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.

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

1. Isoniazid hepatitis incidence

2. Drug-induced fatty liver

3. Mechanisms of cholestasis

4. Herbal preparations implicated in hepatotoxicity

5. Antecedent liver injury and the use of potentially

hepatotoxic drugs

6. Diagnosis of drug-induced liver disease

7. Management 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

= 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)

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

Table 6-18. Factors Leading to Decreased Drug Metabolism in Aging

Decreased liver blood flow

Decreased liver mass

Pseudo-capillarization

Decline in hepatic oxygenation?

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

Table 6-9. Genetic Polymorphism of Cytochrome P450 and Acetylation

Enzyme P450IID6 P450IIC N-Acetyltransferase (NAT)

Designation Debrisoquine/sparteine polymorphism

Mephenytoin polymorphism

Acetylation (INH) polymorphism

Antidepressants Mephobarbital Hydralazine

(Other drugs involved) Antiarrhythmics Hexobarbital Phenelzine

β blockers Omeprazole Procainamide

Codeine, neuroleptics Dapsone

Sulfamethazine

Sulfapyride

Poor metabolism (incidence)

Japanese 5%-10% 18%-23% 40%-70%

Chinese 0%-2% 15%-20% 10%-20%

Whites 5%-10% 2%-5%

Consequences of drug biotransformation

Drug-drug interactions

Effect of cirrhosis on the plasma clearance of diazepam

Factors leading to decreased drug metabolism in aging

Table 6-18. Factors Leading to Decreased Drug Metabolism in Aging

Decreased liver blood flow

Decreased liver mass

Pseudo-capillarization

Decline in hepatic oxygenation?

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

Table 6-4. Drug-induced Liver Disease: General Characteristics

Hepatotoxicity

Predictable Unpredictable*

Incidence High Low

Reproducible in animals Usually No

Dose-dependent Yes Rarely

Example Acetaminophen Diphyenylhydantoin

*Metabolic idiosyncrasy, presumably related to formation of toxic metabolite(s) under genetic control.

Hypersensitivity idiosyncrasy, presumably related to immune reaction, ? to metabolite.

Pathogenesis of drug-induced liver diseases

Mechanisms of acetaminophen toxicity

Mechanisms of isoniazid hepatotoxicity

Halothane hepatitis

Drug-induced fatty liver

Table 6-32. Agents Producing Drug-induced Fatty Liver

Macrovesicular

Methotrexate

Allopurinol

Halothane

Isoniazid

α-Methyldopa

Microvesicular

Tetracycline

Valproic acid

Ibuprofen

Pirprofen

Amineptine

Tianeptine

Salicyclic acid

Tamoxifen

Herbal preparations implicated in hepatotoxicity

Table 6-41. Herbal Preparations Implicated as Possible Hepatotoxins *

Common names

Scientific names Folk uses

Possible toxic component Hepatic disorder

Chaparral Larrea tridentata

Cancer, arthritis, bruises, diarrhea, eczema, colds, bronchitis, menstrual cramps, amenorrhea, venereal disease, "blood purifier", emetic, antiseptic, diuretic

Nordihydroguaiaretic acid (DNGA) and other related compounds

Acute and subacute hepatitis

(Creosote bush, greasewood, governadora)

Larrea divaricata

Chinese herbs Coptis senesia Tonic, to remove "toxic products of pregnancy" in neonates

Unknown Unconjugated hyperbilirubinemia

Chuen-Lin (Huang-Lien, Ma Huang)

Coptis japonicum

Yin-Chen Antemesia scoparia

Neonatal jaundice Unknown Potential kernicterus

Comfrey Symphytum officinate

Fatigue, abdominal pain, allergy

Pyrrolizidine alkaloids Venoocclusive disease

Germander Teucrium chamaedrys

Weight control, bitter tonic, appetizer, choleretic, antiseptic

Furano neoclerodane deterpenoids

Reversible acute hepatitis, fatal massive hepatic necrosis

Gordolobo

Verbascum thaprus, senecio longilobus, gnaphalium macounii

Pyrrolizidine alkaloids Potential for venoocclusive disease

Mistletoe Viscum album, phoradendron flavescens

Infertility, asthma, epilepsy, aphrodisiac

β-Phenylethylamine, tyramine, acetylcholine, propionylcholine

Hepatitis with piecemeal necrosis and distortion of lobular architechture

Senna Cassia angustifolia, cassia acutifolia

Laxative or cathartic Senosides, rhein anthron Hepatitis

Skullcap Scuttelaria galericulata

Sedative, anticonvulsant

Hepatitis with centrilobular and bridging necrosis

Valerian (garden heliotrope)

Valerian officinalis

Sedative, hypnotic, spasmolytic, hypotensive

Hepatitis with piecemeal necrosis, chronic aggressive hepatitis with fibrosis

*Herbal teas vary widely in composition and may contain several potential toxins often containing pyrrolizidine alkaloids from Senecio, Symphytum, Crotalaria, or Heliotropum. Intrauterine damage may also result from maternal consumption of these concoctions. Babies may develop toxic liver disease from consuming herbal beverages or milk from mothers taking toxin-containing herbal drinks.

Isoniazid hepatitis incidence

Mechanisms of cholestasis

Antecedent liver injury and the use of potentially hepatotoxic drugs

Table 6-9. Antecedent Liver Injury and the Use of Potentially Hepatotoxic Drugs

Lower dose in hepatically metabolized dose-dependent hepatotoxins

Consider drug binding in plasma and drug-drug interactions

Consider pharmacodynamic effects ie, sedatives and NSAIDs in cirrhotics)

No basis for avoiding unpredictable hepatotoxins, ie, no increased frequency of drug-induced liver disease*

However, greater risk of increased severity of combined liver disease

Thus, need for good baseline liver tests, monitoring of early therapy, and vigilance

*In patients with chronic hepatitis C, there may be a higher incidence of hepatotoxicity to antituberculous and antiretroviral (ritonavir) medications, as well as chemotherapy regimens.

Diagnosis of drug-induced liver disease

Table 6-45. Diagnosis of Drug-induced Liver Disease

High index of suspicion

Careful history of drug intake

Compatible temporal sequence

Short duration of drug use

Clinical/laboratory profile consistent with known pattern (ie, hepatocellular, cholestatic) of drug injury

Use of drug combinations (ie, isoniazid/rifampin/alcohol/acetaminophen) known to predispose to drug toxicity

Age compatible with particular drug toxicity (ie, > 40 for isoniazid; < 20 for valproic acid)

Systemic manifestations (ie, fever, rash, eosinophilia, multisystem involvement)

Liver biopsy consistent with drug-induced injury (not necessarily specific and not always needed)

Exclusion of other causes

Improvement (clinical/laboratory) after cessation of drug use; usually significant fall in transaminases in 2-4 wk for hepatocellular injury, slower with cholestasis

Rechallenge (almost never indicated)

Management of drug-induced liver disease

Table 6-11. Management of Drug-induced Liver Disease

Prompt cessation of suspected drug use*

Specific antidote (ie, N-acetylcysteine for acetaminophen

Supportive therapy for liver disease (ie, management of complications/transplant)

Corticosteroids offer no proven benefit but may be tried in patients with hypersensitivity (vasculitis) not responding to drug withdrawal

Liver transplantation for fulminant hepatic failure (acute liver failure)

*Clinical and b iochemical monitoring may permit early discontinuation of drug use. The frequency and cost/benefit of biochemical monitoring is presently under discussion and requires more study.