Give an example of a drug inducing hepatotoxicity:
a- Paracetamol.
b- Ketoconazole.
c- Rifampicin.
d- Quinolones.
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The liver is an organ that is affected in numerous inflammatory processes such as viral infections, drug toxicity and its metabolites, metabolopathies, autoimmune processes and various genetic defects. In recent years, numerous publications suggest that adverse drug reactions are responsible for a greater proportion of cases of liver injury than initially thought, constituting a challenge for the primary care physician, who frequently attend patients treated with several drugs that present, often in the course of routine reviews, an alteration in liver analysis.
Hepatotoxicity (HTX) is defined as liver injury or damage caused by exposure to a drug or other non-pharmacological agents. The term adverse drug reaction refers to the appearance of unintended deleterious effects that occur with pharmacological doses used for prophylactic and therapeutic purposes.
These adverse reactions that affect the liver are more difficult to define, so that concept has been established by consensus meetings and includes, at least, one of the following alterations of liver biochemical analyzes:
1) alanine aminotransferase increase exceeding twice the high limit of normality,
2) increased serum direct bilirubin concentration more than twice the high limit of normal,
3) increased aspartate aminotransferase (AST), alkaline phosphatase (FA) and the total bilirubin concentration, provided that one of them exceeds the high limit of normal more than twice.
Scientific and technological advances entail the improvement of the diagnosis and treatment of many pathologies, but they are also increasing the incidence of yatrogenic diseases. Since the liver is the main organ involved in the metabolism of nutrients, drugs and other potentially toxic xenobiotics that must pass through it before reaching the bloodstream and other tissues, it makes it particularly susceptible to chemical toxicity phenomena. Moreover, the number of non-organism substances with biological activity capable of inducing liver disease is very large, with more than 1,100 drugs currently being incriminated in episodes of hepatotoxicity, excluding drugs of abuse and herbal remedies.
Although hepatic adverse reactions (RAH) are considered relatively rare in all adverse reactions (4-10%), they have a special clinical significance due to their potential severity (up to 5% mortality according to the series).
Hepatotoxicity represents a major health problem on the rise in recent decades, since it is one of the leading causes of death secondary to medications and is the main cause of withdrawal, suspension of marketing and restriction of indications of pharmacological products on the market Pharmacist in Europe and the United States.
A recent example of the importance of hepatic adverse reactions is the case of troglitazone, a new oral antidiabetic that was withdrawn from the market three years after its commercialization due to cases of severe liver injury resulting in liver transplantation and even death in some patients Other examples of drugs recently withdrawn from the market due to their hepatotoxic potential are ebrotidine, tolcapone, nefazodone, tetrabamate, nimesulide, trovafloxacin and lumiracoxib.
a- Paracetamol.
b- Ketoconazole.
c- Rifampicin.
d- Quinolones.
----------------------------
The liver is an organ that is affected in numerous inflammatory processes such as viral infections, drug toxicity and its metabolites, metabolopathies, autoimmune processes and various genetic defects. In recent years, numerous publications suggest that adverse drug reactions are responsible for a greater proportion of cases of liver injury than initially thought, constituting a challenge for the primary care physician, who frequently attend patients treated with several drugs that present, often in the course of routine reviews, an alteration in liver analysis.
Hepatotoxicity (HTX) is defined as liver injury or damage caused by exposure to a drug or other non-pharmacological agents. The term adverse drug reaction refers to the appearance of unintended deleterious effects that occur with pharmacological doses used for prophylactic and therapeutic purposes.
These adverse reactions that affect the liver are more difficult to define, so that concept has been established by consensus meetings and includes, at least, one of the following alterations of liver biochemical analyzes:
1) alanine aminotransferase increase exceeding twice the high limit of normality,
2) increased serum direct bilirubin concentration more than twice the high limit of normal,
3) increased aspartate aminotransferase (AST), alkaline phosphatase (FA) and the total bilirubin concentration, provided that one of them exceeds the high limit of normal more than twice.
Scientific and technological advances entail the improvement of the diagnosis and treatment of many pathologies, but they are also increasing the incidence of yatrogenic diseases. Since the liver is the main organ involved in the metabolism of nutrients, drugs and other potentially toxic xenobiotics that must pass through it before reaching the bloodstream and other tissues, it makes it particularly susceptible to chemical toxicity phenomena. Moreover, the number of non-organism substances with biological activity capable of inducing liver disease is very large, with more than 1,100 drugs currently being incriminated in episodes of hepatotoxicity, excluding drugs of abuse and herbal remedies.
Although hepatic adverse reactions (RAH) are considered relatively rare in all adverse reactions (4-10%), they have a special clinical significance due to their potential severity (up to 5% mortality according to the series).
Hepatotoxicity represents a major health problem on the rise in recent decades, since it is one of the leading causes of death secondary to medications and is the main cause of withdrawal, suspension of marketing and restriction of indications of pharmacological products on the market Pharmacist in Europe and the United States.
A recent example of the importance of hepatic adverse reactions is the case of troglitazone, a new oral antidiabetic that was withdrawn from the market three years after its commercialization due to cases of severe liver injury resulting in liver transplantation and even death in some patients Other examples of drugs recently withdrawn from the market due to their hepatotoxic potential are ebrotidine, tolcapone, nefazodone, tetrabamate, nimesulide, trovafloxacin and lumiracoxib.
Epidemiology:
Although epidemiological information on the toxic effect of drugs in the liver is scarce and fragmentary, it is known that the incidence of HTX is increasing in parallel with the introduction of new agents in the market, increasing the hope of life, polymedication and the increasingly widespread use of herbal products. Ignorance of the real incidence of this pathology is due to several causes. First, most of the data available today are retrospective in nature and derive from observations of isolated cases or series published in the literature, spontaneous reporting of incidents to state pharmacovigilance agencies and some additional information obtained. of post-marketing surveillance programs or monitoring of specific populations. Second, there is an under-reporting of cases by health personnel in probable relation to the low index of suspicion by the medical staff; and finally, it must be taken into account that, since there are no specific markers of hepatotoxicity, obtaining an etiological diagnosis of certainty can be extremely difficult. All of the above explains that the notification of HTX cases does not exceed 10% of those that actually occur. A prospective population-based study of the incidence of HTX published in recent years, conducted in a French region, analyzes cases of liver damage secondary to drugs over a period of three years. It includes an annual incidence rate of 13.9 cases ± 2.4 SD of HTX per one hundred thousand inhabitants, with a global standardized incidence of 80 cases per million inhabitants and year, of which 12% required hospitalization and 6% they died The study authors extrapolated these results to the rest of the French population, calculating an incidence of 8,000 new cases of hepatotoxicity per year, among which there would be 500 deaths for that reason. It is important to note that these results involved a number of HTX cases 16 times greater than those notified to the French health authorities, corroborating the existence of the problem of infranotification previously exposed.
In Spain, Ibáñez et al. They conducted a prospective study in Catalonia, whose result obtained an incidence of 7.4 cases of severe acute liver disease secondary to drugs per million inhabitants and year, with a mortality of 0.8 per million and year. Unlike this study, the incidence calculated by another group in Malaga was higher, resulting in a crude annual incidence of 34.2 ± 10.7 cases per million and a serious liver disease incidence of 16.6 ± 6.7 cases per million inhabitants and year. The reason why this incidence is still lower than that found in France probably responds to the fact that in the local study only patients from the hospital were included, not counting the cases studied and followed in primary care and pediatric patients. Finally, a retrospective population case-control study, conducted using a British database, estimated an incidence of serious idiopathic liver disease, possibly drug-related, of 2.4 cases per 100,000 inhabitants per year9. It is estimated that HTX accounts for between 1/600 to 1 / 3,500 of all hospital admissions and it is estimated that drugs are responsible for 2-5% of cases of jaundice admitted to a hospital, of approximately 10% of patients. cases of acute hepatitis and 7-20% of cases of fulminant liver failure.
In Spain, toxic hepatitis constitutes 14% of the cases of liver injury admitted to a hospital (valued as elevation of transaminases above 400 IU / dl). Another important fact is that the drugs have reached first place as a cause of fulminant liver failure (FHF) both in the United States and in Europe. A prospective multicenter study of the Acute Liver Failure Study Group (ALFSG) cooperative group, which assesses the consecutive admissions of patients with acute liver failure in 17 hospitals in the United States, notes the medications (including cases of paracetamol poisoning: 39%) as the most frequent cause of acute liver failure, surpassing even those produced by hepatitis A and B viruses. The percentage of cases of fulminant liver failure secondary to idiosyncratic hepatotoxicity varies from 7% to 16% according to studies conducted in different countries. However, a substantial proportion of cases of severe acute liver failure remain unclassified after a thorough evaluation. The detection of paracetamol-protein adducts (HTX subrogated marker) in 19% of this type of patients has yielded new evidence on the responsibility of drugs in at least part of the cases of idiopathic liver failure. Although it is important to keep in mind that any drug or substance outside the body may be susceptible to liver damage, there is great variability in the hepatotoxic potential of different medications. Such harmful potential or frequency with which a medicinal agent induces liver toxicity is also unknown in practice, since, although for certain medications the number of liver damage cases (numerator) can be calculated with relative precision, it is impossible to determine the total exposed subjects (denominator). Most estimates place the prevalence of idiosyncratic hepatic adverse reactions between 1/10000 to 1/100000 exposures for most drugs. At present, the commercialized drugs that have a higher prevalence of hepatotoxicity (about 1%) are isoniazid, chlorpromazine and tacrine.
In addition to the above, the frequency of drugs charged in liver toxicity events changes over time and from one country to another. In the 60s the most frequent cause of jaundice produced by drugs was chlorpromazine, being replaced by halothane in the 70-8010s. These drugs have been replaced today by others with lower hepatotoxic potential, but more prescriptions, so currently the most frequently incriminated pharmacological groups in the onset of idiosyncratic hepatotoxic reactions are anti-infectives, including antituberculous drugs. Central nervous system and musculoskeletal drugs. As for the geographical difference, paracetamol is the drug that is most frequently attributed as a cause of HTX in the United Kingdom and the United States. In contrast, in our field the drug that independently produces the highest number of HTX cases is the antibiotic amoxicillin-clavulanic acid (14% of all cases included in a hepatotoxicity registry). Finally, other substances that are gaining importance in hepatotoxic reactions are drugs of abuse such as cocaine, ecstasy and amphetamine derivatives, herbal products and excipients of drug formulations.
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