3.3. Type of injury

There is no specific treatment for hepatic toxicity by drugs, which is based on suspending the suspected drug, treating symptoms (use of corticosteroids for hypersensitivity reactions), avoiding other possible hepatotoxic agents and continuous monitoring of laboratory tests [13, 14]. There are some exceptions of antidotes for treating liver toxicity by certain drugs such as the use of N-acetyl cysteine as an antidote for acetaminophen toxicity, or N-acetyl cysteine itself for the treatment of hepatotoxicity by phenytoin and carbamazepine, or carnitine for valproic acid toxicity [25]. With the suspension of the offending drug, in most cases, the health of the patients tends to improve; however, in other cases, the damage continues to progress and hospitalization is necessary, when irreversible liver failure occurs, liver transplantation is

Hepatotoxicity induced by drugs or toxins can be grouped into two types: intrinsic reactions (less common) and idiosyncratic reactions (more common) [6, 7, 26]. Intrinsic reactions are predictable, dose-dependent and reproducible in animal models; injury is produced trough toxic metabolites of drugs such as free radicals (generating lipid peroxidation), electrophilic molecules (formation of covalent bonds with hepatic proteins) or active oxygen molecules (generating peroxidation as well). Idiosyncratic reactions are not predictable, not dosedependent and not reproducible in animals; there are many drugs capable of causing this type of reaction [11, 27]. The underlying mechanism of the idiosyncratic reaction may be a genetic polymorphism of the cytochrome P450 (CYP450) system, responsible for the drugs hepatic biotransformation. There are two types of idiosyncratic reactions: immune (characterized by hypersensitivity-type reaction) and metabolic [7, 13] (related to metabolism of

The hepatocytes, cholangiocytes, Kupffer cells, ductal and endothelial cells are involved in the mechanisms by which drugs cause hepatotoxicity [28]; having direct effects on cellular organelles such as mitochondria, endoplasmic reticulum, cytoskeleton, microtubules or nucleus.

The drug metabolites generated in the liver through biotransformation can cause hepatic damage because formation of toxic or reactive substances such as electrophilic chemicals or free radicals [29], and thus an unchain a variety of chemical reactions may happen. These mechanisms can either generate necrosis or apoptosis or both. The following are some of the

• Mitochondrial dysfunction: may be generated by the disruption of β-oxidation of lipids and oxidative energy production within the hepatocytes. Mitochondrial membrane permeabilization can lead to apoptosis, a rupture in mitochondrial membrane can lead to ATP depletion and subsequent necrosis, and an abnormal function can also lead to fat

required and if the liver tissue damage is severe, patients can die in a few hours.

3. Hepatotoxicity associated to drugs

80 Pharmacokinetics and Adverse Effects of Drugs - Mechanisms and Risks Factors

3.1. Expression of hepatotoxicity

3.2. Mechanisms of hepatotoxicity

main mechanisms of liver injury [30]:

accumulation, so steatosis can be present [31].

substances).

Liver histology is the ideal tool to define the pattern of hepatic toxicity; however, in clinical practice, most hepatotoxic lesions are classified according to biochemical tests [16]. In this way, according to Council for International Organizations of Medical Sciences (CIOMS), liver injury is considered, if at least one of the main hepatic enzymes, such as alanine aminotransferase, aspartate aminotransferase (AST), alkaline phosphatase and total bilirubin (TB), increases by two times, the upper limit of normal (ULN) [33]. Besides, liver injury is classified into the following three types of lesions:


On the other hand, Hy's rule defines liver damage when ALT level increases more than or equal to three times the ULN accompanied by bilirubin elevation [5, 35] and with or without rise of APL levels.
