GI / HEME Gastrointes1nal/Hematologic Toxicology Board Review Michael Policastro, MD Director, Medical Toxicology, QESI Clinical Assistant Professor, WSU 1 Overview GI Heme • Oral/Anal • An1platelet • Hepac • An1coagulants • Pancreas • Procoagulants • An1mo1lity • Thrombolyc • Inflammatory Bowel Meds • Iron • An1ulcer • Erythropoie1n • Promo1lity 2 Oral Discoloraon Tongue • Brown • Bromine, bismuth, arsenic, phenolpthalein, doxrubicin, quinacrine, tobacco • Green • Vanadium • Black, Hairy • Cefoxin, cor1costeroids,lansoprazole, penicillin, sodium perborate, sodium • White peroxide, tetracycline • Chlorhexidine, phenol, caus1c acids, hydrogen peroxide • Blue • Methylene blue • Blue Gray Gums • Bismuth, lead, mercury, copper salts, thallium, zinc 3 1 GI / HEME Fecal Discoloraon • Acetazolamide, aluminum hydroxide, • Black aminophylline,amphotericin b,barium, benzene,bismuth, bromides, charcoal,chloramphenical,chlorpropamide,clindamycin,c or1costeroids,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 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) 5 Selecve IgA deficiency- Drug Associated • Captopril • Penacillamine • phenytoin 6 2 GI / HEME Drugs that undergo primary Synthe1c Phase II Biotransformaon that you may forget • Glucuronidaon : Valproic acid, lamotrigine, opioids, APAP, irinotecan, 5-FU, chloramphenical • Acetylaon: INH, hydrazines, Sulfonamide, Dapsone, amonafidine 7 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 * 10 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 11 Microvesicular steatosis • Tetracycline • Margosa oil • VPA • Nucleoside inhibitors • Hypoglycin • Cerulide • Aflatoxin 12 4 GI / HEME Hepac Veno-Oclussive Disease • Radiaon, An1neoplas1cs ( Cyclophophamide) • Pyrrolinizide alkaloid plants -Symphytum species (Comfrey tea) - Heliotropium, Senecio (Ragwart) -Crotalaria ( Bush teas) 13 Buzzword Hepa1s • Peliosis Hepas: Sinusoidal dilaon, large blood filled cavies : Androgenic Steroids • Vitamin A Toxicity :Increased fat content of sinusoidal Ito cells with increased collagen formaon 14 Xenobio1c Autoimmune Liver injury • Covalent binding of reacPve electrophile with hepatocellular protein creates an Adduct • APAP, minocycline, halothane, dihydrazine, phenytoin, germander 15 5 GI / HEME Toxin-Hepa1s 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 hepa1s: Lymphocyte proliferaon assay 16 Drug Hypersensi1vity Hepa1s • Halothane hepa1s • trimethoprim-sulfamethazole • An1convulsants • Allopurinol 17 Drug induced Cholestasis Without Hepa1s • 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 infiltraon 18 6 GI / HEME Drug Hypersensi1vity Cholestasis • Chlorpromazine • Erythromycin • Penicillin • Rifampin • Sulfonamides 19 Occupaonal chemical cholestasis • Toleune diisocyanate • Methylenediamine • paraquat 20 Hepac 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, 21 7 GI / HEME Liver Carcinogens • Aflatoxin ( Aspergillus flavus/parasi1cus) • Mycotoxins • Pyrrolizidine alkaloids • Nitrosamides,Nitrosamines • Heterocyclic aromac amines • Ethanol • OCP • Androgens, anabolic steroids • Azo dyes • Thoratrast- alpha radiaon 22 Retroperitoneal fibrosis • Methylsergide • Stephania tetrandra • Magnolia officinalis • Bromocripne • LSD 23 Exocrine Pancrea1s 24 8 GI / HEME Exocrine Pancrea1s * Tityus trinitas 25 Xenobio1c Endocrine Pancrea1s • Alpha: Cobalt, biguanide,diguanide • Beta: Aflatoxin, Androgens, cyclizine,Cyproheptadine,Diazoxide,Glucagon, Epinephrine, Growth Hormone,Pentamidine, Streptozocin,sulfonamides, Vacor, Zinc Chelators 26 Pancrelipase ( Pancrease) • Indicaon: malabsorp1on syndrome • Chronic use in Cysc Fibrosis * Fibrosing Colonopathy: abd pain, distension, cons1paons 27 9 GI / HEME An1diarrheal Agents • AnPMoPlity:Opioids: Diphenoxylate, Loperamide, Paregoric/Laudanum • Intraluminal Agents: Silicates, Bulk-forming fibers, Microfloral altering agents • AnPsecretory : Somatostan, Octreo1de 28 Diphenoxylate • Derived from meperidine • Metabolite: diphenoxylic acid ( 5x more ac1ve, 2x ½ life) • Combined with atropine =Lomol Meperidine • Onset: 4.5 hrs ( 1- 8 hrs) • Toxicity: delayed opioid 29 Loperamide • Derived from diphenoxylate • 40 % absorp1on, <1% absorp1on • Poor CNS penetraon, • Rare respiratory • Large safety profile 30 10 GI / HEME Opioids • Paregoric • Laudanum • Camphorated 1ncture of • Deodorized Tincture of opium opium • Morphine (0.4 mg/ml) • Morphine (10 mg/ml) • Other components: • Use in Neonatal Abs1nence essen1al oil, Benzoic Acid, Syndrome /Neonatal Ethanol ( 45 %), glycerol Withdraw syndrome 31 Inflammatory Bowel Meds • Mesalamine, Sulfasalazine • Immunomodulators ( Azathioprine,6-MP, infliximab) • Steroids • An1bio1cs 32 Mesalamine • Salicylate based • Metabolism: acetylaon = n-acetyl- 5-ASA • Topical bowel an1-inflammatory • AE: HA/Diarrhea • OD: low likelyhood salicylate toxicity 33 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 ferPlity, abnormal sperm *** folate inhibitor Other AE: HA,n/v/d, rashes 34 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 • 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 36 12 GI / HEME An1ulcer • Antacids • H2 blockers • Proton pump inhibitors • Misoprostol 37 Antacids • Salts of: aluminum,magnesium,calcium, sodium hydroxide • Increase gastric pH • Toxicity with renal failure • Al = “dilaysis demen1a”, encephalopathy, cons1paon • 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 38 H2 Blockers • Cimedine, rani1dine, famo1dine, roxadine, nizadine,en1dine • Inhibitors: 3A4, 2D6, 1A2, 2C9, 2E1 • AE: AMS, fague, possible thrombocytopenia, vasculi1s, movement disorders • Cimedine: An1androgen ( GynecomasPa ) • Rani1dine: hepa1s Cimedine 39 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 absorp1on: griseofulvin, ketaconazole, iron • AE: diarrhea 40 Misprostol • PGE1 antagonist (↓acid, ↑uterine contrac1on, mucous,bicarbonate, dilate blood vessels ) • Pregnancy X • AE: aborPfacient, HA, diarrhea 41 Laxaves [Epsom Salts] phenolphthalein 42 14 GI / HEME Laxave Overdose ACUTE CHRONIC • Osmoc: • Osmoc: -Magnesium: CNS, + aldosterone = hypoK respiratory↓ - Cathar1c 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 43 Prokinecs • Metoclopramide: 5HT3 antagonist, DA antagonist;