liver is a primary site of drug metabolism . various steps in the drug biotransformation in the liver are entry of the drug in the liver , uptaken by the liver cells , phase i reaction , for example , hydrolysis , hydroxylation , oxidation , reduction , demethylation and phase ii reactions conjugation with glycine , glucuronide sulphate , hippurate , and others . these steps are dependent on two factors , hepatic blood flow and metabolic capacity of the liver . in patients with liver cirrhosis impaired drug handling is due to ( 1 ) liver cell necrosis , ( 2 ) shunting of the blood through porta systemic colaterals , ( 3 ) reduction in the concentration of drug - binding proteins , ( 4 ) abnormal drug volume distribution , ( 5 ) altered drug elimination , ( 6 ) altered drug metabolism , ( 7 ) altered pharmaco dynamics , ( 8) associated renal failure , and ( 9 ) drug - drug interaction . patients with well - compensated cirrhosis and near - normal synthetic function will have a lesser extent of impaired drug metabolism as compared to patients with decompensated cirrhosis with significant synthetic dysfunction and portal hypertension [ 1 , 2 ] . though various tests like liver function test , indocyanine green clearance , megaxx , child pugh score , and meld score are used for prediction of impaired liver function , still no tests can determine drug dosing in these patients . drugs with first pass metabolism require reduction in oral dosages , for high clearance drugs both loading and maintenance dosage need adjustment , for clearance drugs maintenance dose needs adjustment ( figure 1 ) . whenever possible , measuring drug level in the blood and monitoring of adverse events frequently should be done . no evidence - based guidelines exist for the use of medication in patients with liver cirrhosis [ 35 ] . drug - induced liver injury ( dili ) is the commonest cause of drug withdrawal from further development and from the market . nearly 100 drugs are known to cause fulminant hepatic failure , and 10% of all adverse drug reaction are hepatotoxicity [ 8 , 9 ] . approximately 1000 drugs and several herbal remedies have been shown to be causing dili . because of this drugs associated with liver toxicity are usually contraindicated in patients with chronic liver disease ; still most of the drugs can be used safely in patients with chronic liver disease according to the expert opinion [ 1013 ] .   according to the experts ' opinion most of the drugs can be used safely in patients with cirrhosis , but drug - induced hepatotoxicity may be poorly tolerated by patients with cirrhosis ; hence , potential hepatotoxins should be avoided in patients with liver cirrhosis . potentially hepatotoxic drugs may be used in patients with liver cirrhosis based on the clinical needs and when there are no alternatives available . caveat for the prescribing medications in patients with cirrhosis the drug dosing should be individualized depending on a number of factors like nutritional status , renal function , adherence , and drug - drug interaction . monitoring of the liver function at frequent intervals is highly recommended [ 14 , 15 ] . in spite of these recommendations , monitoring of drug - induced liver injury by alanine transaminase is inconvenient and not followed by both patients and physicians . we as clinicians should educate our patients about the warning signs of drug - induced liver injury like abdominal pain , nausea , and jaundice for stopping the drugs and seeking urgent medical attention . in this paper after extensive literature search and expert opinions , i will discuss rational use of various drugs in patients with cirrhosis . hepatic destruction of bacteria and reticular endothelial system - related phagocytosis are impaired in patients with cirrhosis . in cirrhotic patients serum bactericidal opsonic activity and neutrophil function are defective . this leads to 5 to 7 fold increase in bacteremia in these patients requiring antibiotics for therapeutic or prophylactic purpose . extensive literature search was done to identify the antibiotics that need dosage alteration in patients with liver cirrhosis . macrolide antibiotics like erythromycin , azithromycin , chloramphenicol , lincomycine , and clindamycin which are excreted and detoxified by liver should be used with cautions in these patients . metronidazole ketocanozole , miconazole , fluconazole , itraconazole , and nitrofurantoin pyrazinamide should be used with caution . beta - lactum antibiotics can cause leucopenia , while amino glycosides can increase susceptibility to renal failure . tuberculosis was more common in alcoholic and child class c cirrhosis ( table 1 ) . hepatotoxicity requires withdrawal , modification , and sequential reintroduction to achieve cure of tuberculosis . using such hepatotoxic drugs in presence of cirrhosis or advanced liver disease cirrhotic patients with tuberculosis have significantly lower completion of rifamipicin + isoniazid based att , higher hepatotoxicity , and higher mortality . recommended att in child class a cirrhosis is the same as a noncirrhotic population but strict followup is required . isoniazid or rifamipicin with ethambutol and quinolone can be used for 12 to 18 months . in child class c ethambutol , quinolone , and one second line agent may be used for 12 to 18 months [ 2 , 14 , 1719 ] . antifungal drugs like ketocanozole and miconazole though hepatotoxic can be used in patients with cirrhosis but monitor drug concentration in serum is recommended . there is no information of safe use of nitrofurntoin , chloramaphenicol , sodium fusidate and pyrazinamide but they are poentially toxic hence avoid their use in liver disease   ( tables 2 and 3 ) . endoscopic procedures are often necessary in patients with cirrhosis who may need sedation or short anesthesia . benzodiazepines like midazolam administered in single dose have minimal impact in patients with compensated cirrhosis . fentanyl ( opioid ) elimination is near normal in cirrhotics and can be used for sedation . patients with opioid toxicity can be treated with nalaxone ; propofol is preferred to benzodiazepines or opioids for endoscopic sedation for patients with decompensated cirrhosis due to its short half life and lower risk of inducing encephalopathy . in patients without extrahepatic high risk , the gastroenterologist directed propofol is safe . the adverse effects of propofol are hypotension , tachycardia , hypoventilation , and prolongation of qt interval [ 1 , 2022 ] . the new agents like isoflurane , desflurane are not significantly metabolized by the liver ; hence , are safe . pain management in cirrhosis is a challenging task as use of analgesic agents is associated with severe complications like gastrointestinal bleeding , hepatic encephalopathy , hepatorenal syndrome , and mortality . nonsteroid anti - inflammatory agents are contraindicated as they can induce gi bleed and renal failure . acetaminophen at a dose less than 2  gm / day is a reasonably safe option . patients with cirrhosis having visceral or musculoskeletal pain should be treated with acetaminophen less than 2 - 3  gms / day [ 24 , 25 ] . in case of inadequate pain relief , tramadol 25  mg every 8 hours can be used . for intractable pain hydromorphone orally or fentanyl topical patch can be used . neuropathic pain can be treated with nortriptyline , desipramine , and gabapentin , pregabalin with or without acetaminophen . analgesic choice in patients with cirrhosis should be individualized depending on etiology of cirrhosis , nutritional status , adherence , renal function , liver transplant candidacy , and drug - drug interaction [ 14 , 20 , 22 ] . the newer anticonvulsants like lamotrigine , topiramate also need lowering of the dosage in cirrhotic patients . antidepressant , ( selective serotonin reuptake inhibitors ) like fluvoxamine , paroxetine , and fluoxetine need dose modification in patients with cirrhosis . as antiulcer agents proton pump inhibitors are preferred over h2 receptor blockers but they still need half the dosage . patients of nonalcoholic steatosis - related cirrhosis have increased incidence of dyslipidemia , hypertension , and coronary artery disease . drugs like labatolol and methyldopa can cause severe hepatotoxicity and need frequent monitoring and should be used only when there are no other choices . captopril , amiodarone , and ticlopidine can cause hepatotoxicity and should be used with caution . the details of dose adjustments on alpha blockers , ace inhibitors , angiotensin ii receptor antagonist , and other drugs used in cardiovascular diseases have been reviewed in the recent past . drug - induced liver injury has been reported almost in 50% drugs in the physicians ' desk reference . the drugs that have been mentioned to be contraindicated in the patients with liver disease are methotrexate , niacin , naltrexone , metformin , novastatin , felbamate , ticklopidine , clonazipam , gemfibrizil , valproic acid , and estrogens in the physicians ' desk reference , but some of them are used in clinical practice under strict supervision . other antidiabetics like second - generation sulfonylurea like glipizide , glimepride may be the drug of choice in patients with liver cirrhosis . thiazolidinediones can cause drug hepatitis but can be used in reduced dosage with strict monitoring [ 14 , 15 ] . in conclusion prescribing medicines in patients with liver disease is a challenging task . surveillance using liver enzymes though recommended routinely the use of inh can lead to acute liver failure despite the surveillance . the enhanced nephrotoxicity of radio contrast agents aminoglycosides and nsaid may be a more frequent and dangerous challenge than hepatotoxicity .
patients with decompensated liver cirrhosis have various serious complications which require multiple drugs for therapeutic or prophylactic use . majority of the drugs are primarily metabolized and excreted by hepatobiliary system ; hence , liver cell necrosis contributes to impaired drug handling in liver failure while portosystemic shunt can alter drug action in cirrhosis . 
 hence , in order to decide drug dosing in liver failure , 3 important factors need to be considered ( 1 ) pharmacokinetic alterations of drugs , ( 2 ) pharmacodynamic alteration of drugs , and ( 3 ) increased susceptibility of   patients to adverse events particularly hepatotoxicity . 
 though there is no predictable test which can be used to determine drug dosage in patients with decompensated liver cirrhosis , drugs with first pass metabolism require reduction in oral dosages , for high clearance drugs both loading and maintenance dosages need adjustment , for low clearance drugs maintenance dose needs adjustment , whenever possible measuring drug level in the blood and monitoring of adverse events frequently should be done . 
 no evidence - based guidelines exist for the use of medication in patients ' with liver cirrhosis . 
 there are hardly any prospective studies on the safety of drugs in cirrhotic patients . 
 according to the experts opinion , most of the drugs can be used safely in patients with cirrhosis , but drug - induced hepatotoxicity may be poorly tolerated by patients with cirrhosis ; hence , potential hepatotoxins should be avoided in patients with liver cirrhosis . 
 potentially hepatotoxic drugs may be used in patients with liver cirrhosis based on the clinical needs and when there are no alternatives available . 
 caveat for the prescribing medications in patients with cirrhosis the drug dosing should be individualized depending on a number of factors like nutritional status , renal function , adherence , and drug interaction . 
 monitoring of the liver function at frequent intervals is highly recommended .