Drug molecule activate kupffer cell is metabolitically processed by hepatocyte result in hepatocyte stress with the contribution of ROS & nitrogen species from the activated endothelial cell. High dose drug release toxic product and chemotatic factor by damage hepatocyte intracellular damage result in necrotic death.
Drug induce liver disease mita
REVIEWPresented at : Pediatric Sp-1 Program, Dept. of Pediatrics, Airlangga Univ-Dr.Soetomo Teaching Hospital DRUG-INDUCED LIVER INJURY (dili) PRESENTER : MADE ARY SARASMITA, S.FARM, APT HUBBY H.P, S.Si, APT JOSEPHINE P. A., S.FARM, APT ATIKA VITASARI, S.FARM, APT RENNIE PUSPA N., S.FARM, APT A. ADELSA D., S.FARM., APT EMA PRISTI YUNITA, S.FARM., APTPOSTGRADUATED PROGRAM MASTER OF CLINICAL PHARMACY FACULTY OF PHARMACY AIRLANGGA UNIVERSITY 2011 1
LIVER physiologic function Detoxification & Nutrient and inactivation of Formation and vitamin various substancessecretion of bile metabolism (amino (toxin, drug) acid, lipid, glucose) Synthesis of plasma Immune system proteins (albumin, kupffer cells. clotting factor)(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.) 2
DRUG-INDUCED LIVER INJURY / DISEASE (DILI) Liver 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. The central role played by the liver in the clearance and biotransformation of chemical susceptibility to drug-induced injury. Drugs can initiate progressive chronic liver disease and are the single leading cause of acute liver failure. 3Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp.
Risk factors of liver injuryEnviromental Risk Factor Genetic Risk Factor Pharmacokinetics – Metabolism Specific immune system Initial liver injury Cytokine, TNF, ROS Progression of liver injury Chronic liver Acute liver failure failure • 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 4
Environmental Hepatotoxin & Associated Occupations at Risk for ExposureKirchain, 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. 5
A General Diagram of biotransformation Of DrugsKirchain, 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. 6
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. 7Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp.
MECHANISMS OF LIVER INJURYWilliam, 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 DrugsDrug can impair MC function by the impairment of the OXPHOS, inhibition of FAO can induce vesicularsteatosis. Reactive oxygen species (ROS) responsible for oxidative stress and lipid peroxidation (trigger theproduction of different cytokines that favor necroinﬂammation and ﬁbrosis). • 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
•Drugs & its mechanisms to induce liver injury 10
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 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 12
…..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.Ahmed, N., Siddiqi, Z.A., Antiepileptic drugs and liver disease, Seizure (2006)15,156-164 13
…..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. Ahmed, N., Siddiqi, Z.A., Antiepileptic drugs and liver disease, Seizure (2006)15,156-164 14
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 15 diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794
ISONIAZID PIRAZINAMID RIFAMPICIN • Isoniazid-induced • PZA to pyrazinoic • The major pathway hepatotoxicity is acid and oxidized to 5- desacetylation into considered hydroxypyrazinoic acid desacetylrifampicin, idiosyncratic. by xanthine oxidase separately hydrolysis • can affect any organ • In a rat study, PZA produces a 3-formyl system include IgE- inhibited the activity of rifampicin. mediated reactions as several CYP450 • Rifampicin a potent well as reactive isoenzymes (2B, 2C, inducer of the hepatic metabolite syndromes 2E1, 3A), but a study in CYP450S increasing human liver metabolism of many microsomes showed other compounds. that PZA has no inhibitory effect on the CYP450 isoenzymes.Among 148 patient who were given the combination PZA + Rifampicin for 2 month grade 3hepatotoxicity (transaminase >5-20 times the upper limit of reference range) and grade 4hepatotoxicity (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 Reactionsand Interaction, 5 th ed, USA: Elsevier). 17
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 ARVSpengler, U., Lichterfeld, M., Rockstroh, K.J., Review: Antiretroviral drug toxicity,Journal of Hepatology 36 (2002) 283–294 18
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 gKirchain, 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. 19
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 Preplanned LFT, evaluation When a drug is initiated of drug Careful history taking/rule out other etiologies, evualate the type of liver injury When liver dysfunction is recognized DILI is unlikely DILI is suspected Diagnosis of DILI Symptoms related ALT > 8 x ULN at any Hepatocellular type to liver injury such one time or Cholestatic type as jaundice or ALT > 5 x ULN for more or mixed Total bilirubin > 3 x than 2 wk or ULN or ALT > 3 x ULN, and total PT-INR > 1.5 x ULN bilirubin > 2 x ULN or Discontinue the PT-INR > 1.5 x UNL Careful monitoring suspected drugIgnazio G., Leonilde B., Catia V.D, Biochemical mechanisms in drug-induced liver injury, World J Gastroenterol 2009October 21; 15(39): 4865-4876 21
Child-Pugh Scores for Patients with Liver Disease Child-Pugh Scores for Patients with Liver Disease Score 8-9 : 25 % normal dose Score > 10 : 50 % normal doseBauer 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 Remove Monitoring Do not Take a the • Symptom ignore the careful causative • LFT symptoms history agentVictor 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. 23
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 25 role in the pathophysiology of microvesicular steatosis.
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, 26 diclofenac, phenytoin, and carbamazepine
Mechanism of Drug Hepatotoxicity 27Friedman, S.L., McQuaid K.R., 2003, Current Diagnosis and Treatment in Gastroenterology, USA: The McGraw-Hills, Comp.
Victor J. Navarro, M.D., and John R. Senior, M.D., 2006, Drug-Related Hepatotoxicity, The New England Journal of 28Medicine, vol. 354, pp. 731-739.
• Begriche, K., Massart, J., Robin, M.A., Review: Drug induced toxicity on mitochondria and lipid metabolism: 32 Mechanistic diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794
PENJELASAN GAMBAR DI ATAS ini kamu baca aja mita jangan dimasukkan pptA general diagram of biotransformation. (1) The drug is actively transported into thehepatocyte by the organic anion transport pump, a transmembrane protein. (2) Themetabolite (drug) interacts with one of a number of enzymes, the most common beingCYP2C9, 2C19, 2D6, and 3A4. This family of enzymes is regulated by the complementaryDNA 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 ofthese phase I enzymes is the production of an unstable metabolite. (4) The unstablemetabolite then reacts with glucuronidase, various transferases, or hydroxylases to form aconjugated metabolite. The efficacy of these enzymes is affected by the patient’snutritional state and genetic polymorphism, leading to variations in individual risk fortoxicity. (5) The conjugated metabolite is removed from the hepatocyte by the canalicularmembrane export pump, one of a large family of membrane proteins (other members ofthis 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 somAepatients having an increased risk for toxicity. (6) If unable to form a conjugate, theunstable metabolite can participate in oxidative reactions that damage lipids, proteins, oreven DNA. (7) Alternatively the unstable metabolite may form damaging covalent bondswith available anions or cations. (SNP, indicates points in this process that are influencedby an individual’s single nucleotide polymorphisms.) 33
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 presentations Dantrolene, 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 antibodies2) IDIOSYNCRATIC REACTIONS Idiosyncratic 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. 34
3) 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 homeostasis4) METABOLIC ACTIVATION OF THE CYTOCHROME P450 ENZYMES Most 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 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 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 35
ANATOMY OF LIVERTank, Patrick W.; Gest, Thomas R.2009. Atlas of Anatomy, USA: Lippincott Williams & Wilkins. 36
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). • Begriche, K., Massart, J., Robin, M.A., Review: Drug induced toxicity on mitochondria and lipid metabolism: Mechanistic 37 diversity and deleterious consequences for the liver, Journal of Hepatology 2011 vol 54;773-794
KEY POINTS OFDRUG-INDUCED LIVERDISEASE Drug induced lipid dysmetabolism & macrov. steatosis • Drug can impair MC function mechanism: impairment of the OXPHOS, inhibition of FAO • Can induce necrosis/apoptosis • Drug also alter lipid cytolytic hepatitis metabolism in liver by • A severe inhibition of MC FAO can increasing de novo fatty acid induce vesicular steatosis synthesis • Impairment of MC FAO can be • Lipid accumulate within the direct / indirect hepatocytes as large vacuoles macv. steatosis Drug induced mitcochondrial dysfunction• 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 38
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