Clinical Pharmacology and Therapeutics. Группа авторов
pharmacokinetics:Increased bioavailability resulting from reduced first‐pass metabolism or, potentially, decreased first‐pass activation of pro‐drugsDecreased protein binding
2 Altered drug effect
3 Worsening of metabolic state
Altered pharmacokinetics
The liver is the largest organ in the body, has a substantial blood supply (around 1.5 L/min) and is interposed between the gastrointestinal tract and the systemic circulation. For these reasons it is uniquely suited for the purpose of influencing drug pharmacokinetics.
Decreased first‐pass metabolism
A decrease in hepatocellular function decreases the capacity of the liver to perform metabolic processes, while portosystemic shunting directs drugs away from sites of metabolism. Both factors are usually present in patients with severe cirrhosis.
Knowledge of the drugs that undergo first‐pass metabolism is important in situations where it is decreased as a result of disease. Considerably greater quantities of active drug then reach the site of action and any given dose of drug has unexpectedly intense effects.
Examples of changes in bioavailability found in some patients with severe cirrhosis are:
Clomethiazole (chlormethiazole) (100% increase)
Labetalol (91% increase)
Metoprolol (65% increase)
Nicardipine (500% increase)
Paracetamol (50% increase)
Propranolol (42% increase)
Verapamil (140% increase)
Conversely, first‐pass activation of pro‐drugs such as many ACE inhibitors (e.g. enalapril, perindopril, quinapril) may potentially be slowed or reduced.
Decreased elimination by liver metabolism and decreased protein binding
High extraction drugs
These are drugs which the liver metabolises at a very high rate. Their bioavailability is low and their clearance is dependent mainly upon the rate of drug delivery to the enzyme systems. The clearance of these drugs is therefore relatively sensitive to factors that can influence hepatic blood flow, such as congestive cardiac failure, and relatively insensitive to small changes in enzyme activity or protein binding. Examples include labetalol, lidocaine, metoprolol, morphine, propranolol, pethidine, nortriptyline and verapamil.
Low extraction drugs
In low extraction drugs, the rate of metabolism is so sufficiently low that hepatic clearance is relatively insensitive to changes in hepatic blood flow, and dependent mainly on the capacity of the liver enzymes. Examples include chloramphenicol, paracetamol and theophylline. The hepatic clearance of drugs in this group that are also highly protein‐bound, such as diazepam, tolbutamide, phenytoin and valproic acid, depends on both the capacity of the enzymes and the free fraction. It is thus difficult to predict the consequences of hepatic disease on total drug concentration. However, as with renal disease, care must be taken in the interpretation of concentrations of highly protein‐bound drugs such as phenytoin.
The influence of liver disease on drug elimination is complex; the type of liver disease is critical. In acute viral hepatitis, the major change is in hepatocellular function, but drug‐metabolising ability usually remains intact and hepatic blood flow can increase. Mild to moderate cirrhosis tends to result in decreased hepatic blood flow and portosystemic shunting, while severe cirrhosis usually shows reduction in both cellular function and blood flow. Cholestasis leads to impaired fat absorption with deficiencies of fat‐soluble vitamins and impairment of absorption of lipophilic drugs. Alcoholic liver disease is common and chronic ethanol abuse is associated with increased activity of the microsomal ethanol‐oxidising system. This effect is a result primarily of induction by ethanol of a specific cytochrome P450 (CYP2E1) responsible for enhanced oxidation of ethanol and other P450 substrates and, consequently, for metabolic tolerance to these substances. This may lead to enhanced clearance and, hence, decreased response to certain drugs such as benzodiazepine sedatives, anticonvulsants (phenytoin) and warfarin. By contrast, simultaneous alcohol ingestion may decrease clearance of drugs metabolised via the P450 (CYP2E1) enzyme system.
Comment. Unlike the measurement of creatinine clearance in renal disease, there is no simple test that can predict the extent to which drug metabolism is decreased in liver disease. A low serum albumin, raised bilirubin and prolonged prothrombin time give a rough guide.
The fact that a drug is metabolised by the liver does not necessarily mean that its pharmacokinetics is altered by liver disease. It is not easy, therefore, to extrapolate the findings from one drug to another. This is because superficially similar metabolic pathways are mediated by different forms of cytochrome P450.
The documentation of modestly altered pharmacokinetics does not necessarily imply clinical importance. Even normal subjects show quite wide variations in pharmacokinetic indices and therefore pharmacokinetics should not be viewed in isolation from alterations in drug effect, which are much more difficult to assess. However, if a drug is known to be subject to substantial pharmacokinetic changes, clinical significance is much more likely.
If it is clinically desirable to give a drug that is eliminated by liver metabolism to a patient with cirrhosis, it should be started at a low dose and the drug levels or effect monitored very closely.
Altered drug effect deranged brain function
The more severe forms of liver disease are accompanied by poorly understood derangements of brain function that ultimately result in the syndrome of hepatic encephalopathy. However, even before encephalopathy develops, the brain is extremely sensitive to the effects of centrally acting drugs and a state of coma can result from administering normal doses of opiates or benzodiazepines to such patients.
Decreased clotting factors
Patients with liver disease show increased sensitivity to oral anticoagulants. These drugs exert their effect by decreasing the vitamin K‐dependent synthesis of clotting factors II, VII, IX and X. When the production of these factors is already reduced by liver disease, a given dose of oral anticoagulant has a greater effect in these patients than in subjects with normal liver function.
Worsening of metabolic state
Drug‐induced alkalosis
Excessive use of diuretics can precipitate encephalopathy. The mechanism involves hypokalaemic alkalosis, which results in conversion of NH4 + to NH3, the un‐ionised ammonia crossing easily into the central nervous system to worsen or precipitate encephalopathy.
Fluid overload
Patients with advanced liver disease often have oedema and ascites secondary to hypoalbuminaemia and portal hypertension. This problem can be worsened by drugs that cause fluid retention, e.g. NSAIDs, and antacids that contain large amounts of sodium. NSAIDs should be avoided anyway, because of the increased risk of gastrointestinal bleeding.
Hepatotoxic drugs
Where an acceptable alternative exists, it is wise to avoid drugs that can cause liver damage (Table 1.7), e.g. sulphonamides or rifampicin, and repeated exposure to halothane anaesthesia.
Table 1.7 Drugs that can cause liver damage.