Chapter 2  ·  Module 4  ·  Visual Summary

Elimination

Renal excretion, tubular processes, dose adjustment, biliary elimination, and enterohepatic recirculation

Renal Drug Elimination — Three Processes

Process 1

Glomerular Filtration

  • Passive, pressure-driven
  • Only free (unbound) drug filtered
  • Rate proportional to GFR
  • Highly protein-bound drugs: little filtration

Process 2

Tubular Secretion

  • Active carrier-mediated transport into lumen
  • Adds to filtered drug
  • Organic anion transporters: penicillins, methotrexate, furosemide
  • Organic cation transporters: metformin, creatinine
  • Probenecid blocks OAT → extends penicillin half-life

Process 3

Tubular Reabsorption

  • Passive diffusion back into blood
  • Un-ionized, lipophilic drugs reabsorbed
  • Ionized drug trapped in tubular lumen
  • Net excretion = filtered + secreted − reabsorbed
Ion Trapping for Overdose Management:
Alkalinize urine (NaHCO₃): ionizes weak acids (aspirin, phenobarbital) → traps in lumen → increases excretion
Acidify urine (NH₄Cl): ionizes weak bases (amphetamines) → traps in lumen → increases excretion

Renal Dose Adjustment — Key Principles

Category Approach Examples Key Concern
Avoid Use alternative drug Metformin (lactic acidosis), meperidine (normeperidine seizures), nitrofurantoin, NSAIDs Drug or metabolite causes harm regardless of dose
Reduce dose Lower dose, same interval Digoxin, beta-lactams, gabapentin, many antivirals Maintains average exposure; prevents accumulation toxicity
Extend interval Normal dose, longer interval Aminoglycosides, vancomycin Preserves peak (efficacy); reduces trough (toxicity)
Monitor levels Therapeutic drug monitoring Vancomycin, aminoglycosides, digoxin, lithium, phenytoin Variable PK in renal failure; target confirmed by measurement
No change Standard dosing Azithromycin, doxycycline, linezolid, clindamycin Primarily non-renal elimination
Meperidine in renal failure: normeperidine (active metabolite) accumulates → seizures. Avoid meperidine in any patient with renal impairment. Use morphine (with caution — morphine-6-glucuronide also accumulates) or hydromorphone instead.

Biliary Excretion and Enterohepatic Recirculation

Biliary Excretion

Hepatic secretion into bile

  • Preferred for large molecules (>500–600 Da) and conjugates
  • Active transport by canalicular membrane transporters
  • Rifampin: major biliary excretion → colors feces orange-red
  • Erythromycin: high biliary excretion → effective for biliary infections
  • Irinotecan: SN-38 glucuronide excreted → deconjugated in colon → severe diarrhea

Enterohepatic Recirculation

Bile → colon → reabsorption → liver

  • Mechanism: hepatic conjugation → bile → colonic bacterial deconjugation → reabsorption → prolonged half-life
  • Digoxin, morphine, ethinyl estradiol, warfarin undergo EHC
  • Cholestyramine interrupts EHC → accelerates elimination of digoxin in toxicity
  • Rifampin reduces OCP efficacy via CYP3A4 induction (not EHC)
  • Most antibiotics do NOT significantly reduce OCP efficacy

Other Elimination Routes

Pulmonary

Inhaled anesthetic elimination

  • Volatile anesthetics eliminated by exhalation
  • Low blood-gas partition coefficient → fast recovery (desflurane, sevoflurane)
  • High blood-gas partition coefficient → slower recovery (isoflurane, halothane)
  • Ethanol: partial pulmonary elimination → breathalyzer basis

Mammary Excretion

Drugs in breast milk

  • Breast milk slightly acidic (pH 6.8–7.1): ion-traps weak bases from plasma
  • Lipophilic drugs accumulate in fat-rich milk
  • Contraindicated: chemotherapy, amiodarone, lithium, radioactive iodine
  • Codeine: FDA black box — ultra-rapid CYP2D6 mothers → morphine toxicity in infant