Effects Of Pathological Conditions

Although most experimental studies using foreign compounds are carried out in healthy animals or healthy human volunteers, animals and humans with diseases may be exposed to foreign compounds. This is clearly often the case with drugs designed to treat specific diseases, or to be used in particular conditions. The influence of pathological conditions on the disposition and metabolism of such compounds is therefore a very important consideration. Furthermore, chronic exposure to foreign compounds may result in pathological damage which may influence the disposition of the compound on subsequent exposure.

The absorption of foreign compounds from the gastrointestinal tract may be altered in certain malabsorption syndromes, and may be increased after subcutaneous or intramuscular injection if vasodilation accompanies the particular disease. The disposition of foreign compounds, once absorbed, can be influenced by changes in plasma proteins, which are sometimes reduced in certain disease states. Consequently, for foreign compounds which are highly protein-bound, the plasma concentration of the free compound may be significantly increased in such circumstances. This may alter renal excretion, increasing it in some cases, but could also increase the toxicity of a drug with a narrow therapeutic ratio if the compound dissociated from the protein was responsible for the toxicity. Thus, thiopental anaesthesia is prolonged when plasma albumin is reduced by chronic liver disease, and more unbound diphenylhydantoin and sulphonamides result from changes in plasma proteins in chronic liver disease.

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Hepatic disease and damage clearly have the potential to be major factors in the metabolism of foreign compounds. Thus, in patients with liver necrosis due to paracetamol, the half-life of the latter was increased from 2 to 8 h and that of antipyrine from 12 to 24 h. Acute hepatic necrosis in animals caused by the administration of hepatotoxins resulted in the plasma half-lives of barbiturates, diphenylhydantoin and antipyrine being approximately doubled. However, there may be several factors operating such as displacement of a drug from plasma-protein binding sites by bilirubin. In liver damage, plasma-bilirubin levels may be high due to lack of conjugation with glucuronic acid. This may alter elimination of some drugs such as tolbutamide. The level of plasma albumin may often be reduced by liver disease as this is the site of synthesis of albumin, the hence binding to plasma albumin will tend to be reduced. However, the effects of liver disease can be somewhat unpredictable. For example, in patients with cirrhotic liver, the glucuronidation of chloramphenicol and the acetylation of isoniazid are both reduced and hence the half-lives are prolonged. However, chronic liver disease did not affect the hepatic clearance of lorazepam or oxazepam despite the fact that glucuronidation is the route of metabolism for these compounds. In general, the formation of glucuronic acid and sulphate conjugates tend to be impaired in liver diseases such as hepatitis, obstructive jaundice and cirrhosis. Hepatic damage may also affect the disposition of some drugs by altering hepatic blood flow. For example, Indocyanine Green is not metabolized and the clearance is related to hepatic blood flow. In cholestatic liver damage clearance is reduced to 70% of the control. Both antipyrine and aminopyrine are cleared by metabolism in the liver, yet only the clearance of antipyrine is affected by the cholestatic damage. Although it seems that hepatocellular disease will generally affect drug clearance, it is still difficult to extrapolate from the known effects on the disposition of a particular drug to the likely effects on another. It is clearly important to know the relevant factors in the disposition of a particular drug, and also the severity and type of pathological damage. Thus, liver cirrhosis will alter blood flow but will not necessarily affect enzyme levels. Mild to moderate hepatitis in humans was found to have no influence on hepatic cytochromes P-450 content, yet severe hepatitis and cirrhosis reduced the content by 50%. The liver synthesizes cholinesterases, and therefore drugs hydrolysed by these enzymes, such as aspirin, procaine and succinylcholine, show reduced metabolism. Thus, liver damage and disease may have a number of effects on the disposition of a compound which may be due to:

a alteration in enzyme levels or activities b alteration in blood flow c alteration in plasma albumin and hence binding.

Decreased ability to form glucuronides may also occur in Gilbert's disease and the Crigler-Najjer syndrome. In these genetic disorders, glucuronyl transferase is reduced and consequently bilirubin conjugation may be affected when drugs which are also conjugated with glucuronic acid are administered.

Renal disease is another important factor, particularly if renal excretion is the major route of elimination for the pharmacologically or toxicologically active compound. This may be particularly important with drugs showing a low therapeutic ratio, such as digoxin and the aminoglycoside antibiotics. As already mentioned, plasma protein binding may be affected in renal disease, such binding being reduced particularly with regard to organic acids. Increased toxicity of drugs undergoing significant metabolism, such as chloramphenicol, has been found in uraemic patients. The half-lives of a number of drugs are prolonged in renal failure, although this effect is variable and by no means the general rule, different drugs being differently affected.

Chronic renal disease may also affect metabolism, not necessarily because of impaired metabolism in the kidney, but because of an indirect effect of renal failure on liver metabolism. For example, in animals with renal failure it was observed that there was a decrease in hepatic cytochromes P-450 content, and consequently zoxazolamine paralysis time and ketamine narcosis time were prolonged. Cardiac failure may also affect metabolism by altering hepatic blood flow. However even after heart attack without hypotension or cardiac failure, metabolism may be affected. For example, the plasma clearance of lidocaine is reduced in this situation. Other diseases such as those which affect hormone levels: hyper- or hypo-thyroidism, lack of or excess growth hormone, and diabetes can alter the metabolism of foreign compounds.

Infectious diseases may also affect metabolism, partially by increasing levels of the endogenous compound interferon which will inhibit some metabolic pathways.

The disposition or localization, and in some cases metabolism, of foreign compounds may be dependent upon the characteristics of a particular tissue or organ which may in turn affect the toxicity. There are many examples of organotropy in toxicology, but the mechanisms underlying such organ-specific toxic effects are often unknown.

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