/study / lectures / Pharmacokinetics
Hepatic Metabolism and Drug Clearance
TEXTPharmacokinetics · 8 min read
Phase I, Phase II, extraction ratio, first pass. Cirrhosis reshapes all of them. Pick drugs that survive a sick liver.
After this lesson you can
3 min read8 sections- Explain phase I + II metabolism + hepatic extraction.
- Predict drug behavior in cirrhosis.
- Recall Child-Pugh + MELD use in risk stratification.
- Choose hepato-safe agents.
Phase I vs Phase II
Phase II = conjugation (glucuronidation, sulfation, acetylation, glutathione) — makes molecules water-soluble for excretion.
Many drugs go through both.
Cytochrome P450 polymorphism is a major source of inter-individual drug response variability — CYP2D6 ultra-rapid metabolizers convert codeine to lethal morphine levels rapidly.
Hepatic extraction ratio
High extraction (>0.7): propofol, lidocaine, morphine, fentanyl, verapamil.
These are flow-limited — clearance depends on hepatic blood flow.
Low extraction (<0.3): diazepam, warfarin, phenytoin, theophylline.
These are capacity-limited — clearance depends on enzyme activity + protein binding.
Cirrhosis changes both differently.
First-pass effect
High first-pass drugs (morphine, propranolol, lidocaine, verapamil) have low oral bioavailability — IV doses are markedly smaller than equivalent oral doses.
Bypassing first-pass (sublingual, transdermal, rectal) raises plasma levels disproportionately.
This is why oral morphine doses are 3× IV doses for equivalent analgesia.
Cirrhosis effects
Phase I more affected than Phase II in mild-moderate cirrhosis.
Decreased clearance of fentanyl, midazolam, propofol smaller doses, longer durations.
Increased free fraction of highly protein-bound drugs (propofol, thiopental, warfarin).
Reduced first-pass increased oral bioavailability of high-HER drugs.
LOT benzos for cirrhosis
Phase II is relatively preserved in cirrhosis.
These are the benzos to use in chronic liver disease.
Avoid diazepam (Phase I via CYP3A4) and midazolam (Phase I, accumulates with hepatic dysfunction).
Same principle for opioids — fentanyl OK short-term; avoid meperidine (normeperidine accumulates).
Halothane hepatitis
Risk gradient: halothane > enflurane > isoflurane > desflurane > sevoflurane.
SEVOFLURANE does not produce TFA metabolites — safest volatile in patients with prior volatile hepatitis or family history.
Modern incidence very low (halothane essentially gone from US practice).
Presents 5-14 days post-anesthesia with fever, eosinophilia, marked transaminitis (often AST/ALT >1000), eventual fulminant hepatic failure in severe cases.
Diagnosis of exclusion; supportive treatment + N-acetylcysteine if presents like APAP toxicity.
Drug-induced liver injury (DILI) in the OR
4 g/day in healthy adult, >2-3 g/day in liver disease + chronic ETOH hepatotoxicity (saturates glutathione → NAPQI metabolite causes hepatic necrosis).Antidote: N-acetylcysteine (replenishes glutathione) — give within 8 hr of overdose for max effect.
Other DILIs relevant in anesthesia: amiodarone (chronic), rifampin, isoniazid, valproate, methotrexate, statins.
Pre-op LFT screening if chronic potentially-hepatotoxic medication + symptoms.
Document baseline.
Postop transaminitis after a normal pre-op suggests hypoperfusion (shock liver) vs drug effect vs viral.
Pre-op assessment in liver disease
MELD score (Cr, bili, INR) — better perioperative mortality predictor than Child-Pugh.
PORTAL HYPERTENSION work-up: TIPS, varices banding pre-op if elective.
Coagulopathy is rebalanced (both pro + anti coag low) — TEG/ROTEM more accurate than INR alone.
Stress dose steroids may be needed (chronic steroid use in autoimmune hepatitis).
Avoid NSAIDs (variceal bleed + AKI risk).
⚠ Common pitfalls
- Standard doses in cirrhosis — pseudocholinesterase decreased, protein binding altered, clearance reduced.
- Halothane in known liver disease — rare but recognized hepatitis risk; avoid.
- Aggressive APAP after MOR transplant — careful dose monitoring; alternative analgesia.
- Forgetting that ascites + edema alter Vd — loading doses unchanged, maintenance reduced.
💎 Clinical pearls
- High hepatic extraction drugs (propofol, fentanyl, lidocaine) — flow-limited; sensitive to hepatic blood flow.
- Low hepatic extraction (warfarin, diazepam) — capacity-limited; sensitive to enzyme function + protein binding.
- Cis-atracurium + rocuronium (sugammadex reversal) preferred NMBs in liver disease.
- Avoid hepatic-clearance opioids (morphine, meperidine); fentanyl + remifentanil better.
Recap
- High hepatic extraction drugs (propofol, fentanyl, lidocaine) — flow-limited; sensitive to hepatic blood flow.
- Low hepatic extraction (warfarin, diazepam) — capacity-limited; sensitive to enzyme function + protein binding.
- Cis-atracurium + rocuronium (sugammadex reversal) preferred NMBs in liver disease.
- Avoid hepatic-clearance opioids (morphine, meperidine); fentanyl + remifentanil better.
Mark each section done to complete the module.