Principles of Hepatic Dose Adjustment

Hepatic dose adjustment is the modification of drug choice, dose and interval to match reduced hepatic clearance, altered protein binding and altered pharmacodynamic sensitivity in liver disease. Unlike renal adjustment, there is no single continuous marker of hepatic function, so adjustment relies on Child-Pugh class, the drug’s extraction ratio, its route of elimination and its therapeutic index.

Hepatic clearance. Clearance equals hepatic blood flow multiplied by extraction ratio. Extraction depends on intrinsic enzyme capacity and unbound fraction.

High extraction drugs (ratio over 0.7). Clearance depends mainly on hepatic blood flow. Examples are propranolol, labetalol, morphine, verapamil, lidocaine and glyceryl trinitrate. Shunting sharply raises oral bioavailability.

Low extraction drugs (ratio under 0.3). Clearance depends on enzyme capacity and protein binding. Examples are warfarin, phenytoin, diazepam, theophylline, carbamazepine and valproate. Bioavailability is unchanged but half-life lengthens.

Phase I versus phase II. Oxidation through cytochrome P450 declines early in cirrhosis. Glucuronidation is relatively preserved until late disease, which is why lorazepam, oxazepam and temazepam are safer than diazepam.

Biliary excretion. Cholestasis reduces clearance of drugs excreted in bile, such as ceftriaxone in high doses, rifampicin, fusidic acid and some statins.

Choose drugs that: - Are eliminated unchanged by the kidney, for example gabapentin, levetiracetam, most beta-lactams. - Have a wide therapeutic index. - Have no active metabolite that accumulates. - Do not depend on hepatic activation (avoid codeine and tramadol where an alternative exists). - Carry no known intrinsic hepatotoxicity.

Prodrug caution. Reduced activation of clopidogrel, codeine and enalapril makes response unpredictable. Prefer active parent drugs.

Protein binding. For phenytoin, total plasma concentration underestimates free drug when albumin is low. Use free phenytoin levels or correct total level for albumin.

Strategy by drug type.

Examples of label-based hepatic adjustments.

Loading versus maintenance. Loading doses depend on volume of distribution, which is usually normal or increased in liver disease. Maintenance doses depend on clearance, which is reduced. Give full loading doses for urgent therapy such as antibiotics and antiepileptics, then reduce maintenance.

Weight. Use dry weight in ascites for most weight-based dosing. Water-soluble antibiotics may need larger doses in tense ascites.

Special groups. - Kidney impairment: hepatorenal physiology often coexists; apply both adjustments. - Older adults: hepatic blood flow and liver volume fall with age. - Children: dosing advice in paediatric liver disease is limited; involve paediatric hepatology. - Pregnancy and breastfeeding: apply pregnancy-specific advice for each drug; liver disease adds no separate rule.

Monitoring. Monitor clinical effect and toxicity more than levels for most drugs. Use therapeutic drug monitoring where available, for example free phenytoin, tacrolimus, voriconazole trough 1 to 5.5 mg/L.

Signs of accumulation. New drowsiness, confusion, asterixis, hypotension, bradycardia or hypoglycaemia after starting or increasing a drug suggest accumulation.

Stopping. Stop or reduce at the first sign of encephalopathy, acute kidney injury or bleeding attributable to the drug.

Referral and escalation. Seek clinical pharmacology or hepatology input for narrow therapeutic index drugs in Child-Pugh C, for drugs with no hepatic data, and for transplant candidates.