PharmacologyTier 1Medical Sciences concept

Drug metabolism adjustments in liver failure (LOT benzodiazepines)

Core concept

Liver disease affects drug handling by four separate routes, and they do not move together
- dec hepatocyte mass and enzyme activity -> dec intrinsic clearance
- Portosystemic shunting -> inc bioavailability of high-extraction drugs (first pass is bypassed)
- dec albumin -> inc free fraction of highly bound acidic drugs
- Ascites and oedema -> inc Vd of hydrophilic drugs; dec renal perfusion (hepatorenal physiology) -> dec renal clearance too
Phase I (CYP oxidation) is impaired before phase II (glucuronidation)
- CYP2C19 and CYP3A4 fall early; UGT conjugation is relatively preserved

The benzodiazepine example is the model
- Diazepam, midazolam, chlordiazepoxide, alprazolam, clonazepam - phase I oxidation, often to active metabolites -> markedly prolonged half-life, accumulation, precipitation of encephalopathy
- LOT - Lorazepam, Oxazepam, Temazepam - glucuronidation only, no active metabolites -> relatively spared
- The same LOT rule applies in the elderly
Drugs to avoid or reduce in cirrhosis

Drug	Problem
NSAIDs	AKI, variceal bleeding, ascites - avoid entirely
Aminoglycosides	Nephrotoxicity in an already vulnerable kidney
Opioids (especially oral morphine, oxycodone)	inc F from shunting + dec clearance -> encephalopathy; use small doses, avoid codeine
Metformin	Lactic acidosis risk in decompensated disease
Paracetamol	Safe, but cap at 2 g/day in cirrhosis; safer than NSAIDs
Statins	Safe and beneficial in compensated disease; avoid in decompensated
Sedatives generally	Precipitate hepatic encephalopathy
Warfarin	Baseline INR already raised - unreliable target

Child-Pugh (bilirubin, albumin, INR, ascites, encephalopathy) is the score used in drug labelling, but there is no formula equivalent to eGFR-based renal dosing
- Reason from the mechanism: high extraction -> reduce the oral dose; low extraction -> reduce the maintenance dose
Renal function is overestimated in cirrhosis - low muscle mass and low urea synthesis mean creatinine underestimates the true impairment
Acute liver failure differs from cirrhosis: no shunting, but profound loss of synthetic and metabolic function

Hepatic encephalopathy is usually precipitated, and drugs are a leading precipitant - sedatives, opioids, diuretic-induced electrolyte disturbance, GI bleeding, constipation, infection
In alcohol withdrawal with liver disease, use oxazepam or lorazepam - the LOT rule is directly examinable
Diuretics in ascites: spironolactone with frusemide in a 100:40 ratio, monitoring for AKI, hyponatraemia and encephalopathy
Beta-blockers for varices - non-selective (propranolol, carvedilol) reduce portal pressure; withdraw in refractory ascites or spontaneous bacterial peritonitis (the "window hypothesis")
Vaccinate (hepatitis A and B, influenza, pneumococcal), avoid alcohol, and screen 6-monthly for HCC
Always review the whole drug chart in decompensation - the drug is often the cause

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