In-Depth Notes on Drug Excretion

Overview of Drug Excretion

• Routes of Drug Excretion:
  • Hepatobiliary excretion
  • Renal excretion
  • Glomerular filtration
  • Active tubular secretion
  • Passive diffusion across tubular epithelium
  • Additional minor routes: expired air, breast milk, sweat, tears

Key Forms of Drug Excretion

• Forms of Excretion:
  • Unchanged parent drug
  • Functionalized form (Phase I metabolites)
  • Conjugated form (Phase II metabolites)
• Main Routes of Excretion:
  • Renal (urine; primary route for most drugs)
  • Hepatobiliary (bile → feces)
  • Can excrete all forms in different ratios across individuals and via multiple routes

Hepatobiliary Excretion

• Functions of Hepatocytes:
  • Uptake drugs from the blood
  • Metabolism via Phase I and Phase II enzymes
  • Diffusion of metabolites back into blood
  • Secretion of drugs/metabolites into bile
• Transport Mechanisms:
  • Involvement of transporters (e.g., P-glycoprotein, OATs, OCTs)
  • Concentration of hydrophilic drug conjugates (e.g., glucuronides) in bile for intestinal delivery
• Enterohepatic Recirculation:
  • Breakdown by GI bacteria can release active drug, which may be reabsorbed, increasing duration of action
• Exceptions:
  • Some drugs (e.g., vercuronium & rifampicin) primarily excreted in feces

Renal Function and Excretion

• Renal Homeostasis:
  • Regulates blood volume, pressure, ionic concentrations, pH, osmolarity, glucose concentration
  • Excretion of waste products and drugs/metabolites
• Renal Excretion Process:
  • Filtration + secretion - reabsorption = total renal excretion
  • Example: Rapid excretion for penicillin; slow for diazepam

Glomerular Filtration

• Characteristics of Glomerular Capillaries:
  • Highly fenestrated: allows drug molecules (up to $m_w=20,000$) to pass into Bowman’s capsule
  • No active transport; filtration purely driven by concentration gradients
  • Retention of larger molecules (e.g., albumin with $m_w=68,000$)

Active Renal Tubular Secretion

• Mechanism:
  • Accounts for 80% of renal blood flow not filtered through glomerulus
  • Facilitated by SLC transporters (OATs & OCTs)
• Transport Dynamics:
  • OATs transport acidic drugs; OCTs for organic bases
  • Active transport can work against concentration gradients
  • Tubular secretion can lower free drug concentration in plasma, allowing for elimination of protein-bound drugs

Passive Drug Diffusion Across Renal Tubule

• Reabsorption Process:
  • 99% of water filtered is reabsorbed; leads to increased solute concentration in tubular lumen
  • Lipid-soluble drugs reabsorbed passively, while polar drugs remain in the lumen
• Elimination Equation:
  • ext{Elimination} = ext{filtration} + ext{secretion}

Factors Affecting Renal Excretion

• Influential Factors:
  • Some drugs not metabolized (e.g., digoxin, gabapentin) are fully renally eliminated
  • Rate of excretion linked to renal function and glomerular filtration rate (GFR)
  • Ionization of drugs is crucial; acidic drugs are better excreted in alkaline urine (phenomenon of 'ion trapping')
  • Urinary alkalinization (using NaHCO3) enhances excretion of acidic drugs post-overdose
  • Renal function may decline with age, necessitating dose adjustments

Renal Clearance

• Definition:
  • Volume of plasma cleared of drug by kidneys per unit time (e.g., per minute)
• Calculation:
  • C{Lr} = rac{Cp imes Vu}{Cu};
    where:
  • $C_p$ = plasma concentration,
  • $C_u$ = urine concentration,
  • $V_u$ = rate of urine flow
• Clinical Relevance:
  • Creatinine clearance indicates renal function as it's 100% excreted renally
• Variability:
  • Renal clearance varies among different drugs

Summary

• Main Excretion Routes:
  • Renal and hepatobiliary are primary for drugs/metabolites
  • Renal routes involve filtration, active secretion, and passive diffusion
  • Active secretion by SLC transporters is critical
  • Rate of renal excretion influenced by drug properties, age, and urinary pH adjustments

Additional Notes

• Question session offered to clarify aspects of absorption, distribution, metabolism, and excretion (ADME).