Altered Drug Handling in Liver Disease
"Hepatic dysfunction changes both what dose is needed and how long a drug lasts. A large volume of distribution and reduced protein binding may demand a normal or larger initial dose, while impaired metabolism and reduced hepatic blood flow prolong the effect. Titrate to effect, choose drugs with organ-independent clearance, and expect a slower recovery."
Synthesised from Stoelting's Pharmacology & Physiology in Anesthetic Practice & Miller's Anesthesia.Three pharmacokinetic changes
π What changes and why
- β Large volume of distribution (ascites, β total body water) β the initial dose may need to be larger β but because of hepatocellular dysfunction & reduced metabolism the effect is prolonged.
- β‘ β Albumin β β free (unbound) drug fraction β a smaller dose gives the same clinical effect for highly protein-bound drugs (e.g. thiopentone) β reduce and titrate.
- β’ β Rate of metabolism & β hepatic blood flow β prolonged duration of action.
- Overarching goal in theatre: maintain hepatic blood flow & oxygenation β maintain cardiac output (which maintains hepatic & renal flow), avoid hypotension, hypocapnia and high airway pressures.
Hepatic metabolism & the extraction ratio
| High extraction ratio (>0.7) | Low extraction ratio (<0.4) | |
|---|---|---|
| Rate-limiting step | Flow-limited β clearance depends on hepatic blood flow | Capacity-limited β clearance depends on enzyme capacity & protein binding |
| Vulnerable to | β Hepatic blood flow (hypotension, low CO, volatiles) | Enzyme dysfunction / induction / hypoalbuminaemia |
| Examples | Propofol, lignocaine, morphine, pethidine, fentanyl | Thiopentone, diazepam, phenytoin, warfarin, rifampicin |
Phase I reactions (oxidation, reduction, hydrolysis β CYP450) are affected earlier than Phase II (conjugation, glucuronidation, sulfation, acetylation, methylation), which is relatively preserved β hence drugs cleared by conjugation (e.g. lorazepam, oxazepam) are "safer" than those needing oxidation.
Agent-by-agent
| Drug class | Behaviour in liver disease | Preferred? |
|---|---|---|
| Induction β thiopentone | β Albumin β β free drug β reduce the dose; effect prolonged | Use lower dose |
| Induction β propofol | Short-acting; both hepatic (~70%) & extrahepatic (~30%) metabolism β recovery well preserved; watch hypotension | β Reasonable |
| Induction β etomidate | Cardiostable; can be used safely in moderate cirrhosis (single dose) | β Haemodynamically kind |
| Opioid β morphine | β M-3-G + M-6-G (active) β prolonged action & sedation; accumulates in renal impairment | β οΈ Caution / avoid |
| Opioid β pethidine | β norpethidine (active, 8β12 h) β seizures; prolonged | β Avoid |
| Opioid β fentanyl | β inactive norfentanyl; no active metabolite | β Opioid of choice (bolus) |
| Opioid β remifentanil | Ester hydrolysis by plasma / tissue esterases β organ-independent; context-insensitive half-time unchanged | β β Ideal if available (infusion) |
| Relaxant β suxamethonium | Plasma cholinesterase is made in the liver, but effect only prolonged if activity <~50% | OK for RSI |
| Relaxant β atracurium / cisatracurium | Hofmann elimination (spontaneous, pH/temp-dependent) β organ-independent; laudanosine metabolite (seizures at high dose) | β β Relaxant of choice |
| Relaxant β vecuronium / rocuronium / pancuronium | Hepatic/biliary elimination β prolonged block (roc/vec 60β80% protein bound; roc partly renal) | β οΈ Prolonged β monitor TOF; sugammadex available for roc/vec |
| Benzodiazepines | Midazolam β active Ξ±-hydroxymidazolam; diazepam β nordiazepam (tΒ½ ~60 h). Lorazepam/oxazepam/temazepam β no active metabolites | Avoid in/near HE; small midazolam dose acceptable |
| Volatiles | Isoflurane best preserves hepatic blood flow (TFA adducts ~0.2%). Sevoflurane preferred (minimal metabolism). Avoid halothane (20% metabolised β immune "halothane hepatitis") | β Sevoflurane / isoflurane |
β The two drugs to remember for the "organ-independent" answer
- Neuromuscular blocker of choice = atracurium / cisatracurium (Hofmann elimination β no reliance on liver or kidney).
- Opioid of choice = remifentanil (plasma esterase metabolism); fentanyl is the best bolus opioid. Premedication should be minimal β avoid sedatives in encephalopathy (a small dose of midazolam is acceptable in early/mild disease).