Lecture Notes: Drug Clearance and Elimination Kinetics

Introduction to Drug Clearance

• Definition: Clearance is the rate of elimination of a drug over its plasma concentration.
• Equation:
  • Clearance = Rate of Elimination / Plasma concentration
  • Clearance can also be defined as the volume of plasma cleared of a drug per unit time.
• Elimination: Combination of metabolism (primarily by the liver) and excretion (primarily by the kidneys).

Organs Involved in Drug Clearance

• Primary organs:
  • Liver: Responsible for metabolizing and inactivating drugs.
  • Kidneys: Responsible for excreting drugs into the urine.
• Other organs: Lungs (clear inhaled anesthetics), GI tract, and other secretions such as breast milk and saliva.

Renal and Hepatic Dysfunction

• Impact on Clearance:
  • Renal dysfunction decreases clearance due to reduced kidney function.
  • Liver dysfunction decreases clearance due to impaired liver metabolism.
• Consequences: Accumulation of drugs with potential toxicity if primarily cleared by affected organ.

Clearance Equation Considerations

• Factors:
  • Volume of distribution
  • Constant (0.693 or rounded to 0.7)
  • Half-life of the drug
• Half-Life: Time it takes for the drug concentration to reduce from 100% to 50%.
  • Inverse relationship with clearance. Longer half-life means decreased clearance and vice versa.

Elimination Kinetics

• First-Order Kinetics:

  • Most drugs follow this.
  • Characteristics:
    • Constant fraction of drug eliminated per unit time.
    • Half-life is constant.
    • Exponential elimination curve.
    • Directly proportional rate of elimination to drug concentration.

• Zero-Order Kinetics:

  • Drugs: Phenytoin, Ethanol, Aspirin.
  • Characteristics:
    • Constant rate of elimination per hour.
    • Linear elimination curve.
    • Rate of elimination is independent of drug concentration.
    • Saturation of enzymes at Vmax.

Steady State

• Definition: When the rate of drug administration equals the rate of elimination.
• Time to Steady State: Depends on half-life, typically achieved in 4-5 half-lives.

Case Studies and Questions

• Clinical Relevance:
  • Renal disease decreases clearance, affecting dosage and increasing half-life.
  • Example: With renal disease, decrease drug dosage to avoid toxicity.
• Steady State Calculations:
  • Example: A drug with a half-life of 12 hours reaches steady state in about 48 hours (4-5 half-lives).

Conclusion

• Understanding drug clearance and kinetics is essential for proper dosing and avoiding adverse effects.
• Next topic will cover drug dosages and regimen details.