Drug induce liver disease mita

DRUG-INDUCED LIVER INJURY (dili)

POSTGRADUATED PROGRAM MASTER OF CLINICAL PHARMACYFACULTY OF PHARMACY AIRLANGGA UNIVERSITY

2011

PRESENTER : MADE ARY SARASMITA, S.FARM, APT

HUBBY H.P, S.Si, APTJOSEPHINE P. A., S.FARM, APT ATIKA VITASARI, S.FARM, APT

RENNIE PUSPA N., S.FARM, APTA. ADELSA D., S.FARM., APT

EMA PRISTI YUNITA, S.FARM., APT

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REVIEW Presented at : Pediatric Sp-1 Program, Dept. of Pediatrics, Airlangga Univ-Dr.Soetomo Teaching

Hospital

LIVER physiologic function

(Barret, E.K., Barman, S.M., Boitano, S., Brooks, H.L., 2010, Ganong’s Review of Medical Physiology, 23rd edition, USA: The McGraw-Hills Comp.)

Formation and secretion of

bile

Nutrient and vitamin metabolism (amino acid, lipid,

glucose)

Detoxification & inactivation of

various substances (toxin, drug)

Synthesis of plasma proteins (albumin,

clotting factor)

Immune system

kupffer cells.

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DRUG-INDUCED LIVER INJURY / DISEASE (DILI)Liv

er injury may be produced by a large variety of chemical substances

The type and degree of injury produced is extremely varied, and may mimic the entire spectrum of hepatobiliary disorders.

Drugs can initiate progressive chronic liver disease and are the single leading cause of acute liver failure.

Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp.

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Risk factors of liver injury

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Pharmacokinetics – Metabolism

Specific immune system

Initial liver injury

Progression of liver injury

Cytokine, TNF, ROS

Acute liver failure

Chronic liver failure

Enviromental Risk Factor Genetic Risk Factor

• Grattagliano, I., Bonfrate, L. et al., Biochemical mechanisms in drug-induced liver injury: certainly and doubts, World J Gastroenterol 2009 October 21;15(39):4865-4876

Environmental Hepatotoxin & Associated Occupations at Risk

for Exposure

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Kirchain, WR & Allen, RE 2008, ‘Drug-Induced Liver Disease’, In: Joseph T.Dipiro, Barbara, G.Wells, et al., Pharmacotherapy: A Pathophysiologic Approach , 7th Ed., The McGraw-Hill Companies, Inc , New York.


A General Diagram of biotransformation Of Drugs

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Pathway of Drug Hepatic Metabolism

• A, B, and C represent three different drugs. Drugs may undergo primary phase 2 biotransformation (A) or initial phase 1 and subsequent phase 2 metabolism (B). Drug C is secreted from the hepatocyte following phase 1 metabolism only.

• The oxidation-reduction & hydrolytic reactions referred to as phase 1 reactions increase the polarity or water solubility of a molc. through the generation of metabolically active moieties (hydroxyl groups) in the parent comp.


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MECHANISMS OF LIVER INJURY

William, M.Lee, Review Article : Medical Progress Drug-Induced Hepatotoxicity. N Engl J Med 2003;349:474-85)8

Schematic Representation of Toxic Damage of Hepatocyte in Response to High Dose of Drugs

• Grattagliano, I., Bonfrate, L. et al., Biochemical mechanisms in drug-induced liver injury: certainly and doubts, World J Gastroenterol 2009 October 21;15(39):4865-4876 9

Drug can impair MC function by the impairment of the OXPHOS, inhibition of FAO can induce vesicular steatosis. Reactive oxygen species (ROS) responsible for oxidative stress and lipid peroxidation (trigger the production of different cytokines that favor necroinflammation and fibrosis).

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•Drugs & its mechanisms to induce liver injury

IDIOSYNCRATIC DRUG REACTIONS

(William M. Lee, M.D. Review Article : Medical Progress Drug-Induced Hepatotoxicity, N Engl J Med 2003;349:474-85). 11

ANTICONVULSANT DRUG-INDUCED LIVER INJURY

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Virtually all of the major antiepileptic drugs can cause hepatotoxicity, although a fatal outcome is rare.

• Larrey, D., Drug Induced Liver Disease, Journal of Hepatology 2000;32 (Suppl.1): 77-88

Once hepatotoxicity develops, mortality rates are 10–38% with phenytoin and about 25% with carbamazepine. Elderly patients may be at higher risk.

• Aronson, J.K, 2005, Meyler ‘s Side Effect of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interaction, 5 th ed, USA: Elsevier.

Fatal valproate hepatotoxicity may occur with greater frequency in children under the age of 2 years who are receiving multiple drug therapy monitoring of LFT

• Ahmed, N., Siddiqi, Z.A., Antiepileptic drugs and liver disease, Seizure (2006)15,156-164

…..Phenytoin-Induced Hepatotoxicity

• The interval between the initiation of phenytoin therapy and the onset of clinical abnormalities ranges from 1 to 6 weeks in the vast majority of patients.

• Presenting symptoms fever, rash and lymph-adenopathy, Jaundice and hepato-splenomegaly.

• Biochemical features abnormal serum bilirubin, transaminases, and ALP levels

• The morphologic and pathologic abnormalities are non-specific primary hepatocellular degeneration and/or necrosis.

13Ahmed, N., Siddiqi, Z.A., Antiepileptic drugs and liver disease, Seizure (2006)15,156-164

…..Valproic Acid-Induced Hepatotoxicity

• The incidence of valproac acid- induced fatal hepatic dysfunction is 1 : 500, in children under 2 years

• The risk declines with age with a rate of 1/12,000 when used in polytherapy and 1/37,000 when used in monotherapy after the first 2 years of life.

• Certain risk factors Younger age, mental retardation, polypharmacy, stress, infection underlying liver disease, and history of metabolic disorders of metabolism.

• The idiosyncratic hepatic toxicity to valproic acid usually occurs during the first 2—3 months of therapy leads to vomiting, hemorrhage, increased seizures, anorexia, jaundice, edema, and ascites.

14Ahmed, N., Siddiqi, Z.A., Antiepileptic drugs and liver disease, Seizure (2006)15,156-164

Mechanisms of valproic acid-induced inhibition of mitochondrial fatty acid ß-oxidation.

VPA is an analogue of medium-chain fatty acid freely enters the mitochondrion and generates a coenzyme A ester (VPA-CoA) VPA-CoA inhibit carnitine palmitoyltransferase-1 (CPT 1), an enzyme catalyzing the step of MC entry and b-oxidation of long-chain fatty acids reduces mitochondrial levels of CoA (cofactor for FAO).

• Begriche, K., Massart, J., Robin, M.A., Review: Drug induced toxicity on mitochondria and lipid metabolism: Mechanistic diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794

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Antituberculosis Drug-Induced Hepatotoxicity

• The incidence of ATDH during standard multidrug TB treatment has been variably reported as between 2% and 28%.

• Isoniazid, rifampicin and PZA are potentially hepatotoxic drugs. No hepatotoxicity has been described for ethambutol or streptomycin.

• The risk of hepatotoxicity was associated with female sex (OR =4,1; 95% CI = 1.2, 14) and presumed recent infection (OR = 14,3; 95% CI = 1.8, 115)

(Aronson, J.K, 2005, Meyler ‘s Side Effect of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interaction, 5 th ed, USA: Elsevier).

(Alma Tostmann, Martin J Boeree,Rob E Aarnoutse, Wiel C M de Lange, Andre J A M van der Vens and Richard Dekhuijzen, Review : Antituberculosis drug-induced hepatotoxicity: Concise up-to-date review. Journal of Gastroenterology and Hepatology 23 (2008) 192–202 © 2007 The Authors)

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ISONIAZID•Isoniazid-induced hepatotoxicity is considered idiosyncratic.•can affect any organ system include IgE-mediated reactions as well as reactive metabolite syndromes

PIRAZINAMID•PZA to pyrazinoic acid and oxidized to 5-hydroxypyrazinoic acid by xanthine oxidase•In a rat study, PZA inhibited the activity of several CYP450 isoenzymes (2B, 2C, 2E1, 3A), but a study in human liver microsomes showed that PZA has no inhibitory effect on the CYP450 isoenzymes.

RIFAMPICIN•The major pathway desacetylation into desacetylrifampicin, separately hydrolysis produces a 3-formyl rifampicin. •Rifampicin a potent inducer of the hepatic CYP450S increasing metabolism of many other compounds.

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Among 148 patient who were given the combination PZA + Rifampicin for 2 month grade 3 hepatotoxicity (transaminase >5-20 times the upper limit of reference range) and grade 4 hepatotoxicity (transaminase >20 times) were reported in 10 and 4 patient respectively.

Monitoring of LFT and patient’s linical symptoms.

Aronson, J.K, 2005, Meyler ‘s Side Effect of Drugs: The International Encyclopedia of Adverse Drug Reactions and Interaction, 5 th ed, USA: Elsevier).

ANTIRETROVIRAL DRUG-INDUCED LIVER INJURY

• The frequency of hepatic injury associated with ARV is at least 10% • Because co-infection with HBV or HCV in HIV patients increases the risk of

toxicity, all patients should be screened for viral hepatitis before starting ARV

18Spengler, U., Lichterfeld, M., Rockstroh, K.J., Review: Antiretroviral drug toxicity, Journal of Hepatology 36 (2002) 283–294

ACETHAMINOPHEN-INDUCED LIVER INJURY

• Most common cause of DILI, and is an important cause of acute liver failure

• Single doses exceeding 7 to 10 g (140 mg/kg of body weight in children) liver injury severe (as indicated by serum ALT levels > 1000 U/L) or fatal liver injury

• Among persons with an untreated acetaminophen OD, severe liver injury occurred in only 20% among those with severe liver injury, the mortality rate was 20%.

• Risk factors for acetaminophen hepatotoxicity – Age– Dose: >150 mg/kg in children; Severe toxicity possible with dose >15

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Mechanism of Acetaminophen-induced Hepatotoxicty

At usual therapeutic dosages, acetaminophen is metabolized conjugation reactions. The capacity becomes saturated at higher dosages diversion of the drug to the P-450-mediated pathway generates reactive electrophile N-acetyl-p-benzoquinone imine (NAPQI) undergoes phase 2 conjugation with glutathione glutathione depletion allowing the electrophile to exert damaging effects within the cell via covalent binding.

Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp. 20

Practical Guideline for Diagnosis & Early Management of DILI

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Preplanned LFT, evaluation of drug

DILI is unlikely DILI is suspected

Diagnosis of DILI

Hepatocellular type or

mixed

Discontinue the suspected

drug

Cholestatic type

Careful monitoring

ALT > 8 x ULN at any one time or

ALT > 5 x ULN for more than 2 wk or

ALT > 3 x ULN, and total bilirubin > 2 x ULN or

PT-INR > 1.5 x UNL

Symptoms related to liver injury such

as jaundice orTotal bilirubin > 3 x

ULN orPT-INR > 1.5 x ULN

When a drug is initiated

When liver dysfunction is recognized

Ignazio G., Leonilde B., Catia V.D, Biochemical mechanisms in drug-induced liver injury, World J Gastroenterol 2009 October 21; 15(39): 4865-4876

Child-Pugh Scores for Patients with Liver Disease

Child-Pugh Scores for Patients with Liver Disease

Score 8-9 : 25 % normal doseScore > 10 : 50 % normal dose

Bauer L.A. et al, 2008, Applied Clinical Pharmacokinetics, 5TH edition, USA: McGraw-Hill. 22

Key Guideline in the Recognition & Prevention of Hepatotoxicity in Clinical Practice

Do not ignore the symptoms

Take a careful history

Remove the causative

agent

Monitoring• Symptom• LFT

23Victor J. Navarro, M.D., and John R. Senior, M.D., 2006, Drug-Related Hepatotoxicity, The New England Journal

of Medicine, vol. 354, pp. 731-739.

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…THANK YOU… …TERIMA KASIH

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Fig. 2. Metabolic consequences of severe inhibition of mitochondrial fatty acid b-oxidation. A severe impairment of mitochondrial fatty acid oxidation (FAO) can induce accumulation of free fatty acids and triglycerides , reduced ATP synthesis and lower production of ketone bodies. Inhibition of FAO also decreases gluconeogenesis through mechanisms including lower ATP production and reduced pyruvate carboxylase (PC). The accumulation of free fatty acids (and some of their metabolites such as dicarboxylic acids) could play a major role in the pathophysiology of microvesicular steatosis.

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Mechanisms of Drug-Induced Liver Injury

• The clinical features of some cases of DILI (Drug-Induced Direct Hepatotoxicity) strongly suggest an involvement of the adaptive immune system. These clinical characteristics include (1) concurrence of rash, fever, and eosinophilia; (2) delay of the initial reaction (1-8 weeks) or requirement of repeated exposure to the culprit drug; (3) rapid recurrence of toxicity on reexposure to the drug; and (4) presence of antibodies specifi c for native or drug-modifi ed hepatic proteins.

• Drugs suspected to induce these types of reactions include halothane, tienilic acid, dihydralazine, diclofenac, phenytoin, and carbamazepine

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Mechanism of Drug Hepatotoxicity


28Victor J. Navarro, M.D., and John R. Senior, M.D., 2006, Drug-Related Hepatotoxicity, The New England Journal of Medicine, vol. 354, pp. 731-739.

30(The new england journal of medicine. N Engl J Med 2003;349:474-85. Review Article : Medical Progress Drug-Induced Hepatotoxicity. William M. Lee, M.D.)

32• Begriche, K., Massart, J., Robin, M.A., Review: Drug induced toxicity on mitochondria and lipid metabolism:

Mechanistic diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794

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PENJELASAN GAMBAR DI ATAS ini kamu baca aja mita jangan dimasukkan ppt

A general diagram of biotransformation. (1) The drug is actively transported into the hepatocyte by the organic anion transport pump, a transmembrane protein. (2) The metabolite (drug) interacts with one of a number of enzymes, the most common being CYP2C9, 2C19, 2D6, and 3A4. This family of enzymes is regulated by the complementary DNA xenobiotic receptor. The xenobiotic receptor is in turn upregulated by other drugs, changes in cholesterol catabolism, and bile acids. (3) The immediate result of the action of these phase I enzymes is the production of an unstable metabolite. (4) The unstable metabolite then reacts with glucuronidase, various transferases, or hydroxylases to form a conjugated metabolite. The efficacy of these enzymes is affected by the patient’s nutritional state and genetic polymorphism, leading to variations in individual risk for toxicity. (5) The conjugated metabolite is removed from the hepatocyte by the canalicular membrane export pump, one of a large family of membrane proteins (other members of this family pump conjugated metabolites back into the blood for excretion by the kidney). These proteins are subject to genetic polymorphism as well, again leading to somAe patients having an increased risk for toxicity. (6) If unable to form a conjugate, the unstable metabolite can participate in oxidative reactions that damage lipids, proteins, or even DNA. (7) Alternatively the unstable metabolite may form damaging covalent bonds with available anions or cations. (SNP, indicates points in this process that are influenced by an individual’s single nucleotide polymorphisms.)

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MECHANISMS OF DRUG-INDUCED LIVER DISEASE1) STIMULATION OF AUTOIMMUNITY

Autoimmune injuries involve antibody mediated cytotoxicity or direct cellular toxicity This type of injury occurs when enzymedrug adducts migrate to the cell surface and form neoantigens The neoantigens serve as targets for cytolytic attack by T cells The injury may be exacerbated by the recruitment of inflammatory cells Halothane, sulfamethoxazole, carbamazepine, and nevirapine are associated with autoimmune injuries Stimulation of autoimmunity is often associated with some stage of all fulminant presentationsDantrolene, isoniazid, phenytoin, nitrofurantoin, and trazodone are associated with a type of autoimmune-mediated disease in the liver called chronic active hepatitis Antinuclear antibodies appear in most patients These drugs appear to form antiorganelle antibodies

2) IDIOSYNCRATIC REACTIONSIdiosyncratic drug-related hepatotoxicity is rare and usually occurs in a small proportion of individuals. These adverse reactions are often categorized into allergic and nonallergic reactions The allergic reactions are characterized by fever, rash, and eosinophilia. They are usually dose-related and have a short latency period (<1 month). Upon reexposure to the offending agent, the patient will experience rapid recurrence of hepatotoxicity. Studies show that minocycline, nitrofurantoin, and phenytoin can cause allergic reactions. The nonallergic idiosyncratic reactions are devoid of the hypersensitivity features and usually have a long latency period (several months). 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 drugrelated hepatotoxicity.

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3) DISRUPTION OF CALCIUM HOMEOSTASIS AND CELL MEMBRANE INJURYDrug-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

4) METABOLIC ACTIVATION OF THE CYTOCHROME P450 ENZYMESMost hepatocellular injuries 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 formationIn 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 injury. Individual genetic differences can play a role in the significance of this process patients with a single nucleotide polymorphism (SNP) that codes for slow-reacting variants of CYP450 will react differently from those with a SNP that codes for very-fast-reacting variants

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ANATOMY OF LIVER

Tank, Patrick W.; Gest, Thomas R.2009. Atlas of Anatomy, USA: Lippincott Williams & Wilkins.

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Mechanisms of Drug-Induced Macrovacuolar Steatosis and

Steatohepatitis.

• The progression of steatosis into steatohepatitis in some patients involves the production of reactive oxygen species (ROS) responsible for oxidative stress and lipid peroxidation (trigger the production of different cytokines such as TNFa and TGFb that favor necroinflammation and fibrosis).


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• Drug can impair MC function mechanism: impairment of the OXPHOS, inhibition of FAO

• Can induce necrosis/apoptosis cytolytic hepatitis• A severe inhibition of MC FAO can induce vesicular steatosis• Impairment of MC FAO can be direct / indirect

Drug induced mitcochondrial dysfunction


KEY POINTS OF DRUG-INDUCED LIVER DISEASE

Drug induce liver disease mita

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