Do medications such as isoniazid and methyldopa, nitrofurantoin and Phenytoin induce liver disease?

By Sheila Mulhern

Understanding Drug Metabolism

Pharmacokinetics Process (ADME) Conversion process of breaking down drug into

metabolites Absorption Distribution Metabolism (biotransformation in the liver) Excretion

Drug Metabolism Pathway

Reactions in the Liver

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

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

Factors that Effect Drug Metabolism

Disease Age Genetics Environment Drugs Alcohol Nutrition

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

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

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

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

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

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

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

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

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_c

ause_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