Hepato-toxic drugs

Generality

Hepatotoxic drugs are drugs used for the treatment of very different pathologies, which include a potentially harmful effect on the liver, among other side effects.

In fact, hepatotoxicity is defined as the ability possessed by a substance to exert a damaging effect on the liver . More in detail, when hepatotoxicity is induced by drugs, it is preferable to speak of " iatrogenic hepatotoxicity ".

The liver is a fundamental organ, which carries out many activities within our body, including the metabolism of drugs. However, some drugs, or some products deriving from their metabolism, can cause damage - sometimes very serious - to liver cells, thus compromising their correct functionality.

Types of Hepatotoxicity

Hepatotoxic drugs can cause various types of liver damage. These damages can be classified in different ways and with different criteria.

A first possible classification is that which defines liver damage as adverse reactions deriving from the administration of hepatotoxic drugs and which divides these reactions into two categories:

• Type A reactions: are so-called predictable and dose-dependent reactions. These reactions are characterized by a high incidence and are usually represented by hepatocellular necrosis, which can be caused directly by a drug, or by its metabolite. An example may be that of paracetamol, whose metabolism leads to the formation of a toxic metabolite which, at low doses, the liver is able to neutralize, while at high doses no.
• Type B reactions: these reactions are unpredictable, dose-independent and characterized by a low incidence. Typically, type B reactions are idosyncratic or immune-mediated and may occur in the form of acute hepatitis, chronic active hepatitis, granulomatous hepatitis, cholestasis (with or without hepatitis), chronic cholestasis, steatosis, acute hepatocellular necrosis and liver tumors.

The timing with which hepatotoxic drugs can cause type A reactions may vary from a few days up to a few weeks; while type B reactions may appear even months or even years after the administration of the hepatotoxic drugs in question has begun.

A further subdivision can be made depending on the type of damage caused by hepatotoxic drugs. In this case, we can distinguish:

• Hepatocellular damage;
• Cholestatic damage;
• Mixed damage.

Mechanisms of hepatotoxicity

There are many mechanisms of action through which hepatotoxic drugs can induce liver damage. Among these, we recall:

• Formation of radical species that induce oxidative stress thus damaging liver cells;
• Damage to the cellular organelles of hepatocytes, such as, for example, mitochondria;
• Interaction with hepatic microsomal systems;
• Interactions and consequent damage to the bile duct cells;
• Interaction of the drug, or its metabolites, with molecules present on the membrane of hepatocytes, or contained within them, which can lead to the blocking of normal cellular functions or to the blocking of chemical reactions absolutely necessary for cell survival.

Types of Hepatotoxic Drugs

Hepatotoxic drugs are numerous and belong to the most diverse therapeutic classes, from anti-inflammatories, to pass through antidepressants and antibiotics, up to immunosuppressants and anticancer drugs (those just listed are however only some of the classes of drugs that include them) potentially hepatotoxic active ingredients).

However, to get a simpler picture, all these hepatotoxic drugs can be grouped according to the type of liver damage they are able to trigger.

In this regard, we can subdivide these drugs in the following way:

Hepatotoxic drugs that cause hepatocellular type damage

• NSAIDs;
• Antiretrovirals;
• Antidepressants, such as fluoxetine, paroxetine, sertraline, bupropion and trazodone;
• Antihypertensives, such as lisinopril and losartan;
• Antibiotics and antibacterials, such as pyrazinamide, isoniazid, rifampicin and tetracyclines;
• Gastroprotectors, such as omeprazole;
• Antiarrhythmics, such as amiodarone;
• Antitumorals, such as methotrexate;
• Paracetamol (an analgesic-antipyretic);
• Ketoconazole (an antifungal);
• Baclofen (a muscle relaxant).

Hepatotoxic drugs that cause cholestatic damage

• Antibiotics such as amoxicillin and erythromycin;
• Antipsychotics, such as chlorpromazine;
• Antifungals such as terbinafine;
• Estrogens and oral contraceptives;
• Anabolic steroids;
• Tricyclic antidepressants and mirtazapine.

Hepatotoxic drugs that cause mixed-type damage

• Sedative-hypnotics, such as carbamazepine and phenobarbital;
• Antibiotics and antibacterials, such as clindamycin, nitrofurantoin and sulfa drugs;
• ACE inhibitors, such as captopril and enalapril;
• Phenytoin (an anti-epileptic);
• Ciproeptadina (an antihistamine);
• Verapamil (a calcium channel blocker).

These are just some examples of drugs (known) that can give rise to liver toxicity.

Naturally, when the doctor decides to undertake a therapy based on known hepatotoxic drugs, it is very important that the functionality of the patient's liver is regularly monitored, so as to identify in a timely manner the onset of any damage to the liver.

Symptoms

The symptoms that can occur in patients following the use of hepatotoxic drugs vary depending on various factors, such as the type of active ingredient used, the dose of the drug administered, the patient's state of health, the presence of pre-existing liver diseases, etc. .

In any case, among the most common symptoms that can occur in case of liver damage, we recall:

• Temperature;
• Inappetence and anorexia;
• Body weight loss;
• Mild hepatomegaly;
• Nausea and vomit.

Blood analysis

However, any hepatotoxicity can also be detected by blood tests. More in detail, in the case of liver damage, generally occurs:

• Increased blood levels of ALT (alanine-aminotransferase) by two or three times the maximum limit considered normal;
• Increase in alkaline phosphatase levels by two times the maximum value considered normal;
• Increased total bilirubin blood levels by two times the maximum value considered normal, accompanied by an increase in plasma levels of ALT and alkaline phosphatase.

In the event that a drug induces hepatotoxicity - once it has been accurately diagnosed and that it has been ascertained that the drug is the triggering cause - the doctor will suspend the administration and take all appropriate measures to treat the damage that has been created.

Detection of Hepatotoxic Drugs

Sometimes, it can happen that a drug, before becoming hepatotoxic, is marketed and used, even for long periods of time.

For this reason, pharmacovigilance is a fundamental tool for identifying any hepatotoxic drugs not recognized as such in the pre-marketing study phases.

Thanks to this tool, in fact, it is possible to evaluate the safety of use of a medicine even after it is placed on the market, so as to guarantee continuous protection of the patient's health.

Pharmacovigilance, in turn, uses various tools to achieve its purpose, including the spontaneous reporting.

To put it in simple words, if a certain patient has experienced a side effect following the use of a given drug and this effect is not mentioned on the package insert of the same drug, but the doctor suspects that it could derive from its use, then he is required to report it promptly to the appropriate bodies that deal with pharmacovigilance (in Italy, this activity is carried out by AIFA, the Italian Drug Agency).

Thanks to this kind of reports, over the years it has been possible to identify several hepatotoxic drugs, some of which are still under close surveillance (as in the case, for example, of NSAID nimesulide); while others were withdrawn from the market, as the potential benefits of using them were significantly lower than the potential risks to patient health.