Drugs and the Liver

Drugs and the liver

The relationship between the liver and drugs is important for three reasons:

• The liver is the principal site for drug metab-olism. Consequently, while liver disease may impair hepatic drug-metabolizing activity, the drugs themselves may reduce or enhance these processes. This consideration applies primarily to lipophilic drugs, which are normally metabolized to hydrophilic compounds for urinary excretion.

•  Liver impairment has other physiological effects, which affect drug handling and disposition, for example:

– increased volume of distribution of hydrophilic drugs in ascites (Ascites is the accumulation of an abnormal volume of fluid in the peritoneal cavity.);

– reduced plasma binding of acidic drugs by low plasma protein levels;

– reduced biliary excretion (cholestasis) causes hyperbilirubinaemia and reduced excretion, e.g. of rifampicinand fusidic acid;

– morphine and overenthusiastic diuretic therapy may precipitate hepatic encephalopathy (It is characterized by changes in mood and behaviour,confusion, disordered sleep rhythm, drowsiness and, eventually, delirium and coma. There is a strong similarity to senile dementia, and it is important to distinguish between them as encephalopathy is potentially correctable.) in patients with cirrhosis

• Drugs may cause liver damage, e.g.paracetamol (acetaminophen) and antidepressants. The bioavailability of drugs may be influenced by patient factors that are unconnected with liver disease: only those connected with the liver will be discussed here.

Liver and drug metabolism:

A full discussion of this complex subject is out of place here, although some specific aspects are outlined below.

Biological (patient) factors influencing drug availability

Pharmacogenetic factors

Two points are relevant here:

•  Slow acetylators are more likely to experience toxic reactions with normal doses of drugs than fast acetylators.

•  Oxidative drug metabolism varies substan-tially (20-fold) between patients, so some patients fail to respond to doses of drugs that cause unacceptable side-effects in others.

Disease state

Although diseases that compromise the blood supply to the liver may be expected to impairdrug metabolism, the data are conflicting, and it is difficult to draw satisfactory conclusions. It isprobable that liver function needs to be consid-erably impaired before significant effects areseen.The effects of liver disease are complexbecause several factors change simultaneously,e.g. metabolism, protein binding, volume of distribution and elimination in the bile. Thegreatest effects are seen when metabolism, especially first-pass metabolism, is high and protein binding is low, because the free plasma concen-tration is then markedly increased. Conversely, the plasma levels of drugs that undergo little first-pass metabolism and are highly protein-bound will be little changed. These effects are listed in Table 1.

Age

The decline in hepatic function with age leads to reduced levels of serum albumin and decreased hepatic metabolism, and these combine with other age-related changes to influence the avail-ability of many drugs. Interacting factors and interindividual variation make it difficult to predict what the effect will be in a particular patient.

Drugs and liver enzyme activity

The metabolism of many drugs may be either increased or decreased by the effects of other drugs on microsomal mixed function oxidase, of which the cytochrome P450 family of enzymes provide the terminal stage.Table 2 lists the more important drugs that are known to induce or inhibit hepatic microsomal enzymes. Generally,enzyme inductionwill reduce the biological availability of drugs and their activity. However, this is clinically significant only with drugs having a narrow therapeutic window and when loss of activity severely compromises the patient, e.g.warfarin, with which loss of activity may result in thrombosis, stroke or death, and the oral contraceptive pill, as enhanced metabolism of oestrogen may cause an unwanted pregnancy.

There are some drugs whose toxicity may be enhanced by metabolism, because the metabolite causes the damage, e.g.paracetamol (acetaminophen) and isoniazid. Enzyme inhibitionincreases drug activity, if other factors do not change. Again, it is those drugs with a low therapeutic index that are important, e.g.  warfarin, which may provoke severe spontaneous haemorrhage. Phenytoinhas a non-linear dose–response curve, and small increases in plasma levels may give rise to acute toxic reactions, e.g. nausea, vomiting, dizziness, tremor, ataxia and blurred vision, if the steady-state level is near the top of the therapeutic range. With a hypnotic or sedative, enzyme induction only impairs the level of sedation, but enzyme inhibition might result in over-sedation, confusion and serious falls in the elderly. While inhibition occurs rapidly, enzyme induc-tion depends on new synthesis, so the effects take some time to become apparent. Some of the drugs most likely to be affected by changes in liver enzyme activity are also listed in Table 2.

In addition, some drugs inhibit a specific enzyme, leading to higher levels of another drug that is metabolized by the same enzyme, e.g. allopurinol inhibits xanthine oxidase and may cause unacceptable toxicity with azathioprine and mercaptopurine.

Hepatotoxicity

As in other situations, side-effects may be either toxic (type A, predictable) or idiosyncratic(typeB, unpredictable). Table 3. lists some drugs that may produce these effects in the liver, though such adverse reactions are uncommon.

The principal risk factors for hepatic drug injury are given in Table 4, together with the mechanisms involved. Among these effects, paracetamol poisoning is the principal cause of acute hepatic failure in the UK .

Halothane and its congeners are generally very safe general anaesthetics. However, a small pro-portion of patients experience an unexplained fever, with mild signs of liver involvement. Exposure after a patient has been sensitized to halothane or to desflurane, isoflurane and sevoflurane, should be avoided in such patients, as it may cause acute, often fatal, liver failure, usually in obese, elderly females. Reye’s syndrome follows febrile illness in young children, although fortunately only rarely. Affected patients develop signs of liver disease with severe encephalopathy, and there is severe fatty degeneration of the liver. Because there is a high probability that the syndrome can be triggered by aspirin, this is contra-indicated in children under 16 years of age. The mortality rate is about 50%, usually from cerebral oedema.

Reference:  Pathology and Therapeutics for Pharmacists (T H I R D  E D I T I O N)

“Russell J Greene & Norman D Harris”

Regards admin : Hope These helped you ….