decrease in binding correlates with the severity of renal impairment. The binding of basic drugs (to α1‐acid glycoprotein) undergoes little or no change2 The structure of albumin is changed in renal failure and endogenous compounds may compete with drugs for binding
3 Haemodialysis does not return binding to normal, but renal transplantation does.
In most cases, changes in protein binding have limited clinical relevance and do not require alterations in dose. However, protein binding is important for the interpretation of serum phenytoin concentrations.
Influence hepatic disease on pharmacokinetics and pharmacodynamics
Hepatic metabolism
The hepatic metabolism of some drugs (e.g. nicardipine, propranolol) may be decreased in patients with renal failure. The reasons for this are not clear, but may indicate the presence of a metabolic inhibitor in uraemic plasma because regular haemodialysis appears to normalise the clearance of these compounds.
Altered drug effect
There are several examples of increased drug sensitivity in patients with renal failure. Opiates, barbiturates, phenothiazines and benzodiazepines all show greater effects on the nervous system in patients with renal failure than in those with normal renal function. The reasons are not known, but increased meningeal permeability is one possible explanation.
Various antihypertensive drugs have a greater postural effect in renal failure. Again the reasons are not clear, but changes in fluid balance and autonomic dysfunction may be partly responsible.
Worsening of the existing clinical condition
Drug therapy can result in deterioration of the clinical condition in the following ways:
1 By further impairing renal function. In patients with renal failure, it is clearly advisable to avoid drugs that are known to be nephrotoxic and for which alternatives are available. Examples include aminoglycosides, amphotericin, cisplatin, gold, mesalazine, non‐steroidal anti‐inflammatories, penicillamine and vancomycin
2 By causing fluid retention. Fluid balance is a major problem in the more severe forms of renal failure. Drugs that cause fluid retention should therefore be avoided, e.g. carbenoxolone and non‐steroidal anti‐inflammatory drugs (NSAIDs) such as indometacin (indomethacin)
3 By increasing the degree of uraemia. Tetracyclines, except doxycycline, have an anti‐anabolic effect and should be avoided
Enhancement of adverse drug effects
In addition to decreased elimination, digoxin is more likely to cause adverse effects in patients with severe renal failure if there are substantial electrolyte abnormalities, particularly hypercalcaemia and/or hypokalaemia.
Because potassium elimination is impaired in renal failure, diuretics that also conserve potassium (amiloride, spironolactone) are more likely to cause hyperkalaemia.
Influence of liver disease
Impaired liver function can influence the response to treatment
1 Altered 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
