Abstract
Unfortunately, there is no endogenous marker for hepatic clearance that can be used as a guide for drug dosing. In order to predict the kinetic behaviour of drugs in cirrhotic patients, agents can be grouped according to their extent of hepatic extraction. For drugs with a high hepatic extraction (low bioavailability in healthy subjects), bioavailability increases and hepatic clearance decreases in cirrhotic patients. If such drugs are administered orally to cirrhotic patients, their initial dose has to be reduced according to hepatic extraction. Furthermore, their maintenance dose has to be adapted irrespective of the route of administration, if possible, according to kinetic studies in cirrhotic patients. For drugs with a low hepatic extraction, bioavailability is not affected by liver disease, but hepatic clearance may be affected. For such drugs, only the maintenance dose has to be reduced, according to the estimated decrease in hepatic drug metabolism. For drugs with an intermediate hepatic extraction, initial oral doses should be chosen in the low range of normal in cirrhotic patients and maintenance doses should be reduced as for high extraction drugs. In cholestatic patients, the clearance of drugs with predominant biliary elimination may be impaired. Guidelines for dose reduction in cholestasis exist for many antineoplastic drugs, but are mostly lacking for other drugs with biliary elimination. Dose adaptation of such drugs in cholestatic patients is, therefore, difficult and has to be performed according to pharmacological effect and/or toxicity. Importantly, the dose of drugs with predominant renal elimination may also have to be adapted in patients with liver disease. Cirrhotic patients often have impaired renal function, despite a normal serum creatinine level. In cirrhotic patients, creatinine clearance should, therefore, be measured or estimated to gain a guideline for the dosing of drugs with predominant renal elimination. Since the creatinine clearance tends to overestimate glomerular filtration in cirrhotic patients, the dose of a given drug may still be too high after adaptation to creatinine clearance. Therefore, the clinical monitoring of pharmacological effects and toxicity of such drugs is important. Besides the mentioned kinetic changes, the dynamics of some drugs is also altered in cirrhotic patients. Examples include opiates, benzodiazepines, NSAIDs and diuretics. Such drugs may exhibit unusual adverse effects that clinicians should be aware of for their safe use. However, it is important to realise that the recommendations for dose adaptation remain general and cannot replace accurate clinical monitoring of patients with liver disease treated with critical drugs.
References
Pique JM. Portal hypertensive gastropathy. Baillieres Clin Gastroenterol 1997; 11: 257–70
Siringo S, Burroughs AK, Bolondi L, et al. Peptic ulcer and its course in cirrhosis: an endoscopic and clinical prospective study. J Hepatol 1995; 22: 633–41
Fraser AG, Pounder RE, Burroughs AK. Gastric secretion and peptic ulceration in cirrhosis. J Hepatol 1993; 19: 171–82
Parlesak A, Schafer C, Schutz T, et al. Increased intestinal permeability to macromolecules and endotoxemia in patients with chronic alcohol abuse in different stages of alcoholinduced liver disease. J Hepatol 2000; 32: 742–7
Keshavarzian A, Holmes EW, Patel M, et al. Leaky gut in alcoholic cirrhosis: a possible mechanism for alcohol-induced liver damage. Am J Gastroenterol 1999; 94: 200–7
Morgan DJ, McLean AJ. Clinical pharmacokinetic and pharmacodynamic considerations in patients with liver disease: an update. Clin Pharmacokinet 1995; 29: 370–91
Sawhney VK, Gregory PB, Swezey SE, et al. Furosemide disposition in cirrhotic patients. Gastroenterology 1981; 81: 1012–6
Vrhovac B, Sarapa N, Bakran I, et al. Pharmacokinetic changes in patients with oedema. Clin Pharmacokinet 1995; 28: 405–18
Knauf H, Mutschler E. Clinical pharmacokinetics and pharmacodynamics of torasemide. Clin Pharmacokinet 1998; 34: 1–24
Isobe H, Sakai H, Satoh M, et al. Delayed gastric emptying in patients with liver cirrhosis. Dig Dis Sci 1994; 39: 983–7
Ishizu H, Shiomi S, Kawamura E, et al. Gastric emptying in patients with chronic liver diseases. Ann Nucl Med 2002; 16: 177–82
Usami A, Mizukami Y, Onji M. Abnormal gastric motility in liver cirrhosis: roles of secretin. Dig Dis Sci 1998; 43: 2392–7
Frossard JL, Spahr L, Queneau PE, et al. Erythromycin intravenous bolus infusion in acute upper gastrointestinal bleeding: a randomized, controlled, double-blind trial. Gastroenterology 2002; 123: 17–23
Pimpo MT, Frieri G, Saltarelli P, et al. Effects of cisapride on abnormally prolonged endogastric alkalinity time and delayed gastric emptying in cirrhotic patients. Hepatogastroenterology 1996; 43: 1678–84
el Touny M, el Guinaidy MA, Abd el Barry M, et al. Pharmacokinetics of ceftazidime in patients with liver cirrhosis and ascites. J Antimicrob Chemother 1991; 28: 95–100
Shyu WC, Wilber RB, Pittman KA, et al. Pharmacokinetics of cefprozil in healthy subjects and patients with hepatic impairment. J Clin Pharmacol 1991; 31: 372–6
Lam YW, Banerji S, Hatfield C, et al. Principles of drug administration in renal insufficiency. Clin Pharmacokinet 1997; 32: 30–57
Pugh RN, Murray-Lyon IM, Dawson JL, et al. Transection of the oesophagus for bleeding oesophageal varices. Br J Surg 1973; 60: 646–9
Verbeeck RK, Horsmans Y. Effect of hepatic insufficiency on pharmacokinetics and drug dosing. Pharm World Sci 1998; 20: 183–92
Ohkubo H, Okuda K, Iida S, et al. Role of portal and splenic vein shunts and impaired hepatic extraction in the elevated serum bile acids in liver cirrhosis. Gastroenterology 1984; 86: 514–20
Soons PA, De Boer A, Cohen AF, et al. Assessment of hepatic blood flow in healthy subjects by continuous infusion of indocyanine green. Br J Clin Pharmacol 1991; 32: 697–704
Keiding S. Hepatic clearance and liver blood flow. J Hepatol 1987; 4: 393–8
Zeeh J, Lange H, Bosch J, et al. Steady-state extrarenal sorbitol clearance as a measure of hepatic plasma flow. Gastroenterology 1988; 95: 749–59
Oellerich M, Burdelski M, Lautz HU, et al. Lidocaine metabolite formation as a measure of liver function in patients with cirrhosis. Ther Drug Monit 1990; 12: 219–26
Horsmans Y, Desager JP, Daenens C, et al. D-propoxyphene and norpropoxyphene kinetics after the oral administration of D-propoxyphene: a new approach to liver function? J Hepatol 1994; 21: 283–91
Watkins PB, Hamilton TA, Annesley TM, et al. The erythromycin breath test as a predictor of cyclosporine blood levels. Clin Pharmacol Ther 1990; 48: 120–9
Fabre D, Bressolle F, Gomeni R, et al. Identification of patients with impaired hepatic drug metabolism using a limited sampling procedure for estimation of phenazone (antipyrine) pharmacokinetic parameters. Clin Pharmacokinet 1993; 24: 333–43
Pauwels S, Geubel AP, Dive C, et al. Breath 14CO2 after intravenous administration of [14C]aminopyrine in liver diseases. Dig Dis Sci 1982; 27: 49–56
Renner E, Wietholtz H, Huguenin P, et al. Caffeine: a model compound for measuring liver function. Hepatology 1984; 4: 38–46
Vyas K, Gala B, Sawant P, et al. Assessment of portal hemodynamics by ultrasound color Doppler and laser Doppler velocimetry in liver cirrhosis. Indian J Gastroenterol 2002; 21: 176–8
Miyajima H, Nomura M, Muguruma N, et al. Relationship among gastric motility, autonomic activity, and portal hemodynamics in patients with liver cirrhosis. J Gastroenterol Hepatol 2001; 16: 647–59
Pentikainen PJ, Neuvonen PJ, Jostell KG. Pharmacokinetics of chlormethiazole in healthy volunteers and patients with cirrhosis of the liver. Eur J Clin Pharmacol 1980; 17: 275–84
Bergstrand RH, Wang T, Roden DM, et al. Encainide disposition in patients with chronic cirrhosis. Clin Pharmacol Ther 1986; 40: 148–54
Janssen U, Walker S, Maier K, et al. Flumazenil disposition and elimination in cirrhosis. Clin Pharmacol Ther 1989; 46: 317–23
Homeida M, Jackson L, Roberts CJ. Decreased first-pass metabolism of labetalol in chronic liver disease. BMJ 1978; 2: 1048–50
Neal EA, Meffin PJ, Gregory PB, et al. Enhanced bioavailability and decreased clearance of analgesics in patients with cirrhosis. Gastroenterology 1979; 77: 96–102
Pentikainen PJ, Valisalmi L, Himberg JJ, et al. Pharmacokinetics of midazolam following intravenous and oral administration in patients with chronic liver disease and in healthy subjects. J Clin Pharmacol 1989; 29: 272–7
Hasselstrom J, Eriksson S, Persson A, et al. The metabolism and bioavailability of morphine in patients with severe liver cirrhosis. Br J Clin Pharmacol 1990; 29: 289–97
Kleinbloesem CH, van Harten J, Wilson JP, et al. Nifedipine: kinetics and hemodynamic effects in patients with liver cirrhosis after intravenous and oral administration. Clin Pharmacol Ther 1986; 40: 21–8
van Harten J, van Brummelen P, Wilson JH, et al. Nisoldipine: kinetics and effects on blood pressure and heart rate in patients with liver cirrhosis after intravenous and oral administration. Eur J Clin Pharmacol 1988; 34: 387–94
Rocher I, Decourt S, Leneveu A, et al. Hemodynamic and pharmacokinetic study of propranolol and atenolol in cirrhosis patients. Int J Clin Pharmacol Ther Toxicol 1985; 23: 406–10
Somogyi A, Albrecht M, Kliems G, et al. Pharmacokinetics, bioavailability and ECG response of verapamil in patients with liver cirrhosis. Br J Clin Pharmacol 1981; 12: 51–60
George J, Murray M, Byth K, et al. Differential alterations of cytochrome P450 proteins in livers from patients with severe chronic liver disease. Hepatology 1995; 21: 120–8
Iqbal S, Vickers C, Elias E. Drug metabolism in end-stage liver disease: in vitro activities of some phase I and phase II enzymes. J Hepatol 1990; 11: 37–42
Adedoyin A, Arns PA, Richards WO, et al. Selective effect of liver disease on the activities of specific metabolizing enzymes: investigation of cytochromes P450 2C19 and 2D6. Clin Pharmacol Ther 1998; 64: 8–17
Shull HJ, Wilkinson GR, Johnson R, et al. Normal disposition of oxazepam in acute viral hepatitis and cirrhosis. Ann Intern Med 1976; 84: 420–5
Ghabrial H, Desmond PV, Watson KJ, et al. The effects of age and chronic liver disease on the elimination of temazepam. Eur J Clin Pharmacol 1986; 30: 93–7
Klotz U, Avant GR, Hoyumpa A, et al. The effects of age and liver disease on the disposition and elimination of diazepam in adult man. J Clin Invest 1975; 55: 347–59
Andreasen PB, Hendel J, Greisen G, et al. Pharmacokinetics of diazepam in disordered liver function. Eur J Clin Pharmacol 1976; 10: 115–20
George J, Liddle C, Murray M, et al. Pre-translational regulation of cytochrome P450 genes is responsible for disease-specific changes of individual P450 enzymes among patients with cirrhosis. Biochem Pharmacol 1995; 49: 873–81
Kraul H, Truckenbrodt J, Huster A, et al. Comparison of in vitro and in vivo biotransformation in patients with liver disease of differing severity. Eur J Clin Pharmacol 1991; 41: 475–80
Kawata S, Imai Y, Inada M, et al. Selective reduction of hepatic cytochrome P450 content in patients with intrahepatic cholestasis: a mechanism for impairment of microsomal drug oxidation. Gastroenterology 1987; 92: 299–303
Yang LQ, Li SJ, Cao YF, et al. Different alterations of cytochrome P450 3A4 isoform and its gene expression in livers of patients with chronic liver diseases. World J Gastroenterol 2003; 9: 359–63
Furlan V, Demirdjian S, Bourdon O, et al. Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther 1999; 289: 1169–75
Taburet AM, Naveau S, Zorza G, et al. Pharmacokinetics of zidovudine in patients with liver cirrhosis. Clin Pharmacol Ther 1990; 47: 731–9
Macdonald JI, Wallace SM, Mahachai V, et al. Both phenolic and acyl glucuronidation pathways of diflunisal are impaired in liver cirrhosis. Eur J Clin Pharmacol 1992; 42: 471–4
Tegeder I, Lotsch J, Geisslinger G. Pharmacokinetics of opioids in liver disease. Clin Pharmacokinet 1999; 37: 17–40
Crotty B, Watson KJ, Desmond PV, et al. Hepatic extraction of morphine is impaired in cirrhosis. Eur J Clin Pharmacol 1989; 36: 501–6
Parker G, Bullingham R, Kamm B, et al. Pharmacokinetics of oral mycophenolate mofetil in volunteer subjects with varying degrees of hepatic oxidative impairment. J Clin Pharmacol 1996; 36: 332–44
Hildebrand M, Hellstern A, Humpel M, et al. Plasma levels and urinary excretion of lormetazepam in patients with liver cirrhosis and in healthy volunteers. Eur J Drug Metab Pharmacokinet 1990; 15: 19–26
Marcellin P, de Bony F, Garret C, et al. Influence of cirrhosis on lamotrigine pharmacokinetics. Br J Clin Pharmacol 2001; 51: 410–4
Sifton DW. Physicians’ Desk Reference. 56th ed. Montvale (NJ): Medical Economics Company, 2002: 3635
Taeschner W, Vozeh S. Pharmacokinetic drug data. In: Holford NHG, editor. Drug data handbook. 3rd ed. Auckland: Adis International, 1998: 1–48
Hardman JG, Limbird LE, Gilman AG. The pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill, 2001: 2148
Kupferschmidt HH, Ha HR, Ziegler WH, et al. Interaction between grapefruit juice and midazolam in humans. Clin Pharmacol Ther 1995; 58: 20–8
Chowbay B, Cumaraswamy S, Cheung YB, et al. Genetic polymorphisms in MDR1 and CYP3A4 genes in Asians and the influence of MDR1 haplotypes on cyclosporin disposition in heart transplant recipients. Pharmacogenetics 2003; 13: 89–95
Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with Pglycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A 2000; 97: 3473–8
Al-Kareemy EA, Sobh MA, Muhammad AM, et al. Renal dysfunction in liver cirrhosis: renal duplex Doppler US vs scintigraphy for early identification. Clin Radiol 1998; 53: 44–8
Rodriquez A, Martin A, Oterino JA, et al. Renal function in compensated hepatic cirrhosis: effects of an amino acid infusion and relationship with nitric acid. Dig Dis 1999; 17: 235–40
Woitas RP, Heller J, Stoffel-Wagner B, et al. Renal functional reserve and nitric oxide in patients with compensated liver cirrhosis. Hepatology 1997; 26: 858–64
Krähenbühl S, Reichen J. Carnitine metabolism in patients with chronic liver disease. Hepatology 1997; 25: 148–53
Orlando R, Mussap M, Plebani M, et al. Diagnostic value of plasma cystatin C as a glomerular filtration marker in decompensated liver cirrhosis. Clin Chem 2002; 48: 850–8
Takabatake T, Ohta H, Ishida Y, et al. Low serum creatinine levels in severe hepatic disease. Arch Intern Med 1988; 148: 1313–5
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 1976; 16: 31–41
Orlando R, Floreani M, Padrini R, et al. Evaluation of measured and calculated creatinine clearances as glomerular filtration markers in different stages of liver cirrhosis. Clin Nephrol 1999; 51: 341–7
Papadakis MA, Arieff AI. Unpredictability of clinical evaluation of renal function in cirrhosis: prospective study. Am J Med 1987; 82: 945–52
Caregaro L, Menon F, Angeli P, et al. Limitations of serum creatinine level and creatinine clearance as filtration markers in cirrhosis. Arch Intern Med 1994; 154: 201–5
DeSanto NG, Anastasio P, Loguercio C, et al. Creatinine clearance: an inadequate marker of renal filtration in patients with early posthepatitic cirrhosis (Child A) without fluid retention and muscle wasting. Nephron 1995; 70: 421–4
Roy L, Legault L, Pomier-Layrargues G. Glomerular filtration rate measurement in cirrhotic patients with renal failure. Clin Nephrol 1998; 50: 342–6
Sansoe G, Ferrari A, Castellana CN, et al. Cimetidine administration and tubular creatinine secretion in patients with compensated cirrhosis. Clin Sci (Lond) 2002; 102: 91–8
Demotes-Mainard F, Vincon G, Amouretti M, et al. Pharmacokinetics and protein binding of cefpiramide in patients with alcoholic cirrhosis. Clin Pharmacol Ther 1991; 49: 263–9
Gross V, Treher E, Haag K, et al. Angiotensin-converting enzyme (ACE)-inhibition in cirrhosis: pharmacokinetics and dynamics of the ACE-inhibitor cilazapril (Ro 31-2848). J Hepatol 1993; 17: 40–7
Ruhnke M, Yeates RA, Pfaff G, et al. Single-dose pharmacokinetics of fluconazole in patients with liver cirrhosis. J Antimicrob Chemother 1995; 35: 641–7
Diez J, Simon MA, Anton F, et al. Tubular sodium handling in cirrhotic patients with ascites as analysed by the renal lithium clearance method. Eur J Clin Invest 1990; 20: 266–71
Angeli P, Gatta A, Caregaro L, et al. Tubular site of renal sodium retention in ascitic liver cirrhosis evaluated by lithium clearance. Eur J Clin Invest 1990; 20: 111–7
Orlando R, Sawadogo A, Miglioli PA, et al. Oral disposition kinetics of ofloxacin in patients with compensated liver cirrhosis. Chemotherapy 1992; 38: 1–6
Silvain C, Bouquet S, Breux JP, et al. Oral pharmacokinetics and ascitic fluid penetration of ofloxacin in cirrhosis. Eur J Clin Pharmacol 1989; 37: 261–5
Touchette MA, Slaughter RL. The effect of renal failure on hepatic drug clearance. DICP 1991; 25: 1214–24
Leblond F, Guevin C, Demers C, et al. Downregulation of hepatic cytochrome P450 in chronic renal failure. J Am Soc Nephrol 2001; 12: 326–32
Bateman DN, Gokal R, Dodd TR, et al. The pharmacokinetics of single doses of metoclopramide in renal failure. Eur J Clin Pharmacol 1981; 19: 437–41
Van den Berg HW, Desai ZR, Wilson R, et al. The pharmacokinetics of vincristine in man: reduced drug clearance associated with raised serum alkaline phosphatase and dose-limited elimination. Cancer Chemother Pharmacol 1982; 8: 215–9
Leveque D, Jehl F. Clinical pharmacokinetics of vinorelbine. Clin Pharmacokinet 1996; 31: 184–97
Johnson PJ, Dobbs N, Kalayci C, et al. Clinical efficacy and toxicity of standard dose adriamycin in hyperbilirubinaemic patients with hepatocellular carcinoma: relation to liver tests and pharmacokinetic parameters. Br J Cancer 1992; 65: 751–5
Twelves CJ, Richards MA, Smith P, et al. Epirubicin in breast cancer patients with liver metastases and abnormal liver biochemistry: initial weekly treatment followed by rescheduling and intensification. Ann Oncol 1991; 2: 663–6
Hande KR, Wolff SN, Greco FA, et al. Etoposide kinetics in patients with obstructive jaundice. J Clin Oncol 1990; 8: 1101–7
Koren G, Beatty K, Seto A, et al. The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother 1992; 26: 363–71
Zimmerman HJ. Hepatotoxicity. 2nd ed. Philadelphia: Lippincott Williams & Wilkins, 1999: 789
Whiting-O’Keefe QE, Fye KH, Sack KD. Methotrexate and histologic hepatic abnormalities: a meta-analysis. Am J Med 1991; 90: 711–6
Thummel KE, Slattery JT, Ro H, et al. Ethanol and production of the hepatotoxic metabolite of acetaminophen in healthy adults. Clin Pharmacol Ther 2000; 67: 591–9
Slattery JT, Nelson SD, Thummel KE. The complex interaction between ethanol and acetaminophen. Clin Pharmacol Ther 1996; 60: 241–6
Thompson NP, Caplin ME, Hamilton MI, et al. Anti-tuberculosis medication and the liver: dangers and recommendations in management. Eur Respir J 1995; 8: 1384–8
Gronhagen-Riska C, Hellstrom PE, Froseth B. Predisposing factors in hepatitis induced by isoniazid-rifampin treatment of tuberculosis. Am Rev Respir Dis 1978; 118: 461–6
Yue J, Peng RX, Yang J, et al. CYP2E1 mediated isoniazid-induced hepatotoxicity in rats. Acta Pharmacol Sin 2004; 25: 699–704
Fromenty B, Pessayre D. Impaired mitochondrial function in microvesicular steatosis: effects of drugs, ethanol, hormones and cytokines. J Hepatol 1997; 26Suppl. 2: 43–53
Fromenty B, Pessayre D. Inhibition of mitochondrial betaoxidation as a mechanism of hepatotoxicity. Pharmacol Ther 1995; 67: 101–54
Krahenbuhl S, Mang G, Kupferschmidt H, et al. Plasma and hepatic carnitine and coenzyme A pools in a patient with fatal, valproate induced hepatotoxicity. Gut 1995; 37: 140–3
Berson A, Gervais A, Cazals D, et al. Hepatitis after intravenous buprenorphine misuse in heroin addicts. J Hepatol 2001; 34: 346–50
Arai M, Yokosuka O, Fujiwara K, et al. Fulminant hepatic failure associated with benzbromarone treatment: a case report. J Gastroenterol Hepatol 2002; 17: 625–6
Krahenbuhl S, Brandner S, Kleinle S, et al. Mitochondrial diseases represent a risk factor for valproate-induced fulminant liver failure. Liver 2000; 20: 346–8
Kumashiro R, Kubota T, Koga Y, et al. Association of troglitazone-induced liver injury with mutation of the cytochrome P450 2C19 gene. Hepatol Res 2003; 26: 337–42
Watanabe I, Tomita A, Shimizu M, et al. A study to survey susceptible genetic factors responsible for troglitazone-associated hepatotoxicity in Japanese patients with type 2 diabetes mellitus. Clin Pharmacol Ther 2003; 73: 435–55
Hautekeete ML, Horsmans Y, Van Waeyenberge C, et al. HLA association of amoxicillin-clavulanate: induced hepatitis. Gastroenterology 1999; 117: 1181–6
Andrade RJ, Lucena MI, Alonso A, et al. HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease. Hepatology 2004; 39: 1603–12
Laidlaw J, Read AE, Sherlock S. Morphine tolerance in hepatic cirrhosis. Gastroenterology 1961; 40: 389–96
MacGilchrist AJ, Birnie GG, Cook A, et al. Pharmacokinetics and pharmacodynamics of intravenous midazolam in patients with severe alcoholic cirrhosis. Gut 1986; 27: 190–5
Ochs HR, Greenblatt DJ, Eckardt B, et al. Repeated diazepam dosing in cirrhotic patients: cumulation and sedation. Clin Pharmacol Ther 1983; 33: 471–6
Gines P, Arrovo V, Rodes J. Pharmacotherapy of ascites associated with cirrhosis. Drugs 1992; 43: 316–32
Patwardhan RV, Johnson RF, Hoyumpa Jr A, et al. Normal metabolism of morphine in cirrhosis. Gastroenterology 1981; 81: 1006–11
Mazoit JX, Sandouk P, Zetlaoui P, et al. Pharmacokinetics of unchanged morphine in normal and cirrhotic subjects. Anesth Analg 1987; 66: 293–8
Bansky G, Meier PJ, Riederer E, et al. Effects of the benzodiazepine receptor antagonist flumazenil in hepatic encephalopathy in humans. Gastroenterology 1989; 97: 744–50
McConnell JB, Curry SH, Davis M, et al. Clinical effects and metabolism of diazepam in patients with chronic liver disease. Clin Sci (Lond) 1982; 63: 75–80
Robin DW, Lee M, Hasan SS, et al. Triazolam in cirrhosis: pharmacokinetics and pharmacodynamics. Clin Pharmacol Ther 1993; 54: 630–7
Gerber T, Schomerus H. Hepatic encephalopathy in liver cirrhosis: pathogenesis, diagnosis and management. Drugs 2000; 60: 1353–70
Schwartz S, Brater DC, Pound D, et al. Bioavailability, pharmacokinetics, and pharmacodynamics of torsemide in patients with cirrhosis. Clin Pharmacol Ther 1993; 54: 90–7
Gentilini P, La Villa G, Marra F, et al. Pharmacokinetics and pharmacodynamics of torasemide and furosemide in patients with diuretic resistant ascites. J Hepatol 1996; 25: 481–90
Marcantonio LA, Auld WH, Murdoch WR, et al. The pharmacokinetics and pharmacodynamics of the diuretic bumetanide in hepatic and renal disease. Br J Clin Pharmacol 1983; 15: 245–52
Keller E, Hoppe-Seyler G, Mumm R, et al. Influence of hepatic cirrhosis and end-stage renal disease on pharmacokinetics and pharmacodynamics of furosemide. Eur J Clin Pharmacol 1981; 20: 27–33
Villeneuve JP, Verbeeck RK, Wilkinson GR, et al. Furosemide kinetics and dynamics in patients with cirrhosis. Clin Pharmacol Ther 1986; 40: 14–20
Martin PY, Gines P, Schrier RW. Nitric oxide as a mediator of hemodynamic abnormalities and sodium and water retention in cirrhosis. N Engl J Med 1998; 339: 533–41
Bosch-Marce M, Claria J, Titos E, et al. Selective inhibition of cyclooxygenase 2 spares renal function and prostaglandin synthesis in cirrhotic rats with ascites. Gastroenterology 1999; 116: 1167–75
Rossat J, Maillard M, Nussberger J, et al. Renal effects of selective cyclooxygenase-2 inhibition in normotensive salt-depleted subjects. Clin Pharmacol Ther 1999; 66: 76–84
Acknowledgements
The work was supported by a grant from the Swiss National Science Foundation to S. Krähenbühl (3100-59812-03/1). The authors have no conflicts of interest that are directly relevant to the content of this review.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Delcò, F., Tchambaz, L., Schlienger, R. et al. Dose Adjustment in Patients with Liver Disease. Drug-Safety 28, 529–545 (2005). https://doi.org/10.2165/00002018-200528060-00005
Published:
Issue Date:
DOI: https://doi.org/10.2165/00002018-200528060-00005