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Gastroenterology/  Hematology    

Sing-­‐Yi  Feng,  M.D.,  F.A.A.P  Associate  Professor  of  Pediatrics  

Medical  Toxicologist  UT  Southwestern    Dallas,  Texas  

Overview  

•  GI  –  HepaHc  –  Pancreas  –  AnH-­‐moHlity  –  Inflammatory  Bowel  Meds  

•  Heme  –  AnHplatelet  –  AnHcoagulants    –  Procoagulants  –  ThrombolyHc  –  ErythropoieHn  

SecreHons  and  Muscarinic  Receptors  

Goldfrank’s  Toxicologic  Emergencies  9th  ediHon,  Fig.  25-­‐1  

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Regulatory  Substances  in  GI  tract  

Goldfrank’s  Toxicologic  Emergencies,  9th  ediHon,  Table  25-­‐1  

SelecHve  IgA  deficiency-­‐  Drug  Associated  

•  Certain  drugs  can  cause  a  transient  IgA  deficiency  – AnH-­‐inflammatory  agents  –  Sulfasalazine  – Hydantoin  –  Cyclosporine  – Gold  –  Fenclofenac  –  Valproic  acid  –  Captopril  

 Selected  drugs  that  undergo  primary  syntheHc  Phase  II  biotransformaHon  

•  GlucuronidaHon  :    – Valproic  acid  – Lamotrigine  – Opioids  – APAP  –  Irinotecan    – 5-­‐FU  – Chloramphenicol    

•  AcetylaHon:      –  INH  –  Hydrazines  –  Sulfonamide    –  Dapsone  A  –  Amonafidine  

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Hepatotoxin  ClassificaHon  Scheme  

Clinical  Environmental  Health  and  Toxic  Exposures  .Sullivan  and  Kreiger.2001  .Figure18.3.pg  236.  

HepaHc  Toxophysiology  •  Ingested  toxins:  enter  via  portal  blood  •  Inhaled  and  dermal  toxins:  enter  via  hepaHc  artery  

Clinical  Environmental  Health  and  Toxic  Exposures.Sullivan  and  Kreiger.2001.Figure18.1.pg  234.  

Zone  1  (periportal):  highest  O2,highest  glycogen,  highest  mitochondria  concentraHon,  Krebs  cycle,  more  protein  synthesis  

Zone  2  (intermediate)  

Zone  3  (centrilobar  or  peripheral):  Lowest  O2  tension,    Glycogen  storage,  fat  formaHon,  CYP  450  

Zonal  Hepatotoxicity  •  Zone  1  (periportal):  Phosphorus,  Iron,  Allyl  formate,                                

P.  Vulgarus  endotoxin  

•  Zone  2  (intermediate  or  midzonal):  Beryllium,  Ngaione  

•  Zone  3  (centrilobar  or  peripheral):  Bromobenzene,  halothane  carbon  tetrachloride,  ethanol,  APAP,  paraquat,  chlorinated  hydrocarbons    

         -­‐    *Think  2E1  metabolites  *  

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Steatosis  

•  Macrovesicular:  Nucleus  displaced  by  intracellular  fat  accumulaHon  

-­‐  Ethanol,  Amiodarone    -­‐  Amiodarone  has  lamellated  intralysomal  phospholipid  inclusion  bodies,  ethanol  doesn’t  

•  Microvesicular:  No  nuclear  displacement  by  fat;  *failed  β  oxidaBon,  more  severe  

Microvesicular  steatosis  

•  Tetracycline  •  Margosa  oil  •  Valproic  acid  •  Nucleoside  inhibitors  •  Hypoglycin  •  Cerulide  •  Aflatoxin  •  Dimethylformamide  (DMF)  

HepaHc  Veno-­‐Occlusive  Disease  

•  RadiaHon,  AnHneoplasHcs          (Cyclophosphamide)  •  Pyrrolinizide  alkaloid  plants    -­‐  Symphytum  species  (Comfrey  tea)    -­‐  Heliotropium,  Senecio  (Ragwort)    -­‐  Crotalaria  (Bush  teas)      

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Buzzword  HepaHHs  

•  Peliosis  HepaBBs:  Sinusoidal  dilaHon,  large  blood  filled  caviHes  :  Androgenic  Steroids  

•  Vitamin  A  Toxicity  :Increased  fat  content  of  sinusoidal  Ito  cells  with  increased  collagen  formaHon  

XenobioHc  Autoimmune  Liver  Injury  

•  Covalent  binding  of  reacBve  electrophile  with  hepatocellular  protein  creates  an  adduct  

•  APAP,  minocycline,  halothane,  dihydrazine,  phenytoin,  germander  

Toxin-­‐HepaHHs  Immunomarkers    

•  Halothane  :  anH-­‐trifluoroacetylated  proteins  •  Iproniaziad  :  anH-­‐mitochondrial  type  6  autoanHbody  (anH-­‐M6)  

•  Tienilic  acid:  AnH-­‐liver  kidney  type  2  autoanHbody  (anH-­‐LKM2)  autoanHbody  

•  Dihydralazine:  anHliver  microsomal  assay  •  Immunoallergic  drug  hepaHHs:  Lymphocyte  proliferaHon  assay  

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Drug  HypersensiHvity  HepaHHs  

•  Halothane  hepaHHs    •  Trimethoprim-­‐sulfamethazole  •  AnHconvulsants  •  Allopurinol  

Drug  induced  Cholestasis  Without  HepaHHs  

•  Estrogens/OCPs  •  Anabolic  Steroids  •  Cyclosporin  •  4,4’-­‐methylenedianiline  (Epping  Jaundice)  •  Rapeseed  oil  aniline  (Spanish  toxic  oil  syndrome)  

•  Alpha-­‐napthyl-­‐isothiocyanate  (ANIT)  –acute  cholangiHs  with  PMN  infiltraHon  

Drug  HypersensiHvity  Cholestasis  

•  Chlorpromazine  •  Erythromycin  •  Penicillin  •  Rifampin  •  Sulfonamides  

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OccupaHonal  chemical  Cholestasis  

•  Toluene  diisocyanate  •  Methylenediamine  •  Paraquat  

Retroperitoneal  Fibrosis  

•  Methylsergide  •  Stephania  tetrandra  (TCM)  •  Magnolia  officinalis  (TCM)  •  BromocripHne  •  LSD  

Exocrine  PancreaHHs  

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Exocrine  PancreaHHs  

•  Tityus  trinita+s    •  (Central/South  American  scorpion)  

XenobioHc  Endocrine  PancreaHHs  

•  Alpha:  Cobalt,  Biguanide,  Diguanide  •  Beta:  Aflatoxin,  Androgens,  Cyclizine,  Cyproheptadine,  Diazoxide,  Glucagon,  Epinephrine,  Growth  Hormone,  Pentamidine,  Streptozocin,  Sulfonamides,  Vacor,  Zinc  Chelators  

Pancrelipase  (Pancrease)  

•  IndicaHon:  MalabsorpHon  Syndrome  •  Chronic  use  in  CysHc  Fibrosis          *  Fibrosing  Colonopathy:  abdominal  pain,  distension,  consHpaHon  

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Inflammatory  Bowel  Meds  

•  Mesalamine,  Sulfasalazine  •  Immunomodulators  (azathioprine,  6-­‐MP,  infliximab)  

•  Steroids  •  AnHbioHcs  

Mesalamine  

•  Salicylate  based  •  Metabolism:  acetylaHon  =  n-­‐acetyl-­‐  5-­‐ASA  •  Topical  bowel  anH-­‐inflammatory  •  AE:  HA/Diarrhea  •  OD:  low  likelihood  salicylate  toxicity  

Sulfasalazine  

•  Sulfa  +  salicylate  (  5-­‐ASA)  •  Colonic  bacteria  split  sulfa  to  free  5-­‐ASA  •  5-­‐ASA  Not  absorbed  in  colon  •  AE:  due  to  sulfapyridine                      ***  decreased  ferBlity,  abnormal  sperm                        ***  folate  inhibitor  Other  AE:  HA,  n/v/d,  rashes  

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Azathioprine  and  6-­‐MP  

Nature  Reviews  Cancer  8,  24-­‐36  (January  2008)  

6-­‐thioguanine  (6-­‐TG)    

hypoxanthine–guanine  phosphoribosyltransferase  

thiopurine  S-­‐methyltransferase    

xanthine  oxidase    

thiopurine  S-­‐methyltransferase    

Azathioprine/6MP  Adverse  effects  

•  InfecHon  •  Myelosuppression,  Leukemia  •  GI:  diarrhea,mucosiHs  •  Pregnancy  D,  NOT  OK  in  Breasoeeding  •  Congenital  anomalies:  including  polydactyly,  plagiocephaly,  congenital  heart  disease,  hypospadias,  and  bilateral  talipes  equinovarus  have  occurred    

•  Monitoring:  CBC  and  Thiopurine  methyltransferase  (TPMT)  acBvity  

Hemostasis  Pediatric  Emergency  Medicine  Reports  V14  N3  March  2009  

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AnHplatelets  

Pharmacology  Corner  Flavio  Guzmán,  M.D.  on  9/24/09    

ADP  Inhibitors  

Ticlopidine  •  3-­‐5  days  onset  •  2C19  •  AE:  rash,  neutropenia,  TTP  •  Severe  OD:  reversal  with  

platelet  transfusion  

Clopidogrel  •  2  hrs  onset  •  2C19,  3A,  B6  and  CYP1A2  •  SS:  3-­‐7  days  •  AE:  bleeding,  rash  •  1  case  report  of  HSP,  TTP  •  Severe  OD:  reversal  with  

platelet  transfusion  

Drug  Induced  Thrombocytopenia  

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OccupaHonal  Isolated  Toxic  Thrombocytopenia  

•  Immune:  Toluene  diisocyanate  •  Megakaryocyte  hypoplasia:  Dieldrin,  Pyrethrin,  Lindane,  DDT  

Indirect  Thrombin  Inhibitors  

•  Heparin:  UFH  ,LMWH  (3,000-­‐30,000  daltons)  •  Factor  XA  Inhibitors:  Indirect/Direct  •  Vitamin  K  antagonist:  Warfarin  

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Heparin  

Most  sensiHve  to  inhibiHon  of  ATIII/Heparin  complex  

Thrombin  

Increased  ATIII-­‐thrombin  (IIA)  Rx  100-­‐1000  fold  

Protamine  Sulfate  

•  Derived  from  male  salmon  gonads  •  Binds  heparin,  ↓interacHon  with  AT  III  •  1mg/unit  heparin  •  Heparin  rebound  •  ContraindicaHon:  Allergy  (  DM  with  AB  due  to  protamine  containing  insulin)  

Heparin  Induced  Thrombocytopenia  

•  Type  I  =Platelets  ↓  •  Type  II  =  AnBplatelet  IgG  anBbodies  Platelet  4  protein,  paradoxical  thrombosis,  thrombocytopenia,  1  wk  aser  RX  

•  Primarily  UFH,  possible  but  less  likely  with  LMWH  

•  All  UFH/LMWH  contraindicated  in  future,  must  use  direct  thrombin    

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LMWH    

Choices  •  Ardeparin  (Normiflo):  •  Daltaparen  (Fragmin):  •  Enoxaparen  (Lovenox):  •  Tinzoparin  (Innohep):  

Mechanism  •  AnH  thrombin  III  mediated  •  SelecHve  inhibiHon  Xa  and  

to  a  lesser  extent  IIa  

Factor  XA  Inhibitors  

•  Fondaparinux  (Arixtra):  Indirect,  syntheHc  pentasaccharide,  selecHve  Factor  Xa  inhibitor  

•  Rivaroxaban  (Xarelto):  Direct,  oral,  selecHve  factor  Xa  inhibitor  

•  Apaxiban  (Eliquis):  Direct,  oral,  selecHve  factor  Xa  inhibitor  

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Warfarin  

         Vitamin  K  epoxide  reductase  C1  

Mayo  Clinic  Proceedings  July  2010  85  (10)  

 Vitamin  K(H2)  Quinol  Reduced    (AcHve)  

Warfarin  

Reduced  

AcHve   InacHve  

Vitamin  K1  (Phytonadione)  

•  ½  life  :  2  hrs  •  Oral:  mephyton  •  IV:  AquaMephyton  •  IV:  only  if  lifethreat    •  (<  1mg/min)  •  AE:  photosensiHvity,  anaphylaxis  

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Direct  Thrombin  Inhibitors    

•  Hirudin  (Refludan):  Bivalent  :  Exosite  1,  acHve  site  binding  

•  Bivalirudin:    (Angiomax,Hirulog):  Bivalent:  exosite  1,  acHve  site  binding  

•  Argatroban:  Univalent:  AcHve  site  only  binding,  N2-­‐derivaHve  of  arginine  

•  Dabigatran  (Pradaxa):  Univalent:  AcHve  site  ONLY  binding  

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ThrombolyHcs  

Thrombin  specific  fibrinolysis  •  Alteplase  •  Reteplase  •  Tenectaplase  

Non  specific  fibrinolysis  •  Streptokinase    •  Urokinase  Side  effect:  -­‐Allergy  rxn  if  re-­‐exposure  

Aminocaproic  Acid  

•  Reversal  of  fibrinolyHcs  •  Analogue  of  the  amino  acid  lysine  •  Inhibits  plasminogen  acHvators  •  Renal  eliminaHon  •  AE:  hypotension,  rhabdomyolysis  

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ErythropoieHn  

•  SHmulate  stem  cells  to  mature  RBCs  •  Side  effects:  ↑Hct,  ↑plt  acHvity,  ↑systolic  HTN  

   -­‐Hyperviscosity,  HTN,  Thromboembolism  •  Chronic  OD:  Plethora,  Black  toes