Pharmacology Drug Elimination Basics

Drug Elimination

• Drug elimination is the process of removing a drug from the body

Objectives

• Understand drug clearance by various organs (kidney, liver, etc.)
• Compare and contrast first-order and zero-order kinetics
• Calculate loading dose, maintenance dose, and steady-state concentration
• Identify methods for prolonging drug action

Excretion

• Excretion is the passage of absorbed drugs and their metabolites out of the body
• Drugs and metabolites are excreted through:
  • Urine (primarily via the kidney)
  • Feces
  • Exhaled air
  • Saliva
  • Sweat
  • Milk
• Specific examples of drug excretion include:
  • Erythromycin and ampicillin (via feces)
  • General anesthetics and alcohol (via exhaled air)
  • Lithium, potassium iodide (via saliva and sweat)
  • Amphetamine and chloramphenicol (via milk)

Renal Excretion

• Renal excretion involves three main processes:
  • Glomerular filtration: Drugs pass through the glomerular capillaries into the filtrate.
  • Tubular reabsorption: Drugs are reabsorbed from the filtrate back into the blood.
  • Tubular secretion: Drugs move from the blood into the filtrate
• Net renal excretion = (glomerular filtration + tubular secretion) - tubular reabsorption

Renal Excretion (Glomerular Filtration)

• Glomerular capillaries have large pores
• Drug filtration depends on plasma protein binding and renal blood flow
• Glomerular filtration rate (GFR) is typically 120 mL/min and decreases with age and in renal failure

Renal Excretion (Tubular Reabsorption)

• Primarily passive diffusion
• Influenced by lipid solubility and ionization
• Lipid-soluble, unionized drugs are readily reabsorbed
• Clinical significance in poisoning
  • Urine alkalization for barbiturates poisoning (acidic drugs)
  • Urine acidification for morphine poisoning (basic drugs)

Renal Excretion (Tubular Secretion)

• Active transport process
• Primarily occurs in the proximal tubules.
• Important for removing protein-bound drugs

Kinetics of Elimination

• Clearance (CL): Theoretical volume of plasma from which a drug is completely removed per unit time
• CL = Rate of elimination / plasma concentration

First-Order Kinetics

• The rate of elimination is directly proportional to drug concentration.
• Constant fraction of drug is eliminated per unit time.
• Clearance remains constant
• Follows an exponential decay curve

Zero-Order Kinetics

• The rate of elimination is constant, irrespective of drug concentration.
• A constant amount of drug is eliminated per unit time.
• Clearance decreases with increasing concentration
• Follows a linear decline

Plasma Half-Life

• Time required for the plasma concentration of a drug to decrease by half
• Multiple half-lives (4-5) result in near-complete drug elimination

Steady-State Plasma Concentration (Cpss)

• Achieved after repeated dosing when elimination equals input.
• Cpss = Dose rate / Clearance

Loading Dose

• Used to quickly achieve target concentration.
• Loading dose = (Vd) x (desired plasma concentration) / bioavailability

Maintenance Dose

• Maintains steady-state plasma concentration
• Dosing rate = (CL) x (desired plasma concentration) / bioavailability
• CL = clearance

Prolongation of Drug Action

• Methods for maintaining a drug's effect over time:
  • Prolonging absorption rate at the site of administration
  • Increasing plasma protein binding
  • Retarding metabolism
  • Retarding renal excretion