance: Rate of drug elimination divided by the plasma concentration.
• Alternatively defined as the volume of plasma cleared of a drug per unit time.

Elimination Concepts

• Elimination: Removal of drug from the body, involving metabolism and excretion.
  • Metabolism: Primarily by the liver.
  • Excretion: Primarily by the kidneys.
• Organs Involved in Clearance:
  • Primary: Kidney and liver.
  • Others: Lungs (anesthetics), GI tract, breast milk, saliva, lacrimal secretions.

Organ Dysfunction and Clearance

• Reduced kidney/liver function decreases clearance.
• Example: Drug A cleared mainly by kidneys; renal disease decreases clearance, leading to drug accumulation.
  • Result: Increased drug half-life and potential toxicity.

Clearance and Half-Life

• Clearance also calculated as a function of volume of distribution and half-life.
• Half-life: Time to decrease drug concentration by 50%.
  • Inversely proportional to clearance.
  • Longer half-life results in decreased clearance.

Elimination Kinetics

• First Order Kinetics:
  • Most drugs follow this model.
  • Constant fraction of drug eliminated per unit time.
  • Half-life: Constant.
  • Graph: Exponential.
  • Drug concentration and rate of elimination are directly proportional.
• Zero Order Kinetics:
  • Less common (e.g., Phenytoin, Ethanol, Aspirin).
  • Constant rate of elimination (not dependent on concentration).
  • Graph: Linear.
  • Drug concentration does not affect rate of elimination.
  • Risk of toxicity due to saturation of enzymes (Vmax achieved).

Steady-State Concentration

• Steady State: When drug input equals elimination.
• Time to achieve steady-state (or eliminate 95% of drug): 4-5 half-lives.

Clinical Applications

• Case Study 1: Patient with renal disease receiving anti-seizure medication.

  • Renal disease decreases drug clearance, increasing half-life.
  • Decision: Reduce dosage to prevent toxicity.

• Case Study 2: Antihypertensive drug pharmacokinetic study.

  • Drug half-life: 12 hours.
  • Reaches steady-state after approximately 4-5 half-lives (48-60 hours).

Next Steps: Explore drug dosage regimens and their pharmacokinetics in the next lecture.