Renal and Non-renal Excretion

Drug Excretion Fundamentals - The Great Escape!

• Excretion: Irreversible removal of drug/metabolites, primarily terminating drug action and preventing toxicity.
• Major Organs:
  • Kidney: Main route for water-soluble drugs & metabolites.
  • Liver (Biliary Excretion): For larger, lipophilic drugs; may lead to enterohepatic circulation.
  • Lungs: For volatile compounds (e.g., gaseous anesthetics, ethanol).
• Minor Routes: Saliva, sweat, tears, breast milk (important for drug transfer to infants).

⭐ First-order kinetics is the most common mechanism for drug elimination: a constant fraction of drug is eliminated per unit time ($C_t = C_0 e^{-kt}$).

Renal Excretion - Kidney's Clean Sweep

Kidneys are vital for eliminating water-soluble drugs/metabolites. Renal clearance ($Cl_R$) involves three key processes: $Cl_R = (Rate \ of \ filtration + Rate \ of \ secretion - Rate \ of \ reabsorption) / C_p$.

• Glomerular Filtration (GF):
  • Passive; rate depends on GFR & fraction unbound (fu) of drug.
  • Only unbound, low MW (< 60,000 Da) drugs are filtered. Protein-bound drugs are not.
• Active Tubular Secretion (ATS):
  • Proximal tubule; carrier-mediated, saturable, requires energy.
  • Transporters: OATs (for acidic drugs like penicillin; probenecid-sensitive), OCTs (for basic drugs like metformin), P-gp, MRPs.
  • 📌 Probenecid + Penicillin: Probenecid inhibits OATs, ↓ penicillin secretion, ↑ its $t_{1/2}$ ("PROlongs PENicillin").
• Tubular Reabsorption (TR):
  • Mainly passive diffusion in proximal & distal tubules.
  • Favors lipid-soluble, non-ionized drugs.
  • Ion trapping (pH-dependent excretion, based on drug pKa):
    • Acidic drugs (e.g., aspirin): Alkalinize urine (NaHCO₃) → ↑ ionization → ↑ excretion.
    • Basic drugs (e.g., amphetamine): Acidify urine (NH₄Cl) → ↑ ionization → ↑ excretion.

⭐ For drugs eliminated solely by glomerular filtration (e.g., inulin), renal clearance equals GFR multiplied by the unbound fraction ($Cl_R = GFR \times fu$).

Non-Renal Excretion - Beyond the Bladder

Drugs can also be eliminated through routes other than the kidneys. Key non-renal pathways include:

⭐ Enterohepatic circulation significantly prolongs drug half-life (e.g., OCPs, digoxin), affecting dosing schedules and potentially leading to accumulation if not considered.

Clinical Excretion Kinetics - Dosing Decisions

• Clearance ($Cl$): Plasma volume cleared of drug/time.
  • $Cl_{Total} = Cl_{Renal} + Cl_{Hepatic} + Cl_{Other}$.
  • $Cl_{Renal}$ vital for kidney-excreted drugs.
• Elimination Half-life ($t_{1/2}$): Time for drug conc. to halve.
  • $t_{1/2} = (0.693 \times V_d) / Cl$.
  • Steady state in 4-5 $t_{1/2}$; guides dosing interval.
• Renal Impairment: ↓GFR → ↓$Cl_R$ → drug accumulation/toxicity.
  • Dose adjustment crucial for renally cleared drugs.
• Dose Adjustment: Based on Creatinine Clearance (CrCl).
  • Cockcroft-Gault: $CrCl = [(140-age) \times Wt (kg) \times (0.85 \ if \ female)] / (72 \times SCr)$.
  • Methods: ↓dose, ↑interval, or both.
• Dialysis: Removes drugs: Low MW, Low $V_d$, Low protein binding, Water-soluble.
  • Supplemental dose post-dialysis may be needed.

⭐ For narrow therapeutic index drugs mainly kidney-excreted (e.g., aminoglycosides, digoxin), CrCl-based dose adjustment (e.g., if GFR < 50 mL/min) is vital to avoid toxicity.

High‑Yield Points - ⚡ Biggest Takeaways

• Glomerular filtration is passive, affected by plasma protein binding & renal blood flow.
• Tubular secretion is an active, saturable process (e.g., penicillin with probenecid).
• Tubular reabsorption is pH-dependent; ion trapping (e.g., aspirin with NaHCO₃) aids excretion.
• Clearance (CL) = Rate of elimination / Plasma concentration; Total CL sums organ clearances.
• Enterohepatic circulation (e.g., digitoxin, rifampicin) prolongs drug action.
• Pulmonary excretion is key for volatile anesthetics and alcohol.
• Biliary excretion is important for high molecular weight drugs and their conjugates.