By Sheila Mulhern

1. Do medications such as isoniazid and methyldopa, nitrofurantoin and Phenytoin induce liver disease? By Sheila Mulhern

2. Understanding Drug Metabolism • Pharmacokinetics Process (ADME) • Conversion process of breaking down drug into metabolites • Absorption • Distribution • Metabolism (biotransformation in the liver) • Excretion

3. Drug Metabolism Pathway

4. Reactions in the Liver

5. Role of Liver in Drug Metabolism • Principle site for drug metabolism: smooth endoplasmic reticulum of the liver cell • Responsible for concentrating, metabolizing, and eliminating the majority of drugs and toxins that are introduced into the body • Metabolite compounds are generally responsible for damage • Factors • Large organ • First organ perfused by chemicals absorbed in the gut • Contains very high concentrations of most drug-metabolizing enzyme systems • Other drug metabolism sites • Epithelial cells of the GI tract, lungs, kidneys, and the skin • Typically for localized toxicity reactions

6. What Can the Liver do with Drugs? • Activate or inactivate drugs • Make drugs more effective • Increase or decrease drug toxicity • Convert drugs to a new form so the kidneys can easily excrete (convert to more water soluble form) • Convert to be more fat soluble for excretion in the bile/feces

7. Factors that Effect Drug Metabolism • Disease • Age • Genetics • Environment • Drugs • Alcohol • Nutrition

8. How Do Drugs Cause Liver Disease? • Drug can cause injury to the liver • New chemical formed in the liver can harm directly or indirectly • Drug toxicity • Dose-induced • Idiosyncratic (genetic) • Drug allergy

9. The Medications: Isoniazid • Isoniazid • Used alone or with other drugs to treat tuberculosis (TB) and to prevent it in people who have had contact with tuberculosis bacteria • Eliminates only active (growing) bacteria • Typically need for a period of 6-12 months since bacteria exists in non-growing stage for long periods • Role in liver disease • Raise blood levels of AST and ALT • 1-2% develop isoniazid-induced hepatitis and is more common in older adults • Risk of isoniazid liver toxicity is increased with regular use of alcohol intake and with use of other drugs such as Tylenol and rifampin

10. The Medications: Isoniazid • Drug-nutrient interactions • Avoid alcohol – toxic to the liver • Need to take the medication one hour before or two hours after meals as food decreases the absorption • May need Vitamin B6 supplements and niacin • Drug also lowers levels of Vitamin D, calcium and folic acid • Vitamin E and magnesium may be depleted with long term use

11. The Medications: Methyldopa • Methyldopa • Used to treat hypertension • Is an anti-hypertensive that relaxes blood vessels for easier blood flow • Block the enzyme HMG-CoA reductase needed for liver’s production of cholesterol • Liver pulls dietary cholesterol from the blood • Role in liver disease • Satins can cause mild elevations in blood levels of liver enzymes ALT and AST • Clinical studies show that these abnormalities can improve without causing liver damage • However, idiosyncratic liver toxicity which can cause severe liver damage has been found with satins • This includes liver failure leading to liver transplant

12. The Medications: Methyldopa • Drug-nutrient interactions • Grapefruit blocks enzyme that reduces statin absorption (leads to too much statin in the bloodstream • Risk for depletion of coenzyme Q10, which is necessary for production of ATP. Found in diet in fatty fish (tuna, salmon), organ meats and whole grains. Supplements may be needed. • Omega-3 fatty acids – help statins work more effectively • Iron – methyldopa binds to iron and absorption of drug can be reduced (avoid iron supplements) • Continue to reduce sodium – high sodium levels contribute to fluid retention and interfere with intended action of drug lowering blood pressure • Drug reduces B12 levels, supplementation recommended • Protein can interfere with absorption and drug action - take medication 1-2 hours before or after meal

13. The Medications: Nitrofurantoin • Nitrofurantoin • Used to treat urinary tract infections • Antibiotic – kills bacteria which caused infection • Excreted in urine (colors urine brown, but is harmless) • Role in liver disease • Can cause acute and chronic liver disease • Most cases causes mild and reversible elevations in blood levels of liver enzymes without symptoms • Rare cases causes hepatitis • Drug-nutrient interactions • Should be take with food to improve absorption • Not used in patients with glucose-6-phosphate dehydrogenase deficiency because of risk of extravascular hemolysis resulting in anemia

14. The Medications: Phenytoin • Phenytoin • Used for treatment and prevention of seizures • Anticonvulsant – decreases abnormal electrical activity in the brain • Excreted in urine • Role in liver disease • Uncommon cause in liver disease but can happen with toxic levels • More common with factors such as age, overall health and underlying liver problems

15. The Medications: Phenytoin • Drug-nutrient interactions • Avoid alcohol – risks including lowered blood pressure • Grapefruit reduces absorption • Antacids – contain calcium which can prevent absorption of drug • Dairy products are still safe – don’t have same reaction as with antacids • Folic acid – reduces drug efficiency

16. Resources • http://www.thebody.com/content/art875.html • http://www.chainonline.org/content.cfm?content_id=1446&tk=5&dpg=5 • http://www.medscape.org/viewarticle/421137 • http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000673/ • http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000622/ • http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000549/ • http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0000640/ • http://www.hepcprimer.com/tests/test-4.html • http://www.medicinenet.com/drug_induced_liver_disease/page2.htm#how_do_drugs_cause_liver_disease • http://www.medicinenet.com/drug_induced_liver_disease/page9.htm#what_are_some_important_examples_of_drug-induced_liver_disease • http://www.naturalnews.com/DrugWatch_Isoniazid.html