Prof JH van Zyl 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

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

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

Central role of liver in drug metabolism

Principal reactions in drug metabolism

Electron flow pathway in the microsomal drug- oxidizing system

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

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

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

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

FACTORS INFLUENCING HEPATIC UPTAKE OF DRUGS Specific receptor or transport protein

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

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

FACTORS INFLUENCING THE ACTIVITY OF DRUG METABOLIZING ENZYMES Age

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

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

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

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

HEPATOTOXINS Carbon tetrachloride Tetracycline Aminita phalloides Cytotoxic drugs Methotrexate Paracetamol Arsenic

HEPATOTOXINS : PATHOLOGY Necrosis Fatty infiltration Little inflammation

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

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

TOXIC HEPATITIS Treatment - Gastric lavage - Antidotes Cysteamine for paracetamol

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

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

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.

Orphan nuclear receptors and drug metabolism

Genetic polymorphism of cytochrome P450 and acetylation

Consequences of drug biotransformation

Drug-drug interactions

Effect of cirrhosis on the plasma clearance of diazepam

Factors leading to decreased drug metabolism in aging

Primary mechanisms of impaired drug metabolism

Secondary mechanisms of impaired drug reactions

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

Drug-induced liver disease

Pathogenesis of drug-induced liver diseases

Mechanisms of acetaminophen toxicity

Mechanisms of isoniazid hepatotoxicity

Halothane hepatitis

Drug-induced fatty liver

Herbal preparations implicated in hepatotoxicity

Isoniazid hepatitis incidence

Mechanisms of cholestasis

Antecedent liver injury and the use of potentially hepatotoxic drugs

Diagnosis of drug-induced liver disease

Management of drug-induced liver disease