Dosing in hepatic impairment

Hepatic Metabolism - The Liver's Tollbooth

• First-Pass Metabolism: Liver extracts a portion of drug from portal circulation before it reaches systemic circulation. Hepatic impairment ↓ this effect, ↑ bioavailability of high-extraction drugs (e.g., opioids, propranolol).
  • Hepatic Clearance: $Cl_H = Q_H \times E_H$ (Flow x Extraction Ratio)
• Metabolic Pathways:
  • Phase I (Oxidation/Reduction): Primarily via CYP450 enzymes. More sensitive to liver damage.
  • Phase II (Conjugation): Glucuronidation, sulfation. Better preserved in cirrhosis.
• Protein Binding: ↓ synthesis of albumin in cirrhosis → ↑ free fraction of highly protein-bound drugs (e.g., phenytoin, warfarin).

⭐ Exam Favorite: Drugs primarily metabolized by Phase II conjugation (e.g., Lorazepam, Oxazepam, Temazepam - "LOT") are preferred in patients with significant liver disease as their clearance is less affected.

Child-Pugh Score - Grading the Damage

• A clinical tool to assess the prognosis and severity of chronic liver disease, guiding dose adjustments for hepatically cleared drugs.
• Scoring is based on five clinical and lab measures, each graded 1-3 points based on increasing severity.
• 📌 Mnemonic: Pour Another Beer At Eleven
  • PT/INR
  • Ascites
  • Bilirubin (Total)
  • Albumin
  • Encephalopathy (Hepatic)

⭐ The Child-Pugh score's inclusion of subjective variables (Ascites, Encephalopathy) is a key limitation. The MELD score, relying solely on objective labs, is often preferred for transplant allocation lists.

Dosing Strategy - The Hepatic Shuffle

• High Extraction Ratio (ER > 0.7) Drugs

  • Metabolism is flow-dependent.
  • Cirrhosis → portosystemic shunting → ↓ first-pass effect → ↑ oral bioavailability.
  • Action: Significantly ↓ oral doses. IV doses require less adjustment.
  • Examples: Morphine, Lidocaine, Propranolol, Verapamil.

• Low Extraction Ratio (ER < 0.3) Drugs

  • Metabolism is capacity-dependent (relies on enzyme function).
  • Clearance is sensitive to intrinsic liver damage.
  • Action: Adjust dose based on Child-Pugh score; loading dose often unchanged.
    • Class A (Mild): Minimal change.
    • Class B (Mod): ↓ dose by 25-50%.
    • Class C (Severe): Avoid or ↓ dose by >50%.
  • Examples: Warfarin, Diazepam, Theophylline.

⭐ For highly protein-bound drugs (e.g., Warfarin, Phenytoin), ↓ albumin in cirrhosis leads to ↑ free drug fraction, potentiating toxicity even with normal total drug levels.

High‑Yield Points - ⚡ Biggest Takeaways

• Hepatic impairment profoundly ↓ drug metabolism, which ↑ drug half-life and the risk of toxicity.
• Drugs with a high hepatic extraction ratio (e.g., propranolol, morphine) are most affected; their bioavailability can ↑ significantly due to reduced first-pass metabolism.
• In contrast, low-extraction ratio drugs (e.g., warfarin, phenytoin) are less affected.
• The Child-Pugh score is the clinical standard for assessing liver dysfunction to guide dose adjustments.
• Prodrugs that require hepatic activation (e.g., codeine) may have reduced efficacy.