Drug metabolism affected by diseases
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Thyroid disease and renal disease can influence drug metabolism in several ways. Thyroid dysfunction can cause changes in drug metabolism ranging from profound to moderate or negligible, depending on the drug. Renal impairment requires dosage reductions for drugs that are primarily cleared renally. Liver diseases like cirrhosis, jaundice, alcoholic liver disease, viral hepatitis, and hepatoma can also impact drug metabolism through various mechanisms such as decreasing drug clearance or inhibiting metabolic enzyme pathways. The effects are complex and unpredictable, varying with the type and severity of the disease.
Drug metabolism affected by diseases
- 1. Assignment on Effects of Diseases on Drug Metabolism. Sumitted by, Md. Azamu Shahiullah Prottoy ID - 11146018
- 2. Overall, there are a large number of factors that can influence drug metabolism, either by increasing clearance to cause drug failure, or by preventing clearance to lead to toxicity. In the real world, it is often impossible to delineate the different conflicting factors which result in net changes in drug clearance which cause a drug to fall out of, or climb above, the therapeutic window. It may only be possible clinically in many cases to try to change what appears to be the major cause to bring about a resolution of the situation to restore curative and non-toxic drug levels.
- 3. Non Hepatic Drug metabolism in thyroid disease Thyroid dysfunction can influence the physiological disposition of drugs. Depending on the pharmacokinetic properties of the individual drug, changes in the rate of metabolism ranging from profound to moderate or negligible have been observed. Since renal function is also influenced by thyroid disease, changes in renal elimination of drugs which are excreted in the urine mainly as unchanged drugs have to be considered as another reason for altered drugs disposition in thyroid disease. In patients with thyrotoxicosis lower, and in patients with myxoedema, higher, digitalis plasma levels have been observed. The altered disposition of cardiac glycosides in thyroid dysfunction can be attributed to changes in renal elimination and metabolism. These findings may be the kinetic correlate for the clinical observation that larger than the usual dose of digitalis is required in thyrotoxic patients and lower in hypothyroid patients. Antipyrene half-lives are very much shortened during hyperthyroidism and prolonged appreciably during hypothyroidism. The alterations in the disposition of these drugs seen during thyroid dysfunction can be ascribed to changes in its rate of metabolism which is controlled by the levels of circulating thyroid hormones. N-demethylation of aminopyrine is depressed both in hyper- and hypothyroid patients as compared with euthyroid subjects. Changes in the half-life of this drug were observed only during hypothyroidism. The physiological disposition of the antithyroid drug propylthiouracil is not changed during thyrotoxicosis. A decrease in plasma half-life of methimazole is however, observed during hyperthyroidism, whereas in hypothyroid patients half-life is increased. The few data available so far do not allow general prediction of how thyroid disease could alter drug metabolism in man. Thyroid hormone regulates the metabolism of drugs by the hepatic cytochrome p450 enzyme. Examples of drugs with a metabolism that decreases in hypothyroidism are antiseizure medications, digoxin and narcotics. In addition, the effect of warfarin therapy may change because of alteration of the turnover of serum clotting factors. Thus the dose requirements of these medications may change as a result of T4 treatment.
- 4. Obviously renal disease has a marked effect on drug clearance, and impairment in renal function is detected by the measurement of creatinine clearance, which gives an accurate estimate of the glomerular filtration rate (GFR). Effects of Renal diseases on Drug Metabolism If the drug has a narrow therapeutic index, creatinine clearance is poor and the major route of clearance of that drug is renal rather than hepatic, then drug dosage must be reduced. Many antibiotics (aminoglycosides, betalactams) as well as atenolol (mentioned earlier), methotrexate cimetidine and metformin are some of the agents primarily cleared renally. With drugs that undergo extensive hepatic clearance, the metabolites must be eliminated through the urine, although their accumulation is not usually such as problem as most drug Phase II metabolites are effectively prevented by their water solubility from exerting much therapeutic effect. Abnormal drug metabolism in chronic pancreatitis. Treatment with antioxidants. Functional and morphological changes in hepatocytes, indicating induction of the drug metabolizing enzymes and free radical-mediated damage, were found in 4 patients with idiopathic chronic pancreatitis. The possibility that reflux of abnormal bile (rich in lipid peroxidation and other products generated through hepatic metabolism of xenobiotics) into the pancreatic duct may initiate pancreatic damage was negated when bile duct ligation and bile diversion did not abolish attacks of pancreatitis in 3 cases, although the evidence of reflux was indisputable in 1 of them who also had a pancreatoduodenectomy. Pancreatic acinar cells from that patient showed extensive microvesiculation, as did hepatocytes from each case. These observations suggest that pancreatic and liver damage in chronic pancreatitis proceed independently but by the same mechanism-heightened, but unmitigated, oxidative detoxification of xenobiotics by cytochromes P450. Therefore, although bile reflux is not a prerequisite, it could compound injury in the head of the gland. Antioxidants were prescribed to the 3 cases mentioned and, from the outset, to a fourth patient who showed the same liver changes. This unconventional approach has held attacks at bay during a follow-up period of 5 yr.
- 5. Hepatic Diseases Effects of Liver Disease on Drug Metabolism Liver disease may have complex effects on drug clearance, biotransformation, and pharmacokinetics. Pathogenetic factors include alterations in intestinal absorption, plasma protein binding, hepatic extraction ratio, liver blood flow, portal-systemic shunting, biliary excretion, enterohepatic circulation, and renal clearance. Sometimes alterations increase levels of bioavailable drug, causing normal drug doses to have toxic effects. However, levels and effects for an individual drug are unpredictable and do not correlate well with the type of liver injury, its severity, or liver function test results. Thus, no general rules are available for modifying drug dosage in patients with liver disease. Clinical effects can vary independent of drug bioavailability, especially in chronic liver disease; eg, cerebral sensitivity to opioids and sedatives is often enhanced in patients with chronic liver disease. Thus, seemingly small doses of these drugs given to cirrhotic patients may precipitate encephalopathy. The mechanism of this effect probably involves alterations in cerebral drug receptors. Adverse drug reactions do not appear to be more likely in patients with advanced liver disease; however, such patients may tolerate any hepatic adverse effects of drugs less well. Although the liver is the main site of drug metabolism, conflicting results have been reported on drug elimination during liver diseases. Drug metabolism may depend on histological changes in the liver (acute or chronic hepatitis, cirrhosis) but may also depend on their origin (viral, toxic or immunological). Drug metabolism is also influenced by the severity of liver dysfunction. Cytochrome P450 isozymes and conjugation pathways may be differently affected by these conditions, and specific probe drugs have to be used in order to study the effect of diseases on each enzyme of drug metabolism. Probe-based assays must be validated during disease, since the pharmacokinetics of the parent drug and/or of its metabolites may be altered. Because of these limitations, therapeutic drug monitoring may be the most reliable way to adjust drug dosing at present.
- 6. A number of hepatic diseases have showed effects on drug metabolism. These are 1.Cirrhosis of the liver 2.Alcoholic liver disease 3.Cholestqtic jaundice 4.Liver carcinoma 5.Viral hepatitis 6.Hepatoma 7.Tumor growths in liver Cirrhosis Cirrhosis is characterized by *Increase in number of functional hepatocytes due to *Replacement of parts of liver by fibrous tissue. Examples of cirrhosis effects on drug metabolism 1. Oxidative metabolism of Chlordiazepoxide to primary metabolites Desmethyldiazepoxide is slowered. 2. Elimination half life of Lignocaine, Theophylline, Tolbutamide following N- Dealkynation is prolonged in cirrhosis patients. 3. Activation of prodrug is affected in cirrhotic patients. For instance, conversion of prodrug Prednisone to active drug Prednisolone is slowered in cirrhotic condition.
- 7. 4. Great diminish in degree of increase in drug metabolism is also affected by cirrhotic condition. Phenobarbiton pretreatment markedly increases in normal patients whereas the cirrhotic patients has little effects. There are some others drug metabolism process following Clucuronidation route is not affected. For instance, 1. Oxazepam 2. Lorazepam 3. Morphine 4. Paracetamol Jaundice THE EFFECT OF OBSTRUCTIVE JAUNDICE ON DRUG METABOLISM IN RABBITS (Authors - Edwin F. McLuen and James R. Fouts, Department of Pharmacology, College of Medicine, State University of Iowa, Iowa City, Iowa) Obstructive jaundice affects liver microsomal drug metabolism in rough proportion to the degree of histologically observable cell damage. Livers with mild cellular damage often retain essentially normal hexobarbital metabolism while other pathways are markedly reduced from normal levels. Severe cellular damage leads to nearly complete loss of all the drug enzyme activities studied. In vitro, sodium deoxycholate inhibits most drug enzyme activities at about the same final concentration—50% inhibition at approximately 1 x 10-2 M. The curves of enzyme inhibition and those of microsomal solubilization (Palade and Siekevitz, 1956) by deoxycholate can almost be superimposed on one another. This suggests that the two phenomena may be related. Deoxycholate effects on drug metabolism cannot be reversed by dialysis of the enzyme-bile acid
- 8. mixture against distilled water. This too would be consistent with an inhibition-by-destruction mechanism. The prolongation of sleeping times seen when jaundiced and normal rabbits are compared is compatible with the effects of deoxycholate on the drug enzyme systems in vitro. Alcoholic Liver Diseases It is the replacement of fibrous mass of liver following the death of parenchymal cells. The stages in the development of effect of ethanol on hepatic drug metabolism can be described as, Acute Ethanol Exposure = Chronic Ethanol Exposure (Induction Phase) = Alcoholic Cirrhosis (Inhibition Phase) Viral Hepatitis Viral hepatitis causes the decrease of hepatic drug metabolism. Example, Chlordiazepoxide clearence is decreased as is the clearence of Mepridine. Hepatoma It is actually cancerous growth of liver parenchymal cells. The presence of different parenchymal cells can decrease the hepatic drug metabolism by 20%.