GI  /  HEME  

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Gastrointes1nal/Hematologic  Toxicology  Board  Review  

Michael  Policastro,  MD  Director,  Medical  Toxicology,  QESI  

Clinical  Assistant  Professor,  WSU  

1  

Overview  

GI  

•  Oral/Anal    •  Hepa1c  •  Pancreas  •  An1mo1lity  •  Inflammatory  Bowel  Meds  •  An1ulcer  •  Promo1lity  

Heme  

•  An1platelet  •  An1coagulants    •  Procoagulants  •  Thromboly1c  •  Iron  •  Erythropoie1n  

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Oral  Discolora1on  

Tongue  •  Brown  

•  Green  

•  Black,  Hairy  

•  White  

•  Blue  •  Blue  Gray  Gums  

•  Bromine,  bismuth,  arsenic,  phenolpthalein,  doxrubicin,  quinacrine,  tobacco  

•  Vanadium  

•  Cefoxi1n,  cor1costeroids,lansoprazole,  penicillin,  sodium  perborate,  sodium  peroxide,  tetracycline  

•  Chlorhexidine,  phenol,  caus1c  acids,  hydrogen  peroxide  

•  Methylene  blue  •  Bismuth,  lead,  mercury,  copper  salts,  

thallium,  zinc  

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GI  /  HEME  

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Fecal  Discolora1on  

•  Black  

•  Blue  •  Yellow-‐green  •  Orange-‐red  •  Pink  

•  Acetazolamide,  aluminum  hydroxide,  aminophylline,amphotericin  b,barium,  benzene,bismuth,  bromides,  charcoal,chloramphenical,chlorpropamide,clindamycin,cor1costeroids,cyclophosphamide,digitalis,feroous  salts,fluoruracil,formaldehyde,halides,halothane,  metals  (Ag,As,  Cu,Hg,Mn,Pb,Tl),hydralazine,methotrexetae,methylene  blue,  nitrates,NSAIDs,  tetracycline,theophylline,warfarin  

•  Boric  acid,  chloramphenical,  maganese  dioxide,  methylene  blue  

•  Mercurous  chloride,  yellow  phosphorus  

•  Phenazopyridine,  rifampin  

•  Manganese  dioxide,  phenolthalein  

4  

Secre1ons  and  Muscarinic  Receptors  

•  M  1,3,5  =  Phospholipase  C  •  M2,4  =  Adenylate  cyclase  •  M3  =  sphincter  of  oddi,  ciliary  body  •  M4  =agonism  =Clozapine  sialorrhea  •  Also  unusual  drooling:  Aminopyridine  (  CCB  treatment)  

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Selec1ve  IgA  deficiency-‐  Drug  Associated  

•  Captopril  •  Penacillamine  •  phenytoin  

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GI  /  HEME  

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 Drugs  that  undergo  primary  Synthe1c    Phase  II  Biotransforma1on  that  you  may  forget  

•  Glucuronida1on  :  Valproic  acid,  lamotrigine,  opioids,  APAP,  irinotecan,  5-‐FU,  chloramphenical    

•  Acetyla1on:  INH,  hydrazines,  Sulfonamide,  Dapsone,  amonafidine  

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Hepatotoxin  Classifica1on  Scheme  

Clinical  Environmental  Health  and  Toxic  Exposures  .Sullivan  and  Kreiger.2001  .Figure18.3.pg  236.  8  

Hepa1c  Toxophysiology  

•  Ingested  toxins:  enter  via  portal  blood  •  Inhaled,dermal:  enter  via  hepa1c  artery  

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

Zone  1  (periportal):  highest  O2,highest  glycogen,  highest  mitochondria  concentra1on,  Krebs  cycle,  more  protein  synthesis  

Zone  2  (intermediate)  

Zone  3  (Centrilobar  or  peripheral):  Lowest  O2  tension,    Glycogen  storage,  fat  forma1on,  Cyp  450  

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GI  /  HEME  

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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  displace  by  intracellular  fat  accumula1on  

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

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

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Microvesicular  steatosis  

•  Tetracycline  •  Margosa  oil  •  VPA  •  Nucleoside  inhibitors  •  Hypoglycin  •  Cerulide  •  Aflatoxin  

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GI  /  HEME  

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Hepa1c  Veno-‐Oclussive  Disease  

•  Radia1on,  An1neoplas1cs          (  Cyclophophamide)  

•  Pyrrolinizide  alkaloid  plants    -‐Symphytum  species  (Comfrey  tea)  

 -‐  Heliotropium,  Senecio  (Ragwart)  

 -‐Crotalaria  (  Bush  teas)  

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Buzzword  Hepa11s  

•  Peliosis  HepaPPs:  Sinusoidal  dila1on,  large  blood  filled  cavi1es  :  Androgenic  Steroids  

•   Vitamin  A  Toxicity  :Increased  fat  content  of  sinusoidal  Ito  cells  with  increased  collagen  forma1on  

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Xenobio1c  Autoimmune  Liver  injury  

•  Covalent  binding  of  reacPve  electrophile  with  hepatocellular  protein  creates  an  Adduct  

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

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GI  /  HEME  

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Toxin-‐Hepa11s  Immunomarkers    

•  Halothane  :  an1-‐trifluoroacetylated  proteins  •  Iproniaziad  :  an1-‐mitochiondrial    type  6  autoan1body  (  an1-‐M6)  

•  Tienilic  acid:  An1-‐liver  kidney  type  2  autoan1body  (an1-‐LKM2)  autoan1body  

•  Dihydralazine:  an1liver  microsomal  assay  •  Immunoallergic  drug  hepa11s:  Lymphocyte  prolifera1on  assay  

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Drug  Hypersensi1vity  Hepa11s  

•  Halothane  hepa11s    •  trimethoprim-‐sulfamethazole  •  An1convulsants  •  Allopurinol  

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Drug  induced  Cholestasis  Without  Hepa11s  

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

•  Alpha-‐napthyl-‐isothiocyanate  (  ANIT)  –acute  cholangi1s  with  PMN  infiltra1on  

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GI  /  HEME  

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Drug  Hypersensi1vity  Cholestasis  

•  Chlorpromazine  •  Erythromycin  •  Penicillin  •  Rifampin  •  Sulfonamides  

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Occupa1onal  chemical  cholestasis  

•  Toleune  diisocyanate  •  Methylenediamine  •  paraquat  

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Hepa1c  Tumors  

•  Angiosarcoma:  Vinyl  chloride  (chlorethane),  arsenic,  copper  sulfate,  Thoratrast,  cadmium  ?  

•  Adenoma:  Oral  contracep1ves  (  OCP),  androgens  •  Carcinoma:  OCP,  anabolic  steroids,  thoratrast,  anabolic  

steroids  

•  Hepatocellular  carcinoma:  aflatoxin,  dimethylnitrosamine,  ethanol  

•  Focal  Nodular  Hyperplasia:  OCP  •  Peritoneal  Mesothelioma:  asebetos  amphibole  fibers,  

eronite,  thoratrast,  

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GI  /  HEME  

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Liver  Carcinogens  

•  Aflatoxin  (  Aspergillus  flavus/parasi1cus)  •  Mycotoxins  •  Pyrrolizidine  alkaloids  •  Nitrosamides,Nitrosamines  •  Heterocyclic  aroma1c  amines  •  Ethanol  •  OCP  •  Androgens,  anabolic  steroids  •  Azo  dyes  •  Thoratrast-‐  alpha  radia1on  

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Retroperitoneal  fibrosis  

•  Methylsergide  •  Stephania  tetrandra  •  Magnolia  officinalis  •  Bromocrip1ne  •  LSD  

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Exocrine  Pancrea11s  

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GI  /  HEME  

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Exocrine  Pancrea11s  

*  Tityus    trinitaPs  

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Xenobio1c  Endocrine  Pancrea11s  

•  Alpha:  Cobalt,  biguanide,diguanide  •  Beta:  Aflatoxin,  Androgens,  cyclizine,Cyproheptadine,Diazoxide,Glucagon,      Epinephrine,  Growth  Hormone,Pentamidine,  Streptozocin,sulfonamides,  Vacor,  Zinc  Chelators  

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Pancrelipase  (  Pancrease)  

•  Indica1on:  malabsorp1on  syndrome  •  Chronic  use  in  Cys1c  Fibrosis          *  Fibrosing  Colonopathy:  abd  pain,  distension,  cons1pa1ons  

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GI  /  HEME  

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An1diarrheal  Agents  

•  AnPMoPlity:Opioids:  Diphenoxylate,  Loperamide,  Paregoric/Laudanum  

•  Intraluminal  Agents:  Silicates,  Bulk-‐forming  fibers,  Microfloral  altering  agents  

•  AnPsecretory  :  Somatosta1n,  Octreo1de  

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Diphenoxylate  

•  Derived  from  meperidine  •  Metabolite:  diphenoxylic  

acid  (  5x  more  ac1ve,  2x  ½  life)  

•  Combined  with  atropine  =Lomo1l  

•  Onset:  4.5  hrs  (  1-‐  8  hrs)  •  Toxicity:  delayed  opioid  

Meperidine  

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Loperamide  

•  Derived  from  diphenoxylate  

•  40  %  absorp1on,    

GI  /  HEME  

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Opioids  

•  Paregoric  •  Camphorated  1ncture  of  

opium  

•  Morphine  (0.4  mg/ml)  •  Other  components:  

essen1al  oil,  Benzoic  Acid,  Ethanol  (  45  %),  glycerol  

•  Laudanum  •  Deodorized  Tincture  of  

opium  

•  Morphine  (10  mg/ml)  •  Use  in  Neonatal  Abs1nence  

Syndrome  /Neonatal  Withdraw  syndrome  

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Inflammatory  Bowel  Meds  

•  Mesalamine,  Sulfasalazine  •  Immunomodulators  (  Azathioprine,6-‐MP,  infliximab)  •  Steroids  •  An1bio1cs  

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Mesalamine  

•  Salicylate  based  •  Metabolism:  acetyla1on  =  n-‐acetyl-‐  5-‐ASA  •  Topical  bowel  an1-‐inflammatory  •  AE:  HA/Diarrhea  •  OD:  low  likelyhood  salicylate  toxicity  

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GI  /  HEME  

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Sulfasalazine  

•  Sulfa  +  salicylate  (  5-‐ASA)  •  Colonic  bacteria  split  sulfa  to  free  5-‐ASA  •  5-‐ASA  Not  absorbed  in  colon  •  AE:  due  to  sulfapyridine                      ***  decreased  ferPlity,  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    

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Azathioprine/6MP  Adverse  effects  

•  Infec1on  •  Myelosuppression,  Leukemia  •  GI:  diarrhea,mucosi1s  •  Pregnancy  D,  NOT  OK  in  Breasueeding  •  congenital  anomalies:  including  polydactyly,  plagiocephaly,  congenital  heart  disease,  hypospadias,  and  bilateral  talipes  equinovarus  have  occurred.    

•  Monitoring:  CBC  and  Thiopurine  methyltransferase  (TPMT)  acPvity  

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GI  /  HEME  

13  

An1ulcer  

•  Antacids  •  H2  blockers  •  Proton  pump  inhibitors  •  Misoprostol  

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Antacids  

•  Salts  of:  aluminum,magnesium,calcium,  sodium  hydroxide  

•  Increase  gastric  pH  •  Toxicity  with  renal  failure  •  Al  =  “dilaysis  demen1a”,  encephalopathy,  cons1pa1on  •  Mg  =diarrhea,  weakness,  ↓Hr,reflexes,BP  •  Milk-‐Alkali  (headache,  occasional  nausea  and    vomi1ng,  muscle  

ache,  weakness  and  malaise)  (  stones,  bones,  moans,  groans)      –  seen  with  both  calcium,  sodium  binders  +  milk/vitamin  D      −  Hypercalcemia  with  suppressed  PTH  

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H2  Blockers  

•  CimePdine,  rani1dine,  famo1dine,  roxa1dine,  niza1dine,e1n1dine      •  Inhibitors:  3A4,  2D6,  1A2,  2C9,  2E1  •  AE:  AMS,  fa1gue,  possible  thrombocytopenia,  vasculi1s,  movement  

disorders  

•  CimePdine:  An1androgen  (  GynecomasPa  )  •  Rani1dine:  hepa11s  

CimePdine  

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GI  /  HEME  

14  

Proton  pump  inhibitors  

•  Rabeprazole,Lansoprazole,Omeprazole,Esmeprazole  Pantoprazole  

•  Block  the  gastric  acid  pump,  H+/K+  (ATPase)  •   interacPon  2C19,  3A4  •  Alkali  stomach  may  alter  absorp1on:  griseofulvin,  

ketaconazole,  iron  

•  AE:  diarrhea  

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Misprostol  

•  PGE1  antagonist  (↓acid,  ↑uterine  contrac1on,  mucous,bicarbonate,  dilate  blood  vessels  )  

•  Pregnancy  X  •  AE:  aborPfacient,  HA,  diarrhea  

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Laxa1ves  

[Epsom  Salts]  

phenolphthalein  

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GI  /  HEME  

15  

 Laxa1ve  Overdose  

ACUTE  

•  OsmoPc:    -‐Magnesium:  CNS,  

respiratory↓  

-‐Phosphate:  hypocalcemia,QT↑  

•  SPmulant  -‐Phenolthalein:  pulm  edema,  

shock,  met  acidosis  

CHRONIC  

•  Osmo1c:      +  aldosterone  =  hypoK  -‐  Cathar1c  colon  =  

atrophy,atony  

•  SPmulant  -‐psuedomembranosis  

coli=macrophage  pigment  uptake,melanosis  coli,  harmless  

*  Phenolpthalein  =  carcinogen,  fixed  drug  erupPon  

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Prokine1cs  

•  Metoclopramide:  5HT3  antagonist,  DA  antagonist;  AE:  EPS,  NMS,  *  MetHgb,  neutropenia  

•  Cisapride:  5HT4  agonist,  3A4  inhibitor,  Ikr  blockade,  QT  ↑  

•   Tegasarod  (Zelnorm):  par1al  5HT4  agonist,          5HT1B  agonist  =↑vasoconstricPon,  MI,  CVA  

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Hemostasis  Pediatric  Emergency  Medicine  Reports  V14  N3  March  2009  

45  

GI  /  HEME  

16  

An1platelets  

Pharmacology  Corner  Flavio  Guzmán,  M.D.  on  9/24/09    46  

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  

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Drug  Induced  Thrombocytopenia  

48  

GI  /  HEME  

17  

Occupa1onal  Isolated  Toxic  Thrombocytopenia  

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

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Indirect  Thrombin  Inhibitors  

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

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GI  /  HEME  

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Heparin  

Most  sensi1ve  to  inhibi1on  of  ATIII/Heparin  complex  

Thrombin  

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

52  

Protamine  Sulfate  

•  Derived  male  salmon  gonads  •  Binds  heparin,  ↓interac1on  with  AT  III  •  1mg/unit  heparin  •  Heparin  rebound  •  Contraindica1on:  Allergy  (  DM  with  AB  due  to  protamine  containing  insulin)  

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Heparin  Induced  Thrombocytopenia  

•  Type  I  =Platelets  ↓  •  Type  II  =  AnPplatelet  IgG  anPbodies  Platelet  4  protein,  paradoxical  thrombosis,  thrombocytopenia,  1  wk  aer  RX  

•  Primarily  UFH,  possible  but  less  likely  with  LMWH  

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

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GI  /  HEME  

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LMWH  

Choices  

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

Mechanism  

•  An1  thrombin  III  mediated  Selec1ve  inhibi1on  Xa  and  to  a  

lesser  extent  IIa  

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56  

Factor  XA  Inhibitors  

•  Fondaparinux  (  Arixtra):  Indirect,  synthe1c  pentasaccharide,  selec1ve  Factor  Xa  inhibitor  

•  Rivaroxaban  (Xarelto):Direct,oral,Selec1ve  factor  Xa  inhibitor  

•  Apaxiban  (  Eliquis):Direct,  oral,  Selec1ve  factor  Xa  Inhibitor  

57  

GI  /  HEME  

20  

Warfarin  

         Vitamin  K  epoxide  reductase  C1  

Mayo  Clinic  Proceedings  July  2010  85  (10)  

Vitamin  K(H2)  Quinol  Reduced    (Ac1ve)  

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Warfarin  

Reduced  

Ac1ve   Inac1ve  

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Warfarin    Skin  Necrosis  

Skin  necrosis  

•  0.01-‐0.1  %  of  pts  •  Female>  male  •  High  fat  area  •  Rapid  protein  C  loss  

60  

GI  /  HEME  

21  

Fetal  Warfarin  Syndrome  

•  Pregnancy  X  •  Crosses  placenta  •  Nasal/midface  hypoplasia  

•  Bone  sPppling  of  epiphyses  on  plain  x-‐ray  (chrondrodysplasia  puncP)  

•  OpPc  atrophy  •  Metal  retardaPon  

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Warfarin  purple  toe  syndrome  

•  3-‐  8  wks  of  therapy  •  Cholesterol  microemboli  

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Vitamin  K1  (Phytonadione)  

•  ½  life  :  2  hrs  •  Oral:mephyton  •  IV:  AquaMephyton  •  IV:  only  if  lifethreat    •  (  <  1mg/min)  •  AE:  photosensa1vity,  anaphylaxsis  

63  

GI  /  HEME  

22  

64  

65  

Direct  Thrombin  Inhibitors    

•  Hirudin(  Refludan):  Bivalent  :  Exosite  1,  ac1ve  site  binding  

•  Bivalirudin:    (  Angiomax,Hirulog):Bivalent:  Exosite  1,  ac1ve  site  dinding  

•  Argatroban:  Univalent:  Ac1ve  Site  Only  binding,  N2-‐deriva1ve  of  arginine  

•  Dabigatran(  Pradaxa):  Univalent:  Ac1ve  Site  ONLY  binding  

66  

GI  /  HEME  

23  

67  

Thromboly1cs  

Thrombin  specific  fibrinolysis  

•  Alteplase  •  Reteplase  •  tenectaplase  

Non  specific  fibrinolysis  •  Streptokinase    •  urokinase  Side  effect:  

-‐Allergy  rxn  if  re-‐exposure  

68  

Aminocaproic  Acid  

•  Reversal  of  fibrinoly1cs  •  analogue  of  the  amino  acid  lysine  •  Inhibits  plasminogen  ac1vators  •  Renal  elimina1on  •  AE:  hypotension,rhabdomyolysis  

69  

GI  /  HEME  

24  

Iron  

Ionic  

•  Ferrous  gluconate  12  %  •  Ferrous  lactate    19%  •  Ferrous  sulfate  20  %  •  Ferrous  chloride  28  %  •  Ferrous  fumarate  33%  

Nonionic-‐  low  toxicity  

•  Iron  polysaccaride  46%  •  Carbonyl  iron  98  %  

70  

Iron  

•  Fe  2+  (Ferrous)    absorbed  in  duod/jejun,  bound  to  Ferri1n  

•  Changed  to  Fe  3+  (ferric),  bound  to  transferrin  •  Free  iron  (  Fe  3+)  released  •   4-‐5  Stages:  GI,Latent,Shock/Met  Acidosis,Hepa1c  failure,Gut  Stricture  

71  

Iron  

•  >60mg/kg  elemental  iron  (  Be  able  to  calculate)  likely  tox  

•  4  hr  serum  Fe  level  >500mcg/dl  +  symptoms  •  Obtain  radiographs  •  NOT  Useful:  WBC  >15  K,Glc>150mg/dl,TIBC  •  Pregancy:  ?  placental  receptor  mediated  endocytosis    

•  Deferoxamine  therapy  72  

GI  /  HEME  

25  

Deferoxamine  

•  Derived  from  streptomyces  pilosus  

•  Indica1ons:  serum  Fe>350-‐500mcg/dl,  symptoms  

•  Goals:  resolu1on  acidosis,shock,  1trate  dose  

•  AE:  GI-‐  Yersina  enterocoli1ca,  Pulm  ?  24  hrs  PE  

73  

Erythropoie1n  

•  S1mulate  stem  cells  to  mature  RBCs  •  Side  effects:↑Hct  ↑plt  ac1vity,  ↑systolic  HTN      -‐Hyperviscosity,HTN,  Thromboembolism  

Chronic  OD:  Plethora,  Black  toes  

74