Factors affecting drug metabolism

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1 Faculty of Pharmacy- Clinical Pharmacy Program - level 5 - Spring 2016 o Gastroenterology 6th Lecture: Drugs and the liver o Prof.Dr. Nader El-Malky Professor of internal medicine, Gastroenterology & Hepatology Faculty of medicine -Mansoura University Drugs and the liver o The body must process (chemically alter, or metabolize) drugs to be able to use and eliminate them. Most of this processing occurs in the liver, done by liver enzymes. Thus, drugs and the liver can affect each other in several ways: Liver disorders can change the way a drug is metabolized. Some drugs can damage the liver )Drug hepatotoxicity). Drug Metabolism: Many factors (such as foods eaten, a person's genetic makeup, and use of other drugs) can affect the way the liver metabolizes drugs Drugs can affect how quickly certain other drugs are metabolized in the liver. If a drug is metabolized more quickly, it may be broken down and eliminated before it can do what it is supposed to do. If a drug is metabolized more slowly, side effects are more likely Drug Metabolism Drug metabolism is the chemical alteration of a drug by the body. The liver is the major site of drug metabolism. Drugs are converted from fat-soluble to water-soluble substances that can be excreted in the urine or bile. This metabolism of drugs is mediated by a group of mixed-function enzymes, including cytochrome P450, located on the smooth endoplasmic reticulum of the liver cell. It takes place in two stages: Phase I metabolism involves oxidation, reduction or demethylation of the drug.

2 Phase II metabolism involves the conjugation of the derivatives produced in Phase I with glucuronide, sulphate and glutathione. These conjugates are excreted in the urine and bile as they cannot be reabosorbed by renal tubular or bile ductular cells. Factors affecting drug metabolism THE MICROSOMAL ENZYME SYSTEM The speed of metabolism of drugs is dependent on the microsomal enzyme system. Certain drugs, e.g. phenytoin, barbiturates and alcohol, can themselves increase the activity of these enzymes such as cytochrome P450, i.e. cause "enzyme induction", and are known as 'inducing agents'. Therapy with any of these drugs will produce increased metabolism of the drug and consequently a reduction in its effectiveness. Equally, if two drugs are metabolized by the same microsomal enzymes, metabolism of both drugs will be reduced, prolonging their actions ROUTE OF ADMINISTRATION. Many drugs are partially inactivated on passage through the liver (first-pass effect). If this is pronounced, drugs taken orally are inactive LIVER BLOOD FLOW. The rate of removal of the drug from the liver is influenced by the liver blood flow. Hepatic Clearance of Drugs Liver removal of drugs from blood is termed hepatic clearance Hepatic clearance is actually a very complex process due to many steps Can be simplified to three factors 1. Liver blood flow 2. Liver intrinsic clearance 3. Fraction of drug not bound to albumin COMPETITIVE INHIBITION. Some drugs compete with bilirubin at various stages: Uptake by the liver, e.g. rifampicin Conjugation, e.g. novobiocin

3 Excretion into the bile canaliculus, e.g. oral contraceptives Drug -Drug Interactions: Competitive inhibition of CYP o drug A increases toxicity of drug B Induction of CYP o o increased elimination of drug increased production of toxic metabolites Applicable to environmental and natural products as well as drugs Effects of Drugs on the Liver )Drug hepatotoxicity) Many drugs impair liver function and drugs, should always be considered as a cause when mildly abnormal liver tests are found. Damage to the liver by drugs is usually classified as being either predictable (or dose related) or non-predictable (not dose related). This classification should not be used rigidly, as there is considerable overlap and many mechanisms may be involved in the production of damage. predictable This form is dose related. has a high incidence. and occurs with a short latency (within a few days). The classical example of predictable drug toxicity is paracetamol. unpredictable (idiosyncratic):

4 occur with variable latency (1 week to 1 year or more), with low incidence, may or may not be dose related. Mechanisms of Drug hepatotoxicity 1) Biochemical pathways of Drug hepatotoxicity: Hepatocellular injury When a small amount of hepatotoxic drug whose effect is dose dependent, e.g. paracetamol, is ingested, a large proportion of it undergoes conjugation with glucuronide and sulphate, whilst the remainder is metabolized by microsomal enzymes to produce toxic derivatives that are immediately detoxified by conjugation with glutathione. If larger doses are ingested, the former pathway becomes saturated and the toxic derivative is produced at a faster rate. Once the hepatic glutathione is depleted large amounts of the toxic metabolite accumulate and produce damage. The 'predictability' of drugs to produce damage can, however, be affected by metabolic events preceding their ingestion. For example, chronic alcohol abusers may become more susceptible to liver damaged because of the enzyme-inducing effects of alcohol, or ill or starving patients may become susceptible because of the depletion of hepatic glutathione produced by starvation. Many other factors such as environmental or genetic effects may be involved in determining the 'susceptibility' of certain patients to certain drugs. 2)Immunological mechanisms of Drug hepatotoxicity These can be involved in the production of hepatic cell damage by certain drugs. The toxic metabolite produced by the microsomal enzymes may bind to the liver cell protein, thereby altering its antigenicity. The production of antibody against this will lead to immunologically medicated damage. An example of this mechanism is halothane-induced hepatic necrosis, which requires prior sensitization of the patients to halothane, although direct toxicity may also play a part.

5 Other pointers for the involvement of immunological mechanisms are the development of skin rashes, fever and arthralgia (serumsickness syndrome) following ingestion complexes and antibodies may occasionally be detected. 3)Cholestatic liver injury of Drug hepatotoxicity: An example of this mechanism is estrogen-induced liver injury Symptoms of Drug hepatotoxicity Symptoms vary from general symptoms (such as fatigue, a general feeling of being unwell, nausea, itching, and loss of appetite) to more severe symptoms (such as jaundice, an enlarged liver, pain in the upper right part of the abdomen, confusion, disorientation, and reduced alertness). Diagnosis of Drug hepatotoxicity The diagnosis of these conditions is usually by exclusion of other causes. Most reaction occurs within 3 months of starting the drug. Blood tests to check for hepatitis, autoimmune disorders, and other causes are done. Monitoring liver biochemistry in patients on long-term treatment, e.g. antituberculosis therapy, is advisable. If a drug is suspected of causing hepatic damage, it should be stopped immediately. Liver biopsy is of limited help in confirming the diagnosis but occasionally hepatic eosinophilia or granulomas may be seen. Treatment of Drug hepatotoxicity Usually, stopping the drug results in recovery. Drugs to relieve symptoms such as itching can be used. Supportive and symptomatic therapy If the damage is severe, people may be referred to a specialist. Liver transplantation may be required. Only a few drugs have antidotes. For example, acetylcysteine can be used if people have taken an overdose of acetaminophen. Use of glucocorticoids for immune-mediated reactions and ursodeoxycholic acid (UDCA) for cholestatic liver injury remain controversial therapies Paracetamol hepatotoxicity In high doses paracetamol produces liver cell necrosis. The toxic metabolite binds irreversibly to liver cell membranes. Only acetylcysteine can be used as antidote.

6 Halothane hepatotoxicity This commonly used anaesthetic agent rarely produces a hepatitis in patients having repeated exposures. The mechanism is thought to be a hypersensitivity reaction. An unexplained fever occurs approximately 10 days after the second or subsequent halothane anaesthetic and is followed by jaundice, typically with a hepatitic picture. Most patients recover spontaneously but there is a high mortality in severe cases. There are no chronic sequelae. Steroids hepatotoxicity Cholestasis is caused by natural and synthetic oestrognes as well as methyltestosterone. These agents interfere with canalicular biliary flow and cause a pure cholestasis. Cholestasis is rare with the contraceptive pill because of the low dosage used. However, the contraceptive pill is associated with an increased incidence of gallstones, hepatic adenomas (rarely HCCs), the Budd-Chiari syndrome and peliosis hepatic. The latter condition, which also occurs with anabolic steroids, consists of dilatation of the hepatic sinusoids to form blood-filled lakes. Phenothiazines hepatotoxicity Phenothiazines, e.g. chlorpromazine, can produce a cholestatic picture owing to a hypersensitivity reaction. It occurs in 1% of patients, usually within 4 weeks of starting the drug.

7 Typically it is associated with a fever and eosinophilia. Recovery occurs on stopping the drug. Antituberculous chemotherapy Isoniazid produces elevated aminotransferases in 10-20% of patients. Hepatic necrosis with jaundice occurs in a smaller percentage. The hepatotoxicity of isoniazid appears to be related to acetylator status, as the damage is due to the metabolites. Rifampicin produces hepatitis, usually within 3 weeks of starting the drug, particularly in patients of high doses. Pyrazinamide produces abnormal liver biochemical tests and, rarely, liver cell necrosis. Effects of Liver Disorders on Drugs Drug biotransformation and elimination is a liver function Drug elimination may be reduced in patients with significant liver dysfunction - thus blood levels may be higher for longer (toxicity vs effectiveness?) Low clearance drugs often relatively little effect until end stage liver failure/cirrhosis as drug metabolism is relatively well preserved Drug prescribing in patients with liver disease The metabolism of drugs is impaired in severe liver disease (with jaundice and ascites) as the removal of many drugs depends on liver blood flow and the integrity of the hepatocyte.

8 In general, therefore, the effect of drugs is prolonged by liver disease and also by cholestasis. This is further accentuated by protosystemic shunting, which diminishes the firstpass extraction of drugs. With hypoproteinaemia there is decreased protein binding of some drugs and bilirubin competes with many drugs for the binding sites on serum albumin. In patients with portosystemic encephalopathy, care must be taken in prescribing drugs with a central depressant action. Approach to Prevention of Drug-Induced Liver Disease Be aware of problem and check databases for known interactions Screen for initial mild liver damage before it becomes severe - AST/ALT most used Tailor drugs to patient s genetic/environmental/drug profile Reduce oral doses of high extraction drugs such as propranolol Monitor the biologic effect of the drug (heart rate) Monitor blood levels (if possible) Start with low dose and titrate up to biologic effect or blood level

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