2.4 Policastro GI-Heme ACMT.Pptx

GI / HEME

Gastrointesnal/Hematologic Toxicology Board Review

Michael Policastro, MD Director, Medical Toxicology, QESI Clinical Assistant Professor, WSU

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Overview

GI Heme • Oral/Anal • Anplatelet • Hepac • Ancoagulants • Pancreas • Procoagulants • Anmolity • Thrombolyc • Inflammatory Bowel Meds • Iron • Anulcer • Erythropoien • Promolity

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Oral Discoloraon

Tongue • Brown • Bromine, bismuth, arsenic, phenolpthalein, doxrubicin, quinacrine, tobacco • Green • Vanadium

• Black, Hairy • Cefoxin, corcosteroids,lansoprazole, penicillin, sodium perborate, sodium • White peroxide, tetracycline • Chlorhexidine, phenol, causc acids, hydrogen peroxide • Blue • Methylene blue • Blue Gray Gums • Bismuth, lead, mercury, copper salts, thallium, zinc

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1 GI / HEME

Fecal Discoloraon

• Acetazolamide, aluminum hydroxide, • Black aminophylline,amphotericin b,barium, benzene,bismuth, bromides, charcoal,chloramphenical,chlorpropamide,clindamycin,c orcosteroids,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

• Blue • Boric acid, chloramphenical, maganese dioxide, methylene blue • Yellow-green • Mercurous chloride, yellow phosphorus • Orange-red • Phenazopyridine, rifampin • Pink • Manganese dioxide, phenolthalein

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Secreons 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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Selecve IgA deficiency- Drug Associated

• Captopril • Penacillamine • phenytoin

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2 GI / HEME

Drugs that undergo primary Synthec Phase II Biotransformaon that you may forget

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

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

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Hepatotoxin Classificaon Scheme

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

Hepac Toxophysiology

• Ingested toxins: enter via portal blood • Inhaled,dermal: enter via hepac artery Zone 1 (periportal): highest O2,highest glycogen, highest mitochondria concentraon, Krebs cycle, more protein synthesis Zone 2 (intermediate)

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

Clinical Environmental Health and Toxic Exposures.Sullivan and Kreiger.2001.Figure18.1.pg 234. 9

3 GI / HEME

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 accumulaon - Ethanol, Amiodarone - Amiodarone has lamellated intralysomal phospholipid inclusion bodies, ethanol doesn’t • Microvesicular: No nuclear displacement by fat; *failed β oxidaon, more severe

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Microvesicular steatosis

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

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4 GI / HEME

Hepac Veno-Oclussive Disease

• Radiaon, Anneoplascs ( Cyclophophamide) • Pyrrolinizide alkaloid plants -Symphytum species (Comfrey tea) - Heliotropium, Senecio (Ragwart) -Crotalaria ( Bush teas)

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Buzzword Hepas

• Peliosis Hepas: Sinusoidal dilaon, large blood filled cavies : Androgenic Steroids • Vitamin A Toxicity :Increased fat content of sinusoidal Ito cells with increased collagen formaon

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Xenobioc Autoimmune Liver injury

• Covalent binding of reacve electrophile with hepatocellular protein creates an Adduct • APAP, minocycline, halothane, dihydrazine, phenytoin, germander

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5 GI / HEME

Toxin-Hepas Immunomarkers

• Halothane : an-trifluoroacetylated proteins • Iproniaziad : an-mitochiondrial type 6 autoanbody ( an-M6) • Tienilic acid: An-liver kidney type 2 autoanbody (an-LKM2) autoanbody • Dihydralazine: anliver microsomal assay • Immunoallergic drug hepas: Lymphocyte proliferaon assay

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Drug Hypersensivity Hepas

• Halothane hepas • trimethoprim-sulfamethazole • Anconvulsants • Allopurinol

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Drug induced Cholestasis Without Hepas • Estrogens/OCPs • Anabolic Steroids • Cyclosporin • 4,4’-methylenedianiline ( Epping Jaundice) • Rapeseed oil aniline ( Spanish toxic oil syndrome) • Alpha-napthyl-isothiocyanate ( ANIT) –acute cholangis with PMN infiltraon

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6 GI / HEME

Drug Hypersensivity Cholestasis

• Chlorpromazine • Erythromycin • Penicillin • Rifampin • Sulfonamides

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Occupaonal chemical cholestasis

• Toleune diisocyanate • Methylenediamine • paraquat

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Hepac Tumors

• Angiosarcoma: Vinyl chloride (chlorethane), arsenic, copper sulfate, Thoratrast, cadmium ? • Adenoma: Oral contracepves ( 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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7 GI / HEME

Liver Carcinogens

• Aflatoxin ( Aspergillus flavus/parasicus) • Mycotoxins • Pyrrolizidine alkaloids • Nitrosamides,Nitrosamines • Heterocyclic aromac amines • Ethanol • OCP • Androgens, anabolic steroids • Azo dyes • Thoratrast- alpha radiaon

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Retroperitoneal fibrosis

• Methylsergide • Stephania tetrandra • Magnolia officinalis • Bromocripne • LSD

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Exocrine Pancreas

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8 GI / HEME

Exocrine Pancreas

* Tityus trinitas

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Xenobioc Endocrine Pancreas

• 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)

• Indicaon: malabsorpon syndrome • Chronic use in Cysc Fibrosis * Fibrosing Colonopathy: abd pain, distension, conspaons

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9 GI / HEME

Andiarrheal Agents

• AnMolity:Opioids: Diphenoxylate, Loperamide, Paregoric/Laudanum • Intraluminal Agents: Silicates, Bulk-forming fibers, Microfloral altering agents • Ansecretory : Somatostan, Octreode

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Diphenoxylate

• Derived from meperidine • Metabolite: diphenoxylic acid ( 5x more acve, 2x ½ life) • Combined with atropine =Lomol Meperidine • Onset: 4.5 hrs ( 1- 8 hrs) • Toxicity: delayed opioid

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Loperamide

• Derived from diphenoxylate • 40 % absorpon, <1% absorpon • Poor CNS penetraon, • Rare respiratory • Large safety profile

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10 GI / HEME

Opioids

• Paregoric • Laudanum • Camphorated ncture of • Deodorized Tincture of opium opium • Morphine (0.4 mg/ml) • Morphine (10 mg/ml) • Other components: • Use in Neonatal Absnence essenal oil, Benzoic Acid, Syndrome /Neonatal Ethanol ( 45 %), glycerol Withdraw syndrome

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Inflammatory Bowel Meds

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

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Mesalamine

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

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11 GI / HEME

Sulfasalazine

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

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Azathioprine and 6-MP

6-thioguanine (6-TG)

hypoxanthine–guanine phosphoribosyltransferase

thiopurine S- methyltransferase thiopurine S- xanthine methyltransferase oxidase

Nature Reviews Cancer 8, 24-36 (January 2008) 35

Azathioprine/6MP Adverse effects • Infecon • Myelosuppression, Leukemia • GI: diarrhea,mucosis • Pregnancy D, NOT OK in Breaseeding • congenital anomalies: including polydactyly, plagiocephaly, congenital heart disease, hypospadias, and bilateral talipes equinovarus have occurred. • Monitoring: CBC and Thiopurine methyltransferase (TPMT) acvity

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12 GI / HEME

Anulcer

• 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 demena”, encephalopathy, conspaon • Mg =diarrhea, weakness, ↓Hr,reflexes,BP • Milk-Alkali (headache, occasional nausea and voming, 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

• Cimedine, ranidine, famodine, roxadine, nizadine,endine • Inhibitors: 3A4, 2D6, 1A2, 2C9, 2E1 • AE: AMS, fague, possible thrombocytopenia, vasculis, movement disorders • Cimedine: Anandrogen ( Gynecomasa ) • Ranidine: hepas

Cimedine

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13 GI / HEME

Proton pump inhibitors

• Rabeprazole,Lansoprazole,Omeprazole,Esmeprazole Pantoprazole • Block the gastric acid pump, H+/K+ (ATPase) • interacon 2C19, 3A4 • Alkali stomach may alter absorpon: griseofulvin, ketaconazole, iron • AE: diarrhea

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Misprostol

• PGE1 antagonist (↓acid, ↑uterine contracon, mucous,bicarbonate, dilate blood vessels ) • Pregnancy X • AE: aborfacient, HA, diarrhea

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Laxaves

[Epsom Salts]

phenolphthalein

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14 GI / HEME

Laxave Overdose

ACUTE CHRONIC • Osmoc: • Osmoc: -Magnesium: CNS, + aldosterone = hypoK respiratory↓ - Catharc colon = -Phosphate: atrophy,atony hypocalcemia,QT↑ • Smulant • Smulant -psuedomembranosis -Phenolthalein: pulm edema, coli=macrophage pigment shock, met acidosis uptake,melanosis coli, harmless * Phenolpthalein = carcinogen, fixed drug erupon

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Prokinecs

• Metoclopramide: 5HT3 antagonist, DA antagonist; AE: EPS, NMS, * MetHgb, neutropenia • Cisapride: 5HT4 agonist, 3A4 inhibitor, Ikr blockade, QT ↑ • Tegasarod (Zelnorm): paral 5HT4 agonist, 5HT1B agonist =↑vasoconstricon, MI, CVA

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Hemostasis Pediatric Emergency Medicine Reports V14 N3 March 2009

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Anplatelets

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

ADP Inhibitors

Ticlopidine Clopidogrel • 3-5 days onset • 2 hrs onset • 2C19 • 2C19, 3A, B6 and CYP1A2 • AE: rash, neutropenia, TTP • SS: 3-7 days • Severe OD: reversal with • AE: bleeding, rash platelet transfusion • 1 case report of HSP, TTP • Severe OD: reversal with platelet transfusion

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Drug Induced Thrombocytopenia

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16 GI / HEME

Occupaonal 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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Heparin

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

Thrombin

Most sensive to inhibion of ATIII/Heparin complex 52

Protamine Sulfate

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

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Heparin Induced Thrombocytopenia

• Type I =Platelets ↓ • Type II = Anplatelet IgG anbodies 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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18 GI / HEME

LMWH

Choices Mechanism • Ardeparin (Normiflo): • An thrombin III mediated • Daltaparen (Fragmin): Selecve inhibion Xa and to a • Enoxaparen (Lovenox): lesser extent IIa • Tinzoparin (Innohep):

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Factor XA Inhibitors

• Fondaparinux ( Arixtra): Indirect, synthec pentasaccharide, selecve Factor Xa inhibitor • Rivaroxaban (Xarelto):Direct,oral,Selecve factor Xa inhibitor • Apaxiban ( Eliquis):Direct, oral, Selecve factor Xa Inhibitor

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19 GI / HEME

Warfarin

Vitamin K(H2) Quinol Reduced Vitamin K epoxide reductase C1 (Acve)

Mayo Clinic Proceedings July 2010 85 (10) 58

Warfarin

Acve Inacve

Reduced

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Warfarin Skin Necrosis

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

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20 GI / HEME

Fetal Warfarin Syndrome

• Pregnancy X • Crosses placenta • Nasal/midface hypoplasia • Bone sppling of epiphyses on plain x- ray (chrondrodysplasia punc) • Opc atrophy • Metal retardaon

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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: photosensavity, anaphylaxsis

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21 GI / HEME

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Direct Thrombin Inhibitors

• Hirudin( Refludan): Bivalent : Exosite 1, acve site binding • Bivalirudin: ( Angiomax,Hirulog):Bivalent: Exosite 1, acve site dinding • Argatroban: Univalent: Acve Site Only binding, N2-derivave of arginine • Dabigatran( Pradaxa): Univalent: Acve Site ONLY binding

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22 GI / HEME

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Thrombolycs

Thrombin specific fibrinolysis Non specific fibrinolysis • Alteplase • Streptokinase • Reteplase • urokinase • tenectaplase Side effect: -Allergy rxn if re-exposure

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Aminocaproic Acid

• Reversal of fibrinolycs • analogue of the amino acid lysine • Inhibits plasminogen acvators • Renal eliminaon • AE: hypotension,rhabdomyolysis

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23 GI / HEME

Iron

Ionic Nonionic- low toxicity • Ferrous gluconate 12 % • Iron polysaccaride 46% • Ferrous lactate 19% • Carbonyl iron 98 % • Ferrous sulfate 20 % • Ferrous chloride 28 % • Ferrous fumarate 33%

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Iron

• Fe 2+ (Ferrous) absorbed in duod/jejun, bound to Ferrin • Changed to Fe 3+ (ferric), bound to transferrin • Free iron ( Fe 3+) released • 4-5 Stages: GI,Latent,Shock/Met Acidosis,Hepac failure,Gut Stricture

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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

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24 GI / HEME

Deferoxamine

• Derived from streptomyces pilosus • Indicaons: serum Fe>350-500mcg/dl, symptoms • Goals: resoluon acidosis,shock, trate dose • AE: GI- Yersina enterocolica, Pulm ? 24 hrs PE

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Erythropoien

• Smulate stem cells to mature RBCs • Side effects:↑Hct ↑plt acvity, ↑systolic HTN -Hyperviscosity,HTN, Thromboembolism Chronic OD: Plethora, Black toes

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