SN7 SHORT NOTE 5M

Describe the drugs used in hepatic encephalopathy and the principles of prescribing in chronic liver disease.

Pharmacology · 2nd Professional — Para-Clinical

Drugs Used in Hepatic Encephalopathy

Hepatic encephalopathy is a reversible neuropsychiatric syndrome in liver failure or portosystemic shunting, in which nitrogenous substances — chiefly ammonia from gut bacteria — bypass the liver and reach the brain.

Drug	Mechanism	Comment
Lactulose	A non-absorbable disaccharide fermented by colonic bacteria to lactic and acetic acid. The acidic colon converts absorbable ammonia (NH3) to non-absorbable ammonium (NH4+) — ion trapping — and its osmotic laxative effect removes it. It also reduces ammonia-producing bacteria	First-line; the dose is titrated to 2 to 3 soft stools daily. Given by enema if the patient cannot swallow. Over-treatment causes dehydration and hypokalaemia, which themselves worsen encephalopathy
Rifaximin	A non-absorbed rifamycin that reduces ammonia-producing gut bacteria	Added to lactulose for prevention of recurrence; well tolerated but expensive
L-ornithine L-aspartate	Provides substrate for the urea cycle and glutamine synthesis	Adjunctive
Neomycin, metronidazole	Reduce gut flora	Largely superseded — neomycin is ototoxic and nephrotoxic even from the small amount absorbed
Branched-chain amino acids	Nutritional	Limited evidence

CLINICAL PEARL

Lactulose works by trapping ammonia in a form that cannot be absorbed. Ammonia crosses membranes freely; ammonium, being charged, does not. Acidifying the colon shifts the equilibrium toward ammonium, which is then flushed out by the same drug’s laxative action. It is the same ion-trapping principle used to alkalinise urine in salicylate poisoning — applied in the opposite direction, in a different organ.

Precipitants to Look for and Correct

Gastrointestinal bleeding — blood in the gut is a large protein load; treat the varices
Infection, especially spontaneous bacterial peritonitis — must be actively excluded by ascitic tap
Electrolyte disturbance — hypokalaemia and alkalosis from over-diuresis increase renal ammonia production and favour the diffusible form; a very common iatrogenic precipitant
Constipation, dehydration, and a high protein load
Sedatives — benzodiazepines and opioids, which are cleared poorly and are dangerous in liver failure
Renal impairment, and portosystemic shunts including tips

Other Drugs in Chronic Liver Disease

Problem	Treatment
Ascites	Salt restriction; spironolactone first (secondary hyperaldosteronism drives the retention), with frusemide added in about a 100:40 mg ratio; large-volume paracentesis with albumin cover for tense ascites
Variceal bleeding	Terlipressin or octreotide (splanchnic vasoconstriction), endoscopic band ligation, and prophylactic antibiotics which reduce mortality
Prevention of variceal bleeding	Non-selective beta-blockers (propranolol, carvedilol) reduce portal pressure — a selective agent would not work, since the benefit needs unopposed alpha-mediated splanchnic vasoconstriction
Spontaneous bacterial peritonitis	Cefotaxime with albumin (which reduces hepatorenal syndrome and death); then long-term norfloxacin prophylaxis
Hepatorenal syndrome	Terlipressin with albumin; definitive treatment is transplantation
Pruritus of cholestasis	Cholestyramine; rifampicin; naltrexone
Primary biliary cholangitis	Ursodeoxycholic acid
Wilson disease	Penicillamine, trientine, zinc

Prescribing in Liver Disease

Avoid sedatives, opioids and benzodiazepines wherever possible; if essential, use short-acting agents at reduced dose
Avoid NSAIDs — they cause salt retention, precipitate renal failure and increase variceal bleeding risk
Paracetamol is safer than NSAIDs even in liver disease, at a reduced dose of no more than 2 to 3 g a day — a point commonly got wrong in both directions
There is no reliable measure of hepatic drug clearance equivalent to creatinine clearance for the kidney, so prescribing relies on judgement, low doses and close observation; aminoglycosides in particular carry a high risk of renal failure in cirrhosis

Applied Aspects

Always search for a precipitant rather than simply increasing lactulose; treating the bleed, infection or hypokalaemia is usually what resolves the encephalopathy
Titrate lactulose to stool frequency, not to a fixed dose; too much causes dehydration and hypokalaemia that worsen the very condition being treated
Do not restrict protein — the old practice worsened malnutrition and outcomes; adequate protein, given as small frequent meals with a late-evening snack, is now recommended
Alcoholic and non-alcoholic fatty liver disease and hepatitis B and C are all common in India, and each has specific treatment — the direct-acting antivirals now cure hepatitis C, which alters the course of the underlying cirrhosis
Screen for varices and hepatocellular carcinoma in established cirrhosis; both are treatable when found early and untreatable when found late, and traditional and herbal remedies are a recognised cause of liver injury in India that must be asked about specifically, since patients do not regard them as medicines

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