DRUGS THAT MAY CAUSE LIVER DYSFUNCTION OR DAMAGE

The liver is the principal organ that is capable of converting drugs into forms that can be readily eliminated from the body. Given the diversity in use today and the complex burden they impose upon the liver, it is not surprising that a broad spectrum of adverse drug's effects on liver functions and structures has been documented. The reactions range from mild and transient changes in the results of liver function tests to complete liver failure with death of the host. Many drugs may affect the liver adversely in more than one way, as cited below in several listings. The use of the following drugs requires careful monitoring of their effects on the liver during the entire course of treatment.

This list is just a general guideline. Many drugs affect the liver to one degree or another and we can't list all of them here; new drugs are always being approved for general use. Read the accompanying literature with your prescriptions and always consult with your doctor or pharmacist about any new medication if you have liver disease!

Drugs that may cause ACUTE DOSE-DEPENDENT LIVER DAMAGE
(resembling acute viral hepatitis)

• acetaminophen

• salicylates (doses over 2 grams daily)

Drugs that may cause ACUTE DOSE-INDEPENDENT LIVER DAMAGE
(resembling acute viral hepatitis)
 

acebutolol indomethacin phenylbutazone allopurinol isoniazid phenytoin atenolol ketoconazole piroxicam carbamazepine

labetalol probenecid cimetidine maprotiline pyrazinamide dantrolene metoprolol quinidine diclofenac mianserin

quinine diltiazem naproxen ranitidine enflurane para-aminosalicylic acid sulfonamides ethambutol penicillins sulindac

ethionamide phenelzine tricyclic antidepressants halothane phenindione valproic acid ibuprofen phenobarbital verapamil

Drugs that may cause ACUTE FATTY INFILTRATION OF THE LIVER
 

adrenocortical steroids phenothiazines sulfonamides antithyroid drugs phenytoin

tetracyclines isoniazid salicylates valproic acid methotrexate

Drugs that may cause CHOLESTATIC JAUNDICE
 

actinomycin D chlorpropamide erythromycin amoxicillin/clavulanate cloxacillin flecainide azathioprine cyclophosphamide flurazepam captopril cyclosporine flutamide

carbamazepine danazol glyburide carbimazole diazepam gold cephalosporins disopyramide griseofulvin chlordiazepoxide enalapril

enalapril haloperidol ketoconazole norethandrolone sulfonamides mercaptopurine oral contraceptives tamoxifen methyltestosterone oxacillin thiabendazole

nifedipine penicillamine tolbutamide nitrofurantoin phenothiazines tricyclic antidepressants nonsteroidal phenytoin troleandomycin anti-inflammatory drugs propoxyphene verapamil

Drugs that may cause LIVER GRANULOMAS (chronic inflammatory nodules)
 

allopurinol gold phenytoin aspirin hydralazine procainamide carbamazepine isoniazid quinidine chlorpromazine

isoniazid quinidine chlorpromazine nitrofurantoin sulfonamides diltiazem penicillin tolbutamide disopyramide phenylbutazone

Drugs that may cause CHRONIC LIVER DISEASE

Drugs that may cause active chronic hepatitis

• acetaminophen (chronic use, large doses)

• dantrolene

• methyldopa

• isoniazid

• nitrofurantoin

Drugs that may cause liver cirrhosis or fibrosis (scarring)

• methotrexate

• terbinafine HCI (Lamisil, Sporanox)

• nicotinic acid

Drugs that may cause chronic cholestasis (resembling primary biliary cirrhosis)

• chlorpromazine/valproic acid (combination)

• imipramine

• thiabendazole

• phenothiazines

• tolbutamide

• chlorpropamide/erythro-mycin (combination)

• phenytoin

Drugs that may cause LIVER TUMORS (benign and malignant)

• anabolic steroids

• oral contraceptives

• thorotrast

• danazol

• testosterone

Drugs that may cause DAMAGE TO LIVER BLOOD VESSELS

• adriamycin

• dacarbazine

• thioquanine

• anabolic steroids

• mercaptopurine

• vincristine

• azathioprine

• methotrexate

• vitamin A (excessive doses)

• carmustine

• mitomycin

• cyclophosphamide/cyclo-sporine (combination)

• oral contraceptives

http://hepcnet.net/drugsandliverdamage.html

MEDICATIONS AND THE LIVER/HEPATITIS

There are over 1,000 drugs and chemicals that are capable of causing injury to the liver. The terms drug-induced liver disease, drug hepatotoxicity, and drug-induced hepatitis are used to describe those instances in which a medication or chemical substance has caused injury to the liver. Drug-induced liver injury may account for as many as 10 percent of hepatitis cases in adults overall, 40 percent of hepatitis cases in adults over fifty years old, and 25 percent of cases of fulminant liver failure.

    There is a rigorous process - known as clinical trials, that a drug must go through before it is determined to be safe for the public. These clinical trails are conducted on a carefully selected group of people who have met a long list of criteria in order to be able to participate in the testing of the medication. However, after the FDA has approved a particular drug, a larger and more varied group of people will be taking  the drug. This more diverse group of people may have additional medical problems that were not encountered  during the testing of the medication.  This is why occasionally, a drug originally thought to be safe, may be discovered to cause severe liver injury. In fact, drug-induced liver injury is the most common reason for the withdrawal from the market of an already FDA approved drug. Two examples of drugs withdrawn from the market due to severe liver injury include Duract (bromfenac), a nonsteroidal anti-inflammatory medication, and Rezulin (troglitasone) a diabetic medication.

Since all medications are processed through the liver at least to some degree, people with liver disease must become aware of which medications can cause liver damage, which medications can worsen preexisting liver disease, and which medications are safe to take. It is the liver’s job to detoxify any substances that are potentially harmful to the body. An already damaged and weakened liver must work much harder than a healthy liver in order to accomplish this task. When a person with liver disease ingests a potentially hepatotoxic drug, this puts an additional strain on the liver and can result in further liver injury or possibly even liver failure. Even people with a healthy liver can develop liver disease as a consequence of ingesting a toxic medication or drug.

In general, people with liver disease should avoid medications known to be hepatotoxic. People who must be treated with a medication that is potentially hepatotoxic should have their LFTs closely monitored by their doctors. If a person’s LFTs become greater than three times baseline values, the medication causing these elevations should be discontinued. Also, it is essential that people with liver disease inform their liver specialists of every medication or drug that they are taking—including herbs, over-the-counter drugs and/or recreational drugs. There is no reason for the patient to expect the doctor to be judgmental. Her goal is the same as the patient’s. Therefore, complete information should be provided to the doctor concerning prescription medications, over-the-counter medications, and herbal and alternative therapies. Remember, a doctor’s objective is to help her patient get better and to help protect her patient from unintentional additional liver damage. 

     People with cirrhosis must be particularly aware of which drugs are hepatotoxic, as they are typically more sensitive to drugs side effects due to the inability of the liver to clear the drug from the body ( excretion rate).  Even drugs that are not known to be hepatotoxic may have a prolonged excretion rate.  This means that the drug and its metabolites will stay in the body longer.  Therefore, usual dosages of these drugs should not be taken - the dosage of these drugs should be decreased.  Examples of such drugs that require a decrease in the dosage when used for a prolonged period of time in people with cirrhosis include

How Drugs Cause Liver Disease

A particular drug may cause liver damage for many reasons. First, there are some drugs that are intrinsically toxic to the liver. These drugs can cause liver injury when the drug is taken in a dosage that exceeds the recommended dosage. This form of drug hepatotoxicity is what is known as “dose-dependent.” The greater the amount by which the dosage taken exceeds the recommended dose, the more likely it is that the drug will cause liver injury. Drugs in this category are usually broken down by the cytochrome P450 enzyme system, discussed in Chapter 1. Under normal circumstances, the cytochrome P450 enzyme system usually converts toxic substances into nontoxic ones. However, in situations of drug hepatotoxicity, the reverse happens. A nonhepatotoxic drug is broken down into hepatotoxic byproducts. These byproducts cause liver damage as they begin to accumulate. An example of a drug in this category is the headache and minor pain reliever acetaminophen (Tylenol), which is discussed on page xx. The drugs in this category may also cause liver injury if taken in excess in combination with another hepatotoxic substance, such as alcohol.

Second, there are some drugs that can trigger an idiosyncratic reaction (an abnormal, unexpected hypersensitivity), to a normal dose of the drug similar to an allergic reaction, even though a normal dose may have been taken. Such a reaction is not related to the quantity of the drug ingested, and, furthermore, the ensuing liver injury is unpredictable. This type of drug hepatotoxicity is often accompanied by fatigue, fever, and rash. It usually develops after a person has already been taking the drug for a few weeks. An example of a drug in this category is the anticonvulsant phenytoin (Dilantin).

Finally, a person’s susceptibility to a potentially hepatotoxic drug is enhanced by many factors. Some of these factors are within the person’s control, such as cigarette smoking and excessive alcohol intake. But other factors cannot be altered. These include advancing age and being of the female gender. Many of the relevant factors, both alterable as well as permanent, are listed below. (See Table 24.1 on page 380 for more information concerning most of the medications mentioned in this list.)

• Age. Adults are more prone to liver injury from certain hepatotoxic drugs. such as isoniazide (INH), a drug used to treat tuberculosis.

• Gender. Females are more susceptible than males are to most forms of drug-induced liver disease—especially drugs that can cause chronic hepatitis, such as methyldopa (Aldomet)- a drug used to treat hypertension (high blood pressure).

• Genetics. Some people have a genetically based impaired ability to break down potentially hepatotoxic drugs into safe byproducts, such as phenytoin (Dilantin)—a drug used to treat seizures.

• Dose. The higher the dose the greater the risk of liver toxicity. This applies to drugs, such as acetaminophen (Tylenol), which are by nature, potentially toxic to the liver.

• Duration. For some drugs, such as methotrexate (a type of chemotherapy), the longer it is used, the greater the likelihood of liver damage or even cirrhosis.

• Kidney damage. People with poorly functioning kidneys are more prone to the hepatotoxicity of some drugs, such as tetracycline- an antibiotic.

• Alcohol. Alcohol consumption enhances the hepatotoxicity of certain drugs, such as acetaminophen.

• Cigarettes. Cigarette smoking enhances the hepatotoxicity of certain drugs, such as acetaminophen.

• Drug interactions. Taking two hepatotoxic drugs in combination can greatly increase the likelihood of liver damage compared with taking one hepatotoxic drug alone.

-  Hepatitis C.  The presence of hepatitis C may increase the hepatotoxic potential of certain drugs such as the nonsteroidal anti-inflammatory (NSAID) ibuprofen (Motrin), and certain medications used in the treatment of HIV.

• HIV. The presence of HIV (the virus which causes AIDS), increases the likelihood of hepatotoxicity from certain drugs, such as sulfamethoxazole-trimethoprim (Septra).

• Rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). People with these autoimmune disorders are more prone to the hepatotoxic effects of aspirin than people without these disorders.

• Obesity. Obesity increases the susceptibility of halothane-induced liver injury. (Halothane is a type of anesthesia.)

• Nutritional status. Either fasting or a high protein diet can increase a person’s susceptibility to acetaminophen-induced liver injury. 

Characteristics of Drug-Induced Liver Disease

Many drugs have the ability to cause any form of liver disease, including acute and chronic hepatitis as well as a fatty liver and nonalcoholic fatty liver disease (NAFLD).  And, many drugs can cause cirrhosis, liver failure, or even liver tumors. People with drug-induced liver disease may be asymptomatic with only mildly elevated LFTs, or they may be severely ill with liver failure and consequently in need of a liver transplant. Or they may be somewhere in between. Drug-induced liver disease can result in exactly the same symptoms and signs as those that characterize the same disease when not induced by drugs. It is essential for both the patient and the doctor to consider the potential hepatotoxicity of all drugs that the patient is ­taking and to promptly discontinue the use of such medications whenever an ad­verse effect on the liver is suspected. Continuing to use a drug after liver-related symptoms and signs have appeared greatly increases the chances of serious liver damage.

Drug-induced liver injury may be diagnosed through blood work. Some medications may cause hepatocellular liver injury. This is manifested by elevations in the transaminases AST and ALT. Other medications may cause cholestatic liver injury. This is manifested by elevations in AP and GGTP. And some medications may cause both types of liver injury. In addition, there are medications that may cause elevated bilirubin levels. Patients with elevated bilirubin levels exhibit signs of jaundice, including yellowing of the skin and eyes, and a darkening of the urine.

Drug-induced liver disease can be expected to occur in most, but not all cases, within the time frame of between five and ninety days from initial exposure to the hepatotoxic drug. Thus, people taking potentially hepatotoxic drugs should be monitored with blood tests during this time period. If a greater than threefold increase from baseline LFT levels occurs, the medication should be discontinued. LFTs should improve within two to four weeks from when the medication was discontinued.

Since more than 1,000 drugs are potentially hepatotoxic, a comprehensive list detailing every hepatotoxic drug is beyond the scope of this book. However, Table 24.1 on page xx lists some commonly used medications that may cause liver injury in some people. It is important to remember that not everyone will sustain liver injury as a result of using one of these drugs. And it is important to keep in mind that, as discussed on page xx, there are numerous variables that increase a person’s susceptibility to the hepatotoxicity of these medications. Still, any person with liver disease who is using one or more of these medications needs to be carefully monitored. Careful monitoring is particularly crucial when such a person is using two or more hepatotoxic drugs in combination with alcohol. People with liver disease are best advised to use an alternative to one of these potentially hepatotoxic medications whenever possible.

http://liverdisease.com/medications_hepatitis.html

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Plainview, N.Y 11803

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Tobacco

by John C. Martin

Article Date: 07-14-05

Doctors in Italy are issuing a warning to heavy smokers diagnosed with hepatitis C that they face a significantly greater risk of developing a form of cancer known as non-Hodgkin's lymphoma (NHL).¹

HCV Infection Complicates the Risk
While smoking by itself isn't necessarily thought to be a major risk factor for NHL,² smokers with hepatitis C face about 4 times the risk, warn Renato Talamini, ScD, of the Istituto Nazionale Tumori (National Cancer Institute) in Aviano, Italy and his colleagues in the International Journal of Cancer.

"Tobacco smoking is a well-documented risk factor for several cancers, but the role of cigarette smoking in the [origins] of non-Hodgkin lymphoma is inadequately understood," the Italian study team wrote.

While HCV is linked with non-Hodgkin's lymphoma,^3,4 the interactions between the virus and this form of cancer hasn't been studied much either, Talamini and his colleagues added. So, they set out to evaluate the link between the two diseases.

NHL: Many Forms Exist
Non-Hodgkin's lymphoma is a form of cancer that begins in your lymphatic system. This is part of the body's immune system, whose role is to fight infections and other diseases. In the lymphatic system, a network of lymph vessels carries clear fluid known as lymph. These vessels lead to small, round organs known as lymph nodes, which are filled with white blood cells that trap bacteria and other substances that may be in the lymph. Lymph nodes are found in the neck, underarms, chest, abdomen, and groin.

There are many forms of non-Hodgkin's lymphoma, which infects the cells of the lymphatic system. The cancer begins when a lymphocyte (a B-cell or T-cell) becomes abnormal. This abnormal cell divides to make copies of itself, and the process repeats over and over, making more abnormal cancer cells. These cells can then spread to other parts of the body.⁵

Common risk factors for NHL include a weak immune system; certain infections like HIV, Epstein-Barr virus and Helicobacter pylori, which are bacteria that cause stomach ulcers; and older age. Symptoms include swollen, painless lymph nodes; unexplained weight loss; fever; soaking night sweats; coughing, difficulty breathing, or chest pain; sustained weakness or fatigue; and pain, swelling, or a feeling of fullness in the abdomen.⁵

HCV and NHL: Investigating their Relationship
For the study, the researchers followed 225 consecutive patients who had been hospitalized with a diagnosis of NHL, and compared their prognoses with a group of 504 patients admitted to the same hospitals for conditions not related to cancer or tobacco use.

In this study, which ran from 1999 to 2002, it was found that patients who smoked at least 20 cigarettes per day faced twice the risk of NHL, on average, compared to those who had never smoked. This was true for all age groups and both sexes. However, some patients faced only a slightly higher risk.

The researchers then analyzed the risk of developing certain types of NHL—B-cell-low-grade, B-cell-intermediate and high-grade, and T-cell—related to smoking. The risk of developing B-cell NHL was inconclusive (some patients actually faced a lower risk while others faced more than a four-fold risk). However, heavy smokers faced more than 25 times the risk of developing T-cell NHL, on average, Talamini's team noted.

HCV's Impact on Cancer Risk
When the investigators evaluated the risk of developing the cancer in people with hepatitis C, they found it was four times higher.

"Our study confirms that tobacco is related to NHL, and reports on the combined effect of tobacco smoking and HCV," they wrote. "Infection acted together according to a multiplicative model, leading to a 4-fold elevated risk in current [smoking] HCV-positive subjects."
 
While the cause of this increased risk in those with HCV isn't yet known, it appears that cigarette smoking and hepatitis C infection act independently of one another in increasing the risk of non-Hodgkin's lymphoma, Talamini stated.

Physicians can play a key role in preventing NHL in smokers, he said, such as encouraging healthy lifestyles, engaging in anti-smoking campaigns, providing support for those giving up the smoking habit, and endorsing certain interventions against risky behaviors such as IV drug use and unprotected sexual intercourse, the researchers wrote.

1. Talamini R, Polesel J, Montella M et al. Smoking and non-Hodgkin lymphoma: case-control study in Italy. Int J Cancer 2005 Jul 1;115(4):606-10.
2. Zahm SH, Weisenburger DD, Holmes FF, Cantor KP, Blair A. Tobacco and non-Hodgkin's lymphoma: combined analysis of three case-control studies (United States). Cancer Causes Control 1997 Mar;8(2):159-66.
3. Libra M, Gasparotto D, Gloghini A, Navolanic PM, De Re V, Carbone A. Hepatitis C virus (HCV) I hepatitis C virus (HCV) infection and lymphoproliferative disorders. Front Biosci 2005 Sep 1;10:2460-71.
4. Bianco E, Marcucci F, Mele A et al. Prevalence of hepatitis C virus infection in lymphoproliferative diseases other than B-cell non-Hodgkin's lymphoma, and in myeloproliferative diseases: an Italian Multi-Center case-control study. Haematologica 2004 Jan;89(1):70-6.
5. National Cancer Institute. National Institutes of Health. What is non-Hodgkin's lymphoma? Available at: http://www.cancer.gov/cancertopics/wyntk/non-hodgkins-lymphoma/page3. Accessed July 7, 2005.

John Martin is a long-time health journalist and an editor for Priority Healthcare. His credits include overseeing health news coverage for the website of Fox Television's The Health Network, and articles for the New York Post and other consumer and trade publications.

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