Prescribing in Cirrhosis

Cirrhosis is diffuse hepatic fibrosis with regenerative nodules, leading to reduced functional hepatocyte mass, portosystemic shunting and portal hypertension. It is compensated until ascites, variceal bleeding, encephalopathy or jaundice develop, after which median survival falls sharply and prescribing tolerance narrows.

Pharmacokinetic changes. - Reduced cytochrome P450 activity, with CYP2C19 and CYP1A2 affected early and glucuronidation preserved until late. - Portosystemic shunting raises oral bioavailability of high first-pass drugs such as propranolol, morphine, verapamil and labetalol. - Hypoalbuminaemia raises free fraction of phenytoin, valproate and warfarin. - Ascites expands volume of distribution for water-soluble drugs such as beta-lactams and aminoglycosides.

Pharmacodynamic changes. Increased cerebral sensitivity to opioids, benzodiazepines and sedating drugs; renal perfusion that depends on prostaglandins and the renin system; and reduced platelet count and function.

Prodrugs. Activation of codeine, tramadol, clopidogrel and some angiotensin converting enzyme inhibitors may fall, giving unpredictable effect.

Sodium load. Intravenous antibiotics, effervescent and soluble tablets, and sodium-containing antacids worsen ascites.

Compensated cirrhosis (Child-Pugh A). Most drugs can be used at usual or slightly reduced doses. Statins may continue. Metformin may continue if kidney function is adequate and alcohol use has stopped.

Decompensated cirrhosis (Child-Pugh B or C). - Avoid non-steroidal anti-inflammatory drugs, aminoglycosides, angiotensin converting enzyme inhibitors and angiotensin receptor blockers in ascites, and alpha blockers. - Avoid routine benzodiazepines, sedating antihistamines and tramadol. - Use proton pump inhibitors only with a clear indication and stop when it ends, because they are linked to spontaneous bacterial peritonitis and encephalopathy. - Use insulin in preference to most oral glucose-lowering drugs.

Statins. Continue in Child-Pugh A and selected Child-Pugh B patients at moderate dose. In Child-Pugh B, simvastatin should not exceed 20 mg daily because of muscle toxicity at 40 mg. Avoid in Child-Pugh C.

Preferred agents by need. - Pain: paracetamol 2 to 3 g daily; low-dose hydromorphone or fentanyl when an opioid is required. - Insomnia or agitation: melatonin, or low-dose quetiapine; avoid zolpidem in Child-Pugh C. - Infection: third-generation cephalosporins, piperacillin-tazobactam or carbapenems, choosing by local resistance. - Constipation: lactulose, which also reduces encephalopathy risk.

General approach by class.

Non-selective beta blockers for portal hypertension. Carvedilol 6.25 mg orally once daily, increased after 3 days to 6.25 mg twice daily; maximum 12.5 mg daily. Alternatively propranolol 20 to 40 mg orally twice daily, titrated every 2 to 3 days to resting heart rate 55 to 60 bpm; maximum 160 mg daily without ascites and 80 mg daily with ascites.

Diuretics for ascites. Spironolactone 100 mg orally once daily, with furosemide 40 mg once daily added for recurrent or tense ascites. Increase every 3 to 5 days, keeping the 100 to 40 ratio, to a maximum of spironolactone 400 mg and furosemide 160 mg daily.

Weight loss targets on diuretics. Maximum 0.5 kg daily without peripheral oedema and 1 kg daily with peripheral oedema.

Special groups. - Kidney impairment: cirrhosis with creatinine rise needs dose adjustment by estimated clearance, interpreted conservatively given sarcopenia. - Pregnancy: rare in advanced cirrhosis; carvedilol and propranolol may continue with foetal growth monitoring; spironolactone is avoided because of antiandrogenic foetal effects. - Older adults: frailty and sarcopenia magnify sedative and renal effects.

Monitoring. Creatinine, sodium and potassium within 1 week of any diuretic, beta blocker or nephrotoxic change, then every 1 to 4 weeks during titration. Assess mental state at each review for early encephalopathy.

Beta blocker stop rules. Reduce or stop if systolic blood pressure falls under 90 mmHg, sodium falls under 130 mmol/L, or acute kidney injury develops. Reintroduce when the trigger resolves.

Diuretic stop rules. Stop diuretics for sodium under 125 mmol/L, acute kidney injury, worsening encephalopathy or disabling muscle cramps. Stop furosemide if potassium falls under 3 mmol/L and spironolactone if potassium exceeds 6 mmol/L.

Referral and escalation. Refer for transplant assessment when MELD reaches 15 or more, or after first decompensation. Escalate urgently for gastrointestinal bleeding, rising creatinine, fever with ascites, or new confusion.