druginducedliverdisorder-190326032807.pptx

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1. DRUG INDUCED LIVER INJURY (DILI) OR HEPATOTOXICITY By: Dr. Ankit Gaur M.Sc , Pharm.D , RPh

2. LIVER physiologic function 2

3. Hepatotoxicity Hepatotoxicity  refers to liver damage. Certain medicinal agents, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure the organ.  Other chemical agents, such as those used in laboratories and industries, natural chemicals e.g., m icrocystins and herbal remedies can also induce hepatotoxicity . Chemicals that cause liver injury are called hepatotoxin.

4. DRUG-INDUCED LIVER INJURY / DISEASE (DILI)

5. Classification Intrinsic Hepatotoxicity Idiosyncratic Hepatotoxicity Allergic Non-Allergic 5

6. Intrinsic hepatotoxicity is regarded as dose-dependent and predictable above an approximate threshold dose. Whereas idiosyncratic hepatotoxicity occurs without obvious dose-dependency and in an unpredictable fashion. Allergic idiosyncratic hepatotoxicity is characterized by the presence of typical symptoms and signs of adaptive immune reactions, including fever, skin reactions, eosinophilia , formation of autoantibodies , and a short latency time particularly after re-exposure. 6

7. Risk factors of liver injury Pharmacokinetics – Metabolism Specific immune system Initial liver injury Progression of liver injury Cytokine, TNF, ROS Acute liver failure Chronic liver failure Enviromental Risk Factor Genetic Risk Factor

8. 8 Forms of liver toxicity :- Zonal Necrosis - This is the most common type of drug induced liver cell necrosis where the injury is largely confined to a particular zone of the liver lobule. Hepatitis - Disease of the liver causing inflammation. Cholestasis - Cholestasis is a condition where bile cannot flow from the liver to the duodenum. Steatosis - Steatosis is a condition characterised by the build up of fat within the liver, sometimes triggering inflammation of the liver

9. 9 Granuloma - A granuloma is one of a number of forms of localized nodular inflammation found in tissues. Vascular lesions - They result from injury to the vascular endothelium. Neoplasm - Neoplasm or tumor, tissue composed of cells that grow in an abnormal way.

10. MECHANISM OF DRUG INDUCED LIVER INJURY: 10

11. 1.Initial Mechanisms of Toxicity: Direct Cell Stress, Direct Mitochondrial Impairment, and Specific Immune Reactions 2. Direct and Death Receptor-Mediated Pathways Leading to Mitochondrial Permeability Transition 3. Apoptosis and Necrosis 11

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13. 13 Signs and symptoms :- Yellowing of the skin and whites of the eyes (jaundice) Fatigue Loss of appetite Nausea and vomiting Weight loss Dark or tea-colored urine

14. Practical Guideline for Diagnosis & Early Management of DILI ALT > 8 x ULN at any one time or ALT > 5 x ULN for more than 2 wk or ALT > 3 x ULN, and total bilirubin > 2 x ULN or PT-INR > 1.5 x UNL Symptoms related to liver injury such as jaundice or Total bilirubin > 3 x ULN or PT-INR > 1.5 x ULN When a drug is initiated When liver dysfunction is recognized

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18. Drugs & its mechanisms to induce liver injury 18

19. IDIOSYNCRATIC DRUG REACTIONS

20. Drugs causing Liver damage Acetaminophen:- ( Paracetamol , also known by the brand name Tylenol and Panadol ) is usually well tolerated in prescribed dose but overdose is the most common cause of drug induced liver disease and acute liver failure worldwide. 20 Nonsteroidal anti-inflammatory drugs - Aspirin, phenylbutazone , ibuprofen, sulindac , phenylbutazone , piroxicam , diclofenac and indomethacin . 20

21. Glucocorticoids - Glucocorticoids are so named due to their effect on carbohydrate mechanism. they promote glycogen storage in liver. The classical effect of prolonged use both in adult and paediatric population is steatosis . Isoniazid - Isoniazide (INH) is one of the most commonly used drug for tuberculosis; it is associated with mild elevation of liver enzymes in up to 20% of patients and severe hepatotoxicity in 1-2% of patients

22. Natural products - Amanita mushroom, particularly the destroying angels, aflatoxins . Industrial toxin - Arsenic, Carbon tetraChloride , Vinyl Chloride. Herbal and alternative remedies - Ackee fruit, Camphor, Pyrrolizidine alkaloids, Horse chestnut leaf, Valerian, Comfrey (often used in herbal tea). 22

23. 1- Carbon Tetra Chloride Carbon tetrachloride was widely used as a cleaning solvent, fire extinguisher agent, and anthelmintics. Because of its liver toxicity and known carcinogenicity in animals, its role has become limited; it is now used mainly as an intermediate in chemical manufacturing.

24. Mechanism Of Toxicity Carbon tetrachloride is a potent hepatic and renal toxin. The mechanism is thought to be a result of a toxic free-radical intermediate of metabolism. (CCl4) undergoes hepatic reductive metabolism to CCl3 and CCl3OO free radicals toxic intermediates which may initiate hepatocellular damage.. Chronic use of metabolic enzyme inducers such as phenobarbital and ethanol increase the toxicity of carbon tetrachloride. Carbon tetrachloride is a known animal and suspected human carcinogen.

25. Sign & Symptoms Nausea Vomiting Dizziness Depression of conscious level Cardiac Arrythmias Coma Hapatic necrosis Renal Damage

26. Management Remove the subject from exposure area. Maintain normobaric or hyperbaric oxygen. In case of ingestion administer activated charcoal. Ipecac induced vomiting may be useful for initial treatment. N-acetylcysteine may minimize hepatic and renal toxicity by providing a scavenger for the toxic intermediate.

27. 2- Acetaminophen Acetaminophen is a widely used drug found in many over the counter and prescription analgesics medication. In adults, toxicity may occur by ingestion of greater than 7.5-10g (24 regular strength or 15 extra strength caplets or tablets) over a period of 8 hours or less.

28. Mechanism Of Toxicity Acetaminophen is metabolized in the liver by conjugation to non-toxic glutathione. The conjugated product is eliminated in the urine. But in an acute overdose, the liver's normal glutathione reserves are depleted; the excess acetaminophen is then metabolized to highly toxic metabolite: N-acetyl-p-benzoquinone (NABQI). NABQI is very reactive causing hepatocellular death and subsequent massive liver cell necrosis.

29. Mechanism of Acetaminophen-induced Hepatotoxicty At usual therapeutic dosages, acetaminophen is metabolized  conjugation reactions. The capacity becomes saturated at higher dosages  diversion of the drug to the P-450-mediated pathway  generates reactive electrophile N-acetyl-p-benzoquinone imine (NAPQI)  undergoes phase 2 conjugation with glutathione  glutathione depletion  allowing the electrophile to exert damaging effects within the cell via covalent binding.

30. Sign & Symptoms Anorexia Nausea Vomiting Altered mental status Increased Transaminase level Heaptic failure Renal failure

31. Management Ipecac Syrup Activated Charcoal N-Acetyl Cysteine (loading dose is 150mg/kg in 200ml of 5% dextrose infused over 15-60 minutes). Methionine can also be given.

32. 3- Ethanol Commercial beer, wine, and liquors contain various amounts of ethanol. Ethanol is also found in a variety of perfumes, mouthwashes, many food flavorings (eg, vanilla, almond, and lemon extracts), pharmaceutical preparations (eg, elixirs), and many other products. Ethanol is frequently ingested recreationally and is the most common co-ingestant with other drugs in suicide attempts. Ethanol may also serve as an antidote in the emergency treatment of methanol and ethylene glycol poisonings.

33. Mechanism Of Toxicity Ethanol is also oxidized in liver by an ethanol-inducible cytochrome P-450 enzyme that converted the contents to toxic radicals. Induction also results in energy wastage and increased production of acetaldehyde that results in injury to cells and mitochondria with a striking impairment of oxygen utilization. Acetaldehyde also causes glutathione depletion and lipid peroxidation, and stimulates hepatic collagen synthesis, thereby promoting fibrosis and cell damage.

34. Sign & Symptoms Euphoria Impairment of balance & muscle coordination Nausea Vomiting Hypoglycemia Ketoacidosis Respiratory Depression Pale, bluish, cold and clammy skin due to insufficient oxygen Coma

35. Management Protect the airway and provide supportive treatment. Don’t induce vomiting or activated charcoal Give glucose & thiamine to treat alcoholic ketoacidosis Correct hypothermia with gradual rewarming No specific antidote available Perform hemodylasis for efficient ethanol removal.

36. 4- Aflatoxins The aflatoxins are a group of structurally related toxic compounds produced by certain strains of the fungi Aspergillus flavus  and  A. parasiticus. Aflatoxicosis is poisoning that results from ingestion of aflatoxins in contaminated food. Among 18 different types of aflatoxins identified, major members are aflatoxin B1, B2, G1 and G2. Aflatoxin B1 is the most toxic and most prevalent among this family.

37. Mechanism Of Toxicity The major target for the toxicity of aflatoxins is the liver. Oxidation by cytochrome P450, aflatoxins then bind to DNA or proteins and impair their functions. Aflatoxins produce necrosis of liver cells, damage to mitochondria, and proliferation of bile ducts. Aflatoxin also suppress the immune system of the body.

38. Sign & Symptoms Vomiting Abdominal Pain Mental Impairment Convulsion Hemorrhaging Disruption of food digestion & metabolism Liver damage Coma

39. Management The FDA’s goal for aflatoxins has been to minimize contamination by the cause. Provide supportive treatment. There is no specific antidote for toxicity of aflatoxins. Timely administration of methionine (200 mg/kg) and sodium thiosulfate (50 mg/kg), at eight hour intervals, is proven to be of therapeutic value.

40. Phenytoin -Induced Hepatotoxicity The interval between the initiation of phenytoin therapy and the onset of clinical abnormalities ranges from 1 to 6 weeks in the vast majority of patients. Presenting symptoms  fever, rash and lymph- adenopathy , Jaundice and hepato-splenomegaly . Biochemical features  abnormal serum bilirubin , transaminases , and ALP levels The morphologic and pathologic abnormalities are non- specific  primary hepatocellular degeneration and/or necrosis. 40