Drugs The Liver

1. Drugs & The Liver Salem Mohammad Bazarah MD, M.Ed, FACP, FRCPC, FRCPC(GI) & PhD December 14, 2008

2. Principles (Secrets) Knowledge Interactive discussion Exam trics

8. Facts 2 to 5% of all cases of jaundice in hospitalized Ptse 40% of hepatitis cases over age of 50 25% of cases of fulminant hepatic failur

9. Clinical variation Subclinical Subfulminant Fulminant

10. Characterization Intrinsic: Metabolic mediated hepatocellular necrosis or interference with specific hepaocellular pathway e.g Acetaminophin Idiosyncratic: as an expresion of some unidentified reaction. Immunologically mediated. E.g Isonizide, Sulfonamides

11. Examples Acute Hepatitis: Minocine Budd Chiari Syndrome: OCP Cholestatic: Amitriptylin, Augmentin, Ampicillin, Captopril, Tamoxifen Fulminant Failure: Acetaminophin, Fluconazole, Halothane, Isonizide

12. Biotransformation To render agents more hydrophilic and facilitate their excretion Phase 1: Cyt P450 mediated, Oxidative and produce active itermediate metabolites that may cause liver injury Phase 2: Conjugative, convert active metabolites to non toxic more hydrophilic via linkage to glutathione, sulfate or glucuronide

13. P450 inducers and inibitors Inhibitors: cimetidine, Disulfiram, Erythromycin, Ketoconazole, Quinidine Inducers: Carbamazepine, Dexamethasone, Ethanol, OmeprazolePhenobarbital, Phenytoin, Rifampin

14. Diagnosis

15. Acetaminophin approved for OTC use since 1960 Although the drug is remarkably safe, toxicity can occur even with therapeutic doses. Alcoholics are particularly susceptible to hepatotoxicity Therapeutic dose of is 10-15 mg/kg/dose in children and 325-1000 mg/dose every 4-6 hours in adults, with a maximum of 4g/day

16. Biochemical Basis of Acetaminophen Toxicity At therapeutic doses, 90% of is metabolized in the liver to sulfate and glucuronide conjugates that are then excreted in the urine The remaining 10% is metabolized via the cytochrome CYP2E1 (P450 2E1) to a toxic, reactive, N-acetylimidoquinone (NAPQI) NAPQI binds covalently with hepatocyte macromolecules, producing hepatic cell lysis

17. Biochemical Basis of APAP Toxicity With normal doses, NAPQI is rapidly conjugated with hepatic glutathione, forming a nontoxic compound which is excreted in the urine. With toxic doses, however, the sulfate and glucuronide pathways become saturated, resulting in an increased fraction of acetaminophen being metabolized by CYP2E1. NAPQI begins to accumulate once glutathione stores are depleted by about 70%

18. Biochemical Basis of Acetaminophen Toxicity Liver damage due to excess NAPQI can occur in four circumstances Excessive intake of acetaminophen Excessive CYP2E1 activity due to induction by other drugs or chronic alcohol use Competition for conjugation enzymes Depletion of glutathione stores due to malnutrition or chronic alcohol ingestion

19. Factors influencing toxicity Chronic alcoholics are at increased risk of developing severe hepatic disease even at therapeutic doses Other drugs which induce CYP2E1 enzymes include Phenobarbital and antituberculosis drugs such as isoniazid and rifampin Drugs such as TMP-Sulfa and AZT potentiate acetaminophen hepatotoxicity by competing for glucuronidation pathways resulting in increased CYP2E1-dependent metabolism of acetaminophen

20. Factors influencing toxicity Malnutrition may predispose to toxicity by a reduction in glutathione stores There is a genetic predisposition to toxicity Impaired glucuronidation secondary to Gilbert's syndrome also appears to enhance toxicity

21. CLINICAL MANIFESTATIONS 2 to 12 hours after ingestion, nausea, vomiting, diaphoresis, pallor, lethargy and malaise are seen This is followed by temporary symptomatic improvement at 24 to 48 hours Signs of liver involvement begin at this time, including right upper quadrant pain and hepatomegaly, elevations in the plasma levels of hepatic enzymes, and prolongation of the prothrombin time Signs of severe hepatic damage become apparent 72 to 96 hours after ingestion

22. CLINICAL MANIFESTATIONS Systemic symptoms of the first stage reappear in conjunction with confusion, marked elevation in hepatic enzymes, hyperammonemia, and a bleeding diathesis Signs of severe hepatotoxicity include plasma AST levels that often 10,000 IU/L, prolongation of the PT, hypoglycemia, lactic acidosis, and a plasma bilirubin concentration above 4.0 mg/dL Acute renal failure may also be seen at this time, due primarily to ATN

23. CLINICAL MANIFESTATIONS Clinical recovery typically begins within 4 to 14 days, leading to resolution of symptoms and normalization of laboratory values over several weeks Histologic changes vary from cytolysis to centrilobular necrosis Centrilobular region is preferentially involved because it is the area of greatest concentration of CYP2E1 and therefore the site of maximal production of NAPQI Histologic recovery lags behind clinical recovery and may take up to three months

24. DIAGNOSIS In the patient with a history of APAP overdose, a serum APAP level should be measured between 4 and 24 hours after ingestion The value obtained should be evaluated according to the Rumack-Matthew nomogram for determining the risk of hepatotoxicity and the need for NAC therapy

26. DIAGNOSIS Characteristic laboratory findings of APAP hepatotoxicity include marked elevation in plasma hepatic enzyme levels (>5000 IU/L) rising prothrombin time These abnormalities distinguish this syndrome from alcoholic liver disease where transaminase values almost never exceed 500 IU/L AST level typically exceeds that of ALT in both conditions

27. DIAGNOSIS The combination of acute renal failure and liver disease with markedly increased transaminases in a chronic alcoholic should suggest the diagnosis of acetaminophen toxicity

28. TREATMENT The mainstays of the therapy of APAP intoxication include gastric decontamination with activated charcoal and the administration of N-acetylcysteine (NAC) Activated charcoal avidly adsorbs APAP, reducing its absorption by 50 to 90% However, activated charcoal also adsorbs NAC and, by causing nausea and vomiting, may interfere with the administration of NAC

29. TREATMENT NAC should optimally be given within 8 to 10 hours after ingestion More delayed therapy is associated with a progressive increase in hepatic toxicity although some benefit may still be seen 24 hours or later after ingestion

30. TREATMENT NAC is indicated in All patients with a serum APAP concentration above the possible hepatic toxicity line on the Rumack-Matthew nomogram Patients with an estimated ingestion of greater than 140 mg/kg Patients with an unknown time of ingestion Patients with a presentation more than 24 hours after ingestion with elevated transaminases

31. TREATMENT NAC regimen is used in the United States A loading dose of 140 mg/kg in a five percent solution is given either orally or via nasogastric tube This is followed by 70 mg/kg every four hours for 17 doses; any doses vomited should be repeated

32. TREATMENT Cimetidine, an inhibitor of CYP isoenzymes, has been considered for use in acetaminophen intoxication However, studies in humans have shown that cimetidine, given in a dose of 300 mg every 6 hours, does not reduce peak aminotransferase levels when given eight hours after ingestion It is possible that earlier administration of higher doses might be beneficial

33. TREATMENT Dialysis and hemoperfusion In the management of patients who present late in the course (more than 24 hours) when NAC would be of limited value, hemoperfusion may be associated with lesser elevation in plasma transaminases when compared to supportive therapy alone or to the administration of NAC.

34. TREATMENT Liver transplantation Orthotopic liver transplantation should be considered in severe cases which progress to stage three or four hepatic encephalopathy if the patient is otherwise a suitable candidate It is important to appreciate, however, that fulminant hepatic failure due to acetaminophen has a higher rate of spontaneous resolution (particularly if NAC is also given), than other forms of fulminant liver disease, such as viral hepatitis where the mortality rate may approach 100 percent.

35. Drugs & The Liver Salem Bazarah