Drugs can cause liver disease in
several ways. Some drugs are directly injurious to the liver; others are
transformed by the liver into chemicals that can be injurious to the liver
directly or indirectly. (This may seem strange in light of the liver's
important role in transforming toxic chemicals into nontoxic chemicals, but it
happens.) There are three types of liver toxicity; dose-dependent toxicity,
idiosyncratic toxicity, and drug allergy.
Drugs that cause dose-dependent toxicity can
cause liver disease in most people if enough of the drug is taken. The most
important example of dose-dependent toxicity is acetaminophen (Tylenol) overdose.
Drugs that cause idiosyncratic toxicity cause
disease in only those few patients who have inherited specific genes that
control the chemical transformation of that specific drug, causing accumulation
of the drug or products of their transformation (metabolites) that are
injurious to the liver. These inherited idiosyncratic toxicities usually are
rare, and depending on the drug, typically occur in less than 1 to10 per
100,000 patients who are taking that drug; however, with some drugs the
prevalence of toxicity is much higher. Even though the risk of developing
drug-induced idiosyncratic liver disease is low, idiosyncratic liver disease is
the most common form of drug-induced liver disease because tens of millions of
patients are using drugs, and many of them are using several drugs.
Idiosyncratic drug toxicity is
difficult to detect in early clinical trials that usually involve, at most, only a
few thousand patients. Idiosyncratic toxicity will surface only after millions
of patients begin to receive the drug after the drug is approved by the FDA.
Drug allergy also may cause liver disease, though
it is uncommon. In drug allergy, the liver is injured by the inflammation that
occurs when the body's immune system attacks the drugs with antibodies and
immune cells.
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
Age. Adults are more
prone to liver injury from certain hepatotoxic drugs. such as isoniazide (INH),
a drug used to treat tuberculosis. Apart from accidental exposure, hepatic drug
reactions are rare in children. Elderly persons are at increased risk of
hepatic injury because of decreased clearance, drug-to-drug interactions,
reduced hepatic blood flow, variation in drug binding, and lower hepatic
volume. In addition, poor diet, infections, and multiple hospitalizations are
important reasons for drug-induced hepatotoxicity.
Race: Some drugs appear to have
different toxicities based on race. For example, blacks and Hispanics may be
more susceptible to isoniazid (INH) toxicity. The rate of metabolism is under
the control of P-450 enzymes and can vary from individual to individual.
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). Although
the reasons are unknown, hepatic drug reactions are more common in females.
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. A unique gene encodes each P-450 protein. Genetic differences in the
P-450 enzymes can result in abnormal reactions to drugs, including
idiosyncratic reactions. Debrisoquine is an antiarrhythmic drug that undergoes
poor metabolism because of abnormal expression of P-450-II-D6. This can be
identified by polymerase chain reaction amplification of mutant genes. This has
led to the possibility of future detection of persons who can have abnormal
reactions to a drug.
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.
Liver disease:
In general, patients with chronic liver disease are not uniformly at increased
risk of hepatic injury. Although the total cytochrome P-450 is reduced, some
may be affected more than others. The modification of doses in persons with
liver disease should be based on the knowledge of the specific enzyme involved
in the metabolism. Patients with HIV infection who are co-infected with
hepatitis
B or C virus are at increased risk for hepatotoxic effects when treated with
antiretroviral therapy. Similarly, patients with cirrhosis are at increased risk
of decompensation by toxic drugs.
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. Alcoholic persons are susceptible to drug
toxicity because alcohol induces liver injury and cirrhotic changes that alter
drug metabolism. Alcohol causes depletion of glutathione (hepatoprotective)
stores that make the person more susceptible to toxicity by drugs.
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, 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.
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.
Nutritional
status. Either
fasting or a high protein diet can increase a person’s susceptibility to
acetaminophen-induced liver injury.
Other
comorbidities: Persons with AIDS, persons who are malnourished, and persons who
are fasting may be susceptible to drug reactions because of low glutathione
stores. Drug formulation: Long-acting drugs may cause more injury than
shorter-acting drugs.
Figure
6.1. Risk of hepatotoxicity. The
ultimate development of hepatotoxicity is determined by the interplay of the
toxic potential of the drug or its metabolites and the susceptibility of the
host as determined by genetic and environmental factors, both of which
influence gene expresions.
Table.6.1:- Risk factors of hepatotoxicity
Host factors that may
enhance susceptibility to drugs, possibly inducing liver disease
- Female - Halothane, nitrofurantoin, sulindac
- Male - Amoxicillin-clavulanic acid (Augmentin)
- Old age - Acetaminophen, halothane, INH, amoxicillin-clavulanic acid
- Young age - Salicylates, valproic acid
- Fasting or malnutrition - Acetaminophen
- Large body mass index/obesity - Halothane
- Diabetes mellitus - Methotrexate, niacin
- Renal failure - Tetracycline, allopurinol
- AIDS - Dapsone, trimethoprim-sulfamethoxazole
- Hepatitis C - Ibuprofen, ritonavir, flutamide
- Preexisting liver disease - Niacin, tetracycline, methotrexate
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