1. Prof JH van Zyl 2010 01. Central role of liver in drug metabolism 02. Principal reactions in drug metabolism 03. Electron flow pathway in the microsomal drug-oxidizing system 04. Orphan nuclear receptors and drug metabolism 05. Genetic polymorphism of cytochrome P450 and acetylation 06. Consequences of drug biotransformation 07. Drug-drug interactions 08. Effect of cirrhosis on the plasma clearance of diazepam 09. Factors leading to decreased drug metabolism in aging 10. Primary mechanisms of impaired drug metabolism 11. Secondary mechanisms of impaired drug reactions 12. One of the outcomes of drug metabolism is the induction of liver injury 13. Drug-induced liver disease 14. Pathogenesis of drug-induced liver diseases 15. Mechanisms of acetaminophen toxicity 16. Mechanisms of isoniazid hepatotoxicity 17. Halothane hepatitis 18. Drug-induced fatty liver 19. Herbal preparations implicated in hepatotoxicity 20. Diagnosis of drug-induced liver disease Drugs and liver

2. 1.Isoniazid hepatitis incidenceIsoniazid hepatitis incidence 2.Drug-induced fatty liverDrug-induced fatty liver 3.Mechanisms of cholestasisMechanisms of cholestasis 4.Herbal preparations implicated in hepatotoxicityHerbal preparations implicated in hepatotoxicity 5.Antecedent liver injury and the use of potentiallyAntecedent liver injury and the use of potentially hepatotoxic drugs 6.Diagnosis of drug-induced liver diseaseDiagnosis of drug-induced liver disease 7.Management of drug-induced liver diseaseManagement of drug-induced liver disease Management

3. Learning Outcomes 1.Know what the liver does to drugs 2.Know how drugs affect the liver 3.Distinguish between the 2 types of drug induced liver disease: Drug induced hepatitis vs Liver toxins 4.Know what the levels are for “safe” alcohol usage 5.Know the effects of alcohol on the liver 6.Know how to recognise alcohol induced liver disease

4. Central role of liver in drug metabolism

5. Principal reactions in drug metabolism

6. Electron flow pathway in the microsomal drug- oxidizing system

7. How does the liver affect drugs? Change from lipid-soluble to water-soluble Takes place in the intracellular space

8. FACTORS INFLUENCING HEPATIC UPTAKE OF DRUGS Protein binding Blood flow Specific receptor or transport protein

9. FACTORS INFLUENCING HEPATIC UPTAKE OF DRUGS Protein binding Weakly or strongly bound to protein

10. FACTORS INFLUENCING HEPATIC UPTAKE OF DRUGS Blood flow Normal portal flow in man = 1000-1200ml/min Reduced in cirrhosis 100% of blood in portal vein recovered from hepatic vein in health and only 13% in cirrhosis( 87% via collaterals )

11. FACTORS INFLUENCING HEPATIC UPTAKE OF DRUGS Specific receptor or transport protein

12. FACTORS INFLUENCING THE ACTIVITY OF DRUG METABOLIZING ENZYMES Genetic Age Drugs Disease

13. FACTORS INFLUENCING THE ACTIVITY OF DRUG METABOLIZING ENZYMES Genetic Slow and fast acetylation of INH

14. FACTORS INFLUENCING THE ACTIVITY OF DRUG METABOLIZING ENZYMES Age

15. FACTORS INFLUENCING THE ACTIVITY OF DRUG METABOLIZING ENZYMES Drugs Warfarin and Phenytoin

16. FACTORS INFLUENCING THE ACTIVITY OF DRUG METABOLIZING ENZYMES Disease In the metabolizing of the drug – - Weaker? - Stonger?

17. HOW DO DRUGS AFFECT THE LIVER? Increased load – Sulphonamides Disordered metabolism- Anabolic Steroids Hepatotoxins – C Cl4 Sensitivity - Hepatitis - INH, Halothane - Cholestatic – Phenothiazine

18. HEPATOTOXINS Exhibit a distinctive histological pattern for any given hepatotoxin Is dose related Can be elicited in all individuals Are reproducible in laboratory animals. Appear after a predictable and brief exposure

19. HEPATOTOXINS Carbon tetrachloride Tetracycline Aminita phalloides Cytotoxic drugs Methotrexate Paracetamol Arsenic

20. HEPATOTOXINS : PATHOLOGY Necrosis Fatty infiltration Little inflammation

21. HEPATOTOXINS : CLINICAL FEATURES Short latent period Symptom of hepatitis without pre-icteric fever Anorexia, nausea and vomiting Jaundice Hepatomegaly

22. SEVERE TOXIC HEPATITIS Intense abdominal pain Haematemesis Rapid decrease in liver size Ascites, oedema Bleeding tendency Coma Uraemia +/-

23. TOXIC HEPATITIS Treatment - Gastric lavage - Antidotes Cysteamine for paracetamol

24. DRUG INDUCED HEPATITIS They cannot be produced in animals Only some individuals are at risk Severity or occurrence bears no relation to amount consumed No relationship to the institution of therapy Histology varies Often fever, arthralgia, rash and eosinophilia

25. DRUG INDUCED HEPATITIS: TREATMENT Stop offending drug Do not rechallenge Value of corticosteroids uncertain

26. DRUG INDUCED HEPATITIS Patients with atopic allergy and a history of antecedent reactions to other drugs are at risk A drug with other hypersensitivity reactions will sooner or later produce hepatitis in others.

27. Orphan nuclear receptors and drug metabolism

28. Genetic polymorphism of cytochrome P450 and acetylation

29. Consequences of drug biotransformation

30. Drug-drug interactions

31. Effect of cirrhosis on the plasma clearance of diazepam

32. Factors leading to decreased drug metabolism in aging

33. Primary mechanisms of impaired drug metabolism

34. Secondary mechanisms of impaired drug reactions

35. One of the outcomes of drug metabolism is the induction of liver injury

36. Drug-induced liver disease

37. Pathogenesis of drug-induced liver diseases

38. Mechanisms of acetaminophen toxicity

39. Mechanisms of isoniazid hepatotoxicity

40. Halothane hepatitis

41. Drug-induced fatty liver

42. Herbal preparations implicated in hepatotoxicity

43. Isoniazid hepatitis incidence

44. Mechanisms of cholestasis

45. Antecedent liver injury and the use of potentially hepatotoxic drugs

46. Diagnosis of drug-induced liver disease

47. Management of drug-induced liver disease