CLINICAL PHARMACOLOGY 2003 (PART 34)

The liver is the most important organ in which drugs are structurally altered. Some of the resulting metabolites may be biologically inactive, some active and some toxic (see Chapter 7).The liver is exposed to drugs in higher concentrations than are most organs because most are administered orally and are absorbed from the gastrointestinal tract.Thus the whole dose must pass through the liver to reach the systemic circulation. Because of this the liver is a vulnerable target for injury from chemicals and drugs, and disordered hepatic function is an important cause of abnormal drug handling and response. ...
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CLINICAL PHARMACOLOGY 2003 (PART 34) 33Liver, biliary tract, pancreasSYNOPSIS Effects of liver diseaseThe liver is the most important organ in whichdrugs are structurally altered. Some of theresulting metabolites may be biologically PHARMACODYNAMIC CHANGES INinactive, some active and some toxic (see LIVER DISEASEChapter 7).The liver is exposed to drugs in Patients with severe liver disease characteristicallyhigher concentrations than are most organs show abnormal end-organ response to drugs. Forbecause most are administered orally and are example:absorbed from the gastrointestinal tract.Thusthe whole dose must pass through the liver to • CNS sensitivity to opioids, sedatives andreach the systemic circulation. Because of this antiepilepsy drugs is increased.the liver is a vulnerable target for injury from • The effect of oral anticoagulants is increasedchemicals and drugs, and disordered hepatic because synthesis of coagulation factors isfunction is an important cause of abnormal impaired.drug handling and response. • Fluid and electrolyte balance are altered. Sodium Drugs and the liver retention may be more readily induced by NSAIDs or corticosteroids; ascites and oedema• Pharmacodynamic and pharmacokinetic become more resistant to diuretics. changes• Prescribing in liver disease• Drug-induced liver injury• Aspects of therapy PHARMACOKINETIC CHANGES IN LIVER DISEASEBile salts and gallstonesPancreas and drugs The liver has a large metabolic reserve, and it is only when disease becomes decompensated that 65111 LIVER, BILIARY TRACT, PANCREASimportant changes in drug handling occur. Paren- PLASMA PROTEIN-BINDING OF DRUGchymal liver disease e.g. chronic viral or alcoholic Binding of drugs to albumin is reduced whenliver disease, has more impact on hepatic drug- plasma concentrations of the latter are low due tometabolising enzyme activity than primarily defective synthesis. Additionally, endogenous sub-cholestatic conditions, e.g. primary biliary cirrhosis, stances produced in liver disease may displace drugsalthough clearance of drugs eliminated mainly by from plasma protein binding sites. These changesbiliary excretion will be impaired in the latter. provide scope to enhance the biological activity of Hepatocellular injury (toxic, infectious) leads to drugs, but assume importance only for those thatdecreased activity of drug-metabolising enzymes, are extensively (> 90%) protein bound.which is reflected in diminished plasma clearanceof drugs that are metabolised. There is muchvariation between patients, and often overlap with OTHER CONSIDERATIONShealthy subjects. Patients with severe decompensated liver disease usually have associated renal impairment, with obvious consequences for drugs eliminated pre-HEPATIC BLOOD FLOW AND dominantly by the kidney. Where facilities exist,METABOLISM dosing should be guided by plasma concentrationComplex changes in blood flow occur with liver monitoring, e.g. of theophylline, lidocaine anddisease. Resistance to hepatic portal blood flow rises phenytoin.in cirrhosis, and portasystemic and intrahepatic These changes in drug response (in particular)shunts reduce drug delivery to hepatocytes. The and in disposition affect prescribing, as is nowpattern of change caused by disease relates to the discussed.manner in which the healthy liver treats a drug andthere are two general classes:• Drugs that are rapidly metabolised and highly extracted in a single pass through the liver. Prescribing for patients Clearance of such compounds is normally limited by hepatic blood flow but in severe liver with liver disease disease less drug is extracted from the blood as it If liver disease is stable and well compensated, passes through the liver due to poor liver cell prescribing of most drugs is safe. Particular care function, and portasystemic shunts allow a should attend evidence of: proportion of blood to bypass the liver altogether. Therefore the predominant change in • Impaired hepatic synthetic function the kinetics of drugs that are given orally is (hypoalbuminaemia, impaired blood increased systemic availability. Accordingly the coagulation) initial and maintenance doses of such drugs • Current or recent hep ...