Medications and liver

The interaction between drugs and the liver can be divided into three aspects:

1. the effect of liver disease on the metabolism of drugs,
2. toxic effects of drugs on the liver and
3. metabolism of drugs in the liver. The number of possible interactions is enormous.

[1], [2], [3], [4]

The effect of liver disease on the metabolism of drugs

Liver diseases can complexly influence the excretion, biotransformation and pharmacokinetics of medicinal substances. In these effects, a variety of pathogenetic factors are involved: intestinal absorption, binding to plasma proteins, liver excretion rate, intrahepatic blood flow and portosystemic shunting, bile secretion, hepatoenteric circulation and renal clearance. The final result of the action of the drug is unpredictable and does not correlate with the nature of the liver damage, its severity or the results of hepatic laboratory tests. Thus, there are no general rules governing the change in the dosage of drugs in patients with liver disease.

The clinical effect can change regardless of the bioavailability of the drug, especially in chronic liver disease; for example, the sensitivity of the brain to opiates and sedatives is often increased in patients with chronic liver disease; so, sufficiently low doses of these drugs can accelerate the development of encephalopathy in patients with cirrhosis. The mechanism of this effect can be caused by changes in receptors to drugs in the brain.

Liver damage caused by drugs

At the heart of liver damage caused by drugs, there are different mechanisms, complex and often not clear enough. Some medicines have a direct toxic effect, when applied, toxic effects occur frequently, their effect begins within a few hours after ingestion and depends on the dose. Other drugs rarely lead to impairment, and only in susceptible individuals; as a rule, liver damage occurs within a few weeks after taking the drug, but can sometimes be delayed for several months. These lesions do not depend on the dosage. Such reactions are rarely allergic; more precisely, they correspond to the phenomenon of idiosyncrasy. The difference between direct toxicity and idiosyncrasy may not always be clear; for example, some drugs, the toxic effect of which is first associated with increased sensitivity, can damage cell membranes due to direct toxic effects of intermediate metabolites.

Although there is currently no classification system for liver damage caused by drugs, acute reactions (hepatocellular necrosis), cholestasis (with or without inflammation) and mixed reactions can be identified. Some drugs can cause chronic damage, which in rare cases leads to tumor growth.

Frequent reactions of hepatotoxic drugs

A drug	Reaction
Paracetamol	Acute direct hepatocellular toxicity; chronic toxicity
Allopurinol	A variety of acute reactions
Mushroom white grebe (Amanita)	Acute direct hepatocellular toxicity
Aminosalicylic acid	A variety of acute reactions
Amiodarone	Chronic Toxicity
Antibiotics	A variety of acute reactions
Antineoplastic agents	Mixed acute reactions
Derivatives of arsenic	Chronic Toxicity
Aspirin	A variety of acute reactions
C-17-alkylated steroids	Acute cholestasis, steroid type
Chloropropamide	Acute cholestasis, phenothiazine type
Diclofenac	Acute idiosyncratic hepatocellular toxicity
Erythromycin estolate	Acute cholestasis, phenothiazine type
Halothane (anesthetic agent)	Acute idiosyncratic hepatocellular toxicity
Hepatic antitumor drugs for intraarterial administration	Chronic Toxicity
Inhibitors of HMGCOoA reductase	A variety of acute reactions
Hydrocarbonates	Acute direct hepatocellular toxicity
Indomethacin	Acute idiosyncratic hepatocellular toxicity
Iron	Acute direct hepatocellular toxicity
Isoniazid	Acute idiosyncratic hepatocellular toxicity; chronic toxicity
Methotrexate	Chronic Toxicity
Methyldopa	Acute idiosyncratic hepatocellular toxicity; chronic toxicity
Methyltestosterone	Acute cholestasis, steroid type
Inhibitors of monoamine oxidase	Acute idiosyncratic hepatocellular toxicity; chronic toxicity
A nicotinic acid	Chronic Toxicity
Nitrofurantoin	Chronic Toxicity
Phenothiazines (eg, chlorpromazine)	Acute cholestasis, phenothiazine type; chronic toxicity
Phenylbutazone	Acute cholestasis, phenothiazine type
Phenytoin	Acute idiosyncratic hepatocellular toxicity
Phosphorus	Acute direct hepatocellular toxicity
Propylthiouracil	Acute idiosyncratic hepatocellular toxicity
Quinidine	Mixed acute reactions
Sulfonamides	Mixed acute reactions
Tetracycline, high doses in / in	Acute direct hepatocellular toxicity
Tricyclic antidepressants	Acute cholestasis, phenothiazine type
Valproate	A variety of acute reactions
Vitamin A	Chronic Toxicity
Oral contraceptives	Acute cholestasis, steroid type

Hepatocellular necrosis

According to the mechanism of development, hepatocellular necrosis can be associated with direct toxic action and idiosyncrasy, although this difference is somewhat artificial. The main feature is an increase in the level of aminotransferases, often to extremely high values. Patients with mild or moderate hepatocellular necrosis may develop clinical manifestations of hepatitis (eg, jaundice, malaise). Severe necrosis can occur as fulminant hepatitis (eg, liver failure, portosystemic encephalopathy).

Direct toxicity. Most drugs that have a direct hepatotoxic effect cause dose-dependent necrosis of the liver; other organs (for example, the kidneys) are often affected.

Direct hepatotoxic damage in the administration of prescribed drugs can be prevented or minimized if the recommendations regarding the maximum doses of the drug are strictly observed and the patient's condition is monitored. Poisoning with direct hepatotoxins (eg, paracetamol, iron preparations, pallid grebe) often leads to gastroenteritis for several hours. However, liver damage can occur only after 1-4 days. The use of cocaine sometimes causes acute hepatocellular necrosis - probably due to the development of hepatocellular ischemia.

Idiosyncrasy. Drugs can cause acute hepatocellular necrosis, which is even histologically difficult to differentiate from viral hepatitis. The mechanisms of its development are not completely clear and probably differ for different preparations. The most fully explored isoniazid and halothane.

The mechanism of development of rare halothane-induced hepatitis is unclear, but may include the formation of active intermediates, cellular hypoxia, lipid peroxidation and autoimmune damage. Risk factors include obesity (perhaps due to the deposition of halothane metabolites in adipose tissue) and repeated anesthesia in relatively short periods of time. Hepatitis usually develops in a few days (up to 2 weeks) after application of the drug, manifested by fever; the course of hepatitis is often severe. Sometimes there is eosinophilia or a rash on the skin. Mortality reaches 20-40% in the case of severe jaundice, but surviving patients usually recover completely. Methoxyflurane and enflurane - similar to halothane anesthetics - can cause the same syndrome.

Cholestasis

Many drugs cause mainly the reaction of cholestasis. Pathogenesis is not fully understood, but at least clinically and histologically, two forms of cholestasis are distinguished: phenothiazine and steroid types. Diagnostic examination, as a rule, includes a non-invasive instrumental study to exclude biliary obstruction. Further research (for example, magnetic resonance cholangiopancreatography, ERCPH, liver biopsy) is necessary only with the preservation of cholestasis, despite the withdrawal of the drug.

The phenothiazine type of cholestasis is a periportal inflammatory reaction. Immunological mechanisms are confirmed by such changes as periodic eosinophilia or other manifestations of hypersensitivity, but also possible toxic damage to the hepatic ducts. This type of cholestasis occurs in approximately 1% of patients taking chlorpromazine, and more rarely with the use of other phenothiazines. Cholestasis, as a rule, is acute and is accompanied by fever and high levels of aminotransferases and alkaline phosphatase. Differential diagnosis of cholestasis and extrahepatic obstruction can be difficult, even on the basis of liver biopsy. The abolition of the drug usually leads to a complete resolution of the process, although in rare cases progression of chronic cholestasis with fibrosis is possible. Similar in clinical manifestations of cholestasis are tricyclic antidepressants, chlorpropamide, phenylbutazone, erythromycin estolate and many others; but the possibility of chronic liver damage is not fully established.

The steroid type of cholestasis is more the result of the enhancement of the physiological effect of sex hormones on bile formation than immunological sensitivity or cytotoxic action on cell membranes. Damage to excretory ducts, microfilament dysfunction, changes in membrane fluidity, and genetic factors may be important. Hepatocellular inflammation may be minor or nonexistent. The incidence varies from country to country, an average of 1-2% among women taking oral contraceptives. Characteristic gradual asymptomatic beginning of development of cholestasis. The level of alkaline phosphatase increases, but the levels of aminotransferases are usually not very high, and liver biopsy shows only stagnation of bile in the central zones with a small portal or hepatocellular lesion. In most cases, after the discontinuation of the drug, the complete reverse development of cholestasis occurs, but a longer duration may occur.

Cholestasis during pregnancy is closely related to cholestasis caused by steroid drugs. Women with cholestasis of pregnancy can subsequently develop cholestasis when using oral contraceptives and vice versa.

[5], [6], [7], [8], [9], [10], [11]

A variety of acute reactions

Some drugs cause mixed forms of liver dysfunction, granulomatous reactions (eg, quinidine, allopurinol, sulfonamides) or various liver damage that are difficult to classify. HMGCoA reductase inhibitors (statins) cause subclinical increases in aminotransferase levels in 1-2% of patients, although clinically severe liver damage is rare. Many antineoplastic agents also cause liver damage; mechanisms of liver damage are different.

[12], [13], [14], [15], [16],

Chronic liver disease

Certain drugs can cause chronic liver damage. Isoniazid, methyldopa and nitrofurantoin can cause chronic hepatitis. In the absence of fibrosis, the reverse development usually occurs. The disease can begin acutely or imperceptibly. There may be progression with the development of cirrhosis of the liver. In rare cases, a histological pattern similar to chronic hepatitis with sclerosis occurs in patients taking long-term paracetamol at low doses, for example 3 g per day, although higher doses are usually used. People who abuse alcohol are more prone to chronic liver damage, the possibility of which should be borne in mind when an unusually high level of aminotransferases is detected, especially ACT (the increase rarely exceeds 300 IU with only alcoholic hepatitis). Amiodarone sometimes causes chronic liver damage with Mallory's bodies and histological signs resembling alcoholic liver disease; the pathogenesis is based on the phospholipidosis of cell membranes.

A syndrome similar to sclerosing cholangitis can develop with intraarterial hepatic chemotherapy, especially with floxuridine. In patients who receive methotrexate for a long time (usually with psoriasis or rheumatoid arthritis), progressive liver fibrosis can develop imperceptibly, especially when alcohol is used or when the drug is taken every day; functional liver tests are often uninformative, and liver biopsy is necessary. Although methotrexate-induced fibrosis is rarely clinically apparent, most authors recommend a liver biopsy if the total dose of the drug reaches 1.5-2 g, and sometimes after the completion of primary-care treatment. Fibrosis of the liver without cirrhosis, which can lead to the development of portal hypertension, may be due to the use of drugs containing arsenic, excessive doses of vitamin A (for example, more than 15,000 U / day for several months) or nicotinic acid. In many tropical and subtropical countries, chronic liver disease and hepatocellular carcinoma are thought to result from eating foods that contain aflatoxins.

In addition to the occurrence of cholestasis, oral contraceptives can also sometimes cause the formation of benign adenomas of the liver; in very rare cases, hepatocellular carcinoma occurs. Adenomas occur usually subclinically, but can be complicated by a sudden intraperitoneal rupture and bleeding requiring emergency laparotomy. Most adenomas are asymptomatic and are diagnosed accidentally during instrumental examination. Because oral contraceptives cause hypercoagulation, they increase the risk of hepatic vein thrombosis (Badd-Chiari syndrome). The use of these drugs also increases the risk of gallstones, since the lithogenicity of bile increases.

[17], [18], [19], [20]

Diagnosis and treatment of the effect of drugs on the liver

Hepatotoxicity caused by drugs can be assumed if the patient has unusual clinical manifestations of liver disease (for example, mixed or atypical signs of cholestasis and hepatitis); with hepatitis or cholestasis, if the main causes are excluded; when treated with a drug with known hepatotoxicity, even in the absence of symptoms or signs; or if histological changes that indicate a drug etiology are found in liver biopsy. The development of hemolytic jaundice caused by the drug may indicate hepatotoxicity, but in such cases hyperbilirubinemia is observed due to indirect bilirubin with normal results of other functional liver tests.

No diagnostic tests can confirm that liver damage is caused by a drug. The diagnosis requires the exclusion of other possible causes (for example, an instrumental examination to exclude biliary obstruction with symptoms of cholestasis, serological diagnosis in detecting hepatitis), and a temporary link between taking the drug and developing hepatotoxicity. The recurrence of clinical manifestations of hepatotoxicity after resumption of drug administration is the most important confirmation, but because of the risk of severe liver damage with suspected hepatotoxicity, the drug is usually not re-administered. Sometimes a biopsy is necessary to exclude other treatable conditions. If the diagnosis after the examination remains unclear, you can cancel the drug, which will help to establish the diagnosis and will have a therapeutic effect.

For some drugs that have direct hepatotoxicity (eg, paracetamol), the concentration of the drug in the blood can be determined to assess the likelihood of liver damage. However, if the tests are not carried out immediately, the concentration of the drug may decrease. Numerous over-the-counter preparations of plant origin cause toxic damage to the liver; in patients with liver disease of unclear etiology, an anamnesis should be collected regarding the use of such drugs.

Treatment of drug damage to the liver is mainly in the withdrawal of the drug and the measures of maintenance therapy.

[21], [22], [23], [24]