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DRUG INDUCED LIVER
FAILURE
Dr S P Nayak,
PharmD, RPh, (MSc), (Dip.Di)
Assistant Professor.
• The number of drugs associated with adverse
reactions involving the liver is extensive, but in
clinical practice is dominated by alcohol,
antibiotics, antiepileptic medications and
acetaminophen.
• Complementary (herbal) medicines contribute to
Liver Dysfuntion.
HEPATOCELLULAR INJURY
• Hepatocellular injury is characterized by
significant elevations in the
aminotransferases in serum which usually
precede elevations in total bilirubin levels
and alkaline phosphatase levels.
• Acarbose, allopurinol, fluoxetine, and losartan
are capable of causing hepatocellular injury
• Hepatocellular injuries can be further
subdivided by specific histologic patterns and
clinical presentations.
• Centrolobular necrosis,
• steatohepatitis (steatonecrosis),
• phospholipidosis, and
• TOXIC CIRRHOSIS
CENTROLOBULAR NECROSIS
• dose-related
• predictable reaction
• secondary to drugs such as acetaminophen,
aspirin, valproate
• The damage spreads outward from the middle of
a lobe of the liver.
• Impairs urea cycle and gluconeogenesis
• EXAMPLE:
• Acetaminophen
Taken from medscape
steatohepatitis(steatonecrosis)
• Steatohepatitis (also known as steatonecrosis) is a
specialized type of acute necrosis resulting from the
accumulation of fatty acids in the hepatocyte.
• Alcohol is the drug that most commonly produces
steatonecrotic changes in the liver.
• Tetracycline produces steatohepatitis and steatosis.
The mortality of tetracycline steatohepatitis is high
(70% to 80%), and those who do survive often
develop cirrhosis.
• Sodium valproate also can produce steatonecrosis
through the process of bioactivation. Cytochrome
P450 converts valproate to delta-4-valproic acid, a
potent inducer of microvesicular fat accumulation.
• Alcohol dehydrogenase pathway is the main pathway, by
which hydrogen is transferred from ethanol to nicotine
adenine dinucleotide (NAD), reducing it to NADH forming
acetaldehyde, The ratio of NAD to NADH (redox potential)
is therefore dramatically altered which contributes to
the development of metabolic abnormalities such as
1. alcoholic ketoacidosis,
2. impaired gluconeogenesis, and
3. alterations in lipid metabolism.
• The acetaldehyde that is formed is converted to acetic acid
by aldehyde dehydrogenase, which in turn is converted to
acetylcoenzyme A and enters the Krebs (citric acid) cycle
where it is metabolised to carbondioxide and water
PHOSPHOLIPIDOSIS
• Phospholipidosis is the accumulation of phospholipids
instead of fatty acids.
• Amiodarone is associated with this reaction. Patients
treated with amiodarone who develop overt hepatic
disease tend to have received higher doses of the drug.
• Amiodarone and its major metabolite N-desethyl-
amiodarone remain in the liver of all patients for
several months after therapy is stopped.
• Usually the phospholipidosis develops in patients
treated for more than 1 year. The patient can present
with either elevated aminotransferases or
hepatomegaly; jaundice is rare.
TOXIC CIRRHOSIS
• The scarring effect of hepatitis in the liver leads
to the development of cirrhosis.
• Methotrexate causes periportal fibrosis in most
patients who experience hepatotoxicity.
• Vitamin A is normally stored in liver cells, and
causes significant hypertrophy and fibrosis when
taken for long periods in high doses.
Hepatomegaly is a common finding, along with
ascites and portal hypertension. In patients with
vitamin A toxicity, gingivitis and dry skin are also
very common
MECHANISMS OF DRUG INDUCED
LIVER DAMAGE
• Autoimmune injury
• Autoimmune injuries involve antibody mediated
cytotoxicity or direct cellular.
• Halothane, sulfamethoxazole, carbamazepine,
and nevirapine are associated with autoimmune
injuries.
• Dantrolene, isoniazid, phenytoin, nitrofurantoin,
and trazodone are associated with a type of
autoimmune-mediated disease in the liver called
chronic active hepatitis
allergic reactions.
• Studies show that minocycline, nitrofurantoin,
and phenytoin can cause allergic reactions.
• These patients often have normal liver function
tests for 6 months or longer and then suddenly
develop hepatotoxicity. Dependent on the
medication, the incident can be independent of
dose or dose-related.
• Amiodarone, isoniazid, and ketoconazole are
associated with nonallergic drug related
hepatotoxicity.
DISRUPTION OF CALCIUM
HOMEOSTASIS AND CELL MEMBRANE
INJURY
• Drug-induced damage to the cellular proteins
that are involved with calcium homeostasis can
lead to an influx of intracellular calcium that
causes a decline in adenosine triphosphate levels
and disruption of the actin fibril assembly.
• The resulting impact on the cell is blebbing of the
cell membrane, rupture, and cell lysis.
• Lovastatin, venlafaxine, and phalloidin, which is
the active component of mushrooms, impair
calcium homeostasis.
METABOLIC ACTIVATION OF THE
CYTOCHROME P450 ENZYMES
• Most hepatocellular injuries involve the production of
high-energy reactive metabolites by the CYP450
system.
• These reactive metabolites are capable of forming
covalent bonds with cellular proteins (enzymes) and
nucleic acids that lead to adduct formation.
• In the case of acute toxicity, the enzyme-drug adduct
can cause cell injury or cell lysis.
• Adducts that form with DNA can cause longterm
consequences such as neoplasia. Acetaminophen,
furosemide, and diclofenac are examples of this
mechanism of liver.

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Drug induced liver disorders

  • 1. DRUG INDUCED LIVER FAILURE Dr S P Nayak, PharmD, RPh, (MSc), (Dip.Di) Assistant Professor.
  • 2. • The number of drugs associated with adverse reactions involving the liver is extensive, but in clinical practice is dominated by alcohol, antibiotics, antiepileptic medications and acetaminophen. • Complementary (herbal) medicines contribute to Liver Dysfuntion.
  • 3. HEPATOCELLULAR INJURY • Hepatocellular injury is characterized by significant elevations in the aminotransferases in serum which usually precede elevations in total bilirubin levels and alkaline phosphatase levels. • Acarbose, allopurinol, fluoxetine, and losartan are capable of causing hepatocellular injury
  • 4. • Hepatocellular injuries can be further subdivided by specific histologic patterns and clinical presentations. • Centrolobular necrosis, • steatohepatitis (steatonecrosis), • phospholipidosis, and • TOXIC CIRRHOSIS
  • 5. CENTROLOBULAR NECROSIS • dose-related • predictable reaction • secondary to drugs such as acetaminophen, aspirin, valproate • The damage spreads outward from the middle of a lobe of the liver. • Impairs urea cycle and gluconeogenesis • EXAMPLE: • Acetaminophen
  • 7. steatohepatitis(steatonecrosis) • Steatohepatitis (also known as steatonecrosis) is a specialized type of acute necrosis resulting from the accumulation of fatty acids in the hepatocyte. • Alcohol is the drug that most commonly produces steatonecrotic changes in the liver. • Tetracycline produces steatohepatitis and steatosis. The mortality of tetracycline steatohepatitis is high (70% to 80%), and those who do survive often develop cirrhosis. • Sodium valproate also can produce steatonecrosis through the process of bioactivation. Cytochrome P450 converts valproate to delta-4-valproic acid, a potent inducer of microvesicular fat accumulation.
  • 8. • Alcohol dehydrogenase pathway is the main pathway, by which hydrogen is transferred from ethanol to nicotine adenine dinucleotide (NAD), reducing it to NADH forming acetaldehyde, The ratio of NAD to NADH (redox potential) is therefore dramatically altered which contributes to the development of metabolic abnormalities such as 1. alcoholic ketoacidosis, 2. impaired gluconeogenesis, and 3. alterations in lipid metabolism. • The acetaldehyde that is formed is converted to acetic acid by aldehyde dehydrogenase, which in turn is converted to acetylcoenzyme A and enters the Krebs (citric acid) cycle where it is metabolised to carbondioxide and water
  • 9.
  • 10. PHOSPHOLIPIDOSIS • Phospholipidosis is the accumulation of phospholipids instead of fatty acids. • Amiodarone is associated with this reaction. Patients treated with amiodarone who develop overt hepatic disease tend to have received higher doses of the drug. • Amiodarone and its major metabolite N-desethyl- amiodarone remain in the liver of all patients for several months after therapy is stopped. • Usually the phospholipidosis develops in patients treated for more than 1 year. The patient can present with either elevated aminotransferases or hepatomegaly; jaundice is rare.
  • 11. TOXIC CIRRHOSIS • The scarring effect of hepatitis in the liver leads to the development of cirrhosis. • Methotrexate causes periportal fibrosis in most patients who experience hepatotoxicity. • Vitamin A is normally stored in liver cells, and causes significant hypertrophy and fibrosis when taken for long periods in high doses. Hepatomegaly is a common finding, along with ascites and portal hypertension. In patients with vitamin A toxicity, gingivitis and dry skin are also very common
  • 12.
  • 13. MECHANISMS OF DRUG INDUCED LIVER DAMAGE • Autoimmune injury • Autoimmune injuries involve antibody mediated cytotoxicity or direct cellular. • Halothane, sulfamethoxazole, carbamazepine, and nevirapine are associated with autoimmune injuries. • Dantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone are associated with a type of autoimmune-mediated disease in the liver called chronic active hepatitis
  • 14. allergic reactions. • Studies show that minocycline, nitrofurantoin, and phenytoin can cause allergic reactions. • These patients often have normal liver function tests for 6 months or longer and then suddenly develop hepatotoxicity. Dependent on the medication, the incident can be independent of dose or dose-related. • Amiodarone, isoniazid, and ketoconazole are associated with nonallergic drug related hepatotoxicity.
  • 15. DISRUPTION OF CALCIUM HOMEOSTASIS AND CELL MEMBRANE INJURY • Drug-induced damage to the cellular proteins that are involved with calcium homeostasis can lead to an influx of intracellular calcium that causes a decline in adenosine triphosphate levels and disruption of the actin fibril assembly. • The resulting impact on the cell is blebbing of the cell membrane, rupture, and cell lysis. • Lovastatin, venlafaxine, and phalloidin, which is the active component of mushrooms, impair calcium homeostasis.
  • 16. METABOLIC ACTIVATION OF THE CYTOCHROME P450 ENZYMES • Most hepatocellular injuries involve the production of high-energy reactive metabolites by the CYP450 system. • These reactive metabolites are capable of forming covalent bonds with cellular proteins (enzymes) and nucleic acids that lead to adduct formation. • In the case of acute toxicity, the enzyme-drug adduct can cause cell injury or cell lysis. • Adducts that form with DNA can cause longterm consequences such as neoplasia. Acetaminophen, furosemide, and diclofenac are examples of this mechanism of liver.